Involvement of NKR‐P2/NKG2D in DC‐mediated killing of tumor targets: indicative of a common,innate, target‐recognition paradigm?

DC are the most efficient antigen-presenting cells that regulate the immune response. Here, we demonstrate the expression of NK cell receptor protein-2 (NKR-P2) on rat and mouse DC, and we show that NKR-P2 gets reorganized upon antigen contact. DC activated with anti-NKR-P2 mAb exhibit enhanced apoptotic killing of tumor targets, whereas blocking the interaction between NKR-P2 and its ligand with rNKR-P2 abrogated apoptotic killing, suggesting NKR-P2 to function as an activating molecule on DC. In vivo injection of anti-NKR-P2 mAb augmented DC activity and delayed tumor progression. NKR-P2 signaling involved Ca(2+ )influx, culminating in the expression of the apoptosis-inducing molecule, TNF-alpha. Taken together, these observations suggest that NKR-P2 (the rat orthologue of human NKG2D) acts as a target-recognition molecule on DC.     

Nuclear translocation of β‐catenin and decreased expression of epithelial cadherin in human papillomavirus‐positive tonsillar cancer: an early event in human papillomavirus‐related tumour progression?

Stenner M, Yosef B, Huebbers C U, Preuss S F, Dienes H‐P, Speel E‐J M, Odenthal M & Klussmann J P (2011) Histopathology 58 , 1117–1126 Nuclear translocation of β‐catenin and decreased expression of epithelial cadherin in human papillomavirus‐positive tonsillar cancer: an early event in human papillomavirus‐related tumour progression? Aims: High‐risk human papillomaviruses (HPVs) constitute an important risk factor for tonsillar cancer. This study describes changes in cell adhesion molecules during metastasis of HPV‐related and HPV‐unrelated tonsillar carcinomas. Methods and results: We examined 48 primary tonsillar carcinoma samples (25 HPV‐16 DNA‐positive, 23 HPV‐16 DNA‐negative) and their respective lymph node metastases for their HPV status and for the expression of p16, epithelial cadherin (E‐cadherin), β‐catenin, and vimentin. A positive HPV‐specific polymerase chain reaction finding correlated significantly with p16 overexpression in both primary tumours and their metastases (P < 0.0001 for both). In HPV‐unrelated carcinomas, the expression of E‐cadherin was significantly lower in metastases than in primary tumours (P < 0.001). In contrast, the expression of nuclear β‐catenin was significantly higher in metastases than in primary tumours (P = 0.016). In HPV‐related carcinomas, nuclear localization of β‐catenin expression was already apparent in primary tumours (P = 0.030). The expression of vimentin significantly correlated with the grading of the primary tumour (P = 0.021). Conclusions: Our data indicate that the down‐regulation of E‐cadherin and the up‐regulation of nuclear β‐catenin expression might be crucial steps during tumour progression of tonsillar carcinomas, being already present in primary tumours in HPV‐driven carcinomas, but becoming apparent in HPV‐unrelated tumours later in the process of metastasis.     

Does Leptin Exhibit Cytokine‐Like Properties in Tissues of Pregnancy?

PROBLEM: To determine whether leptin exhibits cytokine-like properties in gestational tissues in light of its homologies with the class I family of cytokines. METHOD OF STUDY: WISH and JEG3 cells, and amnion and choriodecidua explants, were treated inflammatory modulators (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha] and bacterial lipopolysaccharide [LPS]) and leptin production was measured by immunoassay. Other agents known to regulate adipocyte leptin production were also tested for comparative purposes. In addition, WISH cells, JAR cells and placental explants were treated with leptin to assess its effects on production of IL-8, IL-6 and prostaglandin E2 (PGE2). RESULTS: Leptin production by all cells and tissues studied was unaffected by treatment with IL-1beta (2.5 ng/mL), TNF-alpha (25 ng/mL) and LPS (2.5 microg/mL). Dexamethasone stimulated leptin production over two-fold by WISH and JEG3 cells, whereas insulin also stimulated a two-fold increase in leptin production in JEG3 cells. IL-6 production by JAR cells and placental explants was stimulated (two- to three-fold) by leptin (300 ng/mL). PGE2 production was unaffected. CONCLUSIONS: Leptin derived from gestational tissues is unlikely to play a role in inflammatory reactions within the placenta, but may regulate placental cytokine production. The physiological significance of amnion-derived leptin remains to be established.     

Are urinary levels of high mobility group box 1 markers of active nephritis in anti‐neutrophil cytoplasmic antibody‐associated vasculitis?

