Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions.

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. CONCLUSIONS: Episodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Leisure-time physical activity, sedentary behavior, and risk of breast cancer: Results from the SUN ('Seguimiento Universidad De Navarra') project.

Evidence is still limited on the influence of sedentary lifestyles on breast cancer (BC) risk. Also, prospective information on the combined effects of both sedentariness and leisure-time physical activity (LTPA) is scarce. We aimed to assess the association of higher sedentary behavior and LTPA (separately and in combination) with the risk of BC in a middle-aged cohort of university graduates. The SUN Project is a follow-up study initiated in 1999 with recruitment permanently open. Baseline assessments included a validated questionnaire on LTPA and sedentary habits. Subsequently, participants completed biennial follow-up questionnaires. Multivariable adjusted Cox models were used to estimate the hazard ratios (HR) for incident BC according to LTPA, TV-watching, the joint classification of both, and a combined 8-item multidimensional active lifestyle score. We included 10,812 women, with 11.8 years of median follow-up of. Among 115,802 women-years of follow-up, we confirmed 101 incident cases of BC. Women in the highest category of LTPA (>16.5 MET-h/week) showed a significantly lower risk of BC (HR = 0.55; 95% CI: 0.34-0.90) compared to women in the lowest category (≤6 MET/h-week). Women watching >2 h/d of TV sh owed a higher risk (HR = 1.67; 95% CI:1.03-2.72) than those who watched TV <1 h/d. Women in the highest category (6-8 points) of the multidimensional combined 8-item score showed a lower BC risk (HR = 0.35; 95% CI: 0.15-0.79) than those in the lowest category (<2 points) group. There was no significant supra-multiplicative interaction between TV-watching and LTPA. Both low LTPA and TV-watching >2 h/d may substantially increase BC risk, independently of each other.

Meta-analysis of prevalence of wheezing and recurrent wheezing in infants

BACKGROUND: Wheezing affects children's quality of life, and is related with asthma in childhood. Although prevalence of wheezing has been previously studied in several countries, there is no reference of worldwide prevalence in infants. The aim of this meta-analysis is to estimate the prevalence of wheezing and recurrent wheezing in infants aged up to two years, and compare the prevalence across world regions. METHODS: Literature search was conducted in MEDLINE and SCOPUS databases, looking for observational studies published up to June 2016, including as keywords "prevalence" or "epidemiology" combined with "wheeze", "wheezing" or "asthma symptoms" and "infant" or "preschool". Fast*Pro software and random effects Bayesian model were used. Heterogeneity was estimated using I2 statistic, and sensitivity analyses were performed. RESULTS: We identified 109 studies after duplicates were removed. After exclusions, 14 studies were included in the meta-analysis. Prevalence of wheezing and recurrent wheezing were 36.06% (95% CI 35.17-36.96), and 17.41% (95% CI 16.74-18.09), respectively. In European countries, prevalence of wheezing was 30.68% (95% CI 28.97-32.45), and 12.35% (95% CI 11.27-13.47) for recurrent wheezing. Prevalence of wheezing and recurrent wheezing in Latin America were higher, 40.55% (95% CI 39.40-41.71), and 19.27% (95% CI 18.44-20.11), respectively. In Africa, prevalence of wheezing was 15.97% (95% CI 14.05-18.00). Low or no heterogeneity was found in all cases. CONCLUSIONS: More than one third of infants suffer from wheezing and almost one fifth from recurrent wheezing, being these illnesses especially prevalent in Latin American countries, pointing out an important public health problem

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Meta-analysis of prevalence of wheezing and recurrent wheezing in infants.

