Keep within target range of blood oxygen levels, new guideline recommends

Health professionals should always specify a target saturation range when prescribing oxygen and should then ensure that patients are monitored to avoid high or low levels that can cause serious...

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Fixed second appointment improves breast screening attendance

Women who miss a breast screening appointment should be given a second appointment with a fixed date and time, researchers recommend in Lancet Oncology.1 Their study found that this approach was...

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Missense variant pathogenicity predictors generalize well across a range of function-specific prediction challenges

ABSTRACT

The steady advances in machine learning and accumulation of biomedical data have contributed to the development of numerous computational models that assess the impact of missense variants. Different methods, however, operationalize impact differently. Two common tasks in this context are the prediction of the pathogenicity of variants and the prediction of their effects on a protein's function. These are related but distinct problems and it is unclear whether methods developed for one are optimized for the other. The Critical Assessment of Genome Interpretation (CAGI) experiment provides a means to address this question empirically. To this end, we participated in various protein-specific challenges in CAGI with two objectives in mind. First, to compare the performance of methods in the MutPred family with the state-of-the-art. Second and more importantly, to investigate the applicability of general-purpose pathogenicity predictors to the classification of specific function-altering variants without additional training or calibration. We find that our pathogenicity predictors performed competitively with other methods, outputting score distributions in agreement with experimental outcomes. Overall, we conclude that binary classifiers learned from disease-causing mutations are capable of modeling important aspects of the underlying biology and the alteration of protein function resulting from mutations.

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Laparoscopic Transhiatal Esophagectomy

Abstract

The operation has three parts:

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Malignancy Incidence, Management, and Prevention in Patients with Rheumatoid Arthritis

Abstract

Traditional and biologic disease-modifying antirheumatic drugs (DMARDs) are effective medications for the management of rheumatoid arthritis (RA). However, the effects of these medications on immune function raises concern that they may increase long-term cancer risk. The baseline risk for some cancers appears to differ in patients with RA compared to the general population, with the former having an increased risk of lymphoma, lung cancer and renal cancer, but a decreased risk of colorectal and breast cancer. Some DMARDs appear to increase the rate of specific cancer types (such as bladder cancer with cyclophosphamide), but few appear to increase the overall cancer risk. Studying the link between lymphoma and disease severity in RA is complicated because patients with persistently active disease are at increased risk for lymphoma, and disease severity correlates with more intense use of immunosuppressive medications. Overall, cancer risk in patients with RA is slightly above that of the general population, with the increased risk likely secondary to an increased risk of lymphomas in those with high disease activity. Risk mitigation includes management of RA disease activity as well as age- and sex-appropriate cancer screening.

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A rounded opacity silhouetting the left heart border and hilum

Pericardial incidentaloma: benign pericardial cyst

από Lin, A. N., Lin, S., Lin, K., Raju, F. στο BMJ Case Reports Last 6 Issues

Μετάφραση άρθρου

Description

A 73-year-old woman with hypertension and atrial fibrillation presented with head and neck injury after mechanical fall. During workup, chest X-ray anteroposterior view (figure 1) revealed a rounded opacity silhouetting the left heart border and hilum. Subsequent contrast-enhanced CT of the chest showed single, 6.4 cm, rounded, well-defined, thin-walled, non-enhanced, low attenuated (–20 and 20 Hounsfield Unit) and homogenous cyst-like structure at the left mediastinum connected to pericardial recesses and not attached to adjacent structures (figure 2A–C). Transthoracic echocardiogram ruled out left ventricular aneurysm, aortic aneurysm, solid tumour and outflow tracts obstruction. Although bronchogenic cyst, oesophageal duplication cyst, thymic tumour and mediastinal lymphoma were considered as possible differentials, radiological features such as CT appearance, homogenous attenuation, unrelated to the underlying structures favoured pericardial cyst. Since patient was asymptomatic, patient and family member were unwilling to undergo surgical removal and pathological confirmation. Follow-up with non-enhanced CT of...

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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6948891480

alsfakia@gmail.com

Distinct phosphodiesterase 5A-containing compartments allow selective regulation of cGMP-dependent signalling in human arterial smooth muscle cells

Publication date: August 2017
Source:Cellular Signalling, Volume 36
Author(s): Lindsay S. Wilson, Manhong Guo, M. Bibiana Umana, Donald H. Maurice
Cyclic GMP (cGMP) translates and integrates much of the information encoded by nitric oxide (NO^·) and several natriuretic peptides, including the atrial natriuretic peptide (ANP). Previously, we reported that integration of a cGMP-specific cyclic nucleotide phosphodiesterase, namely phosphodiesterase 5A (PDE5A), into a protein kinase G (PKG)- and inositol-1,4,5-trisphosphate receptor (IP3R)-containing endoplasmic reticulum (ER) signalosome allows localized control of PDE5A activity and of PKG-dependent inhibition of IP3-mediated release of ER Ca²⁺ in human platelets. Herein, we report that PDE5A integrates into an analogous signalosome in human arterial smooth muscle cells (HASMC), wherein it regulates muscarinic agonist-dependent Ca²⁺ release and is activated selectively by PKG-dependent phosphorylation. In addition, we report that PDE5A also regulates HASMC functions via events independent of PKG, but rather through actions coordinated by competitive cGMP-mediated inhibition of cAMP hydrolysis by the so-called cGMP-inhibited cAMP PDE, namely phosphodiesterase 3A (PDE3A). Indeed, we show that ANP increases both cGMP and cAMP levels in HASMC and promotes phosphorylation of vasodilator-stimulated phospho-protein (VASP) at each the PKG and PKA phospho-acceptor sites. Since selective inhibition of PDE5 decreased DNA synthesis and chemotaxis of HASMC, and that PDE3A knockdown obviated these effects, our findings are consistent with a role for a PDE5A-PDE3A-PKA axis in their regulation. Our findings provide insight into the existence of distinct “pools” of PDE5A in HASMC and support the idea that these discrete compartments regulate distinct cGMP-dependent events. As a corollary, we suggest that it may be possible to target these distinct PDE5A-regulated pools and in so-doing differentially impact selected cGMP-regulated functions in these cells.



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