Search

Background The Oesophago-Gastric Anastomosis Audit (OGAA) is an international collaborative group set up to study anastomotic leak outcomes after oesophagectomy for cancer. This Delphi study aimed to prioritize future research areas of unmet clinical need in RCTs to reduce anastomotic leaks. Methods A modified Delphi process was overseen by the OGAA committee, national leads, and engaged clinicians from high-income countries (HICs) and low/middle-income countries (LMICs). A three-stage iterative process was used to prioritize research topics, including a scoping systematic review (stage 1), and two rounds of anonymous electronic voting (stages 2 and 3) addressing research priority and ability to recruit. Stratified analyses were performed by country income. Results In stage 1, the steering committee proposed research topics across six domains: preoperative optimization, surgical oncology, technical approach, anastomotic technique, enhanced recovery and nutrition, and management of leaks. In stages 2 and stage 3, 192 and 171 respondents respectively participated in online voting. Prioritized research topics include prehabilitation, anastomotic technique, and timing of surgery after neoadjuvant chemo(radio)therapy. Stratified analyses by country income demonstrated no significant differences in research priorities between HICs and LMICs. However, for ability to recruit, there were significant differences between LMICs and HICs for themes related to the technical approach (minimally invasive, width of gastric tube, ischaemic preconditioning) and location of the anastomosis. Conclusion Several areas of research priority are consistent across LMICs and HICs, but discrepancies in ability to recruit by country income will inform future study design.

Background Hepatitis B vaccination has proven to be very safe and highly effective. This study assessed the proportion of successfully vaccinated individuals among cases with acute hepatitis B, the proportion of preventable cases if individuals were vaccinated as recommended, and the reasons for failures. Methods We analyzed data reported to the Italian Surveillance System for Acute Viral Hepatitis from 1993 to 2014. Results A total of 362 of 11 311 (3.2%) cases with acute hepatitis B were vaccinated. Of the 277 cases for whom immunization data were available, 50 (18%) received a complete vaccination course according to the correct schedule and before exposure to hepatitis B virus. Molecular characterization of 17 of these cases showed that 6 were infected with S-gene mutants. Among the 10 949 unvaccinated cases, 213 (1.9%) escaped mandatory vaccination and 2821 (25.8%) were not vaccinated despite being at increased risk of infection. Among the latter, the most common risk factors were cohabitation with hepatitis B surface antigen (HBsAg) carriers, intravenous drug use, and homosexual/bisexual practices. Thirty-seven percent of the unvaccinated households with HBsAg carriers were aware of their risk. Lack of trust in the vaccination, negative attitude, and inaccurate beliefs followed by lack of or poor communication and low perceived severity of the disease were the most frequent reasons for vaccine hesitancy. Conclusions Development of acute disease in successfully vaccinated individuals is a rare event. Further efforts are needed to enhance the vaccine coverage rate in individuals at increased risk of infection.

Due to the lack of experimental measurements, biological variability and experimental errors, the value of many parameters of the systems biology mathematical models is yet unknown or uncertain. A possible computational solution is the parameter estimation, that is the identification of the parameter values that determine the best model fitting respect to experimental data. We have developed an experiment to distribute each run of the parameter estimation algorithm on a different computational resource. The key feature of the implementation is a relational database that allows the user to swap the candidate solutions among the working nodes during the computations. The comparison of the distributed implementation with the parallel one showed that the presented approach enables a faster and better estimation of systems biology models.

