Testicular translocator protein expression is differentially altered by synthetic cannabinoid HU210 in adult and adolescent Rats

Objective: The translocator protein (TSPO) has been implicated in numerous functions including steroid production and regulation of stress and anxiety. Cannabinoids have been shown to reduce plasma testosterone levels and alter anxiety levels. The aim of the present study was to determine whether the synthetic cannabinoid HU210 is able to regulate TSPO expression in several peripheral organs. Methods: HU210 (100 μg/kg) was administered intraperitoneally to both adult and adolescent male ratsfor 14 days. TSPO receptor expression in several organs, including the liver, spleen, kidneys and testes, was quantified by membrane receptor binding using the selective radiolig and, PK11195. In cases where receptor binding data indicated significant cannabinoid-induced differences, further RT-qPCR was carried out to determine the transcriptional regulation of the TSPO gene. Additionally, film-autography was used to identify potential changes in the spatial distribution of the TSPO tissue binding sites. Results: Results indicate that HU210 induces significant reductions in testicular TSPO expression in adult but not adolescent rats. No changes were found in other organs examined. These results are consistent with the previously observed effects of cannabinoids on testosterone production and a presumed role for TSPO in steroidogenesis. Conclusions: Overall, these results suggest that cannabinoids may alter testosterone production by altering the expression of testicular TSPO and that the alteration of TSPO occurs in an age-dependent manner.© 2014 Chan RHY, et al

Confucianism and its contexts: new research in Confucian political learning

This introduction to the special issue explains why political theorists should be interested in Confucianism and what we have to gain by considering Confucian learning in its broader historical and political contexts

Patient satisfaction with community pharmacist-led anticoagulation management services and its relationship with patient characteristics in New Zealand

BACKGROUND: Community pharmacist-led anticoagulation management service (CPAMS) offers international normalised ratio point-of-care testing of warfarin in a community pharmacy setting. It has now expanded with 7,344 patients enrolled in the service across 164 pharmacies in New Zealand. The clinical benefit of CPAMS has been shown to be superior, but patient satisfaction with the service has not been fully explored. OBJECTIVE: To develop a questionnaire to assess patient satisfaction with CPAMS and evaluate its psychometric properties. Additionally, to determine the level of patient satisfaction with CPAMS and identify determinants of satisfaction with CPAMS. Settings 1071 patients enrolled in CPAMS across New Zealand invited to take part in the study. MAIN OUTCOME MEASURE: Satisfaction with CPAMS service. METHODS: Adult patients taking warfarin and currently enrolled in CPAMS were recruited through the national international normalised ratio online system and invited to complete a 36-item survey assessing satisfaction with CPAMS. To identify the most important dimensions of patient satisfaction, exploratory factor analysis was used. Multivariate linear regression models were used to examine the effect of independent variables on patient satisfaction. RESULTS: A total of 305 patients completed the survey. The mean overall satisfaction score was 94.5% ± 13.1 out of maximum possible points. Five dimensions of patient satisfaction were identified by factor analysis: patient-centred communication, confidence in pharmacist competence, patient-pharmacist relationship, confidence in CPAMS, and pharmacy environment. Being older and more frequent visits to a pharmacy were positively associated with patient satisfaction. Living more than 1 km away from a pharmacy, and ‘poor’ self-perceived health status were negative predictors of patient satisfaction. Being Māori or of other ethnic minority was also associated with lower satisfaction scores, exploratory analysis suggests patient-pharmacist relationship is an important driver of these differences. CONCLUSIONS: The high level of patient satisfaction further supports the effectiveness of CPAMS as a delivery model. Patient satisfaction is affected by age, frequency of pharmacy visits, ethnicity, travel distance to pharmacy, and perceived health status. Policy makers and practitioners should consider the characteristics of patients with low levels of satisfaction to improve and enhance CPAMS engagement

Evaluation of Risk-based Re-Authentication Methods

Risk-based Authentication (RBA) is an adaptive security measure that improves the security of password-based authentication by protecting against credential stuffing, password guessing, or phishing attacks. RBA monitors extra features during login and requests for an additional authentication step if the observed feature values deviate from the usual ones in the login history. In state-of-the-art RBA re-authentication deployments, users receive an email with a numerical code in its body, which must be entered on the online service. Although this procedure has a major impact on RBA's time exposure and usability, these aspects were not studied so far. We introduce two RBA re-authentication variants supplementing the de facto standard with a link-based and another code-based approach. Then, we present the results of a between-group study (N=592) to evaluate these three approaches. Our observations show with significant results that there is potential to speed up the RBA re-authentication process without reducing neither its security properties nor its security perception. The link-based re-authentication via "magic links", however, makes users significantly more anxious than the code-based approaches when perceived for the first time. Our evaluations underline the fact that RBA re-authentication is not a uniform procedure. We summarize our findings and provide recommendations.Comment: 14 pages, 5 figures. Paper accepted for IFIP SEC 2020. Keywords: Risk-based Authentication (RBA), Re-authentication, Usable Securit