The objective of this study is to evaluate urinary high mobility group box 1 (HMGB1) levels as markers for active nephritis in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in comparison with urinary CD4⁺ effector memory T cells and urinary monocyte chemoattractant protein-1 (MCP-1). Twenty-four AAV patients with active nephritis and 12 healthy controls (HC) were evaluated. In nine patients, samples were also obtained during remission. Urinary levels of HMGB1 were measured by Western blot. CD4⁺ T cells and CD4⁺ effector memory T cells (CD4⁺CD45RO⁺CCR7^-) were determined in urine and whole blood by flow cytometry. Measurement of urinary levels of MCP-1 and serum HMGB1 levels were performed by enzyme-linked immunosorbent assay (ELISA). AAV patients with active nephritis had higher median intensity of HMGB1 in urine than HC [10·3 (7·05–18·50) versus 5·8 (4·48–7·01); P = 0·004]. Both urinary HMGB1 and MCP-1 levels decreased significantly from active nephritis to remission. The urinary MCP-1/creatinine ratio correlated with Birmingham Vasculitis Activity Score (BVAS) (P = 0·042). No correlation was found between the HMGB1/creatinine ratio and 24-h proteinuria, estimated glomerular filtration rate (eGFR), MCP-1/creatinine ratio, BVAS and serum HMGB1. A positive correlation was found between urinary HMGB1/creatinine ratio and CD4⁺ T cells/creatinine ratio (P = 0·028) and effector memory T cells/creatinine ratio (P = 0·039) in urine. Urinary HMGB1 levels are increased in AAV patients with active nephritis when compared with HC and patients in remission, and urinary HMGB1 levels are associated with CD4⁺ T cells and CD4⁺ effector memory T cells in urine. Measurement of urinary HMGB1 may be of additional value in identifying active glomerulonephritis in AAV patients.     

Are topic‐specific measures of socio‐political control justified? Exploring the realm of citizen participation in natural resource decision making

This study extends the socio‐political control scales developed by Zimmerman and Zahniser (1991) to the context of citizen participation in natural resource agency decision making. The study shows that a natural resource‐specific scale is more appropriate for behaviors related to participation in natural resource decision making. These results confirm the usefulness of topic‐specific measures of socio‐political control. © 2001 John Wiley & Sons, Inc.     

Change in hepatitis C virus genotype in hemodialysis patients after end‐of‐treatment response to interferon monotherapy—relapse or re‐infection?

Hepatitis C virus (HCV) infection remains common among hemodialysis patients and its occurrence is related mainly to nosocomial spread. Although dialysis patients with HCV infection respond well to interferon-based therapy, relapse is frequent. This study aimed at a selected group of hemodialysis patients infected with HCV infection undergoing interferon therapy who achieved end-of-treatment virological response but became HCV-RNA positive again 6 months after end-of-treatment. It was evaluated whether de novo HCV-RNA positivity in these non-sustained responders occurred due to lack of clearance of HCV after the initial response to interferon-alpha (relapse) or due to re-infection with a new strain (re-infection). Genotyping by Inno-LiPA and by phylogenetic tree analysis using partial HCV-NS5B sequences at two evaluation points: pre-treatment (T0) and 6 months after end-of-treatment (T18). Non-sustained responders (n = 15) carried subtypes 1a (8 patients), 1b (4 patients), 3a (2 patients), and 4a (1 patient) before treatment. Identical subtypes were detected in 10 patients at T18. Five patients changed genotypes at T18, suggesting nosocomial re-infection. This study emphasizes the importance of epidemiologic measures to control the re-exposure of hemodialysis patients treated previously for HCV infection.     

Burden of disease in Nari?o,Colombia, 2010

Objective:

This study sought to measure burden of disease and identifies health priorities from the Disability Adjusted Life Years (DALYs) indicator.

Methods:

This is the first study on burden of disease for a department in Colombia by using a standardized methodology. By using the

DALYs indicator, burden of disease was identified in the department of Nariño according to the guidelines established by the World Health Organization.

Results:

The DALYs in the Department of Nariño highlight the emergence of communicable, maternal, perinatal, and nutritional diseases during the first years of life; of accidents and lesions among youth, and non-communicable diseases in older individuals. Also, accidents and lesions are highlighted in men and non-communicable diseases in women.

