Mixed Anxiety Depression Should Not Be Included in DSM-5

Contains fulltext : 102705.pdf (publisher's version ) (Closed access)Subthreshold anxiety and subthreshold depressive symptoms often co-occur in the general population and in primary care. Based on their associated significant distress and impairment, a psychiatric classification seems justified. To enable classification, mixed anxiety depression (MAD) has been proposed as a new diagnostic category in DSM-5. In this report, we discuss arguments against the classification of MAD. More research is needed before reifying a new category we know so little about. Moreover, we argue that in patients with MAD symptoms and a history of an anxiety or depressive disorder, symptoms should be labeled as part of the course trajectories of these disorders, rather than calling it a different diagnostic entity. In patients with incident co-occurring subthreshold anxiety and subthreshold depression, subthreshold categories of both anxiety and depression could be classified to maintain a consistent classification system at both threshold and subthreshold levels.5 p

Epithelial Tissues Have Varying Degrees of Susceptibility to KrasG12D-Initiated Tumorigenesis in a Mouse Model

Activating mutations in the Kras gene are commonly found in some but not all epithelial cancers. In order to understand the susceptibility of different epithelial tissues to Kras-induced tumorigenesis, we introduced one of the most common Kras mutations, KrasG12D, broadly in epithelial tissues. We used a mouse model in which the G12D mutation is placed in the endogenous Kras locus controlled by inducible, Cre-mediated recombination in tissues expressing cytokeratin 19 including the oral cavity, GI tract, lungs, and ducts of the liver, kidney, and the pancreas. Introduction of the KrasG12D mutation in adult mouse tissues led to neoplastic changes in some but not all of these tissues. Notably, many hyperplasias, metaplasias and adenomas were observed in the oral cavity, stomach, colon and lungs, suggesting that exposure to products of the outside environment promotes KrasG12D-initiated tumorigenesis. However, environmental exposure did not consistently correlate with tumor formation, such as in the small intestine, suggesting that there are also intrinsic differences in susceptibility to Kras activation. The pancreas developed small numbers of mucinous metaplasias with characteristics of early stage pancreatic intraepithelial neoplasms (PanINs), supporting the hypothesis that pancreatic ducts have the potential to give rise pancreatic cancer

Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9

Lupus-prone mice develop a chronic inflammatory response to cutaneous injury that depends on the production of type I interferon, TLR7, and TLR9

The prevalence of pain in bipolar disorder: a systematic review and large-scale meta-analysis

Objective: To conduct a meta-analysis investigating the prevalence of pain in people with bipolar disorder (BD). Method: A systematic review and random effects meta-analysis searching major electronic databases from inception till 01/2014 in accordance with the PRISMA statement. We included articles reporting quantitative data on the prevalence of pain in people with BD with or without a healthy control group. Two independent authors conducted searches, extracted data, and completed methodological quality assessment. Results: Twenty two cross-sectional studies were included, representing 12 375 644 individuals (BD n = 171 352, n controls = 12 204 292). The prevalence of pain in people with BD was 28.9% (95% CI = 16.4–43.4%, BD n = 171 352). The relative risk (RR) of pain in BD compared to controls was 2.14 (95% CI = 1.67–2.75%, n = 12 342 577). The prevalence of migraine was 14.2% (95% CI = 10.6–18.3%, BD n = 127 905), and the RR was 3.30 (95% CI = 2.27–4.80%, n = 6 732 220).About 23.7% (95% CI = 13.1–36.3%, n = 106 214) of people with BD experienced chronic pain. Age, percentage of males, methodological quality, and method of BD classification did not explain the observed heterogeneity. Conclusion: People with BD experience significantly increased levels of pain (particularly chronic pain and migraine). The assessment and treatment of pain should form an integral part of the management of BD

Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8

Dendritic cell (DC) responses to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid–recognizing Toll-like receptors (TLRs). In psoriasis, however, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with the antimicrobial peptide LL37. Whether LL37 also interacts with extracellular self-RNA and how this may contribute to DC activation in psoriasis is not known. Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA–LL37 complexes activate TLR7 and, like self-DNA–LL37 complexes, trigger the secretion of IFN-α without inducing maturation or the production of IL-6 and TNF-α. In contrast to self-DNA–LL37 complexes, self-RNA–LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-α and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA–LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis

Medically unexplained pain complaints are associated with underlying unrecognized mood disorders in primary care

