Aterosclerosi i citocines: influència de CCL2 i els seus receptors

La quimiocina (motif C-C) ligand 2 (CCL2) és una molècula quimioatraient que condueixen monòcits als llocs inflamatoris, clau en processos inflamatoris. La funció de CCL2 es produeix a través de la seva unió a receptors funcionals (CCR2), també s'uneix als receptors de quimiocines atípics o silenciosos (ACKRs), amb capacitat d’eliminar o segrestar aquestes quimiocines. Es va mesurar la concentració de CCL2 circulant en pacients amb isquèmia crònica a les extremitats inferiors i es va observar que les artèries d’aquests pacients tenen una major expressió de CCL2 i dels receptors de quimiocines atípics comparades amb artèries normals. Es va analitzar l'associació del polimorfisme Asp42Gly (rs12075) del receptor atípic DARC (ACKR1) amb la concentració de CCL2 circulant, i va resultar significativament major amb la gravetat i la presència de la malaltia; i era dependent del genotip rs12075 (AA>AG>GG), indicant una major expressió de receptors de quimiocines en les artèries dels subjectes AA. Les associacions amb variants genètiques i la sobrepressió dels receptors atípics de quimiocines en artèries malaltes pot tenir implicacions potencials, CCL2 pot representar un factor no reconegut prèviament que necessita ser considerat. Quant al paper de CCL2 en la malaltia arterial coronària, l’ objectiu era investigar on i en quina mesura s’expressa CCL2 i els seus receptors en artèries afectades que han causat la mort del pacient. Es va valorar l'expressió immunohistoquímica de macròfags, CCL2 i els receptors associats que van ser significativament majors en les artèries malaltes. Els increments més significatius van ser els de CCL2 i ACKR1. No hi va haver correlacions amb l'expressió de CCL2, que va ser l'única variable amb exactitud predictiva d’aterosclerosi. L’expressió de CCL2 era marginal en les artèries normals i majoritàriament restringida a les cèl•lules musculars llises. Les nostres dades indiquen que CCL2 és un marcador potencialment útil en el diagnòstic de l'aterosclerosi.La quimiocina (motif C-C) ligand 2 (CCL2) es una molécula quimioatraient que conducen monocitos a los sitios inflamatorios, clave en procesos inflamatorios. La función de CCL2 se produce a través de su unión a receptores funcionales (CCR2), también se une a los receptores de quimiocinas atípicos o silenciosos (ACKRs), con capacidad de eliminar o secuestrar estas quimiocinas. Se midió la concentración de CCL2 circulante en pacientes con isquemia crónica en las extremidades inferiores y se observó que las arterias de estos pacientes tienen una mayor expresión de CCL2 y los receptores de quimiocinas atípicos comparadas con arterias normales. Se analizó la asociación del polimorfismo Asp42Gly (rs12075) del receptor atípico DARC (ACKR1) con la concentración de CCL2 circulante, y resultó significativamente mayor con la gravedad y la presencia de la enfermedad; y era dependiente del genotipo rs12075 (AA> AG> GG), indicando una mayor expresión de receptores de quimiocinas en las arterias de los sujetos AA. Las asociaciones con variantes genéticas y la sobrepresión de los receptores atípicos de quimiocinas en arterias enfermas puede tener implicaciones potenciales, CCL2 puede representar un factor no reconocido previamente que necesita ser considerado. En cuanto al papel de CCL2 en la enfermedad arterial coronaria, el objetivo era investigar dónde y en qué medida se expresa CCL2 y sus receptores en arterias afectadas que han causado la muerte del paciente. Se valoró la expresión inmunohistoquímica de macrófagos, CCL2 y los receptores asociados que fueron significativamente mayores en las arterias enfermas. Los incrementos más significativos fueron los de CCL2 y ACKR1. No hubo correlaciones con la expresión de CCL2, que fue la única variable con exactitud predictiva de aterosclerosis. La expresión de CCL2 era marginal en las arterias normales y mayoritariamente restringida a las células • células musculares lisas. Nuestros datos indican que CCL2 es un marcador potencialmente útil en el diagnóstico de la aterosclerosis.Chemokine (C-C motif) ligand 2 (CCL2) is a molecule quimioatraient leading monocyte inflammatory sites, key in inflammatory processes. CCL2 function occurs through binding to functional receptors (CCR2), also it binds to receptors atypical or silent chemokines (ACKRs), with ability to remove or sequester these chemokines. CCL2 concentration circulating in patients with chronic ischemia in the lower limb was measured and found to arteries of these patients have increased expression of CCL2 and chemokine receptor atypical compared to normal arteries. Asp42Gly polymorphism Association (rs12075) atypical DARC receptor (ACKR1) with the concentration of circulating CCL2 was analyzed, and was significantly increased with the severity and the presence of the disease; and was dependent rs12075 genotype (AA> AG> GG), indicating increased expression of chemokine receptors in the arteries of the AA subjects. Associations with genetic variants and the overpressure of atypical chemokine receptors in diseased arteries may have potential implications, CCL2 may represent a previously unrecognized factor that needs to be considered. As for the role of CCL2 in coronary artery disease, the goal was to investigate where and to what extent CCL2 and its receptors in affected arteries that have caused the patient's death is expressed. immunohistochemical expression of macrophages, CCL2 and associated receptors were significantly higher in diseased arteries was assessed. The most significant increases were in CCL2 and ACKR1. There were no correlations with the expression of CCL2, which was the only variable predictive accuracy of atherosclerosis. CCL2 expression was marginal in normal arteries and mainly restricted to cells • smooth muscle cells. Our data indicate that CCL2 is a potentially useful marker in diagnosis of atherosclerosis

