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Central venous access devices are essential for the management of critically ill patients, but they are potentially associated with many complications, which may occur during or after insertion. Many evidence-based documents-consensus and guidelines-suggest practical recommendations for reducing catheter-related complications, but they have some limitations. Some documents are not focused on critically ill patients; other documents address only some special strategies, such as the use of ultrasound; other documents are biased by obsolete concepts, inappropriate terminology, and lack of considerations for new technologies and new methods. Thus, the Italian Group of Venous Access Devices (GAVeCeLT) has decided to offer an updated compendium of the main strategies-old and new-that should be adopted for minimizing catheter-related complications in the adult critically ill patient. The project has been planned as a consensus, rather than a guideline, since many issues in this field are relatively recent, and few high-quality randomized clinical studies are currently available, particularly in the area of indications and choice of the device. Panelists were chosen between the Italian vascular access experts who had published papers on peer-reviewed journals about this topic in the last few years. The consensus process was carried out according to the RAND/University of California at Los Angeles (UCLA) Appropriateness Methodology, a modification of the Delphi method, that is, a structured process for collecting knowledge from groups of experts through a series of questionnaires. The final document has been structured as statements which answer to four major sets of questions regarding central venous access in the critically ill: (1) before insertion (seven questions), (2) during insertion (eight questions), (3) after insertion (three questions), and (4) at removal (three questions)., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Postoperative pulmonary complications (PPCs) significantly contribute to postoperative morbidity and mortality. We conducted a study to determine the incidence of PPCs after major elective abdominal surgery and their association with early and 1-year mortality in patient without pre-existing respiratory disease., Methods: We conducted a multicenter observational prospective clinical study in 40 Italian centers. 1542 patients undergoing elective major abdominal surgery were recruited in a time period of 14 days and clinically managed according to local protocol. The primary outcome was to determine the incidence of PPCs. Further, we aimed to identify independent predictors for PPCs and examine the association between PPCs and mortality., Results: PPCs occurred in 12.6% (95% CI 11.1-14.4%) of patients with significant differences among general (18.3%, 95% CI 15.7-21.0%), gynecological (3.7%, 95% CI 2.1-6.0%) and urological surgery (9.0%, 95% CI 6.0-12.8%). PPCs development was associated with known pre- and intraoperative risk factors. Patients who developed PPCs had longer length of hospital stay, higher risk of 30-days hospital readmission, and increased in-hospital and one-year mortality (OR 3.078, 95% CI 1.825-5.191; P<0.001)., Conclusions: The incidence of PPCs in patients without pre-existing respiratory disease undergoing elective abdominal surgery is high and associated with worse clinical outcome at one year after surgery. General surgery is associated with higher incidence of PPCs and mortality compared to gynecological and urological surgery.

Background: An adequate stabilization of a vascular device is an important part of insertion bundles and is an effective strategy in reducing complications. Dislodgment has a relevant clinical impact and an increase in healthcare costs., Method: We have retrospectively investigated the safety and efficacy of Subcutaneously Anchored Securement (SAS) for Peripherally Inserted Central Catheters (PICC) in cancer patients., Results: We analyzed 639 patients who had a PICC inserted and secured with SAS, over the past 3 years (2018-2020). No immediate complications during SAS placement were reported. In the first 24-48 h, a slight local ecchymosis was reported in 24 cases with rapid spontaneous resolution. No cases of bleeding or hematoma of the exit site were reported. The total number of catheter days was 93078. Dislodgment occurred only in seven cases (1.1%). In 16 patients, the PICC was removed because of catheter-related bloodstream infection (CRBSI): the overall incidence of CRBSI was 0.17 per 1000 catheter days. Symptomatic venous thrombosis was documented in 12 patients (1.9%) and treated with low molecular weight heparin without PICC removal. We had no cases of irreversible lumen occlusion. In 17 patients, local discomfort-including device-related pressure ulcers and painful inflammation-was reported: these cases were treated without SAS removal or PICC removal., Conclusion: In this retrospective analysis, subcutaneously anchored securement of PICCs was a safe and effective strategy for reducing the risk of dislodgment.

Background: Taurolidine lock is known to be effective in preventing catheter-related infections in a variety of venous access devices, including long term venous access devices for chemotherapy. Though, literature about the use of taurolidine for treating catheter colonization or catheter-related blood stream infection is scarce., Method: We have retrospectively reviewed the safety and efficacy of 2% taurolidine lock for treatment of catheter-colonization and of catheter-related bloodstream infection in cancer patients with totally implanted venous access devices. Diagnosis of colonization or catheter-related infection was based on paired peripheral and central blood cultures, according to the method of Delayed Time to Positivity., Results: We recorded 24 cases of catheter-related infection and two cases of colonization. Taurolidine lock-associated with systemic antibiotic therapy-was successful in treating all cases of catheter-related infection, with disappearance of clinical symptoms, normalization of laboratory values, and eventually negative blood cultures. Taurolidine lock was also safe and effective in treating device colonization. No adverse effect was reported., Conclusion: In our retrospective analysis, 2% taurolidine lock was completely safe and highly effective in the treatment of both catheter-colonization and catheter-related bloodstream infection in cancer patients with totally implanted venous access devices.

