Mineralocorticoid effects in the kidney: correlation between alphaENaC, GILZ, and Sgk-1 mRNA expression and urinary excretion of Na+ and K+.

Aldosterone exerts its effects through interactions with two types of binding sites, the mineralocorticoid (MR) and the glucocorticoid (GR) receptors. Although both receptors are known to be involved in the anti-natriuretic response to aldosterone, the mechanisms of signal transduction leading to modulation of electrolyte transport are not yet fully understood. This study measured the Na(+) and K(+) urinary excretion and the mRNA levels of three known aldosterone-induced transcripts, the serum and glucocorticoid-induced kinase (Sgk-1), the alpha subunit of the epithelial Na(+) channel (alphaENaC), and the glucocorticoid-induced-leucine-zipper protein (GILZ) in the whole kidney and in isolated cortical collecting tubules of adrenalectomized rats treated with low doses of aldosterone and/or dexamethasone. The resulting plasma concentrations of both steroids were close to 1 nmol/L. Aldosterone, given with or without dexamethasone, induced anti-natriuresis and kaliuresis, whereas dexamethasone alone did not. GILZ and alphaENaC transcripts were higher after treatment with either or both hormones, whereas the mRNA abundance of Sgk-1 was increased in the cortical collecting tubule by aldosterone but not by dexamethasone. We conclude the increased expression of Sgk-1 in the cortical collecting tubules is a primary event in the early antinatriuretic and kaliuretic responses to physiologic concentrations of aldosterone. Induction of alphaENaC and/or GILZ mRNAs may play a permissive role in the enhancement of the early and/or late responses; these effects may be necessary for a full response but do not by themselves promote early changes in urinary Na(+) and K(+) excretion.

Association between Inflammatory and Obesity Markers in a Swiss Population-Based Sample (CoLaus Study).

Objective: To assess the associations between obesity markers (BMI, waist circumference and %body fat) and inflammatory markers (interleukin-1β (IL-1β); interleukin-6 (IL-6); tumor necrosis factor-α (TNF-α) and high-sensitivity C-reactive protein (hs-CRP)). Methods: Population sample of 2,884 men and 3,201 women aged 35-75 years. Associations were assessed using ridge regression adjusting for age, leisure-time physical activity, and smoking. Results: No differences were found in IL-1β levels between participants with increased obesity markers and healthy counterparts; multivariate regression showed %body fat to be negatively associated with IL-1β. Participants with high %body fat or abdominal obesity had higher IL-6 levels, but no independent association between IL-6 levels and obesity markers was found on multivariate regression. Participants with abdominal obesity had higher TNF-α levels, and positive associations were found between TNF-α levels and waist circumference in men and between TNF-α levels and BMI in women. Obese participants had higher hs-CRP levels, and these differences persisted after multivariate adjustment; similarly, positive associations were found between hs-CRP levels and all obesity markers studied. Conclusion: Obesity markers are differentially associated with cytokine levels. %Body fat is negatively associated with IL-1β; BMI (in women) and waist circumference (in men) are associated with TNF-α; all obesity markers are positively associated with hs-CRP. Copyright © 2012 S. Karger GmbH, Freiburg.

Ultrasound evaluation of synovitis in RA: Correlation with clinical disease activity and sensitivity to change in an observational cohort study.

OBJECTIVE: To evaluate the correlation between clinical measures of disease activity and a ultrasound (US) scoring system for synovitis applied by many different ultrasonographers in a daily routine care setting within the Swiss registry for RA (SCQM) and further to determine the sensitivity to change of this US Score. METHODS: One hundred and eight Swiss rheumatologists were trained in performing the Swiss Sonography in Arthritis and Rheumatism (SONAR) score. US B-mode and Power Doppler (PwD) scores were correlated with DAS28 and compared between the clinical categories in a cross-sectional cohort of patients. In patients with a second US (longitudinal cohort), we investigated if change in US score correlated with change in DAS and evaluated the responsiveness of both methods. RESULTS: In the cross-sectional cohort with 536 patients, correlation between the B-mode score and DAS28 was significant but modest (Pearson coefficient r=0.41, P<0.0001). The same was true for the PwD score (r=0.41, P<0.0001). In the longitudinal cohort with 183 patients we also found a significant correlation between change in B-mode and in PwD score with change in DAS28 (r=0.54, P<0.0001 and r=0.46, P<0.0001, respectively). Both methods of evaluation (DAS and US) showed similar responsiveness according to standardized response mean (SRM). CONCLUSIONS: The SONAR Score is practicable and was applied by many rheumatologists in daily routine care after initial training. It demonstrates significant correlations with the degree of as well as change in disease activity as measured by DAS. On the level of the individual, the US score shows many discrepancies and overlapping results exist.

Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: high correlation with mRNA levels.

The extended use of brentuximab-vedotin was reported for CD30(+) nonanaplastic peripheral T-cell lymphomas (PTCLs) with promising efficacy. CD30 status assessment is thus a critical factor for therapeutic decision, but the reliability of immunohistochemistry (IHC) in evaluating its expression remains to be defined. This prompted us to investigate the correlation between semiquantitative CD30 protein assessment by IHC and messenger RNA (mRNA) assessment by microarrays in a cohort of 376 noncutaneous PTCLs representative of the main entities. By IHC, CD30 expression was heterogeneous across and within entities and significantly associated with large tumor cell size. In addition to 100% anaplastic large-cell lymphomas, 57% of other PTCL entities were CD30-positive at a 5% threshold. CD30 protein expression was highly correlated to mRNA levels. mRNA levels were bimodal, separating high from low CD30-expressing PTCL cases. We conclude that IHC is a valuable tool in clinical practice to assess CD30 expression in PTCLs.

Visual cortex in Alzheimer's disease: occurrence of neuronal death and glial proliferation, and correlation with pathological hallmarks.

Visual areas 17 and 18 were studied with morphometric methods for numbers of neurons, glia, senile plaques (SP), and neurofibrillary tangles (NFT) in 13 cases of Alzheimer's disease (AD) as compared to 11 controls. In AD cases, the mean neuronal density was significantly decreased by about 30% in both areas 17 and 18, while the glial density was increased significantly only in area 17. The volume of area 17 was unchanged in AD cases but its total number of neurons was decreased by 33% and its total number of glia increased by 45% compared to controls. In AD the number of SP was similar in areas 17 and 18, while that of NFT was significantly higher in area 18. The number of neurons with NFT was only 2% in area 17 and about 10% in area 18. The discrepancy between the loss of neurons and the amount of NFT suggests that neuronal loss can occur without passing through NFT degeneration. The deposition of SP was correlated with glial proliferation, but not with neuronal loss or neurofibrillary degeneration.

Mesurer la stigmatisation perçue chez les personnes souffrant de troubles psychiques : traduction française, validation et adaptation de la Stigma Scale [French translation, validation and adaptation of the Stigma Scale].

AIM: People suffering from mental illness are exposed to stigma. However, only few tools are available to assess stigmatization as perceived from the patient's perspective. The aim of this study is to adapt and validate a French version of the Stigma Scale (King et al., 2007 [8]). This self-report questionnaire has a three-factor structure: discrimination, disclosure and positive aspects of mental illness. Discrimination subscale refers to perceived negative reactions of others. Disclosure subscale refers mainly to managing disclosure to avoid discrimination and finally positive aspects subscale taps into how patients are becoming more accepting, more understanding toward their illness. METHOD: In the first step, internal consistency, convergent validity and test-retest reliability of the French adaptation of the 28-item scale were assessed in a sample of 183 patients. Results of confirmatory factor analyses (CFA) did not confirm the hypothesized structure. In the light of the failed attempts to validate the original version, an alternative 9-item short-form version of the Stigma Scale, maintaining the integrity of the original model, was developed based on results of exploratory factor analyses in the first sample and cross-validated in a new sample of 234 patients. RESULTS: Results of CFA did not confirm that the data fitted well to the three-factor model of the 28-item Stigma Scale (χ(2)/df=2.02, GFI=0.77, AGFI=0.73, RMSEA=0.07, CFI=0.77 and NNFI=0.75). Cronbach's α was excellent for discrimination (0.84) and disclosure (0.83) subscales but poor for potential positive aspects (0.46). External validity was satisfactory. Overall Stigma Scale total score was negatively correlated with the score on Rosenberg's Self-Esteem Scale (r=-0.49), and each subscale was significantly correlated with a visual analogue scale that referred to the specific aspect of stigma (0.43≤|r|≤0.60). Intraclass correlation coefficients between 0.68 and 0.89 indicated good test-retest reliability. The results of the CFA demonstrated that the items chosen for the short version of the Stigma Scale have the expected fit properties (χ(2)/df=1.02, GFI=0.98, AGFI=0.98, RMSEA=0.01, CFI=1.0 and NNFI=1.0). Considering the small number (three) of items in each subscale of the short version of the Stigma Scale, α coefficients for discrimination (0.57), disclosure (0.80) and potential positive aspects subscales (0.62) are considered as good. CONCLUSION: Our results suggest that the 9-item French short version of the Stigma Scale is a useful, reliable and valid self-report questionnaire to assess perceived stigmatization in people suffering from mental illness. The time of completion is really short and questions are well understood and accepted by the patients.