<p>Abstract</p> <p>Background</p> <p>Patients with chronic pain frequently display comorbid depression, but the impact of this concurrence is often underestimated and mistreated. The aim of this study was to determine the prevalence of unrecognized major depression and other mood disorders and comorbid unexplained chronic pain in primary care settings and to explore the associated factors.</p> <p>Also, to compare the use of health services by patients with unexplained chronic pain, both with and without mood disorder comorbidity.</p> <p>Methods</p> <p>A cross-sectional study was carried out in a sample of primary care centers. 3189 patients consulting for "unexplained chronic pain" were assessed by the Visual Analogue Scales (VAS) and the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire.</p> <p>Results</p> <p>We report: a) a high prevalence of unrecognized mood disorders in patients suffering from unexplained chronic pain complaints (80.4%: CI 95%: 79.0%; 81.8%); b) a greater susceptibility of women to mood disorders (OR adjusted = 1.48; CI 95%:1.22; 1.81); c) a direct relationship between the prevalence of mood disorders and the duration of pain (OR adjusted = 1.01; CI 95%: 1.01; 1.02) d) a higher comorbidity with depression if the pain etiology was unknown (OR adjusted = 1.74; CI 95%: 1.45; 2.10) and, e) an increased use of health care services in patients with such a comorbidity (p < 0.0001).</p> <p>Conclusions</p> <p>The prevalence of undiagnosed mood disorders in patients with unexplained chronic pain in primary care is very high, leading to dissatisfaction with treatment processes and poorer outcomes. Consequently, it seems necessary to explore this condition more regularly in general practice in order to reach accurate diagnoses and to select the appropriate treatment.</p

Silencing of Renal DNaseI in Murine Lupus Nephritis Imposes Exposure of Large Chromatin Fragments and Activation of Toll Like Receptors and the Clec4e

Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7–9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease

Plasmacytoid dendritic cells respond directly to apoptotic cells by secreting immune regulatory IL-10 or IFN-α

Plasmacytoid dendritic cells (pDCs) play a pivotal role in driving the autoimmune disease systemic lupus erythematosus, via the secretion of IFNα in response to nuclear self-antigens complexed with auto-antibodies. Apoptotic cells, generated at sites of inflammation or secondary lymphoid organs, are exposed to activated pDCs and also express the same nuclear antigens on their cell surface. Here we show, that in the absence of autoantibodies, activated pDCs respond to apoptotic cell expressed chromatin complexes by secreting IL-10 and IL-6, which also induces T cells to secrete IL-10. Conversely, when activated by the viral mimetic, CpGA, apoptotic cells enhance their secretion of IFNα. This study demonstrates, that activated pDCs respond directly to apoptotic cells and may maintain tolerance via IL-10, or promote inflammation through secretion of IFNα, depending on the inflammatory context

Functional impairment related to painful physical symptoms in patients with generalized anxiety disorder with or without comorbid major depressive disorder: post hoc analysis of a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Generalized anxiety disorder (GAD) is the most frequent anxiety disorder in primary care patients. It is known that painful physical symptoms (PPS) are associated with GAD, regardless the presence of comorbid major depressive disorder (MDD). However the specific role of such symptoms in patients' functional impairment is not well understood. The objective of the present study is to assess functional impairment related to the presence of PPS in patients with GAD.</p> <p>Methods</p> <p>This is a post hoc analysis of a cross-sectional study. Functioning, in the presence (overall pain score >30; Visual Analog Scale) or absence of PPS, was assessed using the Sheehan Disability Scale (SDS) in three groups of patients; 1) GAD and comorbid MDD (GAD+MDD+), 2) GAD without comorbid MDD (GAD+MDD-), 3) controls (GAD-MDD-). ANCOVA models were used.</p> <p>Results</p> <p>Of those patients with GAD+MDD+ (n = 559), 436 (78.0%) had PPS, compared with GAD+MDD- (249 of 422, 59%) and controls (95 of 336, 28.3%). Functioning worsened in both GAD groups in presence of PPS (SDS least squares mean total score: 16.1 vs. 9.8, p < 0.0001, GAD+MDD+; 14.3 vs. 8.2, p < 0.0001, GAD+MDD-). The presence of PPS was significantly associated with less productivity.</p> <p>Conclusions</p> <p>Functional impairment related to the presence of PPS was relevant. Clinical implications should be considered.</p