Lithium clearance (CLi) was studied in the healthy subjects (H) and in patients with chronic renal failure (CRF) with a mean GFR of 36.08 +/- 3.8 ml/min x 1.73 m2 in order to evaluate (1) the variability of CLi measurements; (2) the changes of CLi during the hyperfiltration response to a meat meal (2 g/kg b.w. of protein), and (3) the effects on CLi of different protein intakes. CLi correlated with GFR and with urinary sodium, FeLi correlated with FeNa in H and CRF. The intraindividual standard deviation (IISD) of GRF, CLi and FeLi assessed in triplicate studies in the course of a single experiment averaged 4.70, 7.15 and 10.69% in CRF and 1.77, 4.09 and 4.61% in H. When IISD for GFR, CLi, and FeLi was assessed in triplicate measurements in the course of 3 studies performed at 1-week intervals (day 1, day 8, day 15), it averaged 7.36, 9.21 and 15.72% in CRF and 1.83, 5.08 and 5% in H. During the hyperfiltration response to a meat meal, CLi and FeLi did not change in CRF and increased significantly in H. In 10 patients with CRF who were switched for 3 weeks from a protein intake of 0.85 g/kg to a protein intake of 0.60 g/kg, GFR was significantly (p less than 0.001) reduced by 29%, while CLi was stable. The data indicate that because of its variability, CLi is of little use in experiments designed to study subtle changes in renal Na transport.

The main procedures involved in the electrophysiological investigation of the visual tract are (Alfieri et al., 1970): 1. the electroretinogram (ERG) which demonstrates the activity of the photoreceptors and bipolar cells; this examination conducted in monochromatic light (Sole, 1965) makes it possible to study individually the photopic system in red stimulation (ERG-r) and the scotopic system in blue stimulation (ERG-b); 2. the visual evoked response (VER) which, in our point of view, essentially reflects the permeability of the visual pathways from the ‘optic nerve’ link to the ‘visual cortex’. Such an examination carried out in monochromatic light (Plane, 1969 and Rigal, 1970) allows an individual study of the conduction systems: the macular ones (central cones) in red stimulation (VER-r) on the one hand, and the extramacular ones (peripheral cones and rods) in blue stimulation (VER-b) on the other hand.

Ten patients with chronic renal failure (GFR 29-97 ml/min), on free diets providing 1 g/kg B.W. of proteins, ingested an oral protein load (meat meal, 2 g/kg B.W.). GFR and RPF increased significantly over baseline with no change in filtration fraction. Within 30 min of the meal and for the next 3 h a statistically significant increase was observed in the plasma concentrations of the following amino acid groups: essential, non-essential, total, branched-chain, ketogenic, glycogenic, glycogenic and ketogenic, basic, acid, polar and non-polar. At 30 min the smallest increase was seen in acid and polar amino acids (6.7% and 7.6%, respectively). At 180 min the largest increase (78.8%) was seen for glycogenic and ketogenic amino acids and total plasma amino acids were 1.58 times baseline. After the meat meal plasma glucagon and insulin rose significantly, while growth hormone, plasma renin activity and aldosterone did not vary.

A survey network for congenital toxoplasmosis (TOXO-NET) was set up in December 1996 in Piedmont (Italy). Participants were asked to classify the infections in pregnant mothers and newborns by the criteria of the European Network on Congenital Toxoplasmosis published by Lebech in 1996. Because the IgG Avidity test is largely employed as a 2nd level test in toxoplasmosis diagnosis and it could be helpful to date infection, the co-ordinators of TOXO-NET suggested including it in the "case definition" of "probable" infection and "unlikely" infection. 117 cases of toxoplasmosis in pregnancy divided into the risk categories under Lebech's criteria were re-examined using the "new" case definitions. 77 out of 117 (65.8%) Toxoplasma gondii infections during pregnancy could be defined with only one serum sample using the IgG Avidity test. The IgG Avidity test proved a useful method to classify the Toxoplasma gondii infections in pregnancy, especially when we had only one serum sample.

