International validation of a risk prediction algorithm for patients with malignant colorectal polyps.

AIM: The optimal management strategy for patients with endoscopically resected malignant colorectal polyps (MCP) has yet to be defined. The aim of this study was to validate a published decision-making tool, termed the Scottish Polyp Cancer Study (SPOCS) algorithm, on a large international population. METHODS: The SPOCS algorithm allocates patients to risk groups based on just two variables: the polyp resection margin and the presence of lymphovascular invasion (LVI). The risk groups are termed low (clear margin, LVI absent), medium (clear margin, LVI present) or high (involved/non-assessable margin). The International Polyp Cancer Collaborative was formed to validate the algorithm on data from Australia, Denmark, UK and New Zealand. RESULTS: In total, 1423 patients were included in the final dataset. 680/1423 (47.8%) underwent surgical resection and 108/680 (15.9%) had residual disease (luminal disease 8.8%, lymph node metastases 8.8%). The SPOCS algorithm classified 602 patients as low risk (in which 1.5% had residual disease), 198 patients as medium risk (in which 7.1% had residual disease) and 484 as high risk (in which 14.5% had residual disease) (P < 0.001, χ2 test). Receiver operating characteristic curve analysis demonstrated good accuracy of the algorithm in predicting residual disease (area under the curve 0.732, 95% CI 0.687-0.778, P < 0.001). When patients were designated as low risk, the negative predictive value was 98.5%. CONCLUSION: The SPOCS algorithm can be used to predict the risk of residual disease in patients with endoscopically resected MCPs. Surgery can be safely avoided in patients who have a clear margin of excision and no evidence of LVI.

A Holistic Approach to Assessment of Population Exposure to Radiation: Challenges and Initiatives of a Regulatory Authority.

A regulatory authority for radiation safety should continuously evaluate and improve the national safety framework, in line with current requirements and standards. In this context, the Greek Atomic Energy Commission initiated a series of concerted actions. The radiation dose to the population due to public and medical exposures was assessed. The assessment of dose due to public exposure was based on measurements of radon concentrations in dwellings, radionuclide concentrations in environmental samples, and air dose rates; the assessment of dose due to medical exposure was based on dose measurements for typical examinations or procedures and data on their frequency. The mean effective dose to a member of the population was found to be 4.5 mSv (1.8 mSv and 2.7 mSv from medical and public exposures, respectively). Regarding occupational exposure, aircrew dose assessment, eye lens monitoring, and the national dose registry were significantly improved. With respect to artificial tanning (sun beds), the ultraviolet radiation produced was assessed and the practices followed were observed. Results demonstrated exceedance of the 0.3 W m erythema effective irradiance limit set in European Union standards by 63.5% of the sun beds measured, along with general noncompliance with standards. An overarching activity was the upgrade of the Greek Atomic Energy Commission information system in order to collect and disseminate radiation data electronically, launch a networking strategy for interaction with stakeholders, and facilitate the process of regulatory control. In response to the above findings, regulatory actions have been initiated.

Standardised reporting protocol for endoscopic resection for Barrett oesophagus associated neoplasia: expert consensus recommendations.

Endoscopic resection (ER) is considered the therapy of choice for intraepithelial neoplasia associated with visible lesions and T1a adenocarcinoma. Pathologists are bound to encounter specimens collected via these techniques more frequently in their practice. A standardised protocol for handling, grossing, and assessing ER specimens should be adopted to ensure that all prognostic information and characteristics influencing treatment are included in reports (see Supplementary Video Abstract, http://links.lww.com/PAT/A22). The entire specimen should be appropriately oriented, processed and assessed. An ER specimen will commonly show intraepithelial neoplasia or invasive carcinoma. There are essential features that should be recorded if invasive carcinoma is found as they dictate further management and follow-up. These features are the margin status, depth of invasion, degree of differentiation and presence or absence of lymphovascular invasion. Important features such as duplication of muscularis mucosae should be recognised to avoid misinterpretation of depth of invasion. Key diagnostic and prognostic elements that are essential for optimal clinical decisions have been included in the reporting format proposed by the Structured Pathology Reporting committee of the Royal College of Pathologists of Australasia (RCPA).