MOS-SF-36 in evaluating health-related quality of life in alcohol-dependent patients.

Health-related quality of life (HRQoL) was evaluated in a sample of alcohol-dependent patients with the 36-item Medical Outcome Study Short-Form Health Survey (MOS-SF-36). The instrument was administered to 147 patients (77% males), aged 26-78, with a DSM-III-R diagnosis of alcohol dependence. The Hamilton Depression Scale (HDS), the Severity of Alcohol Dependence Questionnaire (SADQ), and the Addiction Severity Index (ASI) were also administered to the first 100 patients included in the study. The reliability and validity of the MOS-SF-36 were evaluated. Test-retest intraclass coefficients for a 10-day interval were in the range .65 to .79, whereas the Cronbach alpha coefficient indicated good internal consistency (range .70 to .89). Compared to scores observed in the general population, MOS-SF-36 scores for alcohol-dependent patients were relatively low (indicating worse perception of HRQoL), especially in the psychological and role dimensions (range 52/100 to 55/100), but were closer to populational values in the physical and functional dimensions (range 61/100 to 75/100)). The highest correlation between MOS-SF-36 dimensions and HDS was found in the MOS-SF-36 &quot;mental health&quot; dimension (r=-.56, p &lt; .001); this dimension was also correlated highly with the psychiatric dimension of the ASI (r=-.73, p &lt; .001). The eight dimensions of the MOS-SF-36 were 21% to 127% lower in patients with HDS greater than or equal to 16 (major depression) compared to those with HDS less than or equal to 7 (absence of depression). The MOS-SF-36 dimensions were 10% to 141% lower in patients with high &quot;ASI alcohol&quot; scores, indicating worse HRQoL profiles with a higher severity of alcohol dependence. The MOS-SF-36 presents good criteria for reliability and validity in alcohol-dependent patients. The results suggested that alcohol-dependent patients perceived their problems more as psychological than physical. The severity of alcohol dependence and depression seemed to influence the perception of HRQoL negatively.

Sense of coherence and job characteristics in predicting burnout in a South African sample

Orientation: Research that considers the effects of individual characteristics and job characteristics jointly in burnout is necessary, especially when one considers the possibility of curvilinear relationships between job characteristics and burnout. Research purpose: This study examines the contribution of sense of coherence (SOC) and job characteristics to predicting burnout by considering direct and moderating effects. Motivation for this study: Understanding the relationships of individual and job characteristics with burnout is necessary for preventing burnout. It also informs the design of interventions. Research design, approach and method: The participants were 632 working adults (57% female) in South Africa. The measures included the Job Content Questionnaire, the Sense of Coherence Questionnaire and the Maslach Burnout Inventory. The authors analysed the data using hierarchical multiple regression with the enter method. Main findings: Job characteristics and SOC show the expected direct effects on burnout. SOC has a direct negative effect on burnout. Job demands and supervisor social support show nonlinear relationships with burnout. SOC moderates the effect of demands on burnout and has a protective function so that the demands-burnout relationship differs for those with high and low SOC. Practical/managerial implications: The types of effects, the shape of the stressor-strain relationship and the different contributions of individual and job characteristics have implications for designing interventions. Contribution/value add: SOC functions differently when combined with demands, control and support. These different effects suggest that it is not merely the presence or absence of a job characteristic that is important for well-being outcomes but how people respond to its presence or absence.

Reference values and factors associated with renal resistive index in a family-based population study.

