Deletion of Cdh16 Ksp-cadherin leads to a developmental delay in the ability to maximally concentrate urine in mouse.

Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system of the mammalian kidney. The principal aim of the present study was to determine if Ksp-cadherin played a critical role in the development and maintenance of the adult mammalian kidney by generating and evaluating a mouse line deficient in Ksp-cadherin. Ksp-null mutant animals were viable and fertile, and kidneys from both neonates and adults showed no evidence of structural abnormalities. Immunolocalization and Western blot analyses of Na+-K+-ATPase and E-cadherin indicated that Ksp-cadherin is not essential for either the genesis or maintenance of the polarized tubular epithelial phenotype. Moreover, E-cadherin expression was not altered to compensate for Ksp-cadherin loss. Plasma electrolytes, total CO2, blood urea nitrogen, and creatinine levels were also unaffected by Ksp-cadherin deficiency. However, a subtle but significant developmental delay in the ability to maximally concentrate urine was detected in Ksp-null mice. Expression analysis of the principal proteins involved in the generation of the corticomedullary osmotic gradient and the resultant movement of water identified misexpression of aquaporin-2 in the inner medullary collecting duct as the possible cause for the inability of young adult Ksp-cadherin-deficient animals to maximally concentrate their urine. In conclusion, Ksp-cadherin is not required for normal kidney development, but its absence leads to a developmental delay in maximal urinary concentrating ability.NEW & NOTEWORTHY Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system. Using knockout mice, we found that Ksp-cadherin is in fact not required for kidney development despite its high and specific expression along the nephron. However, its absence leads to a developmental delay in maximal urinary concentrating ability.

Association between imaging response and survival following neoadjuvant chemotherapy in patients with resectable colorectal liver metastases: A cohort study.

BACKGROUND: The association between the imaging response (structural or metabolic) to neoadjuvant chemotherapy (neoCT) before colorectal liver metastasis (CRLM) and survival is unclear. METHOD: A total of 201 patients underwent their first CRLM resection. A total of 94 (47%) patients were treated with neoCT. A multivariable, Cox proportional hazard regression analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between response groups. RESULTS: Multivariable regression analysis of the CT/MRI (n = 94) group showed no difference in survival (OS and PFS) in patients who had stable disease/partial response (SD/PR) or complete response (CR) versus patients who had progressive disease (PD) (OS: HR, 0.36 (95% CI: 0.11-1.19) p = .094, HR, 0.78 (95% CI: 0.13-4.50) p = .780, respectively), (PFS: HR, 0.70 (95% CI: 0.36-1.35) p = .284, HR, 0.51 (0.18-1.45) p = .203, respectively). In the FDG-PET group (n = 60) there was no difference in the hazard of death for patients with SD/PR or CR versus patients with PD for OS or PFS except for the PFS in the small CR subgroup (OS: HR, 0.75 (95% CI: 0.11-4.88) p = .759, HR, 1.21 (95% CI: 0.15-9.43) p = .857), (PFS: HR, 0.34% (95% CI: 0.09-1.22), p = .097, HR, 0.17 (95% CI: 0.04-0.62) p = .008, respectively). CONCLUSION: There was no convincing evidence of association between imaging response to neoCT and survival following CRLM resection.

Platelet function testing in patients with post-operative tonsillectomy bleeding may be a useful early identifier of inherited platelet function disorders.

BACKGROUND: Post-tonsillectomy bleeding is the most frequent complication of tonsillectomy. Inherited platelet function disorders have an estimated prevalence of 1 per cent. Any association between post-tonsillectomy bleeds and undiagnosed inherited platelet function disorders has not been investigated before. OBJECTIVES: To assess the prevalence of inherited platelet function disorders in a cohort of post-tonsillectomy bleed patients. METHODS: An observational cohort study was conducted using hospital digital records. Platelet function analyser 100 ('PFA-100') closure time was tested on post-tonsillectomy bleed patients who presented to hospital. RESULTS: Between 2013 and 2017, 9 of 91 post-tonsillectomy bleed patients who underwent platelet function analyser 100 testing (9.89 per cent) had positive results. Five patients (5.49 per cent) had undiagnosed inherited platelet function disorders. Four patients had false positive results secondary to a non-steroidal anti-inflammatory drug effect (specificity of 95.3 per cent) proven by repeat testing six weeks later, off medication. The false negative rate was 0 per cent. CONCLUSION: The prevalence of inherited platelet function disorders in our post-tonsillectomy bleed cohort is five-fold higher than in the general population. Platelet function analyser 100 testing when patients present with a post-tonsillectomy bleed allows management of their inherited platelet function disorder.