Gastroenterology training in Australia: a perspective from the coal face.

BACKGROUND: The Royal Australasian College of Physicians is developing curricula for training. AIMS: We surveyed gastroenterology trainees on their training experience to establish whether training needs were being met. METHODS: An online anonymous survey of all gastroenterology trainees in 2009. RESULTS: Ninety-one per cent of trainees responded (105/115). Of these, 92% were adult, and 8% were paediatric trainees. Seventy four were core, and 31 were noncore trainees. Of those who had completed core training, the majority (86%) felt that their training had prepared them adequately for independent practice as a gastroenterologist. However, most respondents felt that core advanced training should be 3 years instead of 2 years. The majority (86%) saw a benefit in moving between hospitals during core training. Of the trainees managing inpatients, 57% were managing 10 or more per day, and 63% had three or more consultant ward rounds per week. The top three noncore fellowships were advanced endoscopy (44%), hepatology (28%) and inflammatory bowel disease (17%). Sixty-one per cent and 39% were undertaking a clinical and research fellowship respectively. Seventy-two per cent of core trainees attended up to three endoscopy lists per week, and 76% were on the on-call urgent endoscopy roster. For on-call endoscopy, 27% of third-year noncore trainees and 5% of core trainees were unsupervised. CONCLUSIONS: The majority of trainees felt that their core training would prepare them adequately for independent practice as gastroenterologists. Overall, trainees valued movement between hospitals during training and felt that core training should be 3 years. Some trainees had inadequate consultant support for out-of-hours emergency endoscopy.

Comparison of noninvasive models of fibrosis in chronic hepatitis B.

BACKGROUND AND GOALS: Liver fibrosis influences treatment and surveillance strategies in chronic hepatitis B (CHB). This multicenter study aimed to examine the accuracy of serum fibrosis models in CHB patients including those with low alanine aminotransferase (ALT) levels and serially in those undergoing treatment. METHOD: We examined noninvasive fibrosis models [Hepascore, Fibrotest, APRI, hepatitis e antigen (HBeAg)-positive and -negative models] in 179 CHB patients who underwent liver biopsy and fibrosis assessment by METAVIR and image morphometry. Serial Hepascore measurements were assessed in 40 subjects for up to 8.7 years. RESULTS: Hepascore was more accurate than Fibrotest [area under the curve (AUC) 0.83 vs. 0.72, P = 0.05] and HBeAg-positive model (AUC 0.83 vs. 72, P = 0.03) for significant fibrosis but was not significantly different to APRI or HBeAg-negative scores. Fibrosis area assessed by morphometry was correlated with Hepascore (r = 0.603, P < 0.001), Fibrotest (r = 0.392, P = 0.03), and HBeAg-positive (r = 0.492, P = 0.001) scores only. Among 73 patients with an ALT <60 IU/L, noninvasive models were useful to predict fibrosis (PPV 80-90%) or exclude significant fibrosis (NPV 79-100%). Hepascore increased significantly among patients monitored without treatment and reduced among patients undergoing therapy (0.05/year ± 0.03 vs. -0.04/year ± 0.02, P = 0.007). CONCLUSIONS: Serum fibrosis models are predictive of fibrosis in CHB and assist in identifying subjects with low-normal ALT levels for treatment.

Cerebellar hemorrhage after supratentorial burr hole drainage of a chronic subdural hematoma.

Cerebellar hemorrhage is an unusual, but increasingly recognized complication after supratentorial surgery. Even rarer are the cases of cerebellar hemorrhage after supratentorial burr-hole drainage of a chronic subdural hematoma (CSDH). The pathophysiology of this rare complication still remains unclear. Hypertension and overdrainage of cerebrospinal fluid seem to be causative factors of postoperative cerebellar hemorrhage. The most important key to minimize this hazardous sequel is to be aware of this potential complication and its pathogenetic mechanisms. We report our case of a 43-year old man who developed cerebellar hemorrhage after burr hole trephination for supratentorial CSDH.

Levosimendan following coronary artery bypass grafting in a patient with end-stage renal failure: a case report.

Levosimendan is a novel inotropic agent indicated for patients with decompensated heart failure. It has well recognised mechanisms of action. Its use however, has not been described in patients with end-stage renal failure. This report describes the use of levosimendan in a post-operative coronary artery bypass graft patient with decompensated heart failure and end-stage renal failure previously receiving dialysis six days per week. Levosimendan proved to be a safe and useful agent when used as a continuous intravenous infusion initially at 0.05 microg/kg/min then increasing up to 0.2 microg/kg/min for a total of 42 hours.

Slow sequential conformational changes in Escherichia coli ribosomes induced by lincomycin: kinetic evidence.

In a cell-free system derived from Escherichia coli, lincomycin produces biphasic logarithmic time plots for inhibition of peptide-bond formation when puromycin is used as an acceptor substrate and AcPhe-tRNA as a donor substrate. In a previous study, initial slope analysis of the logarithmic time plots revealed that the encounter complex CI between the initiator ribosomal complex (C) and lincomycin (I) undergoes a slow isomerization to C*I. During this change, the bound AcPhe-tRNA and lincomycin are rearranged to also accommodate puromycin, and this may account for the mixed noncompetitive inhibition (K(i)* = 70 microM) established at higher concentrations of the drug. The above-mentioned effect was further investigated by analyzing the late phase of the logarithmic time plots. It was found that C*I complex reacts with a second molecule of I, giving C*I(2) complex. However, the logarithmic time plots remain biphasic even at high concentrations of lincomycin, making possible the identification of another inhibition constant K(i)*', which is equal to 18 microM. The simplest explanation of this finding is to assume the existence of a second isomerization step C*I(2) <--> C*I(2'), slowly equilibrated. The determination of K(i)*' enables us to calculate the isomerization constant (K(isom) = 2.9) with the formula K(i)*' = K(i)*/(1 + K(isom)). Our results suggest that whenever a fast and reversible interaction of lincomycin with the elongating ribosomal complex C occurs, the latter undergoes a slow isomerization, which may be the result of conformational changes induced by the drug.

Sparsomycin and its analogues: a new approach for evaluating their potency as inhibitors of peptide bond formation.

The ability of several sparsomycin analogues to inhibit peptide bond formation was studied in vitro. Peptide bonds are formed between puromycin (S) and the acetylPhe-tRNA of acetylPhe-tRNA/70 S ribosome/poly(U) complex (complex C), according to the puromycin reaction: [formula: see text] It was shown that the sparsomycin analogues, like sparsomycin itself, inhibit peptide bond formation in a time-dependent manner; they react with complex C according to the equation [formula: see text] where C*I is a conformationally altered species in which I is bound more tightly than in CI. The determination of the rate constant k(7) for the regeneration of complex C from the C*I complex allows evaluation of these analogues as inhibitors of peptide bond formation. According to their k7 values, these analogues are classified in order of descending potency as follows: n-pentyl-sparsomycin (4) > n-butyl-sparsomycin (3) approximately n-butyl-deshydroxy-sparsomycin (6) > benzyl-sparsomycin (2) > deshydroxy-sparsomycin (5) approximately sparsomycin (1) > n-propyl-desthio-deshydroxy-sparsomycin (7). The analogues with an aromatic or a larger hydrophobic side chain are stronger inhibitors of the puromycin reaction than are those with a smaller side chain or those lacking the bivalent sulfur atoms; replacement of the hydroxymethyl group with a methyl group does not affect the position of the compound in this ranking; compare the positions of compounds 1 and 3 with those of 5 and 6. In the case of compound 7, C*I adsorbed on cellulose nitrate disks was not sufficiently stable to allow examination by the method applied to the other analogues, probably due to a relatively large value of k7. This analogue showed also time-dependent inhibition, but after the isomerization of CI to C*I, the kinetics of inhibition become complex, and C*I interacted further with puromycin, either as C*I or after its dissociation to C*.