BACKGROUND: Wheezing affects children's quality of life, and is related with asthma in childhood. Although prevalence of wheezing has been previously studied in several countries, there is no reference of worldwide prevalence in infants. The aim of this meta-analysis is to estimate the prevalence of wheezing and recurrent wheezing in infants aged up to two years, and compare the prevalence across world regions. METHODS: Literature search was conducted in MEDLINE and SCOPUS databases, looking for observational studies published up to June 2016, including as keywords "prevalence" or "epidemiology" combined with "wheeze", "wheezing" or "asthma symptoms" and "infant" or "preschool". Fast*Pro software and random effects Bayesian model were used. Heterogeneity was estimated using I2 statistic, and sensitivity analyses were performed. RESULTS: We identified 109 studies after duplicates were removed. After exclusions, 14 studies were included in the meta-analysis. Prevalence of wheezing and recurrent wheezing were 36.06% (95% CI 35.17-36.96), and 17.41% (95% CI 16.74-18.09), respectively. In European countries, prevalence of wheezing was 30.68% (95% CI 28.97-32.45), and 12.35% (95% CI 11.27-13.47) for recurrent wheezing. Prevalence of wheezing and recurrent wheezing in Latin America were higher, 40.55% (95% CI 39.40-41.71), and 19.27% (95% CI 18.44-20.11), respectively. In Africa, prevalence of wheezing was 15.97% (95% CI 14.05-18.00). Low or no heterogeneity was found in all cases. CONCLUSIONS: More than one third of infants suffer from wheezing and almost one fifth from recurrent wheezing, being these illnesses especially prevalent in Latin American countries, pointing out an important public health problem.

Influence of the Mediterranean diet during pregnancy in the development of wheezing and eczema in infants in Pamplona, Spain.

BACKGROUND: This study examined the relationship between different food groups and the adherence to a Mediterranean diet during pregnancy and the risk of wheezing and eczema in children aged 12-15 months. METHODS: The study involves 1087 Spanish infants from the International Study of Wheezing in Infants (Estudio Internacional de Sibilancias en Lactantes, EISL). The study of the association of the different food consumption and Mediterranean diet with wheezing, recurrent wheezing and eczema was performed using different models of unconditional logistic regression to obtain adjusted prevalence odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: No association was found between a good adherence to the Mediterranean diet during pregnancy and the development of wheezing (p=0.372), recurrent wheezing (p=0.118) and eczema (p=0.315). The consumption once or twice a week of white fish (OR: 1.95[1.01-3.75]), cooked potatoes (OR: 1.75[1.22-2.51]) and industrial pastry (OR: 1.59[1.13-2.24]), and the consumption more than three times a week of industrial pastry (OR: 1.47 [1.01-2.13]) during pregnancy increases the risk of "wheezing" at 12 months. Instead, high fruit consumption during the pregnancy has a protective effect against "wheezing" in 12-month-old infants (OR: 0.44 [0.20-0.99]). No statistically significant differences were observed between food intake during pregnancy and "recurrent wheezing". No statistically significant differences were observed between the consumption of any food during pregnancy and the presence of eczema at 12 months. CONCLUSIONS: The present study showed that the consumption of Mediterranean diet during pregnancy did not have a protective effect for wheezing, recurrent wheezing or eczema.

Prevalencia e incidencia de la enfermedad de Alzheimer en Europa: metaanálisis / Prevalence and incidence of Alzheimer's disease in Europe: A meta-analysis