Interventions to Improve Clinical Outcomes in Indigenous or Remote Patients With Chronic Kidney Disease: A Scoping Review.

BACKGROUND: Chronic kidney disease (CKD) associates with a significant health care burden with a disproportionate impact on indigenous persons or people living in remote areas. Although screening programs have expanded in these communities, there remains a paucity of evidence-based interventions to enhance clinical renal outcomes in these populations. OBJECTIVE: The objective of this study was to identify evidence-based interventions to enhance renal outcomes in these populations. DESIGN: A scoping review was conducted for studies in the Cochrane, MEDLINE, and Embase databases and from major nephrology meetings. SETTING: Chronic kidney disease, including those on dialysis. PATIENTS: Remote or indigenous populations. MEASUREMENTS: Studies that performed an intervention that was followed by measurement of renal outcomes or patient-centered outcomes (ie, quality of life) were included. METHODS: All studies were described by study type, intervention, and clinical outcome, and trends were identified by both authors. Meta-analysis was not conducted due to study heterogeneity. RESULTS: Thirty-two studies met inclusion criteria, only 2 (6.3%) of which were randomized controlled trials. Intervention types included multidisciplinary (34.4%), satellite (32.3%), telehealth (25.0%), or other (9.4%). All multidisciplinary interventions were performed in the CKD (non-dialysis) setting and reported improved patient travel time, waiting time, quality of life, kidney function, proteinuria, and blood pressure. Telehealth interventions improved program cost, patient attendance, hospitalization, and quality of life. Satellite interventions were performed in the hemodialysis setting, with 1 study evaluating acute hemodialysis. Satellite interventions improved patient travel time, dialysis clearance, quality of life, and survival, but increased program costs. LIMITATIONS: The study was restricted to interventional trials assessing clinical outcomes and to studies in developed countries, which likely excluded some research contributing to this field. CONCLUSIONS: There is significant heterogeneity among studies of interventions for patients with CKD who are indigenous or live remotely. Interventions were more likely to be successful when the remote or indigenous community was included in program development, with a culturally safe approach. More large, high-quality studies are needed to identify effective interventions to enhance clinical renal outcomes in indigenous or remote populations. TRIAL REGISTRATION: This trial is registered under PROSPERO, Registration Number 128453.

CONTEXTE: L'insuffisance rénale chronique (IRC) s'accompagne d'un fardeau de santé dont les répercussions touchent de façon disproportionnée les populations autochtones et les résidents des régions éloignées. Bien que les programmes de dépistage se soient répandus dans ces communautés, peu d'interventions fondées sur des données probantes et visant l'amélioration des issues rénales sont en place dans ces populations. OBJECTIF: Répertorier les interventions fondées sur des données probantes et visant l'amélioration des issues rénales dans ces populations. TYPE D'ÉTUDE: Une revue de cadrage menée dans les bases de données Cochrane, Medline et Embase, et à partir des principales conférences en néphrologie. CADRE: L'insuffisance rénale chronique, incluant les patients dialysés. SUJETS: Des patients autochtones ou résidents de régions éloignées. MESURES: Ont été incluses les études qui avaient procédé à une intervention suivie de la mesure des issues rénales ou des résultats axés sur le patient (ex. qualité de vie). MÉTHODOLOGIE: Les études ont été définies par le type d'étude, l'intervention et les résultats cliniques. Les tendances ont été déterminées par les auteurs. L'hétérogénéité des études n'a pas permis de procéder à une méta-analyse. RÉSULTATS: Trente-deux études satisfaisaient les critères d'inclusion, dont seulement deux (6,3 %) étaient des essais contrôlés à répartition aléatoire. L'intervention était multidisciplinaire (34,4 %), satellite (32,3 %), en télésanté (25,0 %) ou autre (9,4 %). Toutes les interventions multidisciplinaires avaient été faites en contexte d'IRC (sans dialyse) et avaient amélioré le temps de déplacement, le temps d'attente, la qualité de vie, la fonction rénale, la protéinurie et la pression artérielle du patient. Les interventions en télésanté avaient permis de réduire les coûts du programme et le nombre d'hospitalisations, tout en améliorant la participation du patient et sa qualité de vie. Les interventions satellites avaient été menées en contexte d'hémodialyse, et l'une d'elles évaluait l'hémodialyse aigüe. Les interventions satellites avaient amélioré la clairance par dialyse, ainsi que le temps de déplacement, la qualité de vie et la survie du patient, mais occasionnaient des coûts plus élevés. LIMITES: L'étude se limitait à des essais sur le terrain analysant les résultats cliniques et à des études en pays développés, ce qui a probablement exclu certaines études contribuant à ce domaine. CONCLUSION: On observe une importante hétérogénéité dans les études analysant les interventions en IRC tournées vers les patients d'origine autochtone ou de régions éloignées. Les interventions avaient plus de chances de réussite si les populations visées participaient à l'élaboration du programme, et si elles s'inscrivaient dans une approche respectueuse des valeurs culturelles. Des études robustes et de plus grande envergure sont nécessaires pour cibler les interventions qui permettent d'améliorer les issues rénales cliniques chez les populations autochtones ou éloignées.

