Pulmonary arterial remodeling revealed by microfocal x-ray tomography

Animal models and micro-CT imaging are useful for understanding the functional consequences of, and identifying the genes involved in, the remodeling of vascular structures that accompanies pulmonary vascular disease. Using a micro-CT scanner to image contrast-enhanced arteries in excised lungs from fawn hooded rats (a strain genetically susceptible to hypoxia induced pulmonary hypertension), we found that portions of the pulmonary arterial tree downstream from a given diameter were morphometrically indistinguishable. This \u27self-consistency\u27 property provided a means for summarizing the pulmonary arterial tree architecture and mechanical properties using a parameter vector obtained from measurements of the contiguous set of vessel segments comprising the longest (principal) pathway and its branches over a range of vascular pressures. This parameter vector was used to characterize the pulmonary vascular remodeling that occurred in rats exposed to a hypoxic (11.5% oxygen) environment and provided the input to a hemodynamic model relating structure to function. The major effect of the remodeling was a longitudinally (pulmonary artery to arterioles) uniform decrease in vessel distensibility that resulted in a 90% increase in arterial resistance. Despite the almost uniform change in vessel distensibility, over 50% of the resistance increase was attributable to vessels with unstressed diameters less than 125 microns

A rapid and inexpensive viability assay for zoospores and zoosporangia of Batrachochytrium dendrobatidis

The fungus Batrachochytrium dendrobatidis is causing global amphibian declines. Here we describe a simple, rapid and inexpensive methylene blue staining protocol to determine B. dendrobatidis viability, regardless of life-stage. The viability of cells in suspension or adherent monolayers can be determined using either manual microscopy counting or colorimetric assay

A time-invariant visco-elastic windkessel model relating blood flow and blood volume

The difference between the rate of change of cerebral blood volume (CBV) and cerebral blood flow (CBF) following stimulation is thought to be due to circumferential stress relaxation in veins (Mandeville, J.B., Marota, J.J.A., Ayata, C., Zaharchuk, G., Moskowitz, M.A., Rosen, B.R., Weisskoff, R.M., 1999. Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J. Cereb. Blood Flow Metab. 19, 679-689). In this paper we explore the visco-elastic properties of blood vessels, and present a dynamic model relating changes in CBF to changes in CBV. We refer to this model as the visco-elastic windkessel (VW) model. A novel feature of this model is that the parameter characterising the pressure-volume relationship of blood vessels is treated as a state variable dependent oil the rate of change of CBV, producing hysteresis in the pressure-volume space during vessel dilation and contraction. The VW model is nonlinear time-invariant, and is able to predict the observed differences between the time series of CBV and that of CBF measurements following changes in neural activity. Like the windkessel model derived by Mandeville, J.B., Marota, J.J.A., Ayata, C., Zaharchuk, G., Moskowitz, M.A., Rosen, B.R., Weisskoff, R.M., 1999. Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J. Cereb. Blood Flow Metab. 19, 679-689, the VW model is primarily a model of haemodynamic changes in the venous compartment. The VW model is demonstrated to have the following characteristics typical of visco-elastic materials: (1) hysteresis, (2) creep, and (3) stress relaxation, hence it provides a unified model of the visco-elastic properties of the vasculature. The model will not only contribute to the interpretation of the Blood Oxygen Level Dependent (BOLD) signals from functional Magnetic Resonance Imaging (fMRI) experiments, but also find applications in the study and modelling of the brain vasculature and the haemodynamics of circulatory and cardiovascular systems. (C) 2009 Elsevier Inc. All rights reserved

IL2 treatment for cancer: from biology to gene therapy.

In this review we shall discuss the biological rationale and the clinical findings obtained using Interleukin 2 (IL2)-based immunotherapy in the management of cancer patients. Objective and long-lived clinical responses have been documented in a proportion of cases, particularly renal cell carcinoma, melanoma and acute myeloid leukaemia. Though encouraging, the clinical use of IL2 has so far been limited by toxicity, as well as by the heterogeneous and unpredictable responses and by the lack of specific anti-tumour effect. These considerations have led to the belief that more sophisticated technologies aimed at introducing the IL2 gene into the neoplastic cells may potentially overcome some of the limitations coupled to the in vivo infusion of high doses of IL2. The data accumulated in animal models and, more recently, also with human tumour cells indicate that the IL2 gene may be successfully inserted into neoplastic cells. The constitutive secretion of IL2 by the tumour cells leads to a reduced or abrogated tumorigenicity in several different tumour models. The evidence that in some experimental tumours the transduction of the IL2 gene into the neoplastic cells may elicit a specific cytotoxic response and confer anti-tumour memory, suggests that vaccination protocols based on this innovative strategy may represent a potential new tool in the management of cancer patients

