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.

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.

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.

[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.

[Analysis of rearrangements in the first exon of c-myc oncogene in squamous cell carcinoma of the head and neck]. / Análisis de reordenamientos en el primer exón del oncogén c-myc en carcinomas epidermoides de cabeza y cuello.

Activation of c-myc has been implicated in the origin of different human tumors, and can be produced by diverse mechanisms as amplifications or rearrangements. We examined 55 squamous cell carcinomas of the upper aerodigestive tract for rearrangements involving the first exon of c-myc, which plays a regulatory role in the c-myc expressión. Polymerase chain reaction (PCR) amplification of different fragments of c-myc exon 1 was performed using four oligonucleotide primers that correspond to consecutive sequences from the 5' end of the c-myc exon 1, combined with one oligonucleotide that corresponds to the 3' end. Amplified c-myc PCR products appear as single bands of 580, 495, 417 and 333 base pairs on the electrophoretic analysis. Only in one case a rearrangement involving the first exon of c-myc was found. We concluded that gene rearrangement is not a common mechanism of activation of c-myc in squamous cell carcinomas of the head and neck.

[Malignant melanoma of the nasal cavity and paranasal sinuses]. / Melanomas malignos de las fosas nasales y los senos paranasales.

Malignant melanomas represent about 3% of all nasosinusal neoplasms. They usually are located in the nasal septum and their maximum incidence is in the sixth and seventh decades. In the early stages they are asymptomatic, which delays diagnosis and reduces the possibilities of cure to 15-30%. Eight cases of nasosinusal melanoma are reported and their characteristics are reviewed with special attention to prognostic factors.

[Nasal endoscopic surgery in complicated ethmoiditis]. / Cirugía endoscópica nasal en etmoiditis complicadas.

Spread of infection from paranasal sinuses is uncommon but, when it occurs may lead to serious ocular or intracranial complications. In this article we present four patients, three of them with orbital complications and one with an intracranial abscess, who were successfully treated with endoscopic surgery of the sinuses and antibiotic therapy. We describe some potential advantages of this approach.

[Idiopathic brain herniation in the middle ear and mastoid]. / Herniación cerebral idiopática en el oído medio y mastoides.

Idiopathic brain herniation into the middle ear and the mastoid process is a rare clinico-pathological entity, with only 41 cases described in the literature. It should be suspected in presence of spontaneous otoliquorrhea/rhinoliquorrhea, refractory serous otitis media, or meningitis following acute otitis media in an adult. A new case is presented, with a brief review of the pathogenesis, clinico-pathological, and radiological characteristics of these lesions.

[Clinicopathologic prognostic factors in laryngeal pharyngolaryngeal tumors. II. Glottic carcinomas]. / Factores pronósticos clinicopatológicos en los tumores laríngeos y faringolaríngeos. II. Carcinomas glóticos.

Prognostic factors of glottic carcinomas were studied in 211 patients. The 5-year determinate survival was 85.3%. Factors that implied a bad prognosis were an advanced local stage, previous tracheostomy and advanced age. On the other side, alcohol and tobacco abuse, second primary tumors, degree of differentiation, involvement of surgical margins, and postoperatory complications had not any prognostic relevance. There were no differences in T1 and T2 survival either with surgery or radiotherapy, but the last had a greater recurrence rate.

[Oncoprotein p21-ras expression in epidermoid carcinoma of the laryngopharynx]. / Expressión de las oncoproteínas p21-ras en el carcinoma epidermoide faringolaríngeo.

Ras genes can acquire transforming properties by qualitative and quantitative mechanisms. The mutated products of ras oncogenes (p21 protein) exhibit a decreased ability to hydrolyze GTP that lead to the stabilization of ras proteins in their active state and cause a continuous flow of signal transduction which may result in malignant transformation. These biochemical aberrant properties can also be achieved by an increased expression of the normal p21 protein. In this work we have analyzed the presence of ras gene mutations and the overexpression of the oncogene product p21 in the same series of squamous cell carcinoma of pharynx and larynx. Of 13 cases studied we have detected mutations in seven cases and in nine we have observed overexpression of the p21 protein. There is no correlation between ras mutations and overexpression of the p21 protein.

[Simultaneous screening of HPV-6b and 16 in pharyngolaryngeal cancer]. / Detección simultánea del HPV-6b y 16 en el cáncer faringolaríngeo.

It has been suggested that some human papilloma viruses (HPV) may play a causal role in cancer of the pharynx, larynx, and oral cavity, together with factors such as smoking, alcohol, toxins, and heredity. Using the polymerase chain reaction (PCR), we detected the two most common genotypes in pharyngolaryngeal cancer, HPV-6b and 16, in 15 patients from a series of 57 cases. One patient had both genotypes. The fact that this was the only positive case in which no other risk factors were present, particularly alcohol and smoking, suggests that the synergetic oncogenic action of both viruses could have played an important role in carcinogenesis.

[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.

[The relation between human papilloma virus and cellular DNA content in epidermoid carcinoma of the head and neck]. / Relación entre el virus del papiloma humano y el contenido celular de ADN en los carcinomas epidermoides de cabeza y cuello.

The relation between the presence of gene sequences of human papilloma virus (HPV) and the development of abnormalities in cellular DNA content was analyzed in 31 squamous-cell carcinomas of the head and neck. The integration of HPV types 16 and 6b by PCR and DNA content was studied by flow cytometry in 31 specimens from patients with squamous-cell carcinoma of the head and neck. Eighteen (58%) cases were aneuploid. HPV DNA was present in seven tumors (22.5%), five of then HPV-6b and two of them HPV-16. Aneuploidy correlated with poorly differentiated tumors. No correlation was found between HPV integration and either cellular DNA content or the degree of histological tumor differentiation. Therefore, the presence of HPV gene sequences did not seem to be associated with a higher incidence of aneuploidy in squamous-cell carcinoma of the head and neck.

[A giant bilateral concha bullosa causing nasal obstruction]. / Concha bullosa bilateral gigante causante de obstrucción nasal.

Pneumatization of the middle turbinate or concha bullosa is the most common anatomical variant of this structure. Although usually small and asymptomatic, a large concha bullosa may obstruct sinus drainage. We present an uncommon case of massive bilateral concha bullosa that produced complete obstruction of the left nasal cavity and partial obstruction of the right nasal cavity.