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Short-term changes observed in multiparametric liver MRI following therapy with direct-acting antivirals in chronic hepatitis C virus patients.

METHODS: We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before direct-acting antiviral (DAA) therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed). RESULTS: We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35 ± 4 ms), transverse relaxation time (T2, 2.5 ± 0.8 ms; T2* 3.0 ± 0.7 ms), and liver perfusion (28.1 ± 19.7 ml/100 g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or superior mesenteric artery blood flow. CONCLUSION: For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2 and T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms. KEY POINTS: • DAAs have revolutionised the treatment of hepatitis C and achieve sustained virological response in over 95% of patients, even with liver cirrhosis. • Currently available non-invasive measures of liver fibrosis are not accurate after HCV treatment with DAAs, this prospective single-centre study has shown that MRI can sensitively measure changes within the liver, which could reflect the reduction in inflammation with viral clearance. • The ability of MRI to characterise changes in structural and haemodynamic MRI measures in the liver after intervention will enhance our understanding of the progression/regression of liver disease and could potentially influence clinical decision algorithms.

A 4-arm randomized controlled pilot trial of innovative solutions for jugular central venous access device securement in 221 cardiac surgical patients.

PURPOSE: To improve jugular central venous access device (CVAD) securement, prevent CVAD failure (composite: dislodgement, occlusion, breakage, local or bloodstream infection), and assess subsequent trial feasibility. MATERIALS AND METHODS: Study design was a 4-arm, parallel, randomized, controlled, nonblinded, pilot trial. Patients received CVAD securement with (i) suture+bordered polyurethane (suture + BPU; control), (ii) suture+absorbent dressing (suture + AD), (iii) sutureless securement device+simple polyurethane (SSD+SPU), or (iv) tissue adhesive+simple polyurethane (TA+SPU). Midtrial, due to safety, the TA+SPU intervention was replaced with a suture + TA+SPU group. RESULTS: A total of 221 patients were randomized with 2 postrandomization exclusions. Central venous access device failure was as follows: suture + BPU controls, 2 (4%) of 55 (0.52/1000 hours); suture + AD, 1 (2%) of 56 (0.26/1000 hours, P=.560); SSD+SPU, 4 (7%) of 55 (1.04/1000 hours, P=.417); TA+SPU, 4 (17%) of 23 (2.53/1000 hours, P=.049); and suture + TA+SPU, 0 (0%) of 30 (P=.263; intention-to-treat, log-rank tests). Central venous access device failure was predicted (P<.05) by baseline poor/fair skin integrity (hazard ratio, 9.8; 95% confidence interval, 1.2-79.9) or impaired mental state at CVAD removal (hazard ratio, 14.2; 95% confidence interval, 3.0-68.4). CONCLUSIONS: Jugular CVAD securement is challenging in postcardiac surgical patients who are coagulopathic and mobilized early. TA+SPU was ineffective for CVAD securement and is not recommended. Suture + TA+SPU appeared promising, with zero CVAD failure observed. Future trials should resolve uncertainty about the comparative effect of suture + TA+SPU, suture + AD, and SSD+SPU vs suture + BPU.

Divergence for residual feed intake of Holstein-Friesian cattle during growth did not affect production and reproduction during lactation.

