7,8,4′-Trihydroxyisoflavone Attenuates DNCB-Induced Atopic Dermatitis-Like Symptoms in NC/Nga Mice

Atopic dermatitis (AD) is characterized by chronic highly pruritic and relapsing inflammatory skin lesions. Despite its growing prevalence, therapeutic treatments remain limited. Natural immune modulators from herbal extracts or derivatives may be useful for treating AD symptoms. This study examined the effect of 7,8,4′-trihydroxyisoflavone (7,8,4′-THIF), a metabolite of soy isoflavone daidzin, on AD-like symptoms. Repeated epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) was performed on the ear and dorsal skin of NC/Nga mice to induce AD-like symptoms and skin lesions, and 7,8,4′-THIF (200 and 400 nmol) or tacrolimus (100 µg) was applied topically for 3 weeks to assess their anti-pruritic effects. We found that 7,8,4′-THIF alleviated DNCB-induced AD-like symptoms as quantified by skin lesion, dermatitis score, ear thickness, and scratching behavior. Histopathological analysis demonstrated that 7,8,4′-THIF decreased DNCB-induced eosinophil and mast cell infiltration into skin lesions. We also found that 7,8,4′-THIF significantly alleviated DNCB-induced loss of water through the epidermal layer. In addition to reducing the DNCB-induced increase in serum IgE, 7,8,4′-THIF also lowered skin lesion levels of the chemokine thymus and activation regulated chemokine; Th2 cytokines interleukin (IL)-4, IL-5, and IL-13; and Th1 cytokines IL-12 and interferon-γ. These results suggest that 7,8,4′-THIF might be a potential therapeutic candidate for the treatment of atopic dermatitis.     

Urinating Standing versus Sitting: Position Is of Influence in Men with Prostate Enlargement. A Systematic Review and Meta-Analysis

Background

It is suggested that the body posture during urination can influence urodynamic parameters in patients with Lower Urinary Tract Symptoms (LUTS) to an extent approaching pharmacological interventions. In this article, the influence of body position during micturition on maximum urinary flow rate (Qmax), voiding time (TQ) and post-void residual volume (PVR) in healthy males and patients with LUTS is analyzed by means of a systematic review and meta-analysis.

Evidence Acquisition

A systematic search was conducted in 14 medical databases. Studies comparing urodynamic parameters in standing versus sitting position were eligible for inclusion. Studies were stratified according to health status of included male participants: healthy individuals and patients with LUTS. Standardized mean differences for Qmax, TQ and PVR were pooled in a random effects model.

Results

Eleven articles were included. In men with LUTS, a significantly lower PVR (−24.96 ml; 95%CI −48.70 to −1.23) was shown in sitting position compared to standing. In accordance, Qmax was increased (1.23 ml/s; 95%CI −1.02 to 3.48), and TQ was decreased (−0.62 s; 95%CI −1.66 to 0.42) in sitting position, although these differences did not reach statistical significance. In healthy men, Qmax (0.18 ml/s; 95% CI −1.67 to 2.02), TQ (0.49 s; 95%CI −3.30 to 4.27) and PVR (0.43 ml; 95%CI −0.79 to 1,65) were similar in sitting and standing position.

Conclusion

For healthy men, no difference is found in any of the urodynamic parameters. In patients with LUTS, the sitting position is linked with an improved urodynamic profile.     

Optimising and Evaluating the Characteristics of a Multiple Antigen ELISA for Detection of Mycobacterium bovis Infection in a Badger Vaccine Field Trial