Introducción: La enfermedad de Alzheimer es el principal tipo de demencia y una enfermedad de etiología desconocida. Con el aumento de la población anciana mundial, el número de pacientes con enfermedad de Alzheimer muestra una tendencia de crecimiento rápido. El objetivo de este metaanálisis es evaluar la prevalencia e incidencia de la enfermedad de Alzheimer en Europa. Metodología: La búsqueda de artículos se realizó en las bases de datos Medline, Scopus y CINAHL Complete utilizando las palabras claves «Alzheimer», «Alzheimer's disease» y «AD», combinadas con «prevalence», «incidence» y «epidemiology». Se utilizó el modelo bayesiano de efectos aleatorios, mostrando intervalos de credibilidad del 95%. Para estimar la heterogeneidad se usó el estadístico I2. Resultados: La prevalencia de enfermedad de Alzheimer en Europa fue 5,05% (IC del 95%, 4,73-5,39). La prevalencia por sexo en los hombres y las mujeres fue 3,31% (IC del 95%, 2,85-3,80) y 7,13% (IC del 95%, 6,56-7,72), respectivamente, y se encontró una tendencia creciente por grupos de edad. La incidencia de enfermedad de Alzheimer en Europa fue 11,08 por 1.000 personas-año (IC del 95%, 10,30-11,89), siendo en los hombres y las mujeres de 7,02 por 1.000 personas-año (IC del 95%, 6,06-8,05) y 13,25 por 1.000 personas-año (IC del 95%, 12,05-14,51), respectivamente, con igual tendencia creciente con el aumento de la edad. Conclusiones: Los resultados del metaanálisis permiten una mejor comprensión de la enfermedad y su impacto en Europa (AU)

Background: A disease of unknown aetiology, Alzheimer's disease (AD) is the most common type of dementia. As the elderly population grows worldwide, the number of patients with AD also increases rapidly. The aim of this meta-analysis is to evaluate the prevalence and incidence of AD in Europe. Methodology: We conducted a literature search on Medline, Scopus, and CINAHL Complete using the keywords «Alzheimer», «Alzheimer's disease», and «AD» combined with «prevalence», «incidence», and «epidemiology». A Bayesian random effects model with 95% credible intervals was used. The I2 statistic was applied to assess heterogeneity. Results: The prevalence of Alzheimer's disease in Europe was estimated at 5.05% (95% CI, 4.73-5.39). The prevalence in men was 3.31% (95% CI, 2.85-3.80) and in women, 7.13% (95% CI, 6.56-7.72), and increased with age. The incidence of Alzheimer's disease in Europe was 11.08 per 1000 person-years (95% CI, 10.30-11.89). Broken down by sex, it was 7.02 per 1000 person-years (95% CI, 6.06-8.05) in men and 13.25 per 1000 person-years (95% CI, 12.05-14.51) in women; again these rates increased with age. Conclusions: The results of our meta-analysis allow a better grasp of the impact of this disease in Europe (AU)

The influence of gender and atopy in the relationship between obesity and asthma in childhood

BACKGROUND: The objective of the study was to examine the relationship between asthma and overweight-obesity in Spanish children and adolescents and to determine whether this relationship was affected by gender and atopy. METHODS: The study involves 8607 Spanish children and adolescents from the International Study of Asthma and Allergies in Childhood phase III. Unconditional logistic regression was used to obtain adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for the association between asthma symptoms and overweight-obesity in the two groups. Afterwards, it was stratified by sex and rhinoconjunctivitis. RESULTS: The prevalence of overweight and obesity in 6-7-year-old children was 18.6% and 5.2% respectively and in 13-14 year-old teenagers was 11.4% and 1.1% respectively. Only the obese children, not the overweight children, of the 6-7 year old group had a higher risk of any asthma symptoms (wheezing ever: OR 1.68 [1.15-2.47], asthma ever: OR 2.29 [1.43-3.68], current asthma 2.56 [1.54-4.28], severe asthma 3.18 [1.50-6.73], exercise-induced asthma 2.71 [1.45-5.05]). The obese girls had an increased risk of suffering any asthma symptoms (wheezing ever: OR 1.73 [1.05-2.91], asthma ever: OR 3.12 [1.67-5.82], current asthma 3.20 [1.65-6.19], severe asthma 4.83[1.94-12.04], exercise-induced asthma 3.68 [1.67-8.08]). The obese children without rhinoconjunctivitis had a higher risk of asthma symptoms. CONCLUSIONS: Obesity and asthma symptoms were associated in 6-7 year-old children but not in 13-14 year-old teenagers. The association was stronger in non-atopic children and obese girls

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Trends of mortality from Alzheimer's disease in the European Union, 1994-2013.