Residual feed intake (RFI) is the difference between actual and predicted dry matter intake (DMI) of individual animals. Recent studies with Holstein-Friesian calves have identified an ~20% difference in RFI during growth (calf RFI) and these groups remained divergent in RFI during lactation. The objective of the experiment described here was to determine if cows selected for divergent RFI as calves differed in milk production, reproduction or in the profiles of BW and body condition score (BCS) change during lactation, when grazing pasture. The cows used in the experiment (n=126) had an RFI of -0.88 and +0.75 kg DM intake/day for growth as calves (efficient and inefficient calf RFI groups, respectively) and were intensively grazed at four stocking rates (SR) of 2.2, 2.6, 3.1 and 3.6 cows/ha on self-contained farmlets, over 3 years. Each SR treatment had equal number of cows identified as low and high calf RFI, with 24, 28, 34 and 40/11 ha farmlet. The cows divergent for calf RFI were randomly allocated to each SR. Although SR affected production, calf RFI group (low or high) did not affect milk production, reproduction, BW, BCS or changes in these parameters throughout lactation. The most efficient animals (low calf RFI) lost similar BW and BCS as the least efficient (high calf RFI) immediately post-calving, and regained similar BW and BCS before their next calving. These results indicate that selection for RFI as calves to increase efficiency of feed utilisation did not negatively affect farm productivity variables (milk production, BCS, BW and reproduction) as adults when managed under an intensive pastoral grazing system.

Hydrodynamic evaluation of aortic cardiopulmonary bypass cannulae using particle image velocimetry.

The high velocity jet from aortic arterial cannulae used during cardiopulmonary bypass potentially causes a "sandblasting" injury to the aorta, increasing the possibility of embolisation of atheromatous plaque. We investigated a range of commonly available dispersion and non-dispersion cannulae, using particle image velocimetry. The maximum velocity of the exit jet was assessed 20 and 40 mm from the cannula tip at flow rates of 3 and 5 L/min. The dispersion cannulae had lower maximum velocities compared to the non-dispersion cannulae. Dispersion cannulae had fan-shaped exit profiles and maximum velocities ranged from 0.63 to 1.52 m/s when measured at 20 mm and 5 L/min. Non-dispersion cannulae had maximum velocities ranging from 1.52 to 3.06 m/s at 20 mm and 5 L/min, with corresponding narrow velocity profiles. This study highlights the importance of understanding the hydrodynamic performance of these cannulae as it may help in selecting the most appropriate cannula to minimize the risk of thromboembolic events or aortic injury.

Outcomes in emergency general surgery following the introduction of a consultant-led unit.

BACKGROUND: Patients presenting with emergency surgical conditions place significant demands on healthcare services globally. The need to improve emergency surgical care has led to establishment of consultant-led emergency surgery units. The aim of this study was to determine the effect of a changed model of service on outcomes. METHODS: A retrospective observational study of all consecutive emergency general surgical admissions in 2009-2012 was performed. A 2-year time frame before and after the establishment of the emergency general surgery (EGS) service was used to determine the number of admissions and operations, emergency department and hospital length of stay, as well as complication rates. RESULTS: The study included 7233 acute admissions. The EGS service managed 4468 patients (61·6 per cent increase) and performed 1804 operations (41·0 per cent increase). The most common diagnoses during the EGS period included acute appendicitis (532, 11·9 per cent), biliary disease (361, 8·1 per cent) and abdominal pain (561, 12·6 per cent). Appendicectomy (536, 29·7 per cent), cholecystectomy (239, 13·2 per cent) and laparotomy (226, 12·5 per cent) were the most commonly performed procedures. In the EGS period, time in the emergency department was reduced (from 8·0 to 6·0 h; P < 0·001), as was length of hospital stay (from 3·0 to 2·0 days; P < 0·001). The number of complications was reduced by 46·8 per cent, from 172 (6·2 per cent) to 147 (3·3 per cent) (P < 0·001), with a 53 per cent reduction in the number of deaths in the EGS period, from 29 (16·9 per cent) to seven (8 per cent) (P = 0·039). CONCLUSION: The establishment of a consultant-led emergency surgical service has been associated with improved provision of care, resulting in timely management and improved clinical outcomes.

The effects of depriving feed to facilitate transport and slaughter in sheep--a case study of cull ewes held off pasture for different periods.

