Ultrastructural pathology of primary ciliary dyskinesia: report about 125 cases in Germany

<p>Abstract</p> <p>Background</p> <p>Primary ciliary dyskinesia (PCD) is a rare genetically induced disorder of cilia inducing mainly respiratory diseases. Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for diagnosis. We report our experience of TEM investigations in a large series of patients.</p> <p>Methods</p> <p>TEM analysis performed of 742 biopsies from patients with suspected PCD was reviewed retrospectively. Ultrastructural defects were analysized further in 125 cases with changes typical for PCD.</p> <p>Results</p> <p>In 18.1% of patients diagnosis of PCD was made because of morphological alterations, in 68.2% secondary changes were seen. In 13.7% material was not feasible for analysis. Mostly defects of dynein arms were detected in PCD (96.8%). In particular defects of the inner arms (51.2%) and combined dynein defects (37.6%) were found. Total loss of dynein arms was dominant. Only in 3.2% deficiencies of central structures were found alone. Associated situs inversus or dextracardia was reported clinically in 21.4%.</p> <p>Conclusions</p> <p>TEM analysis is possible in most patients and a useful tool for diagnosis of PCD. Functional and genetic analysis should be done additionally. Registers should be installed to collect all available informations and push further research.</p

Processing of inconsistent emotional information: an fMRI study

Previous studies investigating the anterior cingulate cortex (ACC) have relied on a number of tasks which involved cognitive control and attentional demands. In this fMRI study, we tested the model that ACC functions as an attentional network in the processing of language. We employed a paradigm that requires the processing of concurrent linguistic information predicting that the cognitive costs imposed by competing trials would engender the activation of ACC. Subjects were confronted with sentences where the semantic content conflicted with the prosodic intonation (CONF condition) randomly interspaced with sentences which conveyed coherent discourse components (NOCONF condition). We observed the activation of the rostral ACC and the middle frontal gyrus when the NOCONF condition was subtracted from the CONF condition. Our findings provide evidence for the involvement of the rostral ACC in the processing of complex competing linguistic stimuli, supporting theories that claim its relevance as a part of the cortical attentional circuit. The processing of emotional prosody involved a bilateral network encompassing the superior and medial temporal cortices. This evidence confirms previous research investigating the neuronal network that supports the processing of emotional information

The Impact of Global Warming and Anoxia on Marine Benthic Community Dynamics: an Example from the Toarcian (Early Jurassic)

The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic-rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of “dead zones” in modern oceans

Reduced Apaf-1 expression in human cutaneous melanomas

Malignant melanoma is a life-threatening skin cancer due to its highly metastatic character and resistance to radio- and chemotherapy. It is believed that the ability to evade apoptosis is the key mechanism for the rapid growth of cancer cells. However, the exact mechanism for failure in the apoptotic pathway in melanoma cells is unclear. p53, the most frequently mutated tumour suppressor gene in human cancers, is a key apoptosis inducer. However, p53 mutation is only found in 15–20% of melanoma biopsies. Recently, it was found that Apaf-1, a downstream target of p53, is inactivated in metastatic melanoma. Specifically, loss of heterozygosity (LOH) of the Apaf-1 gene was found in 40% of metastatic melanoma. To determine if loss of Apaf-1 expression is indeed involved in melanoma progression, we employed the tissue microarray technology and examined Apaf-1 expression in 70 human primary malignant melanoma biopsies by immunohistochemistry. Our data showed that Apaf-1 expression is significantly reduced in melanoma cells compared with normal nevi (χ2=6.02, P=0.014). Our results also revealed that loss of Apaf-1 was not associated with the tumour thickness, ulceration or subtype, patient's gender, age and 5-year survival. In addition, our in vitro apoptosis assay revealed that overexpression of Apaf-1 can sensitise melanoma cells to anticancer drug treatment. Taken together, our data indicate that Apaf-1 expression is significantly reduced in human melanoma and that Apaf-1 may serve as a therapeutic target in melanoma