The purpose of this study was to verify the statistical validity of the score proposed by Thomé et al. for the differential diagnosis between bacterial and viral meningitis and to study the utility of two new parameters (CRP and the patient's age). A retrospective review of 136 consecutive cases of meningitis was made. The cases were classified into three groups according to the culture results and the use or not of intravenous antibiotics. There were 20 cases of bacterial meningitis, 60 non-bacterial and 56 cases of meningitis of uncertain etiology. Considering only the patients in the first two groups, the capacity for differential diagnosis between bacterial and non-bacterial meningitis of the 8 parameters in the original score, the CRP and the patient's age was analyzed with a numeric value of 0, 1, or 2 assigned to each parameter. Finally, the results of applying the score that includes the two new parameters with the original score are compared. We found that all parameters showed statistical significance for the differential diagnosis between bacterial and viral meningitis. The resulting score can be used in order to decide the need for intravenous antibiotic therapy, with only a few cases being uncertain. The score with the two new parameters correctly classified 78 of the 80 cases, while leaving only two case uncertain as compared to the four that remained unclassified with the original score. We conclude that the score is a useful instrument in the differential diagnosis between bacterial and viral meningitis. Furthermore, the introduction of CRP and the patient's age improves the diagnostic value of the test.

One of the fundamental concepts in Grid computing is the creation of Virtual Organizations (VO's): a set of resource consumers and providers that join forces to solve a common problem. Typical examples of Virtual Organizations include collaborations formed around the Large Hadron Collider (LHC) experiments. To date, Grid computing has been applied on a relatively small scale, linking dozens of users to a dozen resources, and management of these VO's was a largely manual operation. With the advance of large collaboration, linking more than 10000 users with a 1000 sites in 150 counties, a comprehensive, automated management system is required. It should be simple enough not to deter users, while at the same time ensuring local site autonomy. The VO Management Service (VOMS), developed by the EU DataGrid and DataTAG projects[1, 2], is a secured system for managing authorization for users and resources in virtual organizations. It extends the existing Grid Security Infrastructure[3] architecture with embedded VO affiliation assertions that can be independently verified by all VO members and resource providers. Within the EU DataGrid project, Grid services for job submission, file- and database access are being equipped with fine- grained authorization systems that take VO membership into account. These also give resource owners the ability to ensure site security and enforce local access policies. This paper will describe the EU DataGrid security architecture, the VO membership service and the local site enforcement mechanisms Local Centre Authorization Service (LCAS), Local Credential Mapping Service(LCMAPS) and the Java Trust and Authorization Manager., Talk from the 2003 Computing in High Energy and Nuclear Physics (CHEP03), La Jolla, Ca, USA, March 2003, 7 pages, LaTeX, 5 eps figures. PSN TUBT005

Esophageal carcinosarcoma (ESC) is a rare malignant lesion of the esophagus with controversial characteristics and prognostic factors.Seventeen consecutive patients with esophageal carcinosarcoma were referred to the Center for Esophageal Diseases located in Padua from January 1, 1980 to December 31, 2011. Clinical characteristics, pathological features, treatment and outcome were retrospectively analyzed in a prospectively collected database.Five patients received palliative treatment and one refused surgery; they died of unresected tumor or progression of disease within 0.6-43.5 months after diagnosis. Eleven patients underwent surgical treatment with complete tumor resection; recurrence rate was 80%, leading to death within 2 years after surgery. Only two resected patients are currently alive and free of disease over 20 years after surgery.Our results did not support the better prognosis concept of esophageal carcinosarcoma and suggested the importance of radical esophagectomy with adequate lymph node dissection.

The importance of the immune system as a potent anti-tumor defense has been consolidated in recent times, and novel immune-related therapies are today demonstrating a strong clinical benefit in the setting of several solid neoplasms. Tumor-infiltrating lymphocytes reflect the attempt of the host to eradicate malignancies, and during the last decades, they have been shown to possess an interesting prognostic utility for breast cancer, especially in case of HER2 positive and triple-negative molecular subtypes. In parallel, the clinical evaluation of tumor-infiltrating lymphocytes has been shown to effectively predict treatment outcomes in both neoadjuvant and adjuvant settings. Currently, tumor-infiltrating lymphocytes are promising further predictive utility in view of novel immune-related therapeutic strategies which are coming into the clinical setting launching a solid rationale for the future next-generation treatment options. In this scenario, tumor-infiltrating lymphocytes might represent an important resource for the selection of the most appropriate therapeutic strategy, as well as further evaluations of the molecular mechanisms underlying tumor-infiltrating lymphocytes and the immunoediting process would eventually provide new insights to augment therapeutic success. Considering these perspectives, we review the potential utility of tumor-infiltrating lymphocytes in the definition of breast cancer prognosis and in the prediction of treatment outcomes, along with the new promising molecular-based therapeutic discoveries.