The 18 kDa translocator protein, microglia and neuroinflammation

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is expressed in the injured brain. It has become known as an imaging marker of “neuroinflammation” indicating active disease, and is best interpreted as a nondiagnostic biomarker and disease staging tool that refers to histopathology rather than disease etiology. The therapeutic potential of TSPO as a drug target is mostly based on the understanding that it is an outer mitochondrial membrane protein required for the translocation of cholesterol, which thus regulates the rate of steroid synthesis. This pivotal role together with the evolutionary conservation of TSPO has underpinned the belief that any loss or mutation of TSPO should be associated with significant physiological deficits or be outright incompatible with life. However, against prediction, full Tspo knockout mice are viable and across their lifespan do not show the phenotype expected if cholesterol transport and steroid synthesis were significantly impaired. Thus, the “translocation” function of TSPO remains to be better substantiated. Here, we discuss the literature before and after the introduction of the new nomenclature for TSPO and review some of the newer findings. In light of the controversy surrounding the function of TSPO, we emphasize the continued importance of identifying compounds with confirmed selectivity and suggest that TSPO expression is analyzed within specific disease contexts rather than merely equated with the reified concept of “neuroinflammation.” © 2014 The Authors© 2014 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice

Apolipoprotein E ε4 (APOE4) is the primary genetic risk factor for the late-onset form of Alzheimer's disease (AD). Although the reason for this association is not completely understood, researchers have uncovered numerous effects of APOE4 expression on AD-relevant brain processes, including amyloid beta (Aβ) accumulation, lipid metabolism, endosomal-lysosomal trafficking, and bioenergetics. In this study, we aimed to determine the effect of APOE4 allelic dosage on regional brain lipid composition in aged mice, as well as in cultured neurons. We performed a targeted lipidomic analysis on an AD-vulnerable brain region (entorhinal cortex; EC) and an AD-resistant brain region (primary visual cortex; PVC) from 14-15 month-old APOE3/3, APOE3/4, and APOE4/4 targeted replacement mice, as well as on neurons cultured with conditioned media from APOE3/3 or APOE4/4 astrocytes. Our results reveal that the EC possesses increased susceptibility to APOE4-associated lipid alterations compared to the PVC. In the EC, APOE4 expression showed a dominant effect in decreasing diacylglycerol (DAG) levels, and a semi-dominant, additive effect in the upregulation of multiple ceramide, glycosylated sphingolipid, and bis(monoacylglycerol)phosphate (BMP) species, lipids known to accumulate as a result of endosomal-lysosomal dysfunction. Neurons treated with conditioned media from APOE4/4 vs. APOE3/3 astrocytes showed similar alterations of DAG and BMP species to those observed in the mouse EC. Our results suggest that APOE4 expression differentially modulates regional neuronal lipid signatures, which may underlie the increased susceptibility of EC-localized neurons to AD pathology

Clinical outcome of instrumented fusion for the treatment of failed back surgery syndrome: a case series of 100 patients

Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function

Cytogenetic and histological studies of the brook trout, Salvelinus fontinalis (Mitchill), and the Arctic char, S-alpinus (L.) hybrids

Although brook trout and the Arctic char hybrids are able to reproduce, individuals with decreased fertility or even fish that are unable to produce any gametes have been also described. Abnormal gonadal development and disturbances in the gamete production in the char hybrid offspring may be triggered by the odd chromosome number and disturbances in their pairing during meiosis. To verify this hypothesis, cytogenetic examination and the gonadal histology analysis of the brook trout x Arctic char hybrids were carried out. Diploid chromosome number in the studied char (F-1) hybrids varied from 82 to 84 (FN = 99-102). Among 28 hybrids, 12 males, three females, nine intersex individuals and two sterile specimens were described. In the case of two individuals, gonads were not found. Diploid chromosome numbers in the males and intersex individuals varied from 82 to 84. Chromosome numbers in the females were 82 and 83 chromosomes. Two sterile fish exhibited karyotypes composed of 82 and 84 chromosomes. Predominance of the ovarian component in the intersex gonads and gonadal sex ratio distortion towards the males suggested hybrid females had problems with gonadal differentiation. However, the lack of the clear relationship between chromosome number and gonadal development in the studied hybrids did not support our hypothesis that odd chromosome number may be responsible for such reproductive disturbances in the hybrid individuals. We have presumed that sterility and intersexual development of the gonads may be caused by interactions between brook trout and Arctic char genes on the sex chromosomes and autosomes rather than unpairing of the parental chromosomes.Polish National Science Center (NCN) [N N311 525240]info:eu-repo/semantics/publishedVersio