BACKGROUND AND PURPOSE: In many countries, Alzheimer's disease (AD) has gradually become a common disease in elderly populations. The aim of this study was to analyse trends of mortality caused by AD in the 28 member countries in the European Union (EU) over the last two decades. METHODS: We extracted data for AD deaths for the period 1994-2013 in the EU from the Eurostat and World Health Organization database. Age-standardized mortality rates per 100 000 were computed. Joinpoint regression was used to analyse the trends and compute the annual percent change in the EU as a whole and by country. Analyses by gender and by European regions were conducted. RESULTS: Mortality from AD has risen in the EU throughout the study period. Most of the countries showed upward trends, with the sharpest increases in Slovakia, Lithuania and Romania. We recorded statistically significant increases of 4.7% and 6.0% in mortality rates in men and women, respectively, in the whole EU. Several countries showed changing trends during the study period. According to the regional analysis, northern and eastern countries showed the steepest increases, whereas in the latter years mortality has declined in western countries. CONCLUSIONS: Our findings provide evidence that AD mortality has increased in the EU, especially in eastern and northern European countries and in the female population. Our results could be a reference for the development of primary prevention policies.

The influence of gender and atopy in the relationship between obesity and asthma in childhood.

BACKGROUND: The objective of the study was to examine the relationship between asthma and overweight-obesity in Spanish children and adolescents and to determine whether this relationship was affected by gender and atopy. METHODS: The study involves 8607 Spanish children and adolescents from the International Study of Asthma and Allergies in Childhood phase III. Unconditional logistic regression was used to obtain adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for the association between asthma symptoms and overweight-obesity in the two groups. Afterwards, it was stratified by sex and rhinoconjunctivitis. RESULTS: The prevalence of overweight and obesity in 6-7-year-old children was 18.6% and 5.2% respectively and in 13-14 year-old teenagers was 11.4% and 1.1% respectively. Only the obese children, not the overweight children, of the 6-7 year old group had a higher risk of any asthma symptoms (wheezing ever: OR 1.68 [1.15-2.47], asthma ever: OR 2.29 [1.43-3.68], current asthma 2.56 [1.54-4.28], severe asthma 3.18 [1.50-6.73], exercise-induced asthma 2.71 [1.45-5.05]). The obese girls had an increased risk of suffering any asthma symptoms (wheezing ever: OR 1.73 [1.05-2.91], asthma ever: OR 3.12 [1.67-5.82], current asthma 3.20 [1.65-6.19], severe asthma 4.83[1.94-12.04], exercise-induced asthma 3.68 [1.67-8.08]). The obese children without rhinoconjunctivitis had a higher risk of asthma symptoms. CONCLUSIONS: Obesity and asthma symptoms were associated in 6-7 year-old children but not in 13-14 year-old teenagers. The association was stronger in non-atopic children and obese girls.

Prevalence and incidence of Alzheimer's disease in Europe: A meta-analysis. / Prevalencia e incidencia de la enfermedad de Alzheimer en Europa: metaanálisis.

BACKGROUND: A disease of unknown aetiology, Alzheimer's disease (AD) is the most common type of dementia. As the elderly population grows worldwide, the number of patients with AD also increases rapidly. The aim of this meta-analysis is to evaluate the prevalence and incidence of AD in Europe. METHODOLOGY: We conducted a literature search on Medline, Scopus, and CINAHL Complete using the keywords «Alzheimer¼, «Alzheimer's disease¼, and «AD¼ combined with «prevalence¼, «incidence¼, and «epidemiology¼. A Bayesian random effects model with 95% credible intervals was used. The I2 statistic was applied to assess heterogeneity. RESULTS: The prevalence of Alzheimer's disease in Europe was estimated at 5.05% (95% CI, 4.73-5.39). The prevalence in men was 3.31% (95% CI, 2.85-3.80) and in women, 7.13% (95% CI, 6.56-7.72), and increased with age. The incidence of Alzheimer's disease in Europe was 11.08 per 1000 person-years (95% CI, 10.30-11.89). Broken down by sex, it was 7.02 per 1000 person-years (95% CI, 6.06-8.05) in men and 13.25 per 1000 person-years (95% CI, 12.05-14.51) in women; again these rates increased with age. CONCLUSIONS: The results of our meta-analysis allow a better grasp of the impact of this disease in Europe.

