Transbronchial Needle Aspiration in the Staging of Bronchogenic Carcinoma

To evaluate the usefulness of transbronchial needle aspiration biopsy (TBNA) for the diagnosis of mediastinal involvement, we have prospectively examined 316 patients with morphologically verified bronchogenic carcinoma. The percentage of positive aspirations (149 of 316) from the three basic lymph node groups in the mediastinum was not significantly different. Tumor cells were aspirated from the mediastinum in 75 of 112 patients with radiologically positive findings and in patients with 74 of 204 radiologically negative findings. Mediastinal involvement was verified even in 61 of 196 patients with a normal endoscopic picture. Metastases were proved in 14 of 39 patients with peripheral versus 135 of 277 patients with central carcinoma. Tumor cells were aspirated in 47 of 76 patients with undifferentiated small cell carcinoma, 92 of 227 patients with squamous cell carcinoma, and 10 of 13 patients with adenocarcinoma. Our results suggest that TBNA being a highly diagnostic and less invasive method, will prove its clinical importance

Protocadherins Mediate Dendritic Self-Avoidance in the Mammalian Nervous System

Dendritic arbors of many neurons are patterned by a process called self-avoidance, in which branches arising from a single neuron repel each other. By minimizing gaps and overlaps within the arbor, self-avoidance facilitates complete coverage of a neuron’s territory by its neurites. Remarkably, some neurons that display self-avoidance interact freely with other neurons of the same subtype, implying that they discriminate self from non-self. Here, we demonstrate roles for the clustered protocadherins (Pcdhs) in dendritic self-avoidance and self/non-self discrimination. The Pcdh locus encodes ~60 related cadherin-like transmembrane proteins, at least some of which exhibit isoform-specific homophilic adhesion in heterologous cells and are expressed stochastically and combinatorially in single neurons. Deletion of all 22 Pcdhs in the mouse gamma subcluster (Pcdhgs) disrupts self-avoidance of dendrites in retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Further genetic analysis of SACs showed that Pcdhgs act cell-autonomously during development, and that replacement of the 22 Pcdhgs with a single isoform restores self-avoidance. Moreover, expression of the same single isoform in all SACs decreases interactions among dendrites of neighboring SACs (heteroneuronal interactions). These results suggest that homophilic Pcdhg interactions between sibling neurites (isoneuronal interactions) generate a repulsive signal that leads to self-avoidance. In this model, heteroneuronal interactions are normally permitted because dendrites seldom encounter a matched set of Pcdhgs unless they emanate from the same soma. In many respects, our results mirror those reported for Dscam1 in Drosophila: this complex gene encodes thousands of recognition molecules that exhibit stochastic expression and isoform-specific interactions, and mediate both self-avoidance and self/non-self discrimination. Thus, although insect Dscams and vertebrate Pcdhs share no sequence homology, they appear to underlie similar strategies for endowing neurons with distinct molecular identities and patterning their arbors.Molecular and Cellular Biolog

Stress echocardiography for left ventricular diastolic dysfunction detection in patients with non-severe chronic obstructive pulmonary disease: a cross-sectional study

Aim To assess whether the simultaneous performance of exercise stress echocardiography and cardio-pulmonary testing (ESE-CPET) may facilitate the timely diagnosis of subclinical left ventricular diastolic dysfunction (LVDD) in patients with non-severe chronic obstructive pulmonary disease (COPD), preserved left ventricular systolic function, and exertional dyspnea or exercise intolerance. Methods This cross-sectional study, conducted between May 2017 and April 2018, involved 104 non-severe COPD patients with exertional dyspnea and preserved ejection fraction who underwent echocardiography before CPET and 1-2 minutes after peak exercise. Based on the peak E/e’ ratio, patients were divided into the group with stressinduced LVDD – E/e’>15 and the group without stress-induced LVDD. We assessed the association between LVDD and the following CPET variables: minute ventilation, peak oxygen uptake (VO2), ventilatory efficiency, heart rate reserve, and blood pressure.Results During ESE-CPET, stress-induced LVDD occurred in 67/104 patients (64%). These patients had lower work load, peak VO2, O2 pulse, and minute ventilation (VE), and higher VE/VCO2 slope than patients without stress-induced LVDD (35.18 ± 10.4 vs 37.01 ± 11.11, P < 0.05). None of the CPET variables correlated with E/e’. Conclusion Combined ESE-CPET may distinguish masked LVDD in patients with non-severe COPD with exertional dyspnea and preserved left ventricular systolic function. None of the CPET variables was a predictor for subclinical LVDD

