Stochasticity of flow through microcirculation as a regulator of oxygen delivery

<p>Abstract</p> <p>Objective</p> <p>Observations of microcirculation reveal that the blood flow is subject to interruptions and resumptions. Accepting that blood randomly stops and resumes, one can show that the randomness could be a powerful means to match oxygen delivery with oxygen demand.</p> <p>Method</p> <p>The ability of the randomness to regulate oxygen delivery is based on two suppositions: (a) the probability for flow to stop does not depend on the time of uninterrupted flow, thus the number of interruptions of flow follows a Poisson distribution; (b) the probability to resume the flow does not depend on the time for flow being interrupted; meaning that time spent by erythrocytes at rest follows an exponential distribution. Thus the distribution of the time to pass an organ is a compound Poisson distribution. The Laplace transform of the given distribution gives the fraction of oxygen that passes the organ.</p> <p>Result</p> <p>Oxygen delivery to the tissues directly depends on characteristics of the irregularity of the flow through microcirculation.</p> <p>Conclusion</p> <p>By variation of vasomotion activity it is possible to change delivery of oxygen to a tissue by up to 8 times.</p

Multidimensional Cosmology: Spatially Homogeneous models of dimension 4+1

In this paper we classify all 4+1 cosmological models where the spatial hypersurfaces are connected and simply connected homogeneous Riemannian manifolds. These models come in two categories, multiply transitive and simply transitive models. There are in all five different multiply transitive models which cannot be considered as a special case of a simply transitive model. The classification of simply transitive models, relies heavily upon the classification of the four dimensional (real) Lie algebras. For the orthogonal case, we derive all the equations of motion and give some examples of exact solutions. Also the problem of how these models can be compactified in context with the Kaluza-Klein mechanism, is addressed.Comment: 24 pages, no figures; Refs added, typos corrected. To appear in CQ

First report of generalized face processing difficulties in möbius sequence.

Reverse simulation models of facial expression recognition suggest that we recognize the emotions of others by running implicit motor programmes responsible for the production of that expression. Previous work has tested this theory by examining facial expression recognition in participants with Möbius sequence, a condition characterized by congenital bilateral facial paralysis. However, a mixed pattern of findings has emerged, and it has not yet been tested whether these individuals can imagine facial expressions, a process also hypothesized to be underpinned by proprioceptive feedback from the face. We investigated this issue by examining expression recognition and imagery in six participants with Möbius sequence, and also carried out tests assessing facial identity and object recognition, as well as basic visual processing. While five of the six participants presented with expression recognition impairments, only one was impaired at the imagery of facial expressions. Further, five participants presented with other difficulties in the recognition of facial identity or objects, or in lower-level visual processing. We discuss the implications of our findings for the reverse simulation model, and suggest that facial identity recognition impairments may be more severe in the condition than has previously been noted

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression

The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect

This is the final version. Available from American Society for Microbiology via the DOI in this record. Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a -1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated A. fumigatus growth inhibition, a phenomenon called the “caspofungin paradoxical effect” (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthaseencoding genes. Here, we demonstrate that the CPE is dependent on the cell wall integrity (CWI) mitogen-activated protein kinase MpkAMPK1 and its associated transcription factor (TF) RlmARLM1, which regulate chitin synthase gene expression in response to different concentrations of caspofungin. Furthermore, the calcium- and calcineurin-dependent TF CrzA binds to and regulates the expression of specific chitin synthase genes during the CPE. These results suggest that the regulation of cell wall biosynthetic genes occurs by several cellular signaling pathways. In addition, CrzA is also involved in cell wall organization in the absence of caspofungin. Differences in the CPE were also observed between two A. fumigatus clinical isolates, which led to the identification of a novel basic leucine zipper TF, termed ZipD. This TF functions in the calcium-calcineurin pathway and is involved in the regulation of cell wall biosynthesis genes. This study therefore unraveled additional mechanisms and novel factors governing the CPE response, which ultimately could aid in developing more effective antifungal therapies.CNPqFAPES

Awareness of genetic risk in the Dominantly Inherited Alzheimer Network (DIAN)

Introduction: Although some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers. / Methods: Mutation carriers and non‐carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined. / Results: Mutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non‐carriers. Carriers who learned their status mid‐study had slightly higher levels of depression and lower cognitive scores. / Discussion: Knowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid‐study may confer short‐term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status

Endo-β-1,3-glucanase (GH16 Family) from Trichoderma harzianum Participates in Cell Wall Biogenesis but Is Not Essential for Antagonism Against Plant Pathogens

