Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10.Q-ncf1*/* mice with collagen-induced chronic arthritis

<p>Abstract</p> <p>Background</p> <p>Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1^*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1^*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis.</p> <p>Methods</p> <p>Female B10.Q-ncf1^*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73), bone mineral density (BMD) was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines.</p> <p>Results</p> <p>Raloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6.</p> <p>Conclusions</p> <p>This is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA.</p

Coping with rheumatic stressors (CORS) questionnaire: Spanish translation and cross-cultural adaptation

Background: Rheumatic and Musculoskeletal Diseases (RMDs) substantially impact the lives of patients, with complex associations between disease severity and self-perceived health status. In this regard, the Coping with Rheumatic Stressors (CORS) questionnaire was developed to measure how patients with RMDs cope with stressors such as pain, limitations or dependency. The CORS is not currently available in Spanish, and therefore the adaptation of this instrument is needed.Objective: First, to cross-culturally adapt the CORS into Spanish for Spain. Secondly, to test the conceptual equivalence of the translated version in patients with axial spondyloarthritis (axSpA). Methods: A translation of the CORS into Spanish was performed adhering to the forward-backward procedure described by Beaton. Two translators produced independent forward translations of the item content, response options, and instructions of the CORS into Spanish. Both versions were harmonized in a consensual version. Another translator back-translated the synthesized version into Dutch. A scientific committee including all the translators, one methodologist and a rheumatologist, held a meeting and reached consensus on discrepancies to develop a final draft version of the Spanish CORS. Then, a field test with cognitive debriefing was conducted, involving a sample of 10 patients with axSpA. Results: The translation process of the CORS was completed after the discussion of some discrepancies throughout the process. The first translation was done without major complications. Back-translation presented some discrepancies. These led to minor modifications in the wording in one response option and 15 questionnaire items. The scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing, led to minor modifications; for example, three respondents indicated that one of the statements in the instructions was syntactically complex ("indique cuan a menudo usted ha llevado a cabo dicho comportamiento") which led to its adjustment. The process indicated that the final CORS Spanish questionnaire was clear and understandable to all patients.Conclusions: The Spanish version of the CORS showed good cross-cultural validity and good face validity according to the field test. Before the Spanish CORS is implemented, further validation is in progress to test the psychometric properties of the instrument in patients with axSpA.Pathophysiology and treatment of rheumatic disease

Estren promotes androgen phenotypes in primary lymphoid organs and submandibular glands

BACKGROUND: Estrogens and androgens have extensive effects on the immune system, for example they suppress both T and B lymphopoiesis in thymus and bone marrow. Submandibular glands are sexually dimorphic in rodents, resulting in larger granular convoluted tubules in males compared to females. The aim of the present experiments was to investigate the estrogenic and androgenic effects of 4-estren-3α,17β-diol (estren) on thymus, bone marrow and submandibular glands, and compare the effects to those of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT), respectively. Estrogen receptors (ERs) were blocked by treatment of mice with the ER-antagonist ICI 182,780; also, knock-out mice lacking one or both ERs were used. RESULTS: As expected, the presence of functional ERs was mandatory for all the effects of E2. Similar to DHT-treatment, estren-treatment resulted in decreased thymus weight, as well as decreased frequency of bone marrow B cells. Treatment with estren or DHT also resulted in a shift in submandibular glands towards an androgen phenotype. All the effects of estren and DHT were independent of ERs. CONCLUSION: Our study is the first to show that estren has similar effects as the androgen DHT on lymphopoiesis in thymus and bone marrow, and on submandibular glands, and that these effects are independent of estrogen receptors. This supports the hypothesis of estren being able to signal through the androgen receptor

Testing the Integral Model of treatment motivation in outpatients with severe mental illness

