Muller's ratchet in a near-critical regime: Tournament versus fitness proportional selection.

Muller's ratchet, in its prototype version, models a haploid, asexual population whose size N is constant over the generations. Slightly deleterious mutations are acquired along the lineages at a constant rate, and individuals carrying less mutations have a selective advantage. The classical variant considers fitness proportional selection, but other fitness schemes are conceivable as well. Inspired by the work of Etheridge et al. (2009) we propose a parameter scaling which fits well to the "near-critical" regime that was in the focus of Etheridge et al. (2009) (and in which the mutation-selection ratio diverges logarithmically as N→∞). Using a Moran model, we investigate the"rule of thumb" given in Etheridge et al. (2009) for the click rate of the "classical ratchet" by putting it into the context of new results on the long-time evolution of the size of the best class of the ratchet with (binary) tournament selection. This variant of Muller's ratchet was introduced in González Casanova et al. (2023), and was analysed there in a subcritical parameter regime. Other than that of the classical ratchet, the size of the best class of the tournament ratchet follows an autonomous dynamics up to the time of its extinction. It turns out that, under a suitable correspondence of the model parameters, this dynamics coincides with the so called Poisson profile approximation of the dynamics of the best class of the classical ratchet.

Clinical profile of idiopathic pulmonary fibrosis patients treated with nintedanib in routine clinical practice in Spain: the BROAD Study / Perfil clínico de pacientes con fibrosis pulmonar idiopática tratados con nintedanib en la práctica clínica habitual en españa: estudio broad

Background. Few data are available on the clinical profile of patients diagnosed with idiopathic pulmonary fibrosis (IPF) treated with nintedanib. The primary objective of the study was to describe, based on pulmonary function variables, disease severity in IPF patients who initiated treatment with nintedanib in routine clinical practice. The secondary objectives were to analyze their clinical characteristics and comorbidities. Methods. A multicenter, retrospective study including 173 patients from 32 Spanish hospitals. Patients were stratified by their forced vital capacity (FVC) % predicted and diffusing capacity for carbon monoxide (DLCO) % predicted. These measures were taken as a marker of IPF severity. Results. Mean age ± SD at treatment initiation was 70.1 ± 8.1, and 76.6% of patients were male. Based on FVC, 57% of patients had mild IPF (FVC ≥ 70%), 38.4% moderate IPF (FVC 50%-69%), and 4.7% severe IPF (FVC < 50%). Based on DLCO, 42.5% of patients had mild IPF (DLCO ≥ 50%), 35.5% moderate IPF (DLCO 35%-49%), and 22.2% severe IPF (DLCO < 35%). Eighty-nine percent of patients had at least one comorbid condition. The most prevalent comorbidities were high blood pressure (45.9%), dyslipidemia (42.4%), gastroesophageal reflux (25.6%), diabetes (19.8%), emphysema (15.7%), and cardiovascular diseases (15.7%). Most patients received concomitant treatment (79.7%). Conclusions. The study provides relevant information on the clinical characteristics of IPF patients who initiate nintedanib treatment. Classification of severity depends on the lung function parameter used. The proportion of patients classified as having severe IPF was up to 4 times greater when DLCO, instead of FVC, was used (AU)

Introducción. Se dispone de pocos datos sobre el perfil clínico de los pacientes diagnosticados de fibrosis pulmonar idiopática (FPI) tratados con nintedanib. El objetivo principal del estudio fue describir, basándose en variables de función pulmonar, la gravedad de la enfermedad en pacientes con FPI que iniciaron tratamiento con nintedanib en la práctica clínica habitual. Los objetivos secundarios fueron analizar sus características clínicas y comorbilidades. Métodos. Estudio retrospectivo y multicéntrico que incluyeron a 173 pacientes de 32 hospitales españoles. Los pacientes fueron estratificados por su capacidad vital forzada (CVF) % predicho y por la capacidad de difusión de monóxido de carbono (DLCO) % predicho. Estas variables se consideraron como marcadores de la gravedad de la FPI. Resultados. La edad media ± DE al inicio del tratamiento fue de 70,1 ± 8,1 y el 76,6% de los pacientes eran varones. Según la CVF, el 57% de los pacientes tenían FPI leve (CVF ≥ 70%), el 38,4% FPI moderada (CVF 50%-69%) y el 4,7% FPI grave (CVF < 50%). Según la DLCO, el 42,5% de los pacientes tenían FPI leve (DLCO ≥ 50%), el 35,5% FPI moderada (DLCO 35%-49%) y el 22,2% FPI grave (DLCO < 35%). El 89% de los pacientes tenían al menos una comorbilidad, siendo las más prevalentes la hipertensión arterial (45,9%), dislipidemia (42,4%), reflujo gastroesofágico (25,6%), diabetes (19,8%), enfisema (15,7%) y enfermedades cardiovasculares (15,7%). La mayoría de los pacientes recibieron tratamientos concomitantes (79,7%) (AU)

The role of connectivity on COVID-19 preventive approaches.