Univariate parametric survival analysis using GS-distributions.

The GS-distribution is a family of distributions that provide an accurate representation of any unimodal univariate continuous distribution. In this contribution we explore the utility of this family as a general model in survival analysis. We show that the survival function based on the GS-distribution is able to provide a model for univariate survival data and that appropriate estimates can be obtained. We develop some hypotheses tests that can be used for checking the underlying survival model and for comparing the survival of different groups.Peer Reviewe

Prediction of cervical intraepithelial neoplasia grade 2+ (CIN2+) using HPV DNA testing after a diagnosis of atypical squamous cell of undetermined significance (ASC-US) in Catalonia, Spain

Background: A protocol for cervical cancer screening among sexually active women 25 to 65 years of age was introduced in 2006 in Catalonia, Spain to increase coverage and to recommend a 3-year-interval between screening cytology. In addition, Human Papillomavirus (HPV) was offered as a triage test for women with a diagnosis of atypical squamous cells of undetermined significance (ASC-US). HPV testing was recommended within 3 months of ASC-US diagnosis. According to protocol, HPV negative women were referred to regular screening including a cytological exam every 3 years while HPV positive women were referred to colposcopy and closer follow-up. We evaluated the implementation of the protocol and the prediction of HPV testing as a triage tool for cervical intraepithelial lesions grade two or worse (CIN2+) in women with a cytological diagnosis of ASC-US. Methods: During 2007-08 a total of 611 women from five reference laboratories in Catalonia with a novel diagnosis of ASC-US were referred for high risk HPV (hrHPV) triage using high risk Hybrid Capture version 2. Using routine record linkage data, women were followed for 3 years to evaluate hrHPV testing efficacy for predicting CIN2+ cases. Logistic regression analysis was used to estimate the odds ratio for CIN2 +. Results: Among the 611 women diagnosed with ASC-US, 493 (80.7%) had at least one follow-up visit during the study period. hrHPV was detected in 48.3% of the women at study entry (mean age 35.2 years). hrHPV positivity decreased with increasing age from 72.6% among women younger than 25 years to 31.6% in women older than 54 years (p < 0.01). At the end of the 3 years follow-up period, 37 women with a diagnosis of CIN2+ (18 CIN2, 16 CIN3, 2 cancers, and 1 with high squamous intraepithelial lesions -HSIL) were identified and all but one had a hrHPV positive test at study entry. Sensitivity to detect CIN2+ of hrHPV was 97.2% (95%confidence interval (CI) = 85.5-99.9) and specificity was 68.3% (95%CI = 63.1-73.2). The odds ratio for CIN2+ was 45.3 (95% CI: 6.2-333.0), when among ASC-US hrHPV positive women were compared to ASC-US hrHPV negative women. Conclusions: Triage of ASC-US with hrHPV testing showed a high sensitivity for the detection of CIN2+ and a high negative predictive value after 3 years of follow-up. The results of this study are in line with the current guidelines for triage of women with ASC-US in the target age range of 25-65. Non adherence to guidelines will lead to unnecessary medical interventions. Further investigation is needed to improve specificity of ASC-US triage