Conclusions:

This study is part of the knowledge management process in the Departmental Health Plan for Nariño - Colombia 2012-2015 and contributes to the system of indicators of the 2012 ten-year public health plan. This research evidences that communicable diseases generate the biggest part of the burden of disease in the Department of Nariño, that DALYs due to non-communicable diseases are on the rise, and that accidents and lesions, especially due to violence are an important cause of DALYs in this region, which is higher than that of the country.     

Myo‐Inositol: a marker of reactive astrogliosis in glial tumors?

In a prospective study, two-dimensional (1)H-MRS with TE of 30 ms was performed before surgery in 56 patients with glial brain tumors. Concentrations of myo-inositol (MI), trimethylamine (TMA) and creatine/phosphocreatine (tCr) were evaluated for the whole tumor and scaled to the normal-appearing contralateral brain tissue. To assign changes in MI to specific tissue pathology, the normalized peak and mean concentrations of MI were correlated with TMA and tCr concentrations. TMA is accepted as a marker of proliferating tumor tissue, and tCr might be a marker of reactive astrogliosis. The mean and peak concentrations of MI and tCr correlated positively (r = 0.7), but not the concentrations of MI and TMA. The absolute concentration of MI was significantly increased in all tumor tissues (5.55 +/- 2.92 mM; mean +/- SD) compared with the normal-appearing white matter (4.33 +/- 1.22 mM, p = 0.005), with the highest concentrations for gliomatoses (n = 10) and grade II oligoastrocytomas (n = 3). Significant differences (P = 0.004) between low- and high-grade astrocytomas were found for TMA (1.67 +/- 0.32 mM and 2.65 +/- 0.86 mM, respectively), but not for MI (5.92 +/- 1.98 mM and 5.49 +/- 3.27 mM, respectively). As increased MI and tCr concentrations were found in gliomatosis and other cerebral diseases associated with marked astrogliosis, this process may also be responsible for the observed changes in MI in other glial tumors.     

Is impairment in cognitive inhibition in the acute phase of major depression irreversible? Results from a 10‐year follow‐up study

Objectives. Even though many studies demonstrate cognitive impairment in the acute phase of depression and several studies indicate that this impairment might be long lasting despite symptom reduction and recovery, there is a lack of longitudinal studies on this field with considerable follow‐up length. The aim of this study was to investigate whether the impairment observed in cognitive inhibition in the acute phase of depression is reversible or irreversible in a 10‐year follow‐up assessment. Design. A longitudinal study of 38 individuals, 19 with recurrent unipolar depression and 19 healthy controls matched for gender, age, and education were included in the study. Method. Cognitive inhibition was investigated using the Stroop test at three different occasions: acute phase, short‐term (6 months), and long‐term (10 years) follow‐up. Results. The results show that recurrent major depressive disorder patients have a long‐lasting impairment in inhibition as measured by the Stroop test in 10‐year follow‐up. Further there is high consistency in inner group performance suggesting that severe impairment in the acute phase of illness is associated with severe impairment 10 years later despite recovery in the patient group. Conclusions. The results show that impairment in cognitive inhibition is long lasting when present in the acute phase of recurrent depression. Impaired cognitive inhibition might be an irreversible vulnerability marker for recurrent depression.     

Is Behçet's disease a ‘class 1‐opathy’? The role of HLA‐B*51 in the pathogenesis of Behçet's disease

The association between carriage of the human leucocyte antigen (HLA)‐B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much‐debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the ‘MHC‐I‐opathies’. Other MHC‐I‐opathies include ankylosing spondylitis and HLA‐B*27‐associated spondyloarthropathies and HLA‐C*0602‐associated skin psoriasis. Recent work analysing the peptidome of HLA‐B*51 suggests that altered peptide presentation by HLA‐B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA‐B*51 or the HLA‐B*51‐peptide complex could lead to development of inflammation in BD. The evidence for CD8⁺ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin‐like receptor (LILR) or killer immunoglobulin‐like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA‐B*51's unique role in BD will probably lead to improved development of therapeutic strategies.     

Demographics,socio‐behavioral factors,and drug use patterns: What matters in spontaneous HCV clearance?