Preventive and modelling approaches to address the COVID-19 pandemic have been primarily based on the age or occupation, and often disregard the importance of heterogeneity in population contact structure and individual connectivity. To address this gap, we developed models based on Erdos-Rényi and a power law degree distribution that first incorporate the role of heterogeneity and connectivity and then can be expanded to make assumptions about demographic characteristics. Results demonstrate that variations in the number of connections of individuals within a population modify the impact of public health interventions such as lockdown or vaccination approaches. We conclude that the most effective strategy will vary depending on the underlying contact structure of individuals within a population and on timing of the interventions.

Neurotoxicidad por exposición a metales pesados: evidencias y cuestiones por resolver / Neurotoxicity due to exposure to heavy metals: evidence and unresolved issues

Los metales pesados son un grupo de agentes químicos que están presentes en la corteza terrestre en concentraciones variables. Muchos de estos compuestos tienen una gran importancia en el mundo actual, ya que se emplean en numerosos procesos industriales. Debido a su abundancia en la naturaleza y considerando que las investigaciones realizadas durante los últimos años han demostrado la implicación de los metales pesados en el desarrollo de numerosos procesos patológicos, se ha realizado una revisión bibliográfica con el objetivo de evaluar la relación entre la exposición a determinados metales pesados y el desarrollo de neurotoxicidad. Este análisis se ha llevado a cabo empleando la base de datos Medline y, tras un primer screening de las referencias encontradas, se ha centrado en la evaluación de siete agentes: aluminio, plomo, arsénico, mercurio, cadmio, manganeso y talio. La neurotoxicidad desarrollada tras la exposición aguda o crónica se debe a su capacidad para atravesar la barrera hematoencefálica. Algunos de los mecanismos de toxicidad no se han podido definir completamente aún, pero en casi todas las investigaciones se han relacionado con la capacidad de interferir con los procesos biológicos y de inducir estrés oxidativo y apoptosis neuronal. Existen determinadas patologías para las que se ha encontrado una relación directa con la exposición. Sin embargo, en el campo de las enfermedades neurodegenerativas la evidencia encontrada es menos concluyente. (AU)

Heavy metals are a group of chemical agents that are present in the Earth crust in varying concentrations. Many of these compounds are of great importance in today’s world, as they are used in many industrial processes. Due to their abundance in nature and considering that research carried out in recent years has shown the involvement of heavy metals in the development of numerous pathological processes, a bibliographic review has been carried out with the aim of evaluating the relationship between exposure to certain heavy metals and the development of neurotoxicity. This analysis has been carried out using the Medline database and, after a first screening of the references, it has focused on the evaluation of seven agents: aluminum, lead, arsenic, mercury, cadmium, manganese and thallium. Neurotoxicity developed after acute or chronic exposure has been shown to be due to its ability to cross the blood-brain barrier. Some of the toxicity mechanisms have not yet been fully defined, but in almost all investigations they have been related to the ability to interfere with biological processes and to induce oxidative stress and neuronal apoptosis. There are certain pathologies for which a direct relationship with exposure has been found. However, in the field of neurodegenerative diseases, the evidence found is less conclusive. (AU)

360-Degree evaluation: Towards a comprehensive, integrated assessment of performance on clinical placement in nursing degrees: A descriptive observational study.