A long-term research programme has been underway in Ireland to evaluate the usefulness of badger vaccination as part of the national bTB (bovine tuberculosis) control strategy. This culminated in a field trial which commenced in county Kilkenny in 2009 to determine the effects of badger vaccination on Mycobacterium bovis transmission in badgers under field conditions. In the present study, we sought to optimise the characteristics of a multiplex chemiluminescent assay for detection of M. bovis infection in live badgers. Our goal was to maximise specificity, and therefore statistical power, during evaluation of the badger vaccine trial data. In addition, we also aimed to explore the effects of vaccination on test characteristics. For the test optimisation, we ran a stepwise logistic regression with analytical weights on the converted Relative Light Units (RLU) obtained from testing blood samples from 215 badgers captured as part of culling operations by the national Department of Agriculture, Food and the Marine (DAFM). The optimised test was applied to two other datasets obtained from two captive badger studies (Study 1 and Study 2), and the sensitivity and specificity of the test was attained separately for vaccinated and non-vaccinated badgers. During optimisation, test sensitivity was maximised (30.77%), while retaining specificity at 99.99%. When the optimised test was then applied to the captive badger studies data, we observed that test characteristics did not vary greatly between vaccinated and non-vaccinated badgers. However, a different time lag between infection and a positive test result was observed in vaccinated and non-vaccinated badgers. We propose that the optimized multiplex immunoassay be used to analyse the vaccine trial data. In relation to the difference in the time lag observed for vaccinated and non-vaccinated badgers, we also present a strategy to enable the test to be used during trial evaluation.     

Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation

Adrenocortical carcinoma (ACC) is a rare, but highly malignant tumor of unknown origin. Inhibin α-subunit (Inha) knockout mice develop ACCs following gonadectomy. In man, INHA expression varies widely within ACC tissues and its circulating peptide inhibin pro-αC has been described as a novel tumor marker for ACC. We investigated whether genetic and epigenetic changes of the INHA gene in human ACC cause loss or variation of INHA expression. To this end, analyses of INHA sequence, promoter methylation and mRNA expression were performed in human adrenocortical tissues. Serum inhibin pro-αC levels were also measured in ACC patients. INHA genetic analysis in 37 unique ACCs revealed 10 novel, heterozygous rare variants. Of the 3 coding bases affected, one variant was synonymous and two were missense variants: S72F and S184F. The minor allele of rs11893842 at −124 bp was observed at a low frequency (24%) in ACC samples and was associated with decreased INHA mRNA levels: 4.7±1.9 arbitrary units for AA, compared to 26±11 for AG/GG genotypes (P = 0.034). The methylation of four proximal INHA promoter CpGs was aberrantly increased in five ACCs (47.7±3.9%), compared to normal adrenals (18.4±0.6%, P = 0.0052), whereas the other 14 ACCs studied showed diminished promoter methylation (9.8±1.1%, P = 0.020). CpG methylation was inversely correlated to INHA mRNA levels in ACCs (r = −0.701, p = 0.0036), but not associated with serum inhibin pro-αC levels. In conclusion, aberrant methylation and common genetic variation in the INHA promoter occur in human ACCs and are associated with decreased INHA expression.     

The Use of Exome Genotyping to Predict Pathological Gleason Score Upgrade after Radical Prostatectomy in Low-Risk Prostate Cancer Patients

Background

Active surveillance (AS) is a promising option for patients with low-risk prostate cancer (PCa), however current criteria could not select the patients correctly, many patients who fulfilled recent AS criteria experienced pathological Gleason score upgrade (PGU) after radical prostatectomy (RP). In this study, we aimed to develop an accurate model for predicting PGU among low-risk PCa patients by using exome genotyping.

Methods

We genotyped 242,221 single nucleotide polymorphisms (SNP)s on a custom HumanExome BeadChip v1.0 (Illuminam Inc.) in blood DNA from 257 low risk PCa patients (PSA <10 ng/ml, biopsy Gleason score (GS) ≤6 and clinical stage ≤T2a) who underwent radical prostatectomy. Genetic data were analyzed using an unconditional logistic regression to calculate an odds ratio as an estimate of relative risk of PGU, which defined pathologic GS above 7. Among them, we selected persistent SNPs after multiple testing using FDR method, and we compared accuracies from the multivariate logistic model incorporating clinical factors between included and excluded selected SNP information.

Results

After analysis of exome genotyping, 15 SNPs were significant to predict PGU in low risk PCa patients. Among them, one SNP – rs33999879 remained significant after multiple testing. When a multivariate model incorporating factors in Epstein definition – PSA density, biopsy GS, positive core number, tumor per core ratio and age was devised for the prediction of PGU, the predictive accuracy of the multivariate model was 78.4% (95%CI: 0.726–0.834). By addition the factor of rs33999879 in aforementioned multivariate model, the predictive accuracy was 82.9%, which was significantly increased (p = 0.0196).