The nonparametric combination of dependent permutation tests method is a useful general tool when a testing problem can be broken down into a set of different k > 1 partial tests. These partial tests, after adjustment of p-values to control for multiplicity, can be marginally analyzed, but jointly considered they can provide information on an overall hypothesis, which might represent the true goal of the testing problem. On the one hand, independence among the partial tests is usually an unrealistic assumption; on the other, even when the underlying dependence relations are known quite often they are difficult to cope with properly. Therefore this combination must be achieved nonparametrically, by implicitly taking into account the dependence structure of tests without explicitly describing it. An important property of the tests based on nonparametric combination methodology, when the number of response variables is high compared to the sample sizes, consists in the finite sample consistency. A practical problem involves choosing the most suitable combining function for each specific testing problem given that the final result can be affected by this crucial choice. The purpose of this article is to present an nonparametric combination solution based on the iterated combination of partial tests, evaluate its power behavior using a Monte Carlo simulation study and apply it to a real medical problem, namely the evaluation of the effects of chemotherapy on the shape of esophageal tumors. R code has been implemented to carry out the analyses.

Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATPcompetitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)- N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.

Ten patients with chronic renal failure (GFR 29–97 ml/min), on free diets providing 1 g/kg B.W. of proteins, ingested an oral protein load (meat meal, 2 g/kg B.W.). GFR and RPF increased significantly over baseline with no change in filtration fraction. Within 30 min of the meal and for the next 3 h a statistically significant increase was observed in the plasma concentrations of the following amino acid groups: essential, nonessential, total, branched-chain, ketogenic, glycogenic, glycogenic and ketogenic, basic, acid, polar and non-polar. At 30 min the smallest increase was seen in acid and polar amino acids (6.7% and 7.6%, respectively). At 180 min the largest increase (78.8%) was seen for glycogenic and ketogenic amino acids and total plasma amino acids were 1.58 times baseline. After the meat meal plasma glucagon and insulin rose significantly, while growth hormone, plasma renin activity and aldosterone did not vary.

A growing body of evidence suggests that ribosome-inactivating proteins (RIPs) remove adenine moieties not only from rRNA, but also from DNA – an effect leading to DNA damage in cultured cells. We herein report that two distinct RIPs of bacterial (shiga toxin 1, Stx1) and plant (ricin) origin, inhibit the repair of the DNA lesions generated by hydrogen peroxide in cultured human cells. This effect is unrelated either to inhibition of protein synthesis or to depletion of cellular antioxidant defenses and is likely to derive from direct interactions with cellular DNA repair machinery. Therefore, the genotoxicity of these toxins on mammalian cells seems to be a complex phenomenon resulting from the balance between direct (DNA damaging activity), indirect (DNA repair inhibition) effects and the eventual presence of other DNA damaging species. In particular, with regard to Stx1, it could be hypothesized that Stx-producing bacteria increase the risk of transformation of surrounding, inflamed tissues in the course of human infections.