Hepatitis C virus (HCV), an emerging bloodborne pathogen, causes chronic liver disease frequently except in about 10–20% of infections which undergo spontaneous resolution. Investigating factors that influence viral clearance is essential to understand the natural history of this infection and establishing novel strategies for prevention and treatment. HCV clearance was estimated in a unique cohort of 1,260 HIV and HBV negative current drug users enrolled for a hepatitis B vaccination study. It was defined as the inability to detect viral RNA using a PCR method in presence of serum anti‐HCV antibody EIA. Associated demographic and socio‐behavioral factors including drug use patterns were identified from the enrolled subjects using multivariate regression analysis. 33.3% (420/1260) of drug users were found positive for anti‐HCV antibodies and 14.8% (62/420) of these individuals achieved viral clearance (negative PCR test). Race or ethnicity of the participants was the only significant factor associated with HCV clearance. Hispanics (OR = 3.4, 95% CI: 1.3–8.5, P = 0.01) and Caucasians (OR = 3.1, 95% CI: 1.5–6.6, P = 0.003) had significantly higher odds of clearing the virus compared to African Americans when adjusted for age and gender. None of the socio‐behavioral factors including alcohol intake and drug use patterns were significant determinants of HCV clearance. Racial or ethnic differences in HCV clearance were observed in this study suggesting an important role of host genetic susceptibility factors in determining the clinical course of this disease. Further research is needed to examine these genetic associations of host–virus relationships. J. Med. Virol. 84:235–241, 2012. © 2011 Wiley Periodicals, Inc.     

What is a role of haeme oxygenase‐1 in psoriasis? Current concepts of pathogenesis

The skin is constantly exposed to endogenous and environmental pro-oxidant agents, which lead to harmful generation of reactive oxygen species (ROS). Healthy skin, being a potential target for oxidative stress, is equipped with a large number of defence mechanisms including antioxidant systems. This protection can be corrupted by an imbalance between ROS and antioxidants with pathological level of oxidants prevailing. There is a great body of evidence indicating that some inflammatory skin diseases, such as psoriasis, are mediated by oxidative stress. Keratinocytes of normal skin, the primary target for pro-oxidant agents, show strong expression of ROS-detoxifying enzymes. In addition, normal keratinocytes express haeme oxygenase (HO), an enzyme which might be involved in the protection of cells against oxidative stress. HO (inducible HO-1, constitutive HO-2 and HO-3) is the rate-limiting enzyme in haeme catabolism, which leads to the generation of biliverdin, iron, and carbon monoxide. HO-1 is a stress-responsive protein whose expression is induced by various oxidative agents. HO-1 is known for its cytoprotective, antioxidant and anti-inflammatory properties. Interestingly, a strong overexpression of HO-1 was observed in psoriatic skin. However, the role of HO-1 in psoriasis remains unclear. In this review, we will discuss some current concepts concerning pathogenesis of psoriasis and the contribution of HO-1 in skin inflammation to show the relationships between HO-1, ROS and cytokine network in psoriatic skin. We will try to answer a question whether enhanced HO-1 expression in keratinocytes results in beneficial or detrimental effect on the development and severity of psoriatic lesions.     

Can out‐of‐context musical sounds convey meaning? An ERP study on the processing of meaning in music

There has been much debate over whether music can convey extra-musical meaning. The experiments presented here investigated whether low level musical features, specifically the timbre of a sound, have a direct access route to meaningful representations. Short musical sounds with varying timbres were investigated with regard to their ability to elicit meaningful associations, and the neural mechanisms underlying the meaningful processing of sounds were compared to those underlying the semantic processing of words. Two EEG experiments were carried out, and N400 effects were found for sound and word targets following sound and word primes in a semantic relatedness judgment task. No N400 effects were found in a memory task. The results show that even short musical sounds outside of a musical context are capable of conveying meaning information, but that sounds require more elaborate processing than other kinds of meaningful stimuli.     

Do health‐related factors predict major depression? A longitudinal epidemiologic study

Major depressive disorder (MDD) is a leading cause of global disease burden. Hence, examining the role of risk and protective factors for MDD is an important target in psychological research. Various studies showed that obesity, smoking, and alcohol consumption are related to depressive symptoms. In contrast, physical activity has been found to be a protective factor. The present population‐based study tested whether these health‐related factors are prospectively associated with incidence of MDD. Data were taken from the Dresden Predictor Study, which was designed to investigate risk and protective factors of mental health in young women. It included two assessments approximately 17 months apart. Results of single logistic regression analyses showed that being overweight, being a smoker, and being in a high‐risk drinking group at baseline were predictive of developing MDD at follow‐up. Engaging in regular physical activity and having good physical health were found to be protective factors of MDD. However, being in a medium‐risk drinking group was not predictive of incidence of MDD, and irregular physical activity was not a protective factor. This is the first prospective, longitudinal study to show that obesity, smoking, and high‐risk drinking are predictive of new onsets of MDD and that physical health is a protective factor. These data provide promising avenues for future research.