BACKGROUND: The assessment of the acquisition of clinical competencies is a critical issue for nursing students. 360-degree evaluations are a widespread practice in professional competency assessment and can be applied to the learning/teaching process of future nurses. OBJECTIVES: To determine the effectiveness of the implementation of a 360-degree evaluation proposal for assessing the competencies acquired by third-year nursing students during their clinical placements. DESIGN: A mixed-methods design was used with a primary component (a cross-sectional descriptive observational design) and a parallel qualitative component. PARTICIPANTS: Sixty-seven third-year nursing students from a public university in Madrid, Spain, who were undertaking their clinical placements during seven weeks in medical/surgical units in hospital settings. METHODS: This study was conducted between September 2017 and May 2018. Quantitative data were obtained using assessment tools specifically developed for this 360-degree evaluation proposal. Qualitative information was collected from two focus groups, one with students and one with teaching staff. A descriptive analysis of the quantitative data was conducted. Qualitative data were studied using a thematic analysis. RESULTS: The mean scores for each of the items in the 360-degree evaluation were high, with the highest grades being observed in the evaluations made by peers and patients (a mean of 9.1 out of 10.0). On average, the 360-degree evaluation method yielded grades 0.067 percentage points higher than did the previous evaluation method (p ≤ 0.001). Students and teaching staff encountered difficulties in the evaluations made by users/families and other members of the healthcare team (nursing assistants and physicians), although they rated the overall proposal as being very powerful in terms of educational value. CONCLUSIONS: The 360-degree evaluation method is an innovative, motivating, and integrating approach to the acquisition of competencies with a focus on excellence.

Nanowire based bioprobes for electrical monitoring of electrogenic cells.

The continuous miniaturization of electronic components and the emergence of nano-biotechnology has opened new perspectives to monitor electrical activities at the single cell level. Here, we describe the creation of very high surface-to-volume ratio passive devices (vertical nanowire probes) using large-scale fabrication process, allowing to follow the electrical activity of mammalian neurons. Based on conventional silicon processing, the silicon nanowires were silicided in platinum in order to improve their electrochemical performances and to guarantee their biocompatibility. Very high signal to noise ratio was achieved (up to 2000) when measuring spontaneous action potentials. Moreover, this bio-platform was used to record the impact of various bio-chemical and electrical stimulations on neuronal activity. To conclude, this study proposes a thorough comparison of the characteristics and performances of these new nanowire-based nanoprobes with the main alternative systems published up to now.

Mechanical stretch increases L-type calcium channel stability in cardiomyocytes through a polycystin-1/AKT-dependent mechanism.

The L-type calcium channel (LTCC) is an important determinant of cardiac contractility. Therefore, changes in LTCC activity or protein levels could be expected to affect cardiac function. Several studies describing LTCC regulation are available, but only a few examine LTCC protein stability. Polycystin-1 (PC1) is a mechanosensor that regulates heart contractility and is involved in mechanical stretch-induced cardiac hypertrophy. PC1 was originally described as an unconventional Gi/o protein-coupled receptor in renal cells. We recently reported that PC1 regulates LTCC stability in cardiomyocytes under stress; however, the mechanism underlying this effect remains unknown. Here, we use cultured neonatal rat ventricular myocytes and hypo-osmotic stress (HS) to model mechanical stretch. The model shows that the Cavß2 subunit is necessary for LTCC stabilization in cardiomyocytes during mechanical stretch, acting through an AKT-dependent mechanism. Our data also shows that AKT activation depends on the G protein-coupled receptor activity of PC1, specifically its G protein-binding domain, and the associated Gßγ subunit of a heterotrimeric Gi/o protein. In fact, over-expression of the human PC1 C-terminal mutant lacking the G protein-binding domain blunted the AKT activation-induced increase in Cav1.2 protein in cardiomyocytes. These findings provide novel evidence that PC1 is involved in the regulation of cardiac LTCCs through a Gißγ-AKT-Cavß2 pathway, suggesting a new mechanism for regulation of cardiac function.

Quantification of the overall measurement uncertainty associated with the passive moss biomonitoring technique: Sample collection and processing.

In this study we examined 6080 data gathered by our research group during more than 20 years of research on the moss biomonitoring technique, in order to quantify the variability generated by different aspects of the protocol and to calculate the overall measurement uncertainty associated with the technique. The median variance of the concentrations of different pollutants measured in moss tissues attributed to the different methodological aspects was high, reaching values of 2851 (ng·g-1)2 for Cd (sample treatment), 35.1 (µg·g-1)2 for Cu (sample treatment), 861.7 (ng·g-1)2 and for Hg (material selection). These variances correspond to standard deviations that constitute 67, 126 and 59% the regional background levels of these elements in the study region. The overall measurement uncertainty associated with the worst experimental protocol (5 subsamples, refrigerated, washed, 5 × 5 m size of the sampling area and once a year sampling) was between 2 and 6 times higher than that associated with the optimal protocol (30 subsamples, dried, unwashed, 20 × 20 m size of the sampling area and once a week sampling), and between 1.5 and 7 times higher than that associated with the standardized protocol (30 subsamples and once a year sampling). The overall measurement uncertainty associated with the standardized protocol could generate variations of between 14 and 47% in the regional background levels of Cd, Cu, Hg, Pb and Zn in the study area and much higher levels of variation in polluted sampling sites. We demonstrated that although the overall measurement uncertainty of the technique is still high, it can be reduced by using already well defined aspects of the protocol. Further standardization of the protocol together with application of the information on the overall measurement uncertainty would improve the reliability and comparability of the results of different biomonitoring studies, thus extending use of the technique beyond the context of scientific research.

Hamartoma condroide endobronquial: a propósito de un caso / No disponible

No disponible

Poor achievement of guidelines-recommended targets in type 2 diabetes: findings from a contemporary prospective cohort study.

AIMS: To prospectively evaluate diabetes management in the primary care setting and explore factors related to guideline-recommended triple target achievement [blood pressure (BP) ≤ 130/80 mmHg, A1C ≤ 7% and low-density lipoprotein (LDL)-cholesterol < 2.5 mmol/l]. METHODS: Baseline, 6 and 12 month data on clinical and laboratory parameters were measured in 3002 patients with type 2 diabetes enrolled as part of a prospective quality enhancement research initiative in Canada. A generalised estimating equation model was fitted to assess variables associated with triple target achievement. RESULTS: At baseline, 54%, 53% and 64% of patients, respectively, had BP, A1C and LDL-cholesterol at target; all three goals were met by 19% of patients. The percentage of individuals achieving these targets significantly increased during the study [60%, 57%, 76% and 26%, respectively, at the final visit, p < 0.0001 except for A1C, p = 0.27]. A much smaller proportion of patients had adequate control during the entire study period [30%, 39%, 53% and 7%, respectively]. In multivariable analysis, women, patients younger than 65 years and patients of Afro-Canadian origin were less likely to achieve the triple target. DISCUSSION: As part of a quality enhancement research initiative, we observed important improvements in the attainment of guidelines-recommended targets in patients with type 2 diabetes followed for a 12-month period in the primary care setting; however, many individuals still failed to achieve and especially maintain optimal goals for therapy, particularly the triple target. Results of the multivariable analysis reinforce the need to address barriers to improve diabetes care, particularly in more susceptible groups.

A haplotype of cyclooxygenase-2 gene is associated with idiopathic pulmonary fibrosis.

BACKGROUND: Cyclooxygenase-2, a key regulatory enzyme in the synthesis of the antifibrotic agent prostaglandin E2, is downregulated in lung tissue from patients with idiopathic pulmonary fibrosis. OBJECTIVE: To investigate the association between COX2.3050 (G --> C), COX2.8473 (C --> T) and COX2.926 (G --> C) single nucleotide polymorphisms (SNP) and the susceptibility to idiopathic pulmonary fibrosis and the progression of the disease. DESIGN: Genetic polymorphisms were analyzed in 121 out of 225 available control subjects and in all of 174 patients with idiopathic pulmonary fibrosis by real time polymerase chain reaction. Logistic regression analysis of covariance and chi-squares test were used for statistical analysis. RESULTS: While analysis of disease development did not find any significant association with single SNP genotype, a haplotype analysis revealed a strong association between the disease development and one haplotype [GC] at loci COX2.3050 and COX2.8473, and suggested a recessive genetic effect of this haplotype. Further analysis concluded that subjects having two copies of [GC] haplotype, or equivalently (GG/CC) genotype at the two SNPs, had an increased risk after adjusting for age and sex. Due to the interaction, this elevated risk increased slowly with age, and the estimated odds ratio (OR) decreased with age from OR = 1.4 at age 30 to OR = 1 at age 74 and OR = 0.96 at age SO. The OR was significantly greater than 1 up to age 66, and not significant for age older than 66. Therefore, the recessive effect of [GC] haplotype increased the risk of IPF of subjects younger than 66 years, but its effect diminished for seniors older than 66. One hundred and forty-nine patients with idiopathic pulmonary fibrosis were followed up for 33.7 +/- 2.1 months. Further analysis of disease progressions, defined by the changes in pulmonary function tests, did not reveal any association with either SNP genotypes or haplotypes. CONCLUSIONS: The carriage of double homozygote (GG/CC) at the SNP loci of COX2.3050 and COX2.8473 polymorphisms may increase the susceptibility to idiopathic pulmonary fibrosis, by approximately 1.4 folds at age 30 and by a smaller fold greater than 1 up to age 66 years, but not the progression of the disease. These findings may help to improve our understanding of idiopathic pulmonary fibrosis pathogenesis and may lead to the development of new therapeutic strategies.

Recently acquired HIV infection in Spain (2003-2005): introduction of the serological testing algorithm for recent HIV seroconversion.

BACKGROUND: Identification of recent HIV infections provides a description of the current pattern of HIV transmission and, consequently, can help to design better preventive interventions. Our study shows the first implementation in Spain of the Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS) strategy. We assess the viability of introducing STARHS in our setting and describe the frequency and epidemiological characteristics of recent infections (RIs). METHODS: Between 2003 and 2005, HIV-positive blood samples drawn for diagnostic purposes were collected from 28 Spanish laboratories to be tested using STARHS. Samples from patients with a previous HIV diagnosis, age <18 years, <200 CD4 cells/microL or clinical AIDS criteria were excluded from the analysis. RESULTS: A total of 660 (19.2%) samples were classified as RI. Most people identified with RI were male (79.8%) with a median age of 33.1 years, and 62.5% occurred among men who have sex with men (MSM). Immigrants made up 26.5% of individuals identified with RIs, with 48.7% coming from South America. Among the individuals with RI, at least 16.5% had reported another sexually transmitted infection (STI) during the year before the HIV diagnosis. CONCLUSION: The study shows that the implementation of STARHS in our setting is feasible and has highlighted important features of the local HIV epidemic, such as the ongoing spread of HIV among MSM, the potential role of STIs in RIs and the vulnerability of immigrants as a new target population.

Lymphangioleiomyomatosis: a study of 72 patients from the Spanish registry.

BACKGROUND: Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease that almost exclusively affects young women of childbearing age. The true incidence and prevalence of LAM are unknown. This study was conducted to evaluate the characteristics of lymphangioleiomyomatosis in Spain. METHODS: Over a 2-year period, a questionnaire designed for this study was collected. This questionnaire included sociodemograhic, clinical, radiological and functional data. Information about the study and this questionnaire were both sent by e-mail to all the participants of the interstitial disease registry of 2004. RESULTS: Seventy-two patients, all of whom were women, were included in the registry, with a mean age of 44.56 +/- 11.1 yr. Sixty-three patients (87.5%) presented the sporadic LAM and 9 (12.5%) presented LAM associated with tuberous sclerosis (LAM-TS). LAM diagnosis was confirmed with an open lung biopsy in 57 patients (79.2%) and was performed with thoracic HRCT compatible with LAM diagnosis in the other 15 cases. The most frequent symptom was dyspnoea (90%) followed by cough (44.4%). Almost 40% of patients presented renal angiomyolipomas in the study and the most frequent spirometric pattern was obstructive in more than half of the patients. Most patients with LAM-TS (88.8%) had renal angiomyolipomas compared with 31.7% in the sporadic LAM group. CONCLUSION: The characteristics of the Spanish population affected with LAM are similar to those of other countries. Most patients were symptomatic, had a history of previous pneumothorax and presented abnormal radiological findings and pulmonary function tests.

Sarcoidosis endobronquial: A propósito de un caso clínico / No disponible

La sarcoidosis es una enfermedad de causa desconocida, que se caracteriza por la formación de granulomas no caseificantes. Para su diagnóstico se precisa de la confirmación histológica, existiendo diversas exploraciones para ello como la fibrobroncoscopia con biopsia endobronquial y transbronquial. Hay otras pruebas más invasivas, como la biopsia pulmonar quirúrgica, que se reservan para casos de maja evolución clínica o dudas diagnósticas. Presentamos un caso clínico con una sarcoidosis endobronquial muy llamativa (AU)

Sarcoidosis is a disease of unknown cause, characterized by the formation of granulomas not caseificantes. For its diagnosis is important histological confirmation, for that reason, we have various diagnostic tests including, bronchoscope with biopsy endobronchial and transbronchial boards that have a high diagnostic yield. There are other more invasive tests, such as open lung biopsy, which reserve in case of bad clinical evolution and doubt diagnostic. We present a case of endobronchial sarcoidosis very striking (AU)