DECODING MICROBIOME DYSBIOSIS THROUGH METAGENOMIC ALPHA DIVERSITY

Background: Sarcoidosis is a chronic inflammatory disease that can affect multiple organs. The aetiology of sarcoidosis is not fully understood, but there is increasing evidence that the microbiome may play a role. The blood microbiome is a collection of microorganisms that live in the bloodstream. It is a complex and dynamic community that is influenced by a variety of factors, including the host’s lifestyle and pathology. Recent studies have shown that people with sarcoidosis have alterations in their blood microbiome. These alterations include changes in the diversity, richness, and evenness of the microbial community. The abundance measures by which the blood microbiome diversity may detect instances of dysbiosis related to sarcoidosis aetiology. It should be clearly distinguished from microbiome changes related to unspecific inflammation or sepsis. However, the available evidence suggests that the microbiome may be a promising target for therapeutic interventions. Aim: The primary goal of this review was to assess and compare the existing metrics of microbiome composition and diversity as established by metagenomic analyses. Additionally, we aim to elucidate the potential causal relationship between these measures, the phenomenon of blood microbiome dysbiosis and the pathogenesis of sarcoidosis. Conclusion: In the present review, we investigated alpha diversity measures as characteristics of microbiome communities, examining their potential as indicators of dysbiosis, and the probablemechanisms of microbiome participation. A descriptive qualitative comparison was conducted between lung microbiome data of sarcoidosis patients and blood microbiome data of healthy adults. This comparison elucidates common taxa between the two microbiomes and identifies taxa potentially involved in sarcoidosis

Mechanism and Function of Dendritic Self-Avoidance and Self/non-Self Discrimination in the Mammalian Nervous System

Dendritic and axonal arbors of many neuronal types exhibit self-avoidance, a phenomenon in which branches repel each other. This process ensures that individual neurons cover all parts of their territory uniformly. Some neurons that self-avoid overlap with neighbors of the same type, suggesting that nominally identical neurons are immune to each other’s repellent forces, a phenomenon called self/non-self discrimination. Here, I describe the roles of the 22 clustered gamma-Protocadherin (Pcdhg) recognition molecules in dendritic self-avoidance and self/non-self discrimination of mammalian neurons, and the roles of these phenomena in a retinal circuit. First, I present studies showing that Pcdhgs are necessary for dendritic self-avoidance and self/non-self discrimination of retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Using loss and gain of function experiments, we showed that no single Pcdhg isoform is necessary and any Pcdhg isoform is sufficient to mediate self-avoidance. However, forcing neighboring SACs to express a single Pcdhg decreases their overlap. Thus, Pcdhg diversity is necessary for SACs to avoid their own dendrites, but interact with their neighbors (self/non-self discrimination). Second, I describe the roles of self-avoidance and self/non-self discrimination in the function of a retinal direction-selective circuit that depends on SACs. Dendrites of SACs compute directional motion and endow classes of retinal ganglion cells with this property by inhibiting them asymmetrically during visual motion. In addition, SACs form inhibitory synapses in order to sharpen each other’s direction-selectivity. I present findings that elucidate the roles self-avoidance and self/non-self discrimination in the function of this direction-selective circuit: (1) In the absence of self-avoidance, SACs form synapses with their own dendrites. (2) In the absence of self/non-self discrimination, SACs form few synapses with each other, (3) Loss of either self-avoidance or self/non-self discrimination degrades directional responses of ganglion cells. Lastly, I describe initial efforts to understand the combinatorial roles of all clustered Pcdh family members, which also include 14 alpha- and 22 beta-Protocadherins (Pcdhas and Pcdhbs, respectively). We used CRISPR-mediated genome engineering to generate Pcdha/Pcdhg double mutants. Initial analysis shows that their defects are more striking than those of either Pcdha or Pcdhg mutants, suggesting redundancy between these two subclusters.Medical Science