Prevalence and risk factors for wheezing in infants in the region of Pamplona, Spain

BACKGROUND: Wheezing in the first year of life affects the baby's and family's quality of life. Risk factors such as male gender, nursery attending or a family history of asthma, and protective factors such as breastfeeding more than six months have been previously described. The aim of this study is to study the prevalence and risk factors for wheezing ever and recurrent wheezing in the first year of life in infants in the region of Pamplona, Spain. MATERIAL AND METHODS: This cross-sectional study was part of the International Study of Wheezing in Infants (Estudio Internacional de Sibilancias en Lactantes, EISL). Between 2006 and 2008, participating families answered a standardised validated questionnaire on respiratory symptoms, environmental factors or family issues. An analysis with the chi square test (statistical significance p < 0.05) identified the risk factors for wheezing ever and recurrent wheezing, which were assessed using logistic regression. RESULTS: 1065 questionnaires were answered. The prevalence of wheezing ever and recurrent wheezing were 31.2% and 12.3%, respectively. Male gender (p=<0.001), a history of pneumonia (p=<0.001) or nursery attendance (p=<0.001) were some of the risk factors found for wheezing ever. Infant eczema (p=<0.001), nursery attendance (p=<0.001) or prematurity (p=<0.001) were risk factors for recurrent wheezing. No associations with duration of breastfeeding (p = 0.116 and p = 0.851) or mould stains at home (p = 0.153 and p = 0.992) were found. CONCLUSION: The study of prevalence and risk factors for wheezing shows the importance of this public health problem, and allows the development of control and treatment strategies against preventable factors

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Prevalence and risk factors for wheezing in infants in the region of Pamplona, Spain.

BACKGROUND: Wheezing in the first year of life affects the baby's and family's quality of life. Risk factors such as male gender, nursery attending or a family history of asthma, and protective factors such as breastfeeding more than six months have been previously described. The aim of this study is to study the prevalence and risk factors for wheezing ever and recurrent wheezing in the first year of life in infants in the region of Pamplona, Spain. MATERIAL AND METHODS: This cross-sectional study was part of the International Study of Wheezing in Infants (Estudio Internacional de Sibilancias en Lactantes, EISL). Between 2006 and 2008, participating families answered a standardised validated questionnaire on respiratory symptoms, environmental factors or family issues. An analysis with the chi square test (statistical significance p<0.05) identified the risk factors for wheezing ever and recurrent wheezing, which were assessed using logistic regression. RESULTS: 1065 questionnaires were answered. The prevalence of wheezing ever and recurrent wheezing were 31.2% and 12.3%, respectively. Male gender (p=<0.001), a history of pneumonia (p=<0.001) or nursery attendance (p=<0.001) were some of the risk factors found for wheezing ever. Infant eczema (p=<0.001), nursery attendance (p=<0.001) or prematurity (p=<0.001) were risk factors for recurrent wheezing. No associations with duration of breastfeeding (p=0.116 and p=0.851) or mould stains at home (p=0.153 and p=0.992) were found. CONCLUSION: The study of prevalence and risk factors for wheezing shows the importance of this public health problem, and allows the development of control and treatment strategies against preventable factors.

