AMST: Alignment to Median Smoothed Template for Focused Ion Beam Scanning Electron Microscopy Image Stacks

Alignment of stacks of serial images generated by focused ion Beam Scanning electron Microscopy (FIB-SEM) is generally performed using translations only, either through slice-by-slice alignments with SIFT or alignment by template matching. However, limitations of these methods are two-fold: the introduction of a bias along the dataset in the z-direction which seriously alters the morphology of observed organelles and a missing compensation for pixel size variations inherent to the image acquisition itself. These pixel size variations result in local misalignments and jumps of a few nanometers in the image data that can compromise downstream image analysis. We introduce a novel approach which enables affine transformations to overcome local misalignments while avoiding the danger of introducing a scaling, rotation or shearing trend along the dataset. Our method first computes a template dataset with an alignment method restricted to translations only. This pre-aligned dataset is then smoothed selectively along the z-axis with a median filter, creating a template to which the raw data is aligned using affine transformations. Our method was applied to FIB-SEM datasets and showed clear improvement of the alignment along the z-axis resulting in a significantly more accurate automatic boundary segmentation using a convolutional neural network

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location

Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure

Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs. Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups. LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted

Interleukin 4: Its Role in Hypertension, Atherosclerosis, Valvular, and Nonvalvular Cardiovascular Diseases

Hypertension is one of the major physiological risk factors for cardiovascular diseases, and it affects more than 1 billion adults worldwide, killing 9 million people every year according to World Health Organization. Also, hypertension is associated with increased risk of kidney disease and stroke. Studying the risk factors that contribute to the pathogenesis of hypertension is key to preventing and controlling hypertension. Numerous laboratories around to globe are very active pursuing research studies to delineate the factors, such as the role of immune system, which could contribute to hypertension. There are studies that were conducted on immune-deficient mice for which experimentally induced hypertension has been ameliorated. Thus, there are possibilities that immune reactivity could be associated with the development of certain type of hypertension. Furthermore, interleukin 4 has been associated with the development of pulmonary hypertension, which could lead to right ventricular remodeling. Also, the immune system is involved in valvular and nonvalvular cardiac remodeling. It has been demonstrated that there is a causative relationship between different interleukins and cardiac fibrosis

Influence of heart failure on nucleolar organization and protein expression in human hearts

[EN] We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n= 38) and DCM (n= 27) patients, undergoing heart transplantation and control donors (n= 6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p< 0.05) and DCM (141%, p< 0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p< 0.05) and DCM (1.70-fold, p< 0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p< 0.0001), and it was increased in pathological hearts (p< 0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p< 0.05 and 131%, p< 0.001) and DCM (56%, p< 0.01 and 69%, p< 0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p< 0.001), perinucleolar chromatin (p< 0.01) and dense fibrillar components (p< 0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p< 0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein. © 2012 Elsevier Inc.This work was supported by grants from the National Institute of Health "Fondo de Investigaciones Sanitarias of Institut de Salud Carlos III" [REDINSCOR 06/0003/1001, Project PI07/0462].Rosello Lleti, E.; Rivera, M.; Cortés, R.; Azorin, I.; Sirera Pérez, R.; Martínez Dolz, L.; Hove, L.... (2012). Influence of heart failure on nucleolar organization and protein expression in human hearts. Biochemical and Biophysical Research Communications. 418(2):222-228. doi:10.1016/j.bbrc.2011.12.151S222228418

A clinical perspective on the utility of alpha 1 antichymotrypsin for the early diagnosis of calcific aortic stenosis

This work was supported by Grants from the Instituto de Salud Carlos III (FIS PI07/0537, PI11/02239, PI14/01917) and Redes Temáticas de Investigación Cooperativa (FONDOS FEDER, RD06/0014/1015, RD12/0042/0071).Background: Calcific aortic stenosis (CAS) is the most common heart valve disease in the elderly, representing an important economic and social burden in developed countries. Currently, there is no way to predict either the onset or progression of CAS, emphasizing the need to identify useful biomarkers for this condition. Methods: We performed a multi-proteomic analysis on different kinds of samples from CAS patients and healthy donors: tissue, secretome and plasma. The results were validated in an independent cohort of subjects by immunohistochemistry, western blotting and selected reaction monitoring. Results: Alpha 1 antichymotrypsin (AACT) abundance was altered in the CAS samples, as confirmed in the validation phase. The significant changes observed in the amounts of this protein strongly suggest that it could be involved in the molecular mechanisms underlying CAS. In addition, our results suggest there is enhanced release of AACT into the extracellular fluids when the disease commences. Conclusions: The significant increase of AACT in CAS patients suggests it fulfils an important role in the physiopathology of this disease. These results permit us to propose that AACT may serve as a potential marker for the diagnosis of CAS, with considerable clinical value.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu