Human papillomavirus-associated cancers: a survey on otorhinolaryngologists' knowledge and attitudes on prevention.

Human papillomavirus (HPV) infection is a recognised causal factor associated with oropharyngeal cancers. The global burden of HPVrelated oropharyngeal cancers is on the increase and is predicted to surpass the burden of cervical cancer in the near future. As evidence is accumulating on the potential effectiveness of an HPV vaccine in controlling the oropharyngeal cancer epidemic; otorhinolaryngologists assume a key role - not only in the diagnosis and treatment of HPV-related cancers - but also in educating and advocating on HPV prevention. We conducted a survey to assess Italian otorhinolaryngologists' knowledge and attitudes regarding HPV infection, HPV-related oropharyngeal diseases and cancers and available prevention measures, including vaccines. This is the first study conducted in Italy and Europe on this topic. A total of 262 Italian otorhinolaryngologists were recruited during the National Conference of the Italian Association of Otorhinolaryngologists. Our results show that Italian otorhinolaryngologists are knowledgeable regarding HPV infection and have a positive attitude towards HPV vaccine. Our findings provide a useful basis to plan, implement and evaluate targeted educational programmes and training. As we show herein, educational programmes and training specifically focusing on HPV are effective in increasing physicians' knowledge and positive attitudes towards prevention; this ultimately contributes to enhance vaccine uptake among patients and the general population. With the overall aim of controlling the burden of HPV-related cancers, resources and efforts should be devoted to promote continuing education among otorhinolaryngologists and the general medical community and to increase awareness on the role of vaccines in prevention of HPV-related cancers. In this context, there is tremendous opportunity for healthcare providers across fields to cooperate and for public health and otorhinolaryngologist communities to join forces and engage in fruitful collaboration.

Duplications in the DMD gene.

The detection of duplications in Duchenne (DMD)/Becker Muscular Dystrophy (BMD) has long been a neglected issue. However, recent technological advancements have significantly simplified screening for such rearrangements. We report here the detection and analysis of 118 duplications in the DMD gene of DMD/BMD patients. In an unselected patient series the duplication frequency was 7%. In patients already screened for deletions and point mutations, duplications were detected in 87% of cases. There were four complex, noncontiguous rearrangements, with two also involving a partial triplication. In one of the few cases where RNA was analyzed, a seemingly contiguous duplication turned out to be a duplication/deletion case generating a transcript with an unexpected single-exon deletion and an initially undetected duplication. These findings indicate that for clinical diagnosis, duplications should be treated with special care, and without further analysis the reading frame rule should not be applied. As with deletions, duplications occur nonrandomly but with a dramatically different distribution. Duplication frequency is highest near the 5' end of the gene, with a duplication of exon 2 being the single most common duplication identified. Analysis of the extent of 11 exon 2 duplications revealed two intron 2 recombination hotspots. Sequencing four of the breakpoints showed that they did not arise from unequal sister chromatid exchange, but more likely from synthesis-dependent nonhomologous end joining. There appear to be fundamental differences therefore in the origin of deletions and duplications in the DMD gene.

[Deletions in the dystrophin gene and its phenotype expression]. / Delecije u genu za distrofin i njihova fenotipska ekspresija.

About 60% of both Duchenne's muscular dystrophy (DMD) and Becker's muscular dystrophy (BMD) is due to deletions of dystrophin gene. For cases with deletion mutations the "reading frame" hypothesis predicts that deletions which result in disruption of the translation reading frame prevent production of stable protein and are associated with DMD. In contrast, intragenic deletions that involve exons encoding an integral number of triplet codons maintain proper reading frame. The resulting abnormal proteins are stable and partially functional, resulting in a milder and more variable BMD phenotype. To test the validity of this theory,we analyzed 40 patients-19 independent deletions at the DMD/BMD locus. Clinical/molecular correlations based on the altera-tions of the reading frame were valid in 69.2% of cases. After exclusion of: --2 patients with del 3-6 (with no consistent clinical expression); --1 DMD patient with large in-frame deletion; --2 patients that were too young to be classified; --4 patients in whom it was impossible to identify the extent of deletion (del 47 and del 44-45), the correlation between deletion and clinical severity was as predicted in 92.4% of cases. The present data should be useful in establishing the prognosis in individual patients even in sporadic cases with no affected relatives.

[Relation between gene mutations and pancreatic exocrine function in patients with cystic fibrosis]. / Povezanost izmedju genskih mutacija i egzokrine funkcije pankreasa kod osoba obolelih od cisticne fibroze.

Cystic fibrosis (CF), is the most common autosomal-recessive disease in Caucasians, with an incidence of approximately 1:2500 live births and a carrier frequency of approximately 4-5%. Causes of the disease are mutations in the CF gene which is located on chromosome 7 (region 7q31). Although a single mutation, a deletion of phenylalanine at position 508 (DF508) in exon 10, accounts for almost 70% of all CF chromosomes, over 900 other mutations have been identified in this large gene. CF gene encodes a membrane protein, which functions as aion channel- CFTR (cystic fibrosis transmembrane regulator protein). The exocrine pancreas is a gland that secretes water, enzymes and electrolytes into the intestinal lumen. These enzymes are needed for the normal digestion of food, and their reduced secretion in cystic fibrosis will cause malabsortion and malnutrition in CF patients. Pancreatic dysfunction in CF begins in uteri. Most patients with CF typically present insufficient pancreatic exocrine function (PI phenotype) and 10-15% of CF patients are pancreatic sufficient (PS phenotype). It has been shown elsewhere that the pancreatic function status in CF could be correlated to mutations in the CFTR gene. To determine the relation between genotype and pancreatic status, we analyzed 32 CF patients in whom both CF gene mutant alleles were identified (Table 1). Patients included in this study attended the Paediatric Department of Mother and Child Health Institute in Belgrade. The diagnosis was based on typical clinical manifestations and high levels of sweat chloride concentration (higher than 60 mmol/L). Of the 32 patients studied, only one (3.12%) was PS and the rest (96.88%) had PI phenotype. For each CF genotype the number of patients who were PI or PS is given in Table 1. The most striking observation was that all given genotypes correlated with either PI or PS, but not with both. On the basis of both preceding hypotheses and our present data (Table 2 and Table 3), it was possible to classify mutations as "severe" or "mild" with respect to pancreatic function (Table 4). This study strengthens the hypothesis that pancreatic function status in CF is genetically determined by specific mutations at the CF locus. Our data also strongly support the hypothesis that, with respect to pancreatic function, "mild" mutant alleles confer a higher residual CFTR activity than do "severe" mutant alleles. Although PS occurs in patients who have one or two "mild" mutations, PI occurs in patients who are homozygous or who are genetic compounds of two "severe" mutant alleles.