Importancia de los polimorfismos de la ciclooxigenasa-2 en la presentación clínica de la sarcoidosis / Importance of cyclooxigenase-2 polymorphismsin the clinical presentation of sarcoidosis

OBJETIVO: Estudiar la posible relación entre las manifestaciones clínicas de la sarcoidosis y los polimorfismos del gen de laciclooxigenasa-2 (COX-2).MÉTODO: Estudio multicéntrico observacional transversal en el que participaron 7 hospitales de España. Se incluyeron pacientes diagnosticados de sarcoidosis según criterios internacionales. De cada caso se recogió edad, sexo, método diagnóstico, enzima convertidora de angiotensina, pruebas de función respiratoria, estadio radiológico y clínica del paciente en el momento del diagnóstico. Los hallazgos clínicos se agruparon en respiratorios y sistémicos. Los estudios genéticos se realizaron a partir del ADN obtenido de linfocitos de sangre periférica. El ADN se amplificó mediante PCR convencional y los polimorfismos fueron analizados por sondas de hibridación fluorescentes y curvas de disociación. Se determinaron4 variantes alélicas del gen de la COX-2: COX2.5909T>G,COX2.8473T>C, COX2.926G>C y COX2.3050G>C. RESULTADOS: La muestra se compuso de 131 casos de sarcoidosis (63 hombres; edad: 47 ± 15 años), todos con diagnóstico histológico menos 5 casos. El polimorfismo COX2.3050G>C en homocigosis resultó estar significativamente presente entre los pacientes con manifestaciones sistémicas frente al resto de pacientes (4,6% vs 0%;p=0,045). La presencia de manifestaciones sistémicas de la enfermedad estuvo significativamente asociada a los pacientes portadores del alelo C de dicho polimorfismo (34,4% vs. 18,6%; p=0,031; OR:2,3; IC 95%: 1,03-5,12). El resto de polimorfismos estudiados no estuvieron relacionados con la expresión clínica de la enfermedad. CONCLUSIÓN: La presencia de manifestaciones sistémicas parece estar relacionada con los portadores del alelo C del polimorfismoCOX2.3050G>C de la COX-2 (AU)

OBJECTIVE: To study clinical manifestations of sarcoidosis according to cyclooxigenase-2 (COX-2) polymorphisms. METHOD: Observational cross-sectional multicentre trial in which 7 Spanish hospitals participated. Patients diagnosed withs arcoidosis according to international criteria were included. Age, gender, diagnostic method, angiontens in converting enzyme, pulmonary function tests, radiological stage and clinical findings at the moment of the diagnosis were recorded for each case included. Clinical findings were grouped as respiratory or systemic. Genetic studies were performed on DNA extracted from peripheral blood lymphocytes. DNA was amplified by conventional PCR and polymorphisms were studied by Fluorescent Hybridization Probe-Melting Curves. COX-2 polymorphisms genotyped were COX2.5909T>G, COX2.8473 T>C, COX2.926 G>C y COX2.3050 G>C.RESULTS: 131 sarcoidosis patients (63 males, age: 47 ± 15years) were included. All included patients had a histological diagnosis except for 5 patients. COX2.3050G>C homozygote polymorphism resulted to be significantly present in patients with a systemic manifestation of the disease as compared with the rest of the sample(4,6% vs 0%; p = 0,045). Systemic manifestations were significantly associated with allele C carriers of this polymorphism (34.4% vs.18.6%; p = 0.031; OR: 2.3; IC 95%: 1.03 – 5.12). The rest of the studied polymorphisms were not significantly related to the clinical manifestations of the disease. CONCLUSION: Our results suggest that allele C carriers ofCOX2.3050G>C polymorphism are associated with the systemic manifestations of sarcoidosis (AU)

Association of the 3050G>C polymorphism in the cyclooxygenase 2 gene with systemic sarcoidosis.

