Cervical cancer screening in women vaccinated against human papillomavirus infection: Recommendations from a consensus conference

In Italy, the cohorts of women who were offered Human papillomavirus (HPV) vaccination in 2007/08 will reach the age (25 years) for cervical cancer (CC) screening from 2017. The simultaneous shift from cytology-based screening to HPV test-based screening gives the opportunity for unprecedented reorganisation of CC prevention. The ONS (National Screening Monitoring Centre) Directive and the GISCi (Italian Group for Cervical Screening) identified the consensus conference as the most suitable method for addressing this topic. A summary of consensus recommendations is reported here. The main objective was to define the best screening methods in girls vaccinated against HPV and the knowledge required for defining evidence-based screening strategies. A Jury made recommendations about questions and proposals formulated by a panel of experts representative of Italian scientific societies involved in CC prevention and based on systematic reviews of literature and evidence. The Jury considered changing the screening protocols for girls vaccinated in their twelfth year as appropriate. Tailored screening protocols based on vaccination status could be replaced by \u201cone size fits all\u201d protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with HPV test. Furthermore, there is a strong rationale for applying longer intervals for re-screening HPV negative women than the currently recommended 5 years, but research is needed to determine the optimal screening time points. For non-vaccinated women and for women vaccinated in their fifteenth year or later, the current protocol should be kept

Ion Conduction Mechanism as a Fingerprint of Potassium Channels

K+-channels are membrane proteins that regulate the selective conduction of potassium ions across cell membranes. Although the atomic mechanisms of K+ permeation have been extensively investigated, previous work focused on characterizing the selectivity and occupancy of the binding sites, the role of water molecules in the conduction process, or the identification of the minimum energy pathways enabling permeation. Here, we exploit molecular dynamics simulations and the analytical power of Markov state models to perform a comparative study of ion conduction in three distinct channel models. Significant differences emerged in terms of permeation mechanisms and binding site occupancy by potassium ions and/or water molecules from 100 μs cumulative trajectories. We found that, at odds with the current paradigm, each system displays a characteristic permeation mechanism, and thus, there is not a unique way by which potassium ions move through K+-channels. The high functional diversity of K+-channels can be attributed in part to the differences in conduction features that have emerged from this work. This study provides crucial information and further inspiration for wet-lab chemists designing new synthetic strategies to produce versatile artificial ion channels that emulate membrane transport for their applications in diagnosis, sensors, the next generation of water treatment technologies, etc., as the ability of synthetic channels to transport molecular ions across a bilayer in a controlled way is usually governed through the choice of metal ions, their oxidation states, or their coordination geometries

Conduction and Gating Properties of the TRAAK Channel from Molecular Dynamics Simulations with Different Force Fields

In recent years, the K2P family of potassium channels has been the subject of intense research activity. Owing to the complex function and regulation of this family of ion channels, it is common practice to complement experimental findings with the atomistic description provided by computational approaches such as molecular dynamics (MD) simulations, especially, in light of the unprecedented timescales accessible at present. However, despite recent substantial improvements, the accuracy of MD simulations is still undermined by the intrinsic limitations of force fields. Here, we systematically assessed the performance of the most popular force fields employed to study ion channels at timescales that are orders of magnitude greater than the ones accessible when these energy functions were first developed. Using 32 μs of trajectories, we investigated the dynamics of a member of the K2P ion channel family, the TRAAK channel, using two established force fields in simulations of biological systems: AMBER and CHARMM. We found that while results are comparable on the nanosecond timescales, significant inconsistencies arise at microsecond timescales

Conduction and Gating Properties of the TRAAK Channel from Molecular Dynamics Simulations with Different Force Fields

In recent years, the K2P family of potassium channels has been the subject of intense research activity. Owing to the complex function and regulation of this family of ion channels, it is common practice to complement experimental findings with the atomistic description provided by computational approaches such as molecular dynamics (MD) simulations, especially, in light of the unprecedented timescales accessible at present. However, despite recent substantial improvements, the accuracy of MD simulations is still undermined by the intrinsic limitations of force fields. Here, we systematically assessed the performance of the most popular force fields employed to study ion channels at timescales that are orders of magnitude greater than the ones accessible when these energy functions were first developed. Using 32 \u3bcs of trajectories, we investigated the dynamics of a member of the K2P ion channel family, the TRAAK channel, using two established force fields in simulations of biological systems: AMBER and CHARMM. We found that while results are comparable on the nanosecond timescales, significant inconsistencies arise at microsecond timescales

Polymorphisms of endothelial nitric oxide gene as strong risk factors of sporadic ascending aorta aneurysm

BACKGROUND: Endothelium-derived nitric oxide (NO) is produced by an oxidative reaction catalyzed by endothelial NO synthase (eNOS). A lot of study shows reduced levels of NO in patients with aneurysm and bicuspid aortic valve (BAV). We want to analyse the role of the influence of polymorphisms of eNOS in patients with sporadic thoracic ascending aneurysm no BAV related (S-TAA). METHODS: Aortic specimens were obtained from 64 patients (44 men and 20 women, age 63± 9.5 years) undergoing surgical repair of S-TAA. A control group of 68 subjects (34 men and 34 woman, age: 61.1 ± 5.8 years) was also enrolled. Histopathological and immunohistochemical analyses were performed. Furthermore, genotyping of two common and functional single nucleotide genetic polymorphisms (SNPs) of eNOS gene was executed. RESULTS: We identified three different phenotypes of S-TAA according to the severity of medial degeneration: low, moderate and elevated. No significant differences were detected in terms of clinical features. In contrast, significant difference were observed in term of apoptosis of smooth muscle cells and metalloproteinase concentrations. Genotyping analysis revealed a significant association between the - 786T/C eNOs SNP and the risk of S-TAA (OR=4.7(1.92-16.32), p=0.0002 by Fisher test). In addition, a significant association was detected between this SNP and elevated medial degeneration. The biological effect of this SNP is in determining low levels of eNOs and consequently a reduced NO amount, that contribute to elevated medial degeneration, plurifocal apoptosis and severe concentration of metalloproteinases. CONCLUSIONS: Thus, polymorphisms of eNOs gene seem to have a key role in the pathophysiology of S- TAA

An observational study of CoSeal for the prevention of adhesions in pediatric cardiac surgery.

We sought to evaluate the utility and safety of CoSeal Surgical Sealant (Baxter) for the prevention of cardiac adhesions in children. Seven cardiac surgery centers in Europe recruited consecutive pediatric patients requiring primary sternotomy for staged repair of congenital heart defects. Exclusion criteria included immune system disorder, unplanned reoperation, or reoperation within three months of primary repair. CoSeal was sprayed onto the surface of the heart at the end of surgery. Evaluation of adhesions took place at first reoperation. Data on safety, duration of surgery, and ease of CoSeal use were also collected. Seventy-nine pediatric patients were recruited between February 2005 and September 2007. Of these, 76 underwent major surgery to repair a wide range of congenital heart defects. Thirty-six patients underwent reoperation >3 months after primary repair, and were included in the efficacy analysis. Mean adhesions score was 8.3 (standard deviation [S.D.] 2.4; range 7-16). Six adverse events (5 serious) were possibly/definitely attributed to CoSeal. CoSeal's ease of use at primary operation was graded by surgeons as 12.1 mm (S.D. 9.8) on a visual analog scale of 0 ('very easy') to 100 mm ('very difficult'). Results of this prospective uncontrolled trial justify further investigation in a randomized, controlled trial