Oral administration of arginine to remnant (REM) rats (5/6 nx) slows the progression of chronic renal failure through a nitric-oxide(NO)-dependent mechanism. We have recently shown that inhibition of arginase, the main metabolic pathway of arginine, was able to induce similar results on renal dynamics (GIN: 2001, 18:285-290). Aim of the present study was to test whether these changes were mediated by increased availability of arginine-derived NO. Methods. Three Groups of REM rats were studied for 8 weeks after surgery: 1) untreated REM (Group REM); 2) REM rats treated with arginine (1%) in tap water (Group ARG); 3) REM rats administered a Mn++-free diet, to induce partial inhibition of arginase (Group MNF). Normal unmanipulated rats were used as controls (Group NOR).Liver arginase activity was significantly depressed only in MNF-rats (-35% vs. REM, p0.01). Blood pressure was significantly lower in Group MNF vs. ARG and REM after 6 weeks (p0.05). Proteinuria was significantly decreased in Group ARG (-42%, p0.05 vs. REM) and even more in Group MNF (-57%, p0.01). ARG plasma levels, decreased in REM rats (-41% vs. Group CON), were normalized in Group ARG (p0.01 vs. Group REM); arginase inhibition was able to increase such levels in Group MNF (+38% vs. REM) and this resulted in a proportional rise in urinary nitrite excretion (+33% vs. REM), grossly depressed in REM rats. Renal arginase activity was lower in all the Groups of remnant rats vs. Group NOR, but intrarenal concentrations of ARG were significantly lower only in rats of Group MNF (p0.05 vs. all the other Groups). Histological examination showed that MNF-rats had a glomerular sclerosis index lower than in the other Groups (p0.05 vs. Group REM and ARG).In conclusion, inhibition of arginase in remnant rats slows the progression of CRF and preserves renal histology through a direct and/or indirect NO-dependent mechanism.

The work was designed to study the effects of a meat meal on glomerular filtration rate (GFR), renal plasma flow (RPF), and plasma concentrations of glucagon, insulin, growth hormone, renin, aldoster-one, total amino acids, and NH3 in healthy humans (H) as well as in patients with Child A liver cirrhosis (LC). The meat meal produced renal hyperaemia and hyperfiltration without changes in the filtration fraction. Fractional Na excretion in urine increased significantly after the meat meal only in LC. Hyperinsulinae-mia and hyperglucagonaemia were seen at baseline in LC and were not affected by the meat meal, whereas in H glucagon concentration increased significantly over baseline within 30 min from the meat meal and insulin within 60 min. Growth hormone concentration was normal at baseline in LC and increased significantly 120–180 min after the meal, whereas it was not affected in H. Renin and aldosterone were stable in both H and LC. Plasma amino acid concentration began to increase 60 min after the meat meal, when hyperfiltration was present. The data indicate that in human Child A cirrhosis of the liver the renal haemodynamic response to a meat meal is independent of changes in glucagon.

Very-low-calorie diets (less than 500 kcal/day; VLCD) are widely used for the treatment of severe obesity. We report the effects of such diets, consisting of proteins only or proteins and carbohydrates (CH), on nitrogen balance and protein nutritional status of morbidly obese patients. Cumulative nitrogen loss, serum albumin, transferrin, prealbumin (PA) and retinol-binding protein (RBP) concentrations, and plasma amino acid profile were determined in two groups of obese patients: 5 subjects (3 women, 2 men: BMI 55.3 +/- 2.2 kg/m2) subjected for 4 weeks to a protein VLCD (40 g protein + 2 g fat) and 7 others (4 women, 3 men: BMI 45.6 +/- 2.8 kg/m2) received for the same length of time a protein + CH VLCD (34 g protein + 26 g CH). Nitrogen balance was determined weekly whilst plasma and serum variables were measured on days 0, 3, 5, 10, 20 and 28 of treatment. Nitrogen balance did not significantly differ between the two groups of patients throughout the treatment. Serum PA and RBP concentrations decreased from day 5 and day 10, respectively, in both groups. Plasma amino acids showed a similar pattern in the protein and protein + CH groups. Alanine gradually decreased below baseline values; after a peak value on day 5, branched-chain amino acids (valine, leucine, isoleucine) returned to baseline values in both groups. In conclusion, in severely obese patients subjected to VLCD, nitrogen balance, labile protein concentrations and plasma amino acid profile are not significantly affected by adding CH to proteins.