New aspects of the kinetics of inhibition by lincomycin of peptide bond formation.

We have investigated the inhibition of peptide bond formation by the antibiotic lincomycin, at 150 mM NH4Cl. We have used an in vitro system in which a ribosomal ternary complex, the acetyl[3H] phenylalanine-tRNA-70 S ribosome-poly(U) complex (complex C), reacts with puromycin, forming peptide bonds. Complex C can be considered an analog of the elongating ribosomal complex and puromycin an analog of aminoacyl-tRNA. In a previous study we reported on the kinetics of inhibition by lincomycin at 100 mM NH4Cl. In the present investigation, we find that an increase of the ammonium ion concentration to 150 mM causes profound changes in the kinetic behavior of the system, which can be summarized as follows. First, the association rate for complex C and lincomycin is increased. At a lincomycin concentration of 10 microM the apparent equilibration rate constant is 4.3 min-1 at 100 mM NH4Cl, whereas it becomes 6.7 min-1 at 150 mM. Second, at 150 mM NH4Cl, with increasing concentrations of lincomycin, there is a transition from competitive to mixed-noncompetitive inhibition. The prevailing notion is that lincomycin acts at the ribosomal A-site, a mechanism that agrees only with competitive kinetics (mutually exclusive binding between puromycin and lincomycin). At the molecular level, the change in the kinetics of inhibition that we observe may mean that the mutually exclusive binding between aminoacyl-tRNA and lincomycin is converted to simultaneous binding, as a result of conformational changes occurring in the elongating ribosomal complex.

Slow-onset inhibition of ribosomal peptidyltransferase by lincomycin.

In a system derived from Escherichia coli, we carried out a detailed kinetic analysis of the inhibition of the puromycin reaction by lincomycin. N-Acetylphenylalanyl-tRNA (Ac-Phe-tRNA; the donor) reacts with excess puromycin (S) according to reaction [1], C+S Ks <--> CS k3 --> C'+P, where C is the Ac-Phe-tRNA-poly(U)-ribosome ternary complex (complex C). The entire course of reaction [1] appears as a straight line when the reaction is analyzed as pseudo-first-order and the data are plotted in a logarithmic form (logarithmic time plot). The slope of this straight line gives the apparent ksobs = k3[S]/(Ks + [S]). In the presence of lincomycin the logarithmic time plot is not a straight line, but becomes biphasic, giving an early slope (ke = k3[S]/(Ks(1 + [I]/Ki) + [S])) and a late slope (k1 = k3[S]/(Ks(1 + [I]/K'i + [S])). Kinetic analysis of the early slopes at various concentrations of S and I shows competitive inhibition with Ki = 10.0 microM. The late slopes also give competitive inhibition with a distinct inhibition constant K'i = 2.0 microM. Excluding alternative models, the two phases of inhibition are compatible with a model in which reaction [1] is coupled with reaction [2], C+I k4 <--> k5 CI k6 <--> k7 C*I, where the isomerization step CI <--> CI* is slower than the first step C+I <--> CI, Ki = k5/k4 and K'i = Ki [k7/(k6 + k7)]. Corroborative evidence for this model comes from the examination of reaction [2] alone in the absence of S. This reaction is analyzed as pseudo-first-order going toward equilibrium with kIeq = k7 + (k6 [I]/(Ki + [I])). The plot of kIeq versus [I] is not linear. This plot supports the two-step mechanism of reaction [2] in which k6 = 5.2 min-1 and k7 = 1.3 min-1. This is the first example of slow-onset inhibition of ribosomal peptidyltransferase which follows a simple model leading to the determination of the isomerization constants k6 and k7. We suggest that lincomycin inhibits protein synthesis by binding initially to the ribosome in competition with aminoacyl-tRNA. Subsequently, as a result of a conformational change, an isomerization occurs (CI <--> C*I), after which lincomycin continues to interfere with the binding of aminoacyl-tRNA to the isomerized complex.