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

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

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

An increased response to experimental muscle pain is related to psychological status in women with chronic non-traumatic neck-shoulder pain

<p>Abstract</p> <p>Background</p> <p>Neck-shoulder pain conditions, e.g., chronic trapezius myalgia, have been associated with sensory disturbances such as increased sensitivity to experimentally induced pain. This study investigated pain sensitivity in terms of bilateral pressure pain thresholds over the trapezius and tibialis anterior muscles and pain responses after a unilateral hypertonic saline infusion into the right legs tibialis anterior muscle and related those parameters to intensity and area size of the clinical pain and to psychological factors (sleeping problems, depression, anxiety, catastrophizing and fear-avoidance).</p> <p>Methods</p> <p>Nineteen women with chronic non-traumatic neck-shoulder pain but without simultaneous anatomically widespread clinical pain (NSP) and 30 age-matched pain-free female control subjects (CON) participated in the study.</p> <p>Results</p> <p>NSP had lower pressure pain thresholds over the trapezius and over the tibialis anterior muscles and experienced hypertonic saline-evoked pain in the tibialis anterior muscle to be significantly more intense and locally more widespread than CON. More intense symptoms of anxiety and depression together with a higher disability level were associated with increased pain responses to experimental pain induction and a larger area size of the clinical neck-shoulder pain at its worst.</p> <p>Conclusion</p> <p>These results indicate that central mechanisms e.g., central sensitization and altered descending control, are involved in chronic neck-shoulder pain since sensory hypersensitivity was found in areas distant to the site of clinical pain. Psychological status was found to interact with the perception, intensity, duration and distribution of induced pain (hypertonic saline) together with the spreading of clinical pain. The duration and intensity of pain correlated negatively with pressure pain thresholds.</p

Validity of the mental health subscale of the SF-36 in persons with spinal cord injury

Study design: Cross-sectional study 5 years after discharge from inpatient rehabilitation. Objective: To examine the psychometric properties of the Mental Health subscale (MHI-5) of the 36-Item Short Form Health Survey (SF-36) in persons with spinal cord injury (SCI). Setting: Eight Dutch rehabilitation centres with specialised SCI units. Methods: Possible floor and ceiling effects were assessed, and Cronbach's alpha coefficient was calculated to assess internal consistency. Concurrent and divergent validity were assessed using Spearman correlations between the MHI-5 and measures of life satisfaction, neuroticism, vitality, general health, functional independence, participation, lesion characteristics and demographics. Results: There were no floor or ceiling effects, but the total MHI-5 score was slightly skewed (-1.15). Internal consistency was good (alpha = 0.79). Concurrent validity was shown by significant Spearman correlations between the MHI-5 and life satisfaction (0.53), neuroticism (-0.55), vitality (0.53) and general health (0.37). Divergent validity was shown by weak and, in part, nonsignificant correlations between the MHI-5 and functional independence (0.09), participation (-0.28) and lesion characteristics (range -0.01-0.19). Conclusion: The MHI-5 showed reliability and validity as a measure of mood in persons with SCI, and is a promising measurement instrument to assess mental health problems in this population. Spinal Cord (2012) 50, 707-710; doi:10.1038/sc.2012.33; published online 10 April 201