Conclusion

The rs33999879 SNP is a predictor for PGU. The addition of genetic information from the exome sequencing effectively enhanced the predictive accuracy of the multivariate model to establish suitable active surveillance criteria.     

Development of a Screening Algorithm for Alzheimer's Disease Using Categorical Verbal Fluency

We developed a weighted composite score of the categorical verbal fluency test (CVFT) that can more easily and widely screen Alzheimer''s disease (AD) than the mini-mental status examination (MMSE). We administered the CVFT using animal category and MMSE to 423 community-dwelling mild probable AD patients and their age- and gender-matched cognitively normal controls. To enhance the diagnostic accuracy for AD of the CVFT, we obtained a weighted composite score from subindex scores of the CVFT using a logistic regression model: logit (case)  = 1.160+0.474× gender +0.003× age +0.226× education level – 0.089× first-half score – 0.516× switching score -0.303× clustering score +0.534× perseveration score. The area under the receiver operating curve (AUC) for AD of this composite score AD was 0.903 (95% CI = 0.883 – 0.923), and was larger than that of the age-, gender- and education-adjusted total score of the CVFT (p<0.001). In 100 bootstrapped re-samples, the composite score consistently showed better diagnostic accuracy, sensitivity and specificity for AD than the total score. Although AUC for AD of the CVFT composite score was slightly smaller than that of the MMSE (0.930, p = 0.006), the CVFT composite score may be a good alternative to the MMSE for screening AD since it is much briefer, cheaper, and more easily applicable over phone or internet than the MMSE.     

Association of Severe Thrombocytopenia and Poor Prognosis in Pregnancies with Aplastic Anemia

Purpose

We sought to estimate the risks of adverse obstetric outcomes and disease outcomes associated with severe thrombocytopenia in pregnant women with aplastic anemia (AA).

Methods

In a retrospective study, we compared demographics, clinical characteristics, laboratory results, and outcomes between severe thrombocytopenia (ST) and non-severe thrombocytopenia (non-ST) groups comprising pregnant women with AA.

Results

Of 61 AA patients, 43 (70%) were diagnosed as AA before pregnancy and 18 (30%) were AA during pregnancy. The ST group exhibited lower gestational age at nadir of platelet count (26.0 versus 37.0 weeks, p<0.001) and at delivery (37.3 versus 39.1 weeks, p = 0.008), and a higher rate of bleeding gums (33.8 versus 7.7%, p = 0.015) than the non-ST group. In addition, the ST group exhibited more transfusions during pregnancy (72.7 versus 15.4%, p<0.001) and postpartum period (45.0 versus 2.7%, p<0.001), and more bone marrow transplant after delivery (25.0 versus 0.0%, p<0.001) than the non-ST group. The ST group had a higher odds ratio of composite disease complications (OR, 9.63; 95% CI, 2.82–32.9; p<0.001) and composite obstetric complications (OR, 6.78; 95% CI, 2.11–21.8; p = 0.001) than the non-ST group.

Conclusions

Severe thrombocytopenia is more associated with obstetric and disease complications than is non-severe thrombocytopenia in pregnant women with AA.     

A Multi-Criteria Index for Ecological Evaluation of Tropical Agriculture in Southeastern Mexico

The aim of this study was to generate an easy to use index to evaluate the ecological state of agricultural land from a sustainability perspective. We selected environmental indicators, such as the use of organic soil amendments (green manure) versus chemical fertilizers, plant biodiversity (including crop associations), variables which characterize soil conservation of conventional agricultural systems, pesticide use, method and frequency of tillage. We monitored the ecological state of 52 agricultural plots to test the performance of the index. The variables were hierarchically aggregated with simple mathematical algorithms, if-then rules, and rule-based fuzzy models, yielding the final multi-criteria index with values from 0 (worst) to 1 (best conditions). We validated the model through independent evaluation by experts, and we obtained a linear regression with an r² = 0.61 (p = 2.4e-06, d.f. = 49) between index output and the experts’ evaluation.     

Inhibition of GM3 Synthase Attenuates Neuropathology of Niemann-Pick Disease Type C by Affecting Sphingolipid Metabolism

In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NPC mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.