AIM: To determine the ability of sheep to mobilise their body reserves after being deprived of feed prior to transport for slaughter. METHODS: A total of 240 3- and 4-year-old cull ewes were held off pasture for 0, 9, 18 or 30 hours (n=60 per group) then transported 1 hour by road, unloaded and washed, held in lairage for 3 hours then slaughtered. Blood samples were collected from a subsample of 60 unfasted ewes 1 week earlier, and from all ewes at exsanguination to determine concentrations of serum metabolites indicative of adaptation to fasting. In addition, several attributes of carcass quality were measured. RESULTS: At slaughter, increased time off pasture prior to transport resulted in no change in glucose concentrations in serum (p=0.140). There were differences (p<0.001) between the group fasted for 30 compared with 0 hours in mean concentrations of free fatty acids (0.98 (SD 0.32) vs. 0.58 (SD 0.23) mmol/L), ß-hydroxybutyrate (0.69 (SD 0.17) vs. 0.42 (SD 0.11) mmol/L), triglycerides (0.29 (min 0.13, max 0.83) vs. 0.22 (min 0.06, max 0.96) mmol/L) and urea (10.17 (SD 1.80) vs. 6.94 (SD 2.03) mmol/L). Different periods of feed deprivation had no effect (p>0.05) on carcass weights (mean 22.7, min 13.2, max 32.9 kg) or dressing out percentages (mean 40.9, min 27, max 49%). Meat ultimate pH was unaffected (p>0.05) by the period of feed deprivation but meat became darker (p<0.05) and had reduced redness (p<0.001) with increasing time off feed. CONCLUSIONS: The results suggest that sheep in variable body condition adapted to the periods of feed deprivation by mobilising their energy reserves without any evidence of metabolic depletion (e.g. depleted blood glucose or high meat pH). However, being deprived of feed they probably experience a degree of hunger.

Effect of the introduction of an emergency general surgery service on outcomes from appendicectomy.

BACKGROUND: Appendicectomy is a common general surgical emergency procedure and may be used as a surrogate marker to evaluate quality in surgical management. The aim of this study was to assess the outcomes of appendicectomy before and after the introduction of a consultant-led emergency general surgery (EGS) service at a large metropolitan tertiary referral centre. METHODS: A retrospective historical control study was performed that included all adult patients undergoing appendicectomy during two 18-month periods, before and after the introduction of the EGS service. Data collected included patient demographics, use of radiological investigations, time to surgery, length of hospital stay and histopathology findings. Outcome measures were time to surgery, hospital length of stay, use of radiological investigations, negative appendicectomy rate and perforation rate. RESULTS: A total of 675 patients were identified of whom 276 had an appendicectomy before the EGS service was introduced (2008-2009) and 399 after its introduction (2011-2012). The EGS service resulted in an increase in time to surgery (15 versus 18 h; P < 0.001) with no increase in length of hospital stay (3 days for both periods; P = 0.424). An increase in the rate of appendicectomies performed within office hours was seen (54.3 versus 64.4 per cent; P < 0.001), with no significant increase in negative appendicectomy (13.0 versus 15.8 per cent; P = 0.322) or perforation (8.3 versus 5.5 per cent; P = 0.149) rates. The use of preoperative computed tomography reduced from 38.4 to 26.6 per cent (P = 0.001). CONCLUSION: The introduction of a consultant-led EGS service resulted in a decrease in the use of computed tomography and a greater proportion of appendicectomies performed within office hours, with no increase in length of stay. Overall negative appendicectomy and perforation rates did not change.

ECG machine QTc intervals are inaccurate in hemodialysis patients.

BACKGROUND: Nephrologists need effective screening tools to identify hemodialysis patients at elevated risk for sudden cardiac death, the leading cause of death in this population. QTc intervals longer than 450 ms in males and 470 ms in females, measured by the gold standard tangent method (trueQTc), are prolonged and increase sudden cardiac death in healthy populations and patients with long QT syndrome. METHODS: We performed a retrospective ECG and chart review of hemodialysis patients. Our first objective was to determine if machine-measured QTc intervals (macQTc) could be used to identify dialysis patients with prolonged trueQTc. Our second objective was to determine at what macQTc could prolonged trueQTc be confidently diagnosed. RESULTS: macQTc differed from the trueQTc by an average of 16.54 ms, and by at least 20 ms in 46.8, 36.1, 53.6, 50.0 and 57.1% of all, short-hours daily hemodialysis, intermittent conventional hemodialysis, frequent nocturnal hemodialysis and intermittent nocturnal hemodialysis patients, respectively. The positive predictive value, negative predictive value, sensitivity and specificity of prolonged macQTc predicting prolonged trueQTc was 57.6, 92.6, 79.1 and 81.8%, respectively. Thus, macQTc is inaccurate at predicting the gold standard trueQTc in hemodialysis patients. macQTc greater than 480 ms in hemodialysis patients predicts trueQTc prolongation with a positive predictive value of 95.2%, but with a low sensitivity of 32.3%. CONCLUSION: In hemodialysis patients, ECG macQTc intervals are insufficiently sensitive or specific to predict prolonged trueQTc intervals, unless >480 ms.