This is the published version. Available on open access from MDPI via the DOI in this recordTrichoderma species are known for their ability to produce lytic enzymes, such as exoglucanases, endoglucanases, chitinases, and proteases, which play important roles in cell wall degradation of phytopathogens. β-glucanases play crucial roles in the morphogenetic-morphological process during the development and differentiation processes in Trichoderma species, which have β-glucans as the primary components of their cell walls. Despite the importance of glucanases in the mycoparasitism of Trichoderma spp., only a few functional analysis studies have been conducted on glucanases. In the present study, we used a functional genomics approach to investigate the functional role of the gluc31 gene, which encodes an endo-β-1,3-glucanase belonging to the GH16 family in Trichoderma harzianum ALL42. We demonstrated that the absence of the gluc31 gene did not affect the in vivo mycoparasitism ability of mutant T. harzianum ALL42; however, gluc31 evidently influenced cell wall organization. Polymer measurements and fluorescence microscopy analyses indicated that the lack of the gluc31 gene induced a compensatory response by increasing the production of chitin and glucan polymers on the cell walls of the mutant hyphae. The mutant strain became more resistant to the fungicide benomyl compared to the parental strain. Furthermore, qRT-PCR analysis showed that the absence of gluc31 in T. harzianum resulted in the differential expression of other glycosyl hydrolases belonging to the GH16 family, because of functional redundancy among the glucanases.CNPq Rede Pró-Centro OesteState of São Paulo Research Foundation (FAPESP

Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

<p>Abstract</p> <p>Background</p> <p>Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-<it>O</it>-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).</p> <p>Results</p> <p>Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p < 0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p < 0.001) and D2L (p = 0.003) isoforms, monoamine oxidase A (p < 0.001) and catechol-<it>O</it>-methyltransferase (p = 0.024) were significantly higher in neonates and infants as was catechol-<it>O</it>-methyltransferase protein (32 kDa, p = 0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002) and dopamine D1 receptor protein expression increased throughout development (p < 0.001) with adults having the highest D1 protein levels (p ≤ 0.01). Monoamine oxidase B mRNA and protein (p < 0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r = -0.31, p = 0.018) in an expression profile opposite to that of the dopamine D1 receptor.</p> <p>Conclusions</p> <p>We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.</p

Semi-automated quantification of left ventricular volumes and ejection fraction by real-time three-dimensional echocardiography

<p>Abstract</p> <p>Background</p> <p>Recent studies have shown that real-time three-dimensional (3D) echocardiography (RT3DE) gives more accurate and reproducible left ventricular (LV) volume and ejection fraction (EF) measurements than traditional two-dimensional methods. A new semi-automated tool (4DLVQ) for volume measurements in RT3DE has been developed. We sought to evaluate the accuracy and repeatability of this method compared to a 3D echo standard.</p> <p>Methods</p> <p>LV end-diastolic volumes (EDV), end-systolic volumes (ESV), and EF measured using 4DLVQ were compared with a commercially available semi-automated analysis tool (TomTec 4D LV-Analysis ver. 2.2) in 35 patients. Repeated measurements were performed to investigate inter- and intra-observer variability.</p> <p>Results</p> <p>Average analysis time of the new tool was 141s, significantly shorter than 261s using TomTec (<it>p </it>< 0.001). Bland Altman analysis revealed high agreement of measured EDV, ESV, and EF compared to TomTec (<it>p </it>= <it>NS</it>), with bias and 95% limits of agreement of 2.1 ± 21 ml, -0.88 ± 17 ml, and 1.6 ± 11% for EDV, ESV, and EF respectively. Intra-observer variability of 4DLVQ vs. TomTec was 7.5 ± 6.2 ml vs. 7.7 ± 7.3 ml for EDV, 5.5 ± 5.6 ml vs. 5.0 ± 5.9 ml for ESV, and 3.0 ± 2.7% vs. 2.1 ± 2.0% for EF (<it>p </it>= <it>NS</it>). The inter-observer variability of 4DLVQ vs. TomTec was 9.0 ± 5.9 ml vs. 17 ± 6.3 ml for EDV (<it>p </it>< 0.05), 5.0 ± 3.6 ml vs. 12 ± 7.7 ml for ESV (<it>p </it>< 0.05), and 2.7 ± 2.8% vs. 3.0 ± 2.1% for EF (<it>p </it>= <it>NS</it>).</p> <p>Conclusion</p> <p>In conclusion, the new analysis tool gives rapid and reproducible measurements of LV volumes and EF, with good agreement compared to another RT3DE volume quantification tool.</p