Relationships between self-reported childhood traumatic experiences, attachment style, neuroticism and features of borderline personality disorders in patients with mood disorders

Background: Co-occurring borderline personality disorder (BPD) features have a marked impact on treatment of patients with mood disorders. Overall, high neuroticism, childhood traumatic experiences (TEs) and insecure attachment are plausible aetiological factors for BPD. However, their relationship with BPD features specifically among patients with mood disorders remains unclear. We investigated these relationships among unipolar and bipolar mood disorder patients. Methods: As part of the Helsinki University Psychiatric Consortium study, the McLean Screening Instrument (MSI), the Experiences in Close Relationships-Revised (ECR-R), the Short Five (S5) and the Trauma and Distress Scale (TADS) were filled in by patients with mood disorders (n=282) in psychiatric care. Correlation coefficients between total scores of scales and their dimensions were estimated, and multivariate regression (MRA) and mediation analyses were conducted. Results: Spearman's correlations were strong (rho=0.58; p <0.001) between total scores of MSI and S5 Neuroticism and moderate (rho=0.42; p <0.001) between MSI and TADS as well as between MSI and ECR-R Attachment Anxiety. In MRA, young age, S5 Neuroticism and TADS predicted scores of MSI (p <0.001). ECR-R Attachment Anxiety mediated 33% (CI=17-53%) of the relationships between TADS and MSI. Limitations: Cross-sectional questionnaire study. Conclusions: We found moderately strong correlations between self-reported BPD features and concurrent high neuroticism, reported childhood traumatic experiences and Attachment Anxiety also among patients with mood disorders. Independent predictors for BPD features include young age, frequency of childhood traumatic experiences and high neuroticism. Insecure attachment may partially mediate the relationship between childhood traumatic experiences and borderline features among mood disorder patients.Peer reviewe

A Pharmacokinetic and Metabolism Study of the TRPC6 Inhibitor SH045 in Mice by LC-MS/MS

TRPC6, the sixth member of the family of canonical transient receptor potential (TRP) channels, contributes to a variety of physiological processes and human pathologies. This study extends the knowledge on the newly developed TRPC6 blocker SH045 with respect to its main target organs beyond the description of plasma kinetics. According to the plasma concentration-time course in mice, SH045 is measurable up to 24 h after administration of 20 mg/kg BW (i.v.) and up to 6 h orally. The short plasma half-life and rather low oral bioavailability are contrasted by its reported high potency. Dosage limits were not worked out, but absence of safety concerns for 20 mg/kg BW supports further dose exploration. The disposition of SH045 is described. In particular, a high extravascular distribution, most prominent in lung, and a considerable renal elimination of SH045 were observed. SH045 is a substrate of CYP3A4 and CYP2A6. Hydroxylated and glucuronidated metabolites were identified under optimized LC-MS/MS conditions. The results guide a reasonable selection of dose and application route of SH045 for target-directed preclinical studies in vivo with one of the rare high potent and subtype-selective TRPC6 inhibitors availabl

Associations between non-suicidal self-injury and experiential avoidance: A systematic review and Robust Bayesian Meta-analysis

Objectives: Non-suicidal self-injury (NSSI) is the intentional and deliberate damage to an individual's own body tissue without the intent to suicide. Individuals who have higher self-reported levels of experiential avoidance are more likely to report a history of NSSI. The current study systematically reviewed the literature and meta-analysed studies assessing associations between experiential avoidance and self-injury. Method: An extensive review was conducted of several databases (including ProQuest, Joanna Briggs, Web of Science, PsychArticles, PubMed, Scopus, and Ovid). Nineteen articles (two dissertations) met the inclusion criteria for the systematic review and 14 were analysed in a Robust Bayesian Meta-analysis. This review was registered through PROSPERO (CRD42020198041). Results: There was a small to medium, pooled effect size (d = 0.48, 95 % Credibility Interval 0.00–0.85). There was strong evidence for this effect size (Bayes Factor = 12.16), although there was considerable heterogeneity between studies (τ =0.68, 95 % CI [0.44, 0.1.05]). The analysis testing whether these findings may be due to publication bias was inconclusive (Bayes Factor = 2.45). Limitations: The majority of studies included were cross-sectional, in English, and most studies were of university students. While some studies reported on recency/frequency of NSSI there was not enough data to conduct meta-analysis. Conclusion: These results suggest there is a robust association between history of NSSI and experiential avoidance. However, as most studies operationalise avoidance as a unidimensional construct, it is not clear which aspects of avoidance differentiate individuals with and without a history of NSSI