The current study tested the Integral Model of treatment motivation (IM) in a sample of 294 outpatients with severe mental illness, using structural equation modelling. The obtained structural model was not consistent with original theory, nor was the model invariant across time and patient groups (psychotic disorders and personality disorders). The patient’s perceived suitability of treatment, perceived costs of treatment and outcome expectancy were most strongly associated with motivation and treatment engagement. The model explained between 22 and 86% of variance in clinical outcomes, depending on the timing of the assessment. Currently, the IM does not constitute a robust framework for patterns through which patients become motivated to engage in treatment, but does explain substantial amounts of variance in clinical outcomes. The future potential of IM as a basis for interventions in the mental health care is discussed, including suggestions for subsequent research and potential alterations of the IM to improve its utility for application in clinical practice

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms

Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study.In our center, 2294 patients were screened between 2004 and 2014 by 68Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90Yttrium or 177Lutetium-based PRRT. Progression free survival was determined by 68Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria.Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare.PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy

Clinical outcomes and end-of-life treatment in 596 patients with isolated traumatic brain injury:a retrospective comparison of two Dutch level-I trauma centers

Purpose: With an increasingly older population and rise in incidence of traumatic brain injury (TBI), end-of-life decisions have become frequent. This study investigated the rate of withdrawal of life sustaining treatment (WLST) and compared treatment outcomes in patients with isolated TBI in two Dutch level-I trauma centers. Methods: From 2011 to 2016, a retrospective cohort study of patients aged ≥ 18 years with isolated moderate-to-severe TBI (Abbreviated Injury Scale (AIS) head ≥ 3) was conducted at the University Medical Center Rotterdam (UMC-R) and the University Medical Center Utrecht (UMC-U). Demographics, radiologic injury characteristics, clinical outcomes, and functional outcomes at 3–6 months post-discharge were collected. Results: The study population included 596 patients (UMC-R: n = 326; UMC-U: n = 270). There were no statistical differences in age, gender, mechanism of injury, and radiologic parameters between both institutes. UMC-R patients had a higher AIShead (UMC-R: 5 [4–5] vs. UMC-U: 4 [4–5], p &lt; 0.001). There was no difference in the prehospital Glasgow Coma Scale (GCS). However, UMC-R patients had lower GCSs in the Emergency Department and used more prehospital sedation. Total in-hospital mortality was 29% (n = 170), of which 71% (n = 123) occurred after WLST. Two percent (n = 10) remained in unresponsive wakefulness syndrome (UWS) state during follow-up. Discussion: This study demonstrated a high WLST rate among deceased patients with isolated TBI. Demographics and outcomes were similar for both centers even though AIShead was significantly higher in UMC-R patients. Possibly, prehospital sedation might have influenced AIS coding. Few patients persisted in UWS. Further research is needed on WLST patients in a broader spectrum of ethics, culture, and complex medical profiles, as it is a growing practice in modern critical care. Level of evidence: Level III, retrospective cohort study.</p

Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection.

International audienceHuman immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4(+) T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. The ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing

Microinvasion by Streptococcus pneumoniae induces epithelial innate immunity during colonisation at the human mucosal surface

Control of Streptococcus pneumoniae colonisation at human mucosal surfaces is critical to reducing the burden of pneumonia and invasive pneumococcal disease, interrupting transmission, and achieving herd protection. Here, we use an experimental human pneumococcal carriage model (EHPC) to show that S. pneumoniae colonisation is associated with epithelial surface adherence, micro-colony formation and invasion, without overt disease. Interactions between different strains and the epithelium shaped the host transcriptomic response in vitro. Using epithelial modules from a human epithelial cell model that recapitulates our in vivo findings, comprising of innate signalling and regulatory pathways, inflammatory mediators, cellular metabolism and stress response genes, we find that inflammation in the EHPC model is most prominent around the time of bacterial clearance. Our results indicate that, rather than being confined to the epithelial surface and the overlying mucus layer, the pneumococcus undergoes micro-invasion of the epithelium that enhances inflammatory and innate immune responses associated with clearance