It is usual in anatomical and physiological research to assess the effects of some intervention on extremities (e.g., training programmes or injury recovery protocols) using one muscle for the intervention and its contralateral as control. However, the existence of laterality (left-handedness or right-handedness) in athletes of different specialities is widely recognized. In rats, gastrocnemius is one of the muscles most widely used because of its importance in locomotion and high relative limb mass. Since we have not found studies reporting laterality assessment on the morphology and function in rat gastrocnemius, our study aimed to evaluate the fibre histochemical, morphometrical and muscle force contractile properties between right and left gastrocnemius of the laboratory rat. Fibre-type proportion, fibre morphometrical measurements, muscle capillarization and muscle force properties were analysed in the right and left gastrocnemius of six male rats. No statistically significant differences (p = 0.265) were found in gastrocnemius to body weight ratio (‰) between right (6.55 ± 0.40) and left (6.49 ± 0.40) muscles. The muscles analysed showed a great degree of heterogeneity in fibre type distribution, having three clearly distinguished regions named red, mixed and white. In the three regions, there were no statistical differences in fibre type proportions between right and left gastrocnemius, as is indicated by the p-values (from 0.203 to 0.941) obtained after running t-Student paired tests for each fibre type. When analysing fibre cross-sectional area, individual fibre capillarization and fibre circularity, no significant differences between right and left gastrocnemius in any of these morphometrical parameters were found in any muscle region or fibre type. Most of the p-values (70%) resulting from running t-Student paired tests were higher than 0.400, and the lowest p-value was 0.115. Seemingly, global capillary and fibre densities were not statistically different between right and left sides in all muscle regions with p-values ranging from 0.337 to 0.812. Force parameters normalized to gastrocnemius mass (mN g -1 ) did not show any significant difference between right (PF = 74.0 ± 13.4, TF = 219.4 ± 13.0) and left (PF = 70.9 ± 10.7, TF = 213.0 ± 18.0) muscles with p = 0.623 (PF) and p = 0.514 (TF). Twitch time parameters (ms) also lacked significant differences between the two sides (CT: 43.4 ± 8.6 vs. 45.0 ± 14.3, p = 0.639; HRT: 77.6 ± 15.0 vs. 82.3 ± 25.3, p = 0.475). Finally, both muscles also showed similar (p = 0.718) fatigue properties. We did find an absence of laterality at the morphological and functional levels, which raises the possibility of using right and left gastrocnemius muscles interchangeably for experimental designs where one muscle is used to analyse data after a physiological intervention and its contralateral muscle plays the control role, thus allowing unbiased paired comparisons to derive accurate conclusions., (© 2022 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Germline pathogenic variants (PVs) in oncogenes and tumour suppressor genes are responsible for 5 to 10% of all diagnosed cancers, which are commonly known as hereditary cancer predisposition syndromes (HCPS). A total of 104 individuals at high risk of HCPS were selected by genetic counselling for genetic testing in the past 2 years. Most of them were subjects having a personal and family history of breast cancer (BC) selected according to current established criteria. Genes analysis involved in HCPS was assessed by next-generation sequencing (NGS) using a custom cancer panel with high- and moderate-risk susceptibility genes. Germline PVs were identified in 17 of 104 individuals (16.3%) analysed, while variants of uncertain significance (VUS) were identified in 21/104 (20.2%) cases. Concerning the germline PVs distribution among the 13 BC individuals with positive findings, 8/13 (61.5%) were in the BRCA1/2 genes, whereas 5/13 (38.4%) were in other high- or moderate-risk genes including PALB2 , TP53 , ATM and CHEK2 . NGS genetic testing showed that 6/13 (46.1%) of the PVs observed in BC patients were detected in triple-negative BC. Interestingly, the likelihood of carrying the PVs in the moderate-to-high-risk genes calculated by the cancer risk model BOADICEA was significantly higher in pathogenic variant carriers than in negative subjects. Collectively, this study shows that multigene panel testing can offer an effective diagnostic approach for patients at high risk of hereditary cancers.

Background: PICC-ports may be defined as totally implantable central venous devices inserted in the upper limb using the current state-of-the-art techniques of PICC insertion (ultrasound-guided venipuncture of deep veins of the arm, micro-puncture kits, proper location of the tip preferably by intracavitary ECG), with placement of the reservoir at the middle third of the arm. A previous report on breast cancer patients demonstrated the safety and efficacy of these devices, with a very low failure rate., Methods: This retrospective multicenter cohort study-developed by GAVeCeLT (the Italian Group of Long-Term Venous Access Devices)-investigated the outcomes of PICC-ports in a large cohort of unselected patients. The study included 4480 adult patients who underwent PICC-port insertion in five Italian centers, during a period of 60 months. The primary outcome was device failure, defined as any serious adverse event (SAE) requiring removal. The secondary outcome was the incidence of temporary adverse events (TAE) not requiring removal., Results: The median follow-up was 15.5 months. Device failure occurred in 52 cases (1.2%), the main causes being local infection ( n  = 7; 0.16%) and CRBSI ( n  = 19; 0.42%). Symptomatic catheter-related thrombosis occurred in 93 cases (2.1%), but removal was required only in one case (0.02%). Early/immediate and late TAE occurred in 904 cases (20.2%) and in 176 cases (3.9%), respectively., Conclusions: PICC-ports are safe venous access devices that should be considered as an alternative option to traditional arm-ports and chest-ports when planning chemotherapy or other long-term intermittent intravenous treatments.

Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.

Epidermolysis bullosa simplex is a disease that belongs to a group of genodermatoses characterised by the formation of superficial bullous lesions caused by minor mechanical trauma to the skin. The skin fragility observed in the EBS is mainly caused by pathogenic variants in the KRT5 and KRT14 genes that compromise the mechanical stability of epithelial cells. By performing DNA sequencing in a female patient with EBS, we found the pathogenic variant c.967G>A (p.Val323Met) in the KRT5 gene. This variant co-segregated with EBS in the family pedigree and was transmitted in an autosomal dominant inheritance manner. This is the first report showing a familial form of EBS due to this pathogenic variant.

Reliable venous access should be part of the clinical-therapeutic path of all cancer patients. A correct preliminary ultrasound evaluation of the patient's veins and the choice of the suitable vein are the fundamental requirements to guarantee a stable and long-lasting venous access.

The mitochondrial quality control network includes several epigenetically-regulated genes involved in mitochondrial dynamics, mitophagy, and mitochondrial biogenesis under physiologic conditions. Dysregulated expression of such genes has been reported in various disease contexts, including cancer. However, their expression pattern and the possible underlying epigenetic modifications remain to be defined within plasma cell (PC) dyscrasias. Herein, we compared the mRNA expression of mitochondrial quality control genes from multiple myeloma, plasma cell leukemia patients and human myeloma cell lines (HMCLs) with healthy plasma cells; moreover, by applying the Sequenom MassARRAY EpiTYPER technology, we performed a pilot investigation of their CpG methylation status in HMCLs. Overall, the results provided indicate dysregulated expression of several mitochondrial network's genes, and alteration of the CpG methylation profile, underscoring novel potential myeloma biomarkers deserving in-depth functional investigation in the future.

A well-known property of linear resistive electrical networks is that the current distribution minimizes the total dissipated power. When the circuit includes resistors with nonlinear monotonic characteristic, the current distribution minimizes in general a different functional. We show that, if the nonlinear characteristic is a threshold-like function and the current generator is concentrated in a single point, as in the case of lightning or dielectric discharge, then the current flow is concentrated along a single path, which is a minimum path to the ground with respect to the threshold. We also propose a dynamic model that explains and qualitatively reproduces the lightning transient behavior: initial generation of several plasma branches and subsequent dismissal of all branches but the one reaching the ground first, which is the optimal one.

Phenotypic heterogeneity is a phenomenon in which genetically identical individuals have different characteristics. This behavior can also be found in bacteria, even if they grow as monospecies in well-mixed environments such as bioreactors. Here it is discussed how phenotypic heterogeneity is generated by internal factors and how it is promoted under nutrient-limited growth conditions. A better understanding of the molecular levels that control phenotypic heterogeneity could improve biotechnological production processes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A complex relationship exists between environmental factors, signaling networks and phenotypic individuality in bacteria. In this review, we will focus on the organization, function and control points of multiple-input histidine kinase-based signaling cascades as a source of phenotypic heterogeneity. In particular, we will examine the quorum sensing cascade in Vibrio harveyi and the pyruvate sensor network in Escherichia coli. We will describe and compare these histidine kinase-based signaling networks in terms of robustness, the molecular mechanisms of signal transduction and the role of RNA switches. Finally, we will discuss the biological significance of phenotypic heterogeneity for the respective bacteria in relation to environmental factors., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: Ultrasound-guided cannulation of the axillary vein in the infraclavicular area has several potential advantages for both short-term and long-term venous access devices. Currently, there are two techniques to approach axillary vein for ultrasound-guided cannulation: out-of-plane puncture in the short-axis view and the in-plane puncture in the long-axis view. We propose a novel ultrasound-guided puncture technique of axillary vein for centrally inserted central catheter placement, which consists in the oblique-axis view of the axillary vein coupled with the in-plane puncture. The main objectives of this study were feasibility and safety of this approach. The primary endpoints were the success rate and early complications; the secondary endpoints were late complications., Methods: We analyzed data from a retrospective cohort of 80 ultrasound-guided cannulation of axillary vein performed with the oblique axis-in-plane technique in 80 cancer patients requiring a totally implantable central venous access, at CRO Aviano National Cancer Institute, during the period from January 2016 up to October 2017. We focused on the percentage of successful venous cannulation at the first attempt and on the cumulative incidence of early and late complications., Results: Axillary vein cannulation was successful at the first attempt in 77 out of 80 patients (96%). We had no significant complications during placement or in the first 48 h. The total number of catheter days was 27,432. The cumulative incidence of catheter-related bloodstream infection was of 0.036 per 1000 catheter days (only one case). We had no infection of the pocket of the reservoir, no symptomatic venous thrombosis, and no catheter migration., Conclusion: Our data show that the oblique axis-in-plane technique of the ultrasound approach to the axillary vein is feasible and safe.

Taxane-related peripheral neuropathy (TrPN) is a dose-limiting toxicity with important interindividual variability. Genetic polymorphisms in absorption, distribution, metabolism, and excretion (ADME) genes may account for variability in drug efficacy and/or toxicity. By the use of Affymetrix drug-metabolizing enzyme and transporter microarray platform, in a retrospective case-control study, the correlation between ADME polymorphic variants and grades ≥ 2-3-TrPN was investigated. In a breast cancer (BC) training set, five single-nucleotide polymorphisms in NR1I3 and UDP-glucuronosyltransferase (UGT)2B7 genes were correlated to grades ≥ 2-3-TrPN protection. By receiver operating characteristic curves, the grades ≥ 2-3-TrPN-related candidate biomarkers in an independent series of 54 patients with BC (17 cases and 37 controls) were validated. NR1I3 was correlated to paclitaxel-TrPN and UGT2B7 to docetaxel-TrPN. Moreover, a genetic signature of prognostic relevance for BC outcome was found. Our findings might have potential relevance for personalized management of patients with BC for prevention of treatment failure in ultrametabolizer genetic variants., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Pseudoxanthoma elasticum is an autosomal recessive heritable disorder caused by mutations in ABCC6 . We describe two siblings showing typical skin lesions and a clinical diagnosis of pseudoxanthoma elasticum. Genetic analysis of ABCC6 revealed a novel homozygous c.4041G > A variant located in the last position of exon 28 that compromises the splicing donor site, resulting in a shorter messenger RNA. The deletion impairs the nucleotide-binding fold region, which is crucial for ABCC6 function., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest.

We report a real-life 3D therapy failure in a patient treated with ombitasvir (OMV)/paritaprevir/ritonavir and dasabuvir without ribavirin (3D-R). He had therapy failure at week 12 after the end of treatment. We detected resistance-associated substitutions (RASs) plus polymorphisms on NS3, NS5A, and NS5B target regions by population sequencing (15% cut-off) at baseline, at relapse and during follow-up. About this, NS5A RASs generally persist longer than resistances in the other target genes and may impact treatment outcome. Therefore, to evaluate OMV drug-resistance mechanism, we studied the acquired RAS plus polymorphisms on NS5A phosphoprotein by computational studies. OMV showed a higher affinity towards baseline and 93H/108 K mutant structure (follow-up) with respect to 93H/R108 mutant structure (relapse) on phosphoprotein. By Molecular Dynamics simulations (MDs), structural information about the protein stability in presence of OMV were observed. According to our data, molecular modeling approach has proved to be a powerful method to evaluate the impact of these RASs plus specific amino acid (AA) changes on phosphoprotein., (© 2018 Wiley Periodicals, Inc.)

Every living cell possesses numerous transmembrane signalling systems that receive chemical and physical stimuli from the environment and transduce this information into an intracellular signal that triggers some form of cellular response. As unicellular organisms, bacteria require these systems for survival in rapidly changing environments. The receptors themselves act as 'sensory organs', while subsequent signalling circuits can be regarded as forming a 'neural network' that is involved in decision making, adaptation and ultimately in ensuring survival. Bacteria serve as useful biosensors in industry and clinical diagnostics, in addition to producing drugs for therapeutic purposes. Therefore, there is a great demand for engineered bacterial strains that contain transmembrane signalling systems with high molecular specificity, sensitivity and dose dependency. In this review, we address the complexity of transmembrane signalling systems and discuss principles to rewire receptors and their signalling outputs., (© 2018 The Authors.)

The investigation of the subcellular localization, dynamics and interaction of proteins and protein complexes in prokaryotes is complicated by the small size of the cells. Super-resolution microscopy (SRM) comprise various new techniques that allow light microscopy with a resolution that can be up to ten-fold higher than conventional light microscopy. Application of SRM techniques to living prokaryotes demands the introduction of suitable fluorescent probes, usually by fusion of proteins of interest to fluorescent proteins with properties compatible to SRM. Here we describe an approach that is based on the genetically encoded self-labelling enzymes HaloTag and SNAP-tag. Proteins of interest are fused to HaloTag or SNAP-tag and cell permeable substrates can be labelled with various SRM-compatible fluorochromes. Fusions of the enzyme tags to subunits of a type I secretion system (T1SS), a T3SS, the flagellar rotor and a transcription factor were generated and analysed in living Salmonella enterica. The new approach is versatile in tagging proteins of interest in bacterial cells and allows to determine the number, relative subcellular localization and dynamics of protein complexes in living cells.

Background: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated., Objective: We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG., Methods: We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions., Results: We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis., Conclusions: Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Pain in cancer patients is often related to oncologic therapies and diagnostic procedures. The placement of fully implantable venous access systems is a very common procedure in oncology patients. Local anaesthesia is the method most commonly used to overcome pain related to this surgical procedure, but the local anaesthetic may be unable to completely eradicate all pain. This study investigates the effectiveness and safety of fentanyl buccal tablet (FBT), administered by OraVescent® technology, in reducing procedural pain related to the placement of indwelling central venous access systems (Ports) in opioid-naïve cancer patients., Methods: Inpatients who required an indwelling vascular access (Port) were preoperatively assessed with a self-assessment questionnaire on anxiety and pain. A 100 μg FBT was administered 10 min before preparation of the operating field. A self-assessment scale for pain experienced during the procedure was administered at the end of the procedure. Vital signs and the presence of any side effects or bothersome symptoms were monitored during the procedure, at the end, and 4 h later., Results: From October 2012 to June 2014, 65 patients were enrolled in the study. A total of 61 (93.9 %) patients perceived no or a little pain during the procedure. Four patients (6.2 %) reported a lot of pain. No patient reported very severe pain. This data is significant in terms of the lower than expected presence of pain (Fisher test p = 0.0018) as assessed in our previous experience without procedural analgesia. The most common side effects of FBT was drowsiness, experienced by 28 patients at the end of the procedure (43.1 %), significantly reduced (p < 0.01) to 8 patients after 4 h (12.5 %). Nausea was present in 6 cases at the end of the procedure (9.2 %) and in 7 cases 4 h later (10.9 %). Vomiting was present in 3 cases at the end (4.7 %) and in 2 other patients after 4 h (7.8 %). No significant change of vital parameters was observed between the baseline and the subsequent measurements in all patients studied., Conclusions: The significant improvement in the number of patients experiencing little or no pain, accompanied by a lower number of non-severe side effects, suggests that FBT is a valid, practical and safe method of procedural analgesia. It will be necessary to perform further studies, taking into account the need for standard antiemetic pre-medication to minimise the incidence of nausea and vomiting.

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by respiratory and extrarespiratory components referring both to systemic complications of COPD, like skeletal muscle myopathy, weight loss and others, and frequently associated comorbidities, interesting various organs and systems (cardiovascular diseases, malignancies, osteoporosis, diabetes, etc.). These comorbidities may increase the rate of hospitalization of COPD patients and have a huge effect on the outcomes of the respiratory disease. Inhalation therapy of COPD with bronchodilators and steroid is primary driven by airflow obstruction, symptoms like dyspnoea, and acute exacerbations. INDACO project has been developed in 2013 to assess the prevalence and type of comorbidities in COPD patients referred to the outpatient wards of some hospitals in Central and South Italy and a preliminary report has recently been published. In the present study, after widening that database, we evaluate the prevalence of comorbidities and the relationships between comorbidities and sex, age, symptoms, lung function and inhalation therapy in COPD patients., Methods: In each enrolled patient, anthropometric and anamnestic data, smoking habits, respiratory function, GOLD (Global initiative for Chronic Obstructive Lung Disease) severity stage, Body Mass Index (BMI), number of acute COPD exacerbations in previous years, presence and type of comorbidities, and the Charlson Comorbidity Index (CCI) were recorded., Results: We collected data of 569 patients (395 males and 174 females, mean age 73 ± 8.5 yrs). The prevalence of patients with comorbidities was 81.2%. Overall number of comorbidities was not related to airflow obstruction and age, but to acute exacerbation of COPD, dyspnoea measured with MRC scale, and male gender. A subgroup analysis revealed that ischaemic heart disease was predominant in males, whereas mood disorders in females. The use of a more complex (multi-drug) inhalation therapy was related with bronchial obstruction measured by FEV1/FVC (p for trend = 0.003) and number of comorbidities (p for trend = 0.001). In multivariate analysis, only airflow obstruction and number of comorbidities were determinant of complexity of therapy, but not MRC and acute exacerbation of COPD. However, the statistical model reached an extreme low degree of significance (r^2 = 0.07)., Conclusions: Our study showed a high prevalence of comorbidities in COPD, with some differences related to gender. Number of comorbidities and airflow obstruction represent the determinant of inhalation therapy prescription. Dyspnoea and acute exacerbation of COPD, unlikely suggested by guidelines, are not significant drivers of therapy in the real life setting of our study.

Patients with castration-resistant prostate cancer are burdened not only with an unavoidable risk of mortality but also by severe mobility issues. This disease has a high tendency to induce bone metastases with concomitant general suffering, impaired mobility, and reduced self-sufficiency. The treatment of bone pain consists of opioids, nonsteroidal anti-inflammatory drugs, radiopharmaceuticals, and radiotherapy. To date, abiraterone, enzalutamide, zoledronate and denosumab are the only drugs able to delay skeletal events, and docetaxel is the only chemotherapeutic agent able to prolong survival after castration progression. Recently, 5 new drugs have proven to be efficacious in prolonging survival. Sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium-223 have broadened the therapeutic choices, thus changing the clinical paradigm. This review analyzes the data supporting the use of all presently available therapeutic approaches for the management of pain, skeletal events, and survival in castration-resistant prostate cancer patients with bone metastases. Data based on phase 3 trials could identify new approaches depending on patient, disease, and therapy characteristics., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Antiphospholipid syndrome (APS) is characterized by the presence circulating antiphospholipid (aPL) antibodies in patients with thrombosis or pregnancy morbidity. Recently it has been shown that multiple positive results define a higher risk of clinical manifestation in APS patients. However, utilizing combined results generates challenges for a physician. Therefore, the antiphospholipid score. (aPL-S), a new variable that encompasses all aPL assays, has been described. We analyze clinical performance of different aPL-Ss based on ELISA or chemiluminescent immunoassays (CIAs)., Methods: A total of 39 patients and 77 controls were included in this study. All patients were tested for lupus anticoagulant (LAC). In addition, IgM/IgG anticardiolipin (aCL) and anti-β2 glycoprotein 1 (aβ2GP1) autoantibodies were tested by ELISA and CIA. Anti-β2GP1 Domain 1 IgG (D1) autoantibodies were tested by CIA. Three aPL-Ss were calculated (ELISA, CIA and CIA with D1 instead of β2GP1 IgG) using the Otomo equation: aPL-S=5×exp([OR]-5)/4., Results: IgG assays showed a good correlation while IgM assays showed moderate correlation. The relative risk of having clinical manifestation of APS was calculated for each aPL test. All three aPL-Ss were higher in individuals with thrombosis or pregnancy morbidity than in those without APS manifestations (p<0.001) and the prevalence of APS manifestations increased with increasing aPL-Ss., Conclusion: The CIAs are comparable with the ELISAs for the detection of aPL antibodies. aβ2GPI-D1 antibodies seem to represent a strong indicator for clinical manifestations of APS. Any of the aPL-Ss studied represents a useful quantitative index for APS diagnosis and could be helpful to physicians in managing APS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Interleukin 27 (IL-27) has pleiotropic properties that can either limit or enhance immune responses. Recent studies revealed that single nucleotide polymorphisms (SNPs) of the IL-27 promoter region modulate the development of infectious diseases and individual's susceptibility to therapeutic response. Little is known about the relationship between IL-27 single nucleotide polymorphisms and therapy response in patients infected by hepatitis C virus (HCV). In this study we have investigated the potential role of SNPs in the promoter region of IL27 p28 gene (alleles rs153109) on the outcome of HCV infected patients., Methods: rs153109, corresponding to position c.-964A>G of the IL-27 locus, was amplified from genomic DNA extracted from 15 patients with chronic hepatitis C stratified by sustained viral response (SVR), relapser and non-responder, after treatment with peginterferon-α (PegIFN- α) combined with ribavirin (RBV). Amplification products were studied by direct sequencing., Results: This method has been applied in a preliminary study on patients with chronic hepatitis C to provide information for a standardized assay useful to genotyping of rs153109 SNPs of IL-27p28. The genotype distribution of the c.-964 A>G polymorphism was more present in patients who did not achieve a SVR. By contrast, the genotype G/G was absent in non-responder and relapser patients. Moreover, the analysis of allelic distribution of rs153109 highlighted a predominance of allele A in all genotypes in spite of allele G., Conclusions: Our work provides preliminary information for a standardized method potentially useful for genotyping rs153109, and suggests its utility as a candidate approach to evaluate IL-27 p28 polymorphisms as additional clinical predictors of response to therapies in HCV infected patients.

Recent therapeutic advances have changed the treatment landscape of metastatic renal cell carcinoma. Unfortunately, the seven agents now available are not based on biomarkers that would indicate which one could provide the best benefit for every patient. We have reviewed the avaliable information concerning the impact of each treatment on comorbidities or status that are frequently seen before commencing treatment for the advanced disease: elderly and patients with cardiovascular complications, metabolic and endocrinology disorders, and infections, as well as impaired organ function (kidney, liver and heart). Additional new drugs will be launched, but no predictive biomarkers are available. Head-to-head studies to evaluate the safety of the different drugs are rare. In this quite complex scenario, we believe that a decision-making approach focused on the patient may represent a suitable strategy.

Hyperglycerolemia is a very rare genetic disorder caused by glycerol kinase deficiency. Although usually is presented unexpectedly in routine checks, there are severe forms, especially in children. In general, glycerol and glycerol kinase activity analyses are not included in routine laboratory determination. Glycerol presents positive interferences with some biochemical analytic techniques, e.g. in serum triglycerides and plasma ethylene glycol levels assays. Here, we report a Spanish patient with a pseudo-hypertriglyceridaemia, a falsely elevated triglycerides concentration that was not corrected with lipid-lowering therapy for 3 years., (Copyright © 2013 Elsevier España, S.L. and SEA. All rights reserved.)

Background: Chronic Obstructive Pulmonary Disease (COPD) is often associated with comorbidities, especially cardiovascular, that have a heavy burden in terms of hospitalization and mortality. Since no conclusive data exist on the prevalence and type of comorbidities in COPD patients in Italy, we planned the INDACO observational pilot study to evaluate the impact of comorbidities in patients referred to the outpatient wards of four major hospitals in Rome., Methods: For each patient we recorded anthropometric and anamnestic data, smoking habits, respiratory function, GOLD (Global initiative for chronic Obstructive Lung Disease) severity stage, Body Mass Index (BMI), number of acute COPD exacerbations in previous years, presence and type of comorbidities, and the Charlson Comorbidity Index (CCI)., Results: Here we report and discuss the results of the first 169 patients (124 males, mean age 74±8 years). The prevalence of patients with comorbidities was 94.1% (25.2% of cases presented only one comorbidity, 28.3% two, 46.5% three or more). There was a high prevalence of arterial hypertension (52.1%), metabolic syndrome (20.7%), cancers (13.6%) and diabetes (11.2%) in the whole study group, and of anxiety-depression syndrome in females (13%). Exacerbation frequency was positively correlated with dyspnea score and negatively with BMI. Use of combination of bronchodilators and inhaled corticosteroids was more frequent in younger patients with more severe airways obstruction and lower CCI., Conclusions: These preliminary results show a high prevalence of comorbidities in COPD patients attending four great hospitals in Rome, but they need to be confirmed by further investigations in a larger patients cohort.