Protecting the underscreened women in developed countries: the value of HPV test

Background: Poor attendance to cervical cancer (CC) screening is a major risk factor for CC. Efforts to capture underscreened women are considerable and once women agree to participate, the provision of longitudinal validity of the screening test is of paramount relevance. We evaluate the addition of high risk HPV test (HPV) to cervical cytology as a primary screening test among underscreened women in the longitudinal prediction of intraepithelial lesions grade 2 or worse (CIN2+). Methods: Women were included in the study if they were older than 39 years and with no evidence of cervical cytology in the previous five years within the Public Primary Health Care System in Catalonia (Spain). 1,832 underscreened women from eight public primary health areas were identified during 2007-2008 and followed-up for over three years to estimate longitudinal detection of CIN2+. Accuracy of each screening test and the combination of both to detect CIN2+ was estimated. The risk of developing CIN2+ lesions according to histology data by cytology and HPV test results at baseline was estimated using the Kaplan-Meier method. Results: At baseline, 6.7% of participants were HPV positive, 2.2% had an abnormal cytology and 1.3% had both tests positive. At the end of follow-up, 18 out of 767 (2.3%) underscreened women had a CIN2+, two of which were invasive CC. The three-year longitudinal sensitivity and specificity estimates to detect CIN2+ were 90.5% and 93.0% for HPV test and 38.2% and 97.8% for cytology. The negative predictive value was >99.0% for each test. No additional gains in validity parameters of HPV test were observed when adding cytology as co-test. The referral to colposcopy was higher for HPV but generated 53% higher detection of CIN2+ compared to cytology. Conclusions: Underscreened women had high burden of cervical disease. Primary HPV screening followed by cytology triage could be the optimal strategy to identify CIN2+ leading to longer and safe screen intervals

Prediction of cervical intraepithelial neoplasia grade 2+ (CIN2+) using HPV DNA testing after a diagnosis of atypical squamous cell of undetermined significance (ASC-US) in Catalonia, Spain

<p>Abstract</p> <p>Background</p> <p>A protocol for cervical cancer screening among sexually active women 25 to 65 years of age was introduced in 2006 in Catalonia, Spain to increase coverage and to recommend a 3-year-interval between screening cytology. In addition, Human Papillomavirus (HPV) was offered as a triage test for women with a diagnosis of atypical squamous cells of undetermined significance (ASC-US). HPV testing was recommended within 3 months of ASC-US diagnosis. According to protocol, HPV negative women were referred to regular screening including a cytological exam every 3 years while HPV positive women were referred to colposcopy and closer follow-up. We evaluated the implementation of the protocol and the prediction of HPV testing as a triage tool for cervical intraepithelial lesions grade two or worse (CIN2+) in women with a cytological diagnosis of ASC-US.</p> <p>Methods</p> <p>During 2007-08 a total of 611 women from five reference laboratories in Catalonia with a novel diagnosis of ASC-US were referred for high risk HPV (hrHPV) triage using high risk Hybrid Capture version 2. Using routine record linkage data, women were followed for 3 years to evaluate hrHPV testing efficacy for predicting CIN2+ cases. Logistic regression analysis was used to estimate the odds ratio for CIN2 +.</p> <p>Results</p> <p>Among the 611 women diagnosed with ASC-US, 493 (80.7%) had at least one follow-up visit during the study period. hrHPV was detected in 48.3% of the women at study entry (mean age 35.2 years). hrHPV positivity decreased with increasing age from 72.6% among women younger than 25 years to 31.6% in women older than 54 years (<it>p </it>< 0.01).</p> <p>At the end of the 3 years follow-up period, 37 women with a diagnosis of CIN2+ (18 CIN2, 16 CIN3, 2 cancers, and 1 with high squamous intraepithelial lesions -HSIL) were identified and all but one had a hrHPV positive test at study entry. Sensitivity to detect CIN2+ of hrHPV was 97.2% (95%confidence interval (CI) = 85.5-99.9) and specificity was 68.3% (95%CI = 63.1-73.2). The odds ratio for CIN2+ was 45.3 (95% CI: 6.2-333.0), when among ASC-US hrHPV positive women were compared to ASC-US hrHPV negative women.</p> <p>Conclusions</p> <p>Triage of ASC-US with hrHPV testing showed a high sensitivity for the detection of CIN2+ and a high negative predictive value after 3 years of follow-up. The results of this study are in line with the current guidelines for triage of women with ASC-US in the target age range of 25-65. Non adherence to guidelines will lead to unnecessary medical interventions. Further investigation is needed to improve specificity of ASC-US triage.</p