Epigenetic Targets for Therapeutic Approaches in COPD and Asthma. Nutrigenomics – Possible or Illusive

Oxidative stress generated by cigarette smoking, environmental pollution, or other noxious particles leads to epigenetic changes in the cells of the respiratory tract. They reflect cell adaptation in response to chronic exposure to external factors. Although there is no change in the genetic code, epigenetic changes may be heritable and translated from one generation to another, accumulating abnormalities and rendering cells into entirely different phenotype, causing disease. DNA methylation, post-translation histone modification, ubiquitination, sumoylation and miRNA transcriptional regulation are the major processes that are responsible for the epigenetic control of gene expression. All of them are reversible. They can be regulated by targeting specific enzymes/proteins involved in the process in order to mitigate inflammation. Chronic respiratory diseases have epigenetic signatures that affect gene expression in the lung. Targeting them provides the development of novel diagnostic and therapeutic approaches in respiratory medicine. Nutrigenomics reveals the beneficial effect of natural phytochemicals, affecting key steps in the signaling pathways of chronic respiratory diseases

Reward signals in the cerebellum: origins, targets, and functional implications

The cerebellum has long been proposed to play a role in cognitive function, although this has remained controversial. This idea has received renewed support with the recent discovery that signals associated with reward can be observed in the cerebellar circuitry, particularly in goal-directed learning tasks involving an interplay between the cerebellar cortex, basal ganglia, and cerebral cortex. Remarkably, a wide range of reward contingencies-including reward expectation, delivery, size, and omission-can be encoded by specific circuit elements in a manner that reflects the microzonal organization of the cerebellar cortex. The facts that reward signals have been observed in both the mossy fiber and climbing fiber input pathways to the cerebellar cortex and that their convergence may trigger plasticity in Purkinje cells suggest that these interactions may be crucial for the role of the cerebellar cortex in learned behavior. These findings strengthen the emerging consensus that the cerebellum plays a pivotal role in shaping cognitive processing and suggest that the cerebellum may combine both supervised learning and reinforcement learning to optimize goal-directed action. We make specific predictions about how cerebellar circuits can work in concert with the basal ganglia to guide different stages of learning

Protocadherin-dependent dendritic self-avoidance regulates neural connectivity and circuit function

Dendritic and axonal arbors of many neuronal types exhibit self-avoidance, in which branches repel each other. In some cases, these neurites interact with those of neighboring neurons, a phenomenon called self/non-self discrimination. The functional roles of these processes remain unknown. In this study, we used retinal starburst amacrine cells (SACs), critical components of a direction-selective circuit, to address this issue. In SACs, both processes are mediated by the gamma-protocadherins (Pcdhgs), a family of 22 recognition molecules. We manipulated Pcdhg expression in SACs and recorded from them and their targets, direction-selective ganglion cells (DSGCs). SACs form autapses when self-avoidance is disrupted and fail to form connections with other SACs when self/non-self discrimination is perturbed. Pcdhgs are also required to prune connections between closely spaced SACs. These alterations degrade the direction selectivity of DSGCs. Thus, self-avoidance, self/non-self discrimination, and synapse elimination are essential for proper function of a circuit that computes directional motion. DOI: http://dx.doi.org/10.7554/eLife.08964.00

Biomarkers in COPD – Challenging, Real or Illusive

Biomarker research in COPD is becoming the most rapidly progressing sphere in respiratory medicine. Although “omics” generate a huge amount of biomarkers, fibrinogen is the only one validated by the European Medicines Agency. Thousands of studies analyzing different biological samples from the respiratory tract, collected in different ways, using various kits and techniques are generating more and more data, rendering biomarkers very confusing rather than having practical value. It seems that in order to be applicable and validated, biomarkers should be analysed in an accurately described cohort of patients, homogeneous in disease severity and activity. As COPD has multiple mechanisms of pathobiology it raises the issue of which is the most appropriate biological sample reflecting each of them. Unified criteria for tissue sampling, validated kits for respiratory tract probes and standardized technologies should be announced. The review presents the biomarkers that are currently validated and raises the problem of standardization