BACKGROUND: We investigated the potential association between cyclooxygenase-2 (COX-2) gene polymorphisms and clinical manifestations of sarcoidosis. METHODS: This observational cross-sectional study involved seven hospitals in Spain. We diagnosed patients with sarcoidosis according to the International Criteria. The following variables were recorded: age, gender, initial diagnostic methods, serum angiotensin-converting enzyme (ACE) levels, pulmonary function tests, radiological stage, and clinical findings at diagnosis. Manifestations of sarcoidosis were classified as systemic vs. nonsystemic. Genotyping of four COX-2 polymorphisms (COX2.5909T>G, COX2.8473T>C, COX2.926G>C, and COX2.3050G>C) was undertaken on DNA extracted from peripheral blood lymphocytes using fluorescent hybridization probes and melting curves. RESULTS: A total of 131 sarcoid patients (63 males, mean age: 47 +/- 15 years) were studied. One hundred twenty-six of these patients had one or more positive biopsies. The results demonstrated that genotype distribution for the COX2.3050G>C polymorphism was significantly different between patients with systemic sarcoidosis and those with nonsystemic forms (p = 0.046). After adjustment for age, gender, and serum ACE levels, a significant association between the carriage of at least one C allele of the COX2.3050G>C polymorphism and systemic sarcoidosis was observed (odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.03-5.12, p = 0.031). Other polymorphisms were not associated with either clinical manifestations of the disease or serum ACE levels. CONCLUSIONS: Our results indicate for the first time that the C allele of the COX2.3050G>C polymorphism is associated with systemic sarcoidosis.

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression.

Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case-control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37+/-0.7 mmHg (0.049+/-0.093 kPa) per month) compared to GA genotype (0.12+/-1 mmHg (0.016+/-0.133 kPa) per month) and GG genotype (0.2+/-0.6 mmHg (0.027+/-0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.

Impact of hepatitis C virus coinfection on immune restoration during successful antiretroviral therapy in chronic human immunodeficiency virus type 1 disease.

The effect of coinfection with hepatitis C virus (HCV) on immune restoration in 39 human immunodeficiency virus (HIV)-infected patients during treatment with combined antiretroviral therapy (cART) was prospectively evaluated. After 48 weeks of treatment, HCV-coinfected patients had lower increases in CD4% (P = .05), total CD4+ (P = .01), and naïve CD4+ (P = .06) T cells than did single-infected subjects. Higher baseline naïve CD4+ T-cell levels were associated with better CD4+ (P = .05) and naïve CD4+ (P < .001) T-cell recovery. After a 4-year follow up, the differences disappeared (median CD4+ increase: 291 and 306 cells for HCV-positive and HCV-negative patients, respectively, P = .9). No significant differences were seen in memory CD4+ T cells (P = .30), and CD8+ cells expressing CD38 (P = .10) and CD28 (P = .73). These results suggest that, independently of other factors, infection with HCV blunts early CD4+ T-cell recovery in HIV-infected patients treated with combined antiretroviral therapy (cART). However, as good control of viral replication is maintained, satisfactory long-term immune restoration can nonetheless be achieved.

Preliminary results of treatment with pegylated interferon alpha 2A for chronic hepatitis C virus in kidney transplant candidates on hemodialysis.

INTRODUCTION: At present, there is little published information on the outcome of treatment with pegylated interferon (Peg-IF alpha 2a) in hepatitis C virus (HCV)-infected hemodialysis patients awaiting renal transplantation. The objective of this study was to assess the efficacy and tolerance of Peg-IF alpha 2a in this population. PATIENTS AND METHODS: Twelve noncirrhotic HCV-infected patients (10 men, 50 +/- 8 years of age, genotype 1b 84%), were prescribed Peg-IF alpha 2a, at 135 microg/wk for 48 weeks. Liver biopsy was performed in 11 of 12 cases. RESULTS: Six patients completed 48 weeks of treatment, with one end of treatment response (ETR), two sustained viral responses (SVRs), and three HCV relapses. Treatment was shorter in the six remaining patients: two cases 24 weeks (one due to medical reasons with relapse, one due to nonresponse), one patient chose to discontinue at 14 weeks (with relapse), one patient died of stroke at 10 weeks, and in two additional patients interferon was withdrawn at 18 weeks because of severe anemia (SVR) and at 26 weeks due to prolonged fever (relapse). Other secondary treatment-related events included anemia (requiring transfusion in two patients and major erythropoietin administration in six), and fever in four patients. CONCLUSIONS: Peg-IF had limited efficacy in this group, with ETR in 83%, SVR in only 25%, and recurrence in 50%. Tolerance was moderate, with 4/12 (33%) discontinuing treatment due to adverse events, personal decision, or death. Large randomized controlled studies are needed to determine the role of Peg-IF treatment in this population.