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated in multiple cancers including ovarian carcinoma (OC). However, the relative contribution of the single components within the PI3K pathway to AKT activation in OC is still unclear. We examined 98 tumor samples from Italian OC patients for alterations in the members of the PI3K pathway. We report that AKT is significantly hyperactive in OC compared to normal tissue (n = 93; p<0.0001) and that AKT activation is preferentially observed in the elderly (>58 years old; n = 93; p<0.05). The most frequent alteration is the overexpression of the p110α catalytic subunit of PI3K (63/93, ∼68%); less frequent alterations comprise the loss of PTEN (24/89, 27%) and the overexpression of AKT1 (18/96, 19%) or AKT2 (11/88,12.5%). Mutations in the PIK3CA or KRAS genes were detected at lower frequency (12% and 10%, respectively) whereas mutations in AKT1 or AKT2 genes were absent. Although many tumors presented a single lesion (28/93, of which 23 overexpressed PIK3CA, 1 overexpressed AKT and 4 had lost PTEN), many OC (35/93) presented multiple alterations within the PI3K pathway. Apparently, aberrant PI3K signalling was mediated by activation of the canonical downstream AKT-dependent mTOR/S6K1/4EBP1 pathway and by regulation of expression of oncogenic transcription factors that include HMGA1, JUN-B, FOS and MYC but not by AKT-independent activation of SGK3. FISH analysis indicated that gene amplification of PIK3CA, AKT1 and AKT2 (but not of PI3KR1) and the loss of PTEN are common and may account for changes in the expression of the corresponding proteins. In conclusion, our results indicate that p110α overexpression represents the most frequent alteration within the PI3K/AKT pathway in OC. However, p110α overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration.

Background: Open colorectal cancer (CRC) surgery induces severe and prolonged postoperative pain. The optimal method of postoperative analgesia in CRC surgery has not been established. We evaluated the efficacy of preperitoneal continuous wound infusion (CWI) of ropivacaine for postoperative analgesia after open CRC surgery in a multicenter randomized controlled trial., Methods: Candidates for open CRC surgery randomly received preperitoneal CWI analgesia or continuous epidural infusion (CEI) analgesia with ropivacaine 0.2% 10 mL/h for 48 hours after surgery. Fifty-three patients were allocated to each group. All patients received patient-controlled IV morphine analgesia., Results: Over the 72-hour period after the end of surgery, CWI analgesia was not inferior to CEI analgesia. The difference of the mean visual analog scale score between CEI and CWI patients was 1.89 (97.5% confidence interval = -0.42, 4.19) at rest and 2.76 (97.5% confidence interval = -2.28, 7.80) after coughing. Secondary end points, morphine consumption and rescue analgesia, did not differ between groups. Time to first flatus was 3.06 ± 0.77 days in the CWI group and 3.61 ± 1.41 days in the CEI group (P = 0.002). Time to first stool was shorter in the CWI than the CEI group (4.49 ± 0.99 vs 5.29 ± 1.62 days; P = 0.001). Mean time to hospital discharge was shorter in the CWI group than in the CEI group (7.4 ± 0.41 and 8.0 ± 0.38 days, respectively). More patients in the CWI group reported excellent quality of postoperative pain control (45.3% vs 7.6%). Quality of night sleep was better with CWI analgesia, particularly at the postoperative 72-hour evaluation (P = 0.009). Postoperative nausea and vomiting was significantly less frequent with CWI analgesia at 24 hours (P = 0.02), 48 hours (P = 0.01), and 72 hours (P = 0.007) after surgery evaluations., Conclusions: Preperitoneal CWI analgesia with ropivacaine 0.2% continuous infusion at 10 mL/h during 48 hours after open CRC surgery provided effective postoperative pain relief not inferior to CEI analgesia.

Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs (miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene expression by targeting protein-coding mRNAs. However, miRNAs involvement in the regulation of the epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here, we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in MM cells. Moreover, we show that miR-29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA methylation in MM cells. In vitro transfection of MM cells with synthetic miR-29b mimics significantly impairs cell cycle progression and also potentiates the growth-inhibitory effects induced by the demethylating agent 5-azacitidine. Most importantly, in vivo intratumor or systemic delivery of synthetic miR-29b mimics, in two clinically relevant murine models of human MM, including the SCID-synth-hu system, induces significant anti-tumor effects. All together, our findings demonstrate that aberrant DNMTs expression is efficiently modulated by tumor suppressive synthetic miR-29b mimics, indicating that methyloma modulation is a novel matter of investigation in miRNA-based therapy of MM.

Background: Mycetoma is generally understood to be a chronic suppurative infection involving the skin and the underlying tissue. Mycetomas may be classified as those produced by true fungi (eumycetoma) versus those due to aerobic bacteria Actinomycetales (actinomycetoma)., Methods: We report the atypical case of a mycetomatoid infection of the penile shaft and glans in a 36-year-old man, originally from Senegal, affected by Takayasu's arteritis., Results: Extensive investigations excluded any other causative pathogen other than Candida albicans, and the ailment accordingly healed after fluconazole monotherapy., Conclusion: The authors discuss the unusual site of the disease and the singular clinical features related to the fungal etiology and put forward considerations on the pathogenic role of common microorganisms., (© 2012 The International Society of Dermatology.)