Peritoneal dialysis versus hemodialysis in patients with delayed graft function.

Delayed graft function (DGF) in kidney transplantation affects adverse outcomes. It remains unclear whether the post-transplant dialysis modality alters perioperative or long-term graft outcomes. We performed a retrospective observational quality initiative at two Canadian renal transplant centers, in which DGF occurred in the recipient, necessitating one of peritoneal dialysis (PD) or hemodialysis (HD). There was no difference in baseline factors between patients with post-transplant PD (n = 14) or HD (n = 63). The use of PD was associated with an increased risk of wound infection/leakage (PD 5/14 vs. HD 6/63, p = 0.024), shorter length of hospitalization (13.7 vs. 18.7 d, p = 0.009) and time requiring dialysis post-operatively (6.5 vs 11.0 d, p = 0.043). There were no differences in readmission to hospital within 6 months (4/14 vs. 23/63, p = 0.759), graft loss (0/14 vs. 2/63, p = 1.000) or acute rejection episodes (1/14 vs. 4/63, p = 1.000) at one yr, and GFR did not differ between the PD or HD groups at 30 d (35.7 vs. 33.8 mL/min/m(2), p = 0.731), six months (46.9 vs. 45.5 mL/min/m(2), p = 0.835) or one yr (46.6 vs. 44.5 mL/min/m(2), p = 0.746). Further research is needed to determine which transplant patients are most appropriate to undergo PD catheter removal at the time of transplantation.

Mannan binding lectin-associated serine protease 1 is induced by hepatitis C virus infection and activates human hepatic stellate cells.

Mannan binding lectin (MBL)-associated serine protease type 1 (MASP-1) has a central role in the lectin pathway of complement activation and is required for the formation of C3 convertase. The activity of MASP-1 in the peripheral blood has been identified previously as a highly significant predictor of the severity of liver fibrosis in hepatitis C virus (HCV) infection, but not in liver disease of other aetiologies. In this study we tested the hypotheses that expression of MASP-1 may promote disease progression in HCV disease by direct activation of hepatic stellate cells (HSCs) and may additionally be up-regulated by HCV. In order to do so, we utilized a model for the maintenance of primary human HSC in the quiescent state by culture on basement membrane substrate prior to stimulation. In comparison to controls, recombinant MASP-1 stimulated quiescent human HSCs to differentiate to the activated state as assessed by both morphology and up-regulation of HSC activation markers α-smooth muscle actin and tissue inhibitor of metalloproteinase 1. Further, the expression of MASP-1 was up-regulated significantly by HCV infection in hepatocyte cell lines. These observations suggest a new role for MASP-1 and provide a possible mechanistic link between high levels of MASP-1 and the severity of disease in HCV infection. Taken together with previous clinical observations, our new findings suggest that the balance of MASP-1 activity may be proinflammatory and act to accelerate fibrosis progression in HCV liver disease.

Preoperative immunonutrition and its effect on postoperative outcomes in well-nourished and malnourished gastrointestinal surgery patients: a randomised controlled trial.

BACKGROUND/OBJECTIVES: Invasive procedures such as surgery cause immunosuppression, leading to increased risk of complications, infections and extended hospital stay. Emerging research around immune-enhancing nutrition supplements and their ability to reduce postoperative complications and reduce treatment costs is promising. This randomised controlled trial aims to examine the effect of preoperative immunonutrition supplementation on length of hospital stay (LOS), complications and treatment costs in both well-nourished and malnourished gastrointestinal surgery patients. SUBJECTS/METHODS: Ninety-five patients undergoing elective upper and lower gastrointestinal surgery were recruited. The treatment group (n=46) received a commercial immuno-enhancing supplement 5 days preoperatively. The control group (n=49) received no supplements. The primary outcome measure was LOS, and secondary outcome measures included complications and cost. RESULTS: A nonsignificant trend towards a shorter LOS within the treatment group was observed (7.1 ± 4.1 compared with 8.8 ± 6.5 days; P=0.11). For malnourished patients, this trend was greater with hospital stay reduced by 4 days (8.3 ± 3.5 vs 12.3 ± 9.5 days; P=0.21). Complications and unplanned intensive care admission rates were very low in both the groups. The average admission cost was reduced by AUD1576 in the treatment group compared with the control group (P=0.37). CONCLUSIONS: Preoperative immunonutrition therapy in gastrointestinal surgery has