Adequate assessment of cardiac function in patients who have undergone open intracardiac operations requires determination of cardiac output. Electric impedance technique of determining cardiac output in intensive care unit is presented. Routine measurement of cardiac output in the immediate postoperative period has allowed important innovations in the care of the patients: a) preclinical diagnosis of low cardiac output and prophylactic treatment, b) artificial pacing at optimal rate, c) accurate assessment of the effectiveness of the treatment measures.

Exogenous arginine slows the progression of chronic renal failure (CRF) in remnant rats through a nitric oxide (NO)-dependent mechanism. We tested whether the inhibition of arginase could induce similar results through the increased availability of endogenous arginine. Three groups of remnant rats were studied for 8 wk: 1) untreated rats (REM); 2) remnant rats treated with 1% l-arginine (ARG); and 3) remnant rats administered a Mn2+-free diet to inhibit arginase (MNF). Normal rats (NOR) were used as controls. Liver arginase activity was depressed in MNF rats (−35% vs. REM, P < 0.01). No difference in metabolic data was detected among the groups throughout the study; blood pressure was significantly lower in MNF vs. ARG and REM rats after 6 wk ( P < 0.001). The glomerular filtration rate (GFR) was greatly depressed in REM rats (−47% vs. NOR, P < 0.03) but was higher in ARG and MNF rats (+40 and +43% vs. REM, respectively, P < 0.05), with comparable changes in renal hemodynamics. Despite the better GFR, proteinuria was decreased in both ARG and MNF rats (−42%, P < 0.05, and −57%, P < 0.01, respectively, vs. REM rats). Arginine plasma levels, significantly reduced in REM rats (−41% vs. NOR, P < 0.01), were partially restored in MNF rats (+38% vs. REM), and urinary nitrite excretion, greatly depressed in REM rats (−76% vs. NOR, P < 0.01), was significantly increased in MNF rats (+209% vs. REM, P < 0.05). At the renal level, arginase activity was only slightly depressed in MNF rats (−18% vs. REM), but intrarenal concentrations of arginine were lower in this latter group ( P < 0.05 vs. other groups). Beyond the hemodynamic modifications, MNF rats showed a lower glomerular sclerosis index ( P < 0.05 vs. REM and ARG). Inhibition of arginase slows the progression of CRF in remnant rats similarly to arginine-treated rats; the better histological protection in MNF rats, however, suggests that additional factors are involved in these modifications.

Conventional chemotherapeutic regimens have reached an efficacy plateau against most solid tumors and deal with significant toxicity. Recently, the goal of oncologic research to improve outcome and reduce treatment-related side-effects has led to the development of novel anticancer treatments targeting specific proteins or genes involved in cancer growth and progression. In particular, the tyrosine- kinase inhibitors (TKIs) gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) have been approved for the treatment of non-small-cell lung cancer (NSCLC). Their clinical activity has been related to different clinical and biological parameters, such as the presence of activating mutations in the kinase domain of the target. Disappointingly, their clinical efficacy is limited by the development of resistance which is caused in more than 50% of the cases by the emergence of a secondary point-mutation (T790M) in the ATP-binding cleft of EGFR. Several novel EGFR inhibitors, able to covalently bind the target and prolong its inactivation, have been developed with the aim to overcome such resistance and are evaluated in ongoing clinical studies. However, not all clinical outcomes, including tolerability, are explained, and the identification/validation of novel biomarkers of sensitivity or resistance to such agents is a viable area of research to improve their clinical use. This review summarizes the current knowledge on the functional role of activating mutations of EGFR, pivotal primary/acquired resistance mechanisms as well as clinical data of small molecule EGFR-TKIs, and discusses the future of such therapeutic approach in NSCLC. © 2013 Bentham Science Publishers.