Marginalization of end-use technologies in energy innovation for climate protection

Mitigating climate change requires directed innovation efforts to develop and deploy energy technologies. Innovation activities are directed towards the outcome of climate protection by public institutions, policies and resources that in turn shape market behaviour. We analyse diverse indicators of activity throughout the innovation system to assess these efforts. We find efficient end-use technologies contribute large potential emission reductions and provide higher social returns on investment than energy-supply technologies. Yet public institutions, policies and financial resources pervasively privilege energy-supply technologies. Directed innovation efforts are strikingly misaligned with the needs of an emissions-constrained world. Significantly greater effort is needed to develop the full potential of efficient end-use technologies

Assessing the outcomes of participatory research: protocol for identifying, selecting, appraising and synthesizing the literature for realist review

<p>Abstract</p> <p>Background</p> <p>Participatory Research (PR) entails the co-governance of research by academic researchers and end-users. End-users are those who are affected by issues under study (<it>e.g.</it>, community groups or populations affected by illness), or those positioned to act on the knowledge generated by research (<it>e.g.</it>, clinicians, community leaders, health managers, patients, and policy makers). Systematic reviews assessing the generalizable benefits of PR must address: the diversity of research topics, methods, and intervention designs that involve a PR approach; varying degrees of end-user involvement in research co-governance, both within and between projects; and the complexity of outcomes arising from long-term partnerships.</p> <p>Methods</p> <p>We addressed the above mentioned challenges by adapting realist review methodology to PR assessment, specifically by developing inductively-driven identification, selection, appraisal, and synthesis procedures. This approach allowed us to address the non-uniformity and complexity of the PR literature. Each stage of the review involved two independent reviewers and followed a reproducible, systematic coding and retention procedure. Retained studies were completed participatory health interventions, demonstrated high levels of participation by non-academic stakeholders (<it>i.e.</it>, excluding studies in which end-users were not involved in co-governing throughout the stages of research) and contained detailed descriptions of the participatory process and context. Retained sets are being mapped and analyzed using realist review methods.</p> <p>Results</p> <p>The librarian-guided search string yielded 7,167 citations. A total of 594 citations were retained after the identification process. Eighty-three papers remained after selection. Principle Investigators (PIs) were contacted to solicit all companion papers. Twenty-three sets of papers (23 PR studies), comprising 276 publications, passed appraisal and are being synthesized using realist review methods.</p> <p>Discussion</p> <p>The systematic and stage-based procedure addressed challenges to PR assessment and generated our robust understanding of complex and heterogeneous PR practices. To date, realist reviews have focussed on evaluations of relatively uniform interventions. In contrast our PR search yielded a wide diversity of partnerships and research topics. We therefore developed tools to achieve conceptual clarity on the PR field, as a beneficial precursor to our theoretically-driven synthesis using realist methods. Findings from the ongoing review will be provided in forthcoming publications.</p

Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making

The pregenual anterior cingulate cortex (pACC) has been implicated in human anxiety disorders and depression, but the circuit-level mechanisms underlying these disorders are unclear. In healthy individuals, the pACC is involved in cost-benefit evaluation. We developed a macaque version of an approach-avoidance decision task used to evaluate anxiety and depression in humans and, with multi-electrode recording and cortical microstimulation, we probed pACC function as monkeys performed this task. We found that the macaque pACC has an opponent process-like organization of neurons representing motivationally positive and negative subjective value. Spatial distribution of these two neuronal populations overlapped in the pACC, except in one subzone, where neurons with negative coding were more numerous. Notably, microstimulation in this subzone, but not elsewhere in the pACC, increased negative decision-making, and this negative biasing was blocked by anti-anxiety drug treatment. This cortical zone could be critical for regulating negative emotional valence and anxiety in decision-making.National Institutes of Health (U.S.) (Javits Merit Grant R01 NS025529)United States. Office of Naval Research (N000140710903)National Parkinson Foundation (U.S.) (Lynn Diamond Fellowship