Increased renal resistive index (RRI) has been recently associated with target organ damage and cardiovascular or renal outcomes in patients with hypertension and diabetes mellitus. However, reference values in the general population and information on familial aggregation are largely lacking. We determined the distribution of RRI, associated factors, and heritability in a population-based study. Families of European ancestry were randomly selected in 3 Swiss cities. Anthropometric parameters and cardiovascular risk factors were assessed. A renal Doppler ultrasound was performed, and RRI was measured in 3 segmental arteries of both kidneys. We used multilevel linear regression analysis to explore the factors associated with RRI, adjusting for center and family relationships. Sex-specific reference values for RRI were generated according to age. Heritability was estimated by variance components using the ASSOC program (SAGE software). Four hundred women (mean age±SD, 44.9±16.7 years) and 326 men (42.1±16.8 years) with normal renal ultrasound had mean RRI of 0.64±0.05 and 0.62±0.05, respectively (P<0.001). In multivariable analyses, RRI was positively associated with female sex, age, systolic blood pressure, and body mass index. We observed an inverse correlation with diastolic blood pressure and heart rate. Age had a nonlinear association with RRI. We found no independent association of RRI with diabetes mellitus, hypertension treatment, smoking, cholesterol levels, or estimated glomerular filtration rate. The adjusted heritability estimate was 42±8% (P<0.001). In a population-based sample with normal renal ultrasound, RRI normal values depend on sex, age, blood pressure, heart rate, and body mass index. The significant heritability of RRI suggests that genes influence this phenotype.

Beta-catenin Status in P?aediatric Medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics.

Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for beta-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/beta-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2 months) from diagnosis. All three patients with focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de-escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved.

Review of CT features of saprophytic aspergillosis (Aspergilloma) and correlation with final diagnosis : P21

Purpose: 1. To review Ct features suggestive of saprophytic aspergillosis (aspergilloma) and to correlate them with the final pathological results. 2. To illustrate the wide range of differential diagnosis. Methods and materials: The electronic database of our department from 1995 to 2007 revealed CT reports of 48 patients that had been considered very suggestive of aspergilloma. Two radiologists with 6 and 12 years experience in thoracic radiology jointly reviewed the corresponding CT features including ancillary findings and the underlying lung diseases and correlated them with the final pathological diagnosis. Results: Forty patients could be included in the study (12 women, mean age 52), while in 8 patients there was no adequate clinical follow-up. In 17 patients the diagnosis "mycetoma" due to aspergillus fumigatus infection was confirmed, either by surgery, biopsy or bronchoscopy. In 23 patients, differential diagnoses were found, such as cavitating bronchial carcinoma (n = 7), bacterial abscess (n = 3), typical (n = 2) and atypical (n = 2) tuberculosis, as well as inflammatory changes due to mucoviscidosis (n = 1), Wegener's disease (n = 1) or chronic obstructive pulmonary disease (n = 3). Fibromyxoide hamartoma, lung infarction and bronchomucocele were responsible for the typical CT feature in one patient each. Conclusion: 1. The typical CT feature suggesting mycetoma is softtissue proliferation within a pre-existing wall-thickened lung cavity, oten even considered "pathognomonic". However, this diagnosis was finally confirmed by surgery or laboratory findings in less than 50% of patients only. 2. Since differential diagnoses are very large, not only including cavitating lung cancer and tuberculosis, the individual underlying lung disease needs strongly being taken into account often giving the best clue for the correct diagnosis.

Predictive value of the MGMT promoter methylation status in metastatic melanoma patients receiving first-line temozolomide plus bevacizumab in the trial SAKK 50/07.

The O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical trials with temozolomide plus bevacizumab therapy in metastatic melanoma patients are ongoing, although the predictive value of the MGMT promoter methylation status in this setting remains unclear. We assessed MGMT promoter methylation in formalin-fixed, primary tumor tissue of metastatic melanoma patients treated with first-line temozolomide and bevacizumab from the trial SAKK 50/07 by methylation-specific polymerase chain reaction. In addition, the MGMT expression levels were also analyzed by MGMT immunohistochemistry. Eleven of 42 primary melanomas (26%) revealed a methylated MGMT promoter. Promoter methylation was significantly associated with response rates CR + PR versus SD + PD according to RECIST (response evaluation criteria in solid tumors) (p<0.05) with a trend to prolonged median progression-free survival (8.1 versus 3.4 months, p>0.05). Immunohistochemically different protein expression patterns with heterogeneous and homogeneous nuclear MGMT expression were identified. Negative MGMT expression levels were associated with overall disease stabilization CR + PR + SD versus PD (p=0.05). There was only a poor correlation between MGMT methylation and lack of MGMT expression. A significant proportion of melanomas have a methylated MGMT promoter. The MGMT promoter methylation status may be a promising predictive marker for temozolomide therapy in metastatic melanoma patients. Larger sample sizes may help to validate significant differences in survival type endpoints.