Prevalencia de los dientes supernumerarios en la población infantil asturiana / Prevalence of supernumerary teeth in the child population of Asturias

La odontogénesis, que es un proceso extraordinariamente complejo, como el resto del desarrollo embrionario, está expuesta a determinados factores que pueden alterar su normal evolución. En ocasiones podemos observar un número de dientes adicional a la fórmula dental normal y en ese caso se habla de dientes supernumerarios, hiperodoncia o hipergenesia. Los dientes supernumerarios son más frecuentes en varones que en mujeres. Y no es raro que puedan dar lugar a retención de dientes permanentes o dificultar su erupción en la arcada dentaria. El diagnóstico de hipergenesia se realiza a partir de una exhaustiva exploración clínica con un completo estudio radiográfico, mediante radiografía panorámica, complementado con radiografías periapicales, oclusales, etc. Los dientes supernumerarios se localizan sobretodo en la línea media anterior del maxilar, en cuyo caso hablamos de mesiodens. El mesiodens es el diente supernumerario que se observa con mayor frecuencia. Los dientes supernumerarios son más frecuentes en dentición permanente y más habitual en el maxilar superior que en el maxilar inferior. El abordaje más habitual de los dientes supernumerarios es la exodoncia, aunque en ocasiones se debe complementar con tratamiento ortodóncico (AU)

Odontogenesis, which is an extraordinarily complex process, like rest of embryonic development, is exposed to certain factors that may alter its normal evolution. Sometimes we see a number of additional teeth to normal dental formula, and if we speak of supernumerary teeth, hyperdontia or hipergenesia. Supernumerary teeth are more common in men than in women. And no wonder that may lead to retention of permanent teeth or hinder its eruption in the dental arch. Hipergenesia diagnosis is made from a though clinical examination with a complete radiographic study by panoramic radiography supplemented with periapical radiographs, occlusal, etc. Supernumerary teeth are located mainly in the anterior midline of the maxilla, in which case we speak of mesiodens. The supernumerary tooth mesiodens is seen more often. Supernumerary teeth are more common in permanent dentition and more common in the maxilla than the mandibule. The most common approach of supernumerary teeth is extraction, but sometimes must be supplemented by orthodontic treatment (AU)

[The relationship between human papillomavirus and cyclin D1 gene amplification in squamous cell carcinomas of the head and neck]. / Relación entre el virus del papiloma humano y la amplificación del gen de la ciclina D1 en los carcinomas epidermoides de cabeza y cuello.

INTRODUCTION: infection by oncogenic subtypes of human papillomavirus (HPV) and cyclin D1 gene (CCND1) amplification are frequent events in head and neck squamous cell carcinomas. The objective of this paper is to establish the relationship between the presence of human papillomavirus (HPV) gene sequences and the development of CCND1 gene amplification in these tumours. MATERIALS AND METHODS: 59 squamous cell carcinomas of the head and neck were studied for HPV types 6b and 16 and CCND1 gene amplification by polymerase chain reaction. RESULTS: HPV DNA was detected in 14 tumors (24%). Ten of them were positive for the HPV type 6b and 4 for the HPV type 16. CCND1 gene amplification was found in 15 cases (25%). Although we have found a higher frequency of CCND1 amplification in the HPV-positive cases (36%, versus 22% in the HPV-negative cases), these differences were not statistically significant (P= 0,32). CONCLUSIONS: The presence of HPV gene sequences does not seem to be related to a significative higher incidence of CCND1 gene amplification in the squamous cell carcinomas of the head and neck.

Relación entre el virus del papiloma humano y la amplificación del gen de la ciclina D1 en los carcinomas epidermoides de cabeza y cuello / The relationship between human papillomavirus and cyclin D1 gene amplification in squamous cell carcinomas of the head and neck