The aim of the present work was to identify protein tyrosine phosphatases (PTPs) as novel, candidate tumor suppressor genes in lung cancer. Among the 38 PTPs in the human genome that show specificity for phosphotyrosine, we identified six PTPs by quantitative RT-PCR whose mRNA expression levels were significantly down-regulated in lung cancer-derived cell lines (ie, PTPRE, PTPRF, PTPRU, PTPRK, PTPRD, and PTPN13). After validation in primary samples of non-small cell lung cancer (NSCLC), we selected PTPN13 for further studies. The results presented here demonstrate that PTPN13 is a candidate tumor suppressor gene that is frequently inactivated in NSCLC through the loss of either mRNA and protein expression (64/87, 73%) or somatic mutation (approximately 8%). Loss of PTPN13 expression was apparently due to the loss of one or both copies of the PTPN13 locus at 4q (approximately 26% double deletion and approximately 37% single deletion) but not to promoter methylation. Finally, the manipulation of PTPN13 expression in lung cancer cells (ie, NCI-H292, A549) demonstrated that PTPN13 negatively regulates anchorage-dependent and anchorage-independent growth in vitro and restrains tumorigenicity in vivo, possibly through the control of the tyrosine phosphorylation of both EGFR and HER2. In conclusion, the expression screening of PTPs in lung cancer reported here has identified PTPN13 as a novel candidate tumor suppressor in NSCLC whose loss increases signaling from epidermal growth factor receptor and HER2 tyrosine kinase receptors., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Aberrant activation of PI3K/AKT signalling represents one of the most common molecular alterations in lung cancer, though the relative contribution of the single components of the cascade to the NSCLC development is still poorly defined. In this manuscript we have investigated the relationship between expression and genetic alterations of the components of the PI3K/AKT pathway [KRAS, the catalytic subunit of PI3K (p110α), PTEN, AKT1 and AKT2] and the activation of AKT in 107 surgically resected NSCLCs and have analyzed the existing relationships with clinico-pathologic features. Expression analysis was performed by immunohistochemistry on Tissue Micro Arrays (TMA); mutation analysis was performed by DNA sequencing; copy number variation was determined by FISH. We report that activation of PI3K/AKT pathway in Italian NSCLC patients is associated with high grade (G3-G4 compared with G1-G2; n = 83; p<0.05) and more advanced disease (TNM stage III vs. stages I and II; n = 26; p<0.05). In addition, we found that PTEN loss (41/104, 39%) and the overexpression of p110α (27/92, 29%) represent the most frequent aberration observed in NSCLCs. Less frequent molecular lesions comprised the overexpression of AKT2 (18/83, 22%) or AKT1 (17/96, 18%), and KRAS mutation (7/63, 11%). Our results indicate that, among all genes, only p110α overexpression was significantly associated to AKT activation in NSCLCs (p = 0.02). Manipulation of p110α expression in lung cancer cells carrying an active PI3K allele (NCI-H460) efficiently reduced proliferation of NSCLC cells in vitro and tumour growth in vivo. Finally, RNA profiling of lung epithelial cells (BEAS-2B) expressing a mutant allele of PIK3 (E545K) identified a network of transcription factors such as MYC, FOS and HMGA1, not previously recognised to be associated with aberrant PI3K signalling in lung cancer.

Recent findings have disclosed the role of UDP-glucuronosyltransferase (UGT) 1A1*28 on the haematological toxicity induced by irinotecan (CPT-11), a drug commonly used in the treatment of metastatic colorectal cancer (mCRC). We investigated the pharmacogenomic profile of irinotecan-induced gastrointestinal (GI) toxicity by the novel drug-metabolizing enzyme and transporter (DMET) microarray genotyping platform. Twenty-six mCRC patients who had undergone to irinotecan-based chemotherapy were enrolled in a case (patients experiencing ≥ grade 3 gastrointestinal, (GI) toxicity) - control (matched patients without GI toxicity) study. A statistically significant difference of SNP genotype distribution was found in the case versus control group. The homozygous genotype C/C in the (rs562) ABCC5 gene occurred in 6/9 patients with GI toxicity versus 1/17 patients without GI toxicity (P=0.0022). The homozygous genotype G/G in the (rs425215) ABCG1 was found in 7/9 patients with GI toxicity versus 4/17 patients without GI toxicity (P=0.0135). The heterozygous genotype G/A in the 388G>A (rs2306283) OATP1B1/SLCO1B1 was found in 3/9 patients with grade ≥ 3 GI toxicity vs. 14/17 patients without GI toxicity (P=0.0277). DNA extracted from peripheral blood cells was genotyped by DMET Plus chip on Affymetrix array system. Genotype association was calculated by Fisher's exact test (two tailed) and relevant SNPs were further analyzed by direct sequencing. We have identified 3 SNPs mapping in ABCG1, ABCC5 and OATP1B1/SLCO1B1 transporter genes associated with GI toxicity induced by irinotecan in mCRC patients expanding the available knowledge of irinogenomics. The DMET microarray platform is an emerging technology for easy identification of new genetic variants for personalized medicine.