Introducción: La infección por los subtipos oncogénicos del virus del papiloma humano (HPV) y la amplificación del gen de la ciclina D1 (CCND1) son dos alteraciones frecuentes en los carcinomas epidermoides de cabeza y cuello. El objetivo de este trabajo es estudiar la relación entre la presencia del HPV y el desarrollo de la amplificación delCCND1 en dichos carcinomas. Material y métodos: Se estudian 59 carcinomas epidermoides de cabeza y cuello, en los cuales se determina la presencia de los tipos 6b y 16 del HPV y la amplificación del CCND1 mediante la reacción en cadena de la polimerasa (PCR). Resultados: Se detectó el ADN del HPV en 14 tumores (24%). Diez de ellos eran positivos para el HPV 6b y 4 para el HPV 16. El gen CCND1 se hallaba amplificado en 15 casos (25%). Aunque la amplificación del CCND1 fue más frecuente en los casos con integración del HPV (36% en los casos HPV-positivos frente al 22%en los HPV-negativos), estas diferencias no fueron estadísticamente significativas (P=0,32). Conclusiones: La presencia del HPV en las células tumorales no parece relacionarse con una incidencia significativamente mayor de amplificación del gen CCND1 en los carcinomas epidermoides de cabeza y cuello (AU)

Introduction: infection by oncogenic subtypes of human papilloma virus (HPV) and cyclin D1 gene (CCND1) amplification are frequent events in head and neck squamous cell carcinomas. The objective of this paper is to establish the relationship between the presence of human papilloma virus (HPV) gene sequences and the development of CCND1 gene amplification in these tumours. Materials and methods: 59 squamous cell carcinomas of the head and neck were studied for HPV types 6b and 16 and CCND1 gene amplification by polymerase chain reaction. Results: HPVDNA was detected in 14 tumors (24%). Ten of them were positive for the HPV type 6b and 4 for the HPV type 16.CCND1 gene amplification was found in 15 cases (25%). Although we have found a higher frequency of CCND1 amplification in the HPV-positive cases (36%, versus 22% in the HPV-negative cases), these differences were not statisticallysignificant (P= 0,32). Conclusions: The presence of HPV gene sequences does not seem to be related to a significative higher incidence of CCND1 gene amplification in the squamous cell carcinomas of the head and neck (AU)

Evaluación económica del cambio de tratamientode doxazosina estándar a doxazosina deliberación modificada en pacientes conhipertensión leve a moderada en condicioneshabituales de cuidado médico / Economic evaluation of switching from standard doxazosin to doxazosin gastro-intestinal-therapeutic system in patients with mild to moderate hypertension under usual medical care

Objetivo. El objetivo de este estudio ha sido realizar una evaluación económica con costes españoles de un estudio clínico, prospectivo, naturalístico que comparaba la efectividad del cambio de doxazosina estándar, en dosis de 1 a 16 mg/día, a doxazosina de liberación modificada, 4 a 8 mg/día, en el tratamiento de la hipertensión leve a moderada en condiciones de cuidado médico habitual en Atención Primaria. La evaluación económica consistió en una análisis coste-efectividad realizado desde la perspectiva del Sistema Nacional de Salud utilizando los precios de venta al público publicados de especialidad de marca para doxazosina de liberación moderada (DLM) y de genérico para doxazosina estándar, computándose el coste total, coste medio por paciente, coste por paciente tratado con éxito y coste incremental, e incluyó análisis de sensibilidad univariado con el coste de la medicación y la proporción de éxito terapéutico. Ambos tratamientos redujeron significativamente la presión arterial sistólica (PAS), diastólica (PAD) y media (PAM), logrando DLM una reducción adicional en todos los casos. La proporción de pacientes con la presión arterial controlada (PAS <140 mmHg y PAD<90 mmHg) fue significativamente superior con DLM que con estándar; 63,4 por ciento frente a 47,9 por ciento; p < 0,00001. El coste anual medio por paciente con presión arterial controlada fue menor con DLM; 468,12 euros (457,30-479,46 euros) frente a 561,67 euros (543,51-581,07 euros), con un coste incremental por paciente adicional con presión arterial controlada de 179,04 euros (149,20-223,80 euros).El cambio de tratamiento de la formulación estándar de doxazosina a una formulación de liberación modificada se acompaña de un mayor número de pacientes con la presión arterial controlada a un menor coste por paciente que logra el objetivo terapéutico. (AU)

[Relationship between the integration of human papillomavirus and loss of heterozygosity of the P53 gene in squamous cell carcinomas of the head and neck]. / Asociación entre la integración del virus del papiloma humano y la pérdida de heterozigosidad del gen p53 en los carcinomas epidermoides de cabeza y cuello.

Human papillomavirus integration in cellular DNA and loss of heterozygosity of P53 gene are both related with tumour formation process by promoting genomic instability that leads to DNA abnormalities accumulation. In order to analyze the relationship between both events, 26 squamous cell carcinomas of the head and neck were studied. HPV 16 and 6b DNA was detected by PCR in 8 cases (31%), whereas P53 loss of heterozygosity was present in 16 cases (61%). No correlation was found between both events and they were not related to clinical factors neither the prognosis. Consequently, HPV integration and loss of heterozygosity of P53 seem to act independently in the genesis of these tumours.

Asociación entre la integración del virus del papiloma humano y la pérdida de heterozigosidad del gen P53en los carcinomas epidermoides de cabeza y cuello / Relationship between human papillomavirus integration and loss of heterozygosity of the P53 gene in squamous cell carcinomas of the head and neck

La integración del virus del papiloma humano (HPV) en el genoma celular y la pérdida de heterozigosidad del gen P53 son ambos fenómenos relacionados con el proceso de la carcinogénesis a través de la inducción de una inestabilidad genética que favorece el acúmulo de anomalías en el ADN. Con el fin de analizar la posible asociación entre estos dos eventos, estudiamos un grupo de 26 pacientes intervenidos de carcinoma epidermoide de cabeza y cuello. Se demostró la integración de los HPV 16 y 6b mediante PCR en 8 casos (31 por ciento), mientras que la pérdida de heterozigosidad del P53apareció en 16 pacientes (61 por ciento). No se encontró una asociación significativa entre ambos fenómenos, ni se halló que estuvieran correlacionados con factores clínicos ni con el pronóstico. Por lo tanto, la integración del HPV y la pérdida de heterozigosidad del P53son factores que parecen actuar independientemente en la producción de estos tumores (AU)

Human papillomavirus integration in cellular DNA and loss of heterozygosity of P53 gene are both related with tumour formation process by promoting genomic instability that leads to DNA abnormalities accumulation. In order to analyze the relationship between both events, 26 squamous cell carcinomas of the head and neck were studied. HPV 16 and 6b DNA was detected by PCR in 8 cases (31%), whereas P53 loss of heterozygosity was present in 16 cases (61%). No correlation was found between both events and they were not related to clinical factors neither the prognosis. Consequently, HPV integration and loss of heterozygosity of P53 seem to act independently in the genesis of these tumours (AU)

[Molecular changes in epidermoid carcinoma of the oropharynx]. / Alteraciones moleculares en los carcinomas epidermoides de la orofaringe.

In most of the studies about molecular alterations in squamous cell carcinomas of the head and neck there is not distinction between the different subsites of this area. The objective of this study is to describe the molecular alterations in squamous cell carcinomas of the oropharynx. Twenty-nine oropharyngeal carcinomas, with a minimum follow-up of 36 months, were studied. The molecular alterations analyzed were: the amplification of 11q13 region (in the 29 cases), and the MYC and ERBB1 oncogenes (in 22 cases); the integration of Human Papillomavirus (HPV) types 6b and 16 (in 22 cases); the loss of heterozygosity (LOH) of p53 and N-acetyltransferase-2 (NAT2) gene (in 12 and 13 informative cases, respectively); and the cellular DNA content (in 13 cases). The most frequent alterations found were the LOH at p53 (67%), and NAT2 (54%) locus, followed by 11q13 amplification (49%). ERBB1 amplification was found in 14% of the cases, and MYC amplification only in one (5%). Integration of the HPV was found in 23% of the cases. Nine (69%) of the 13 analyzed cases were aneuploid. The only alteration with a prognostic significance was 11q13 amplification that showed a tendency to be associated with a higher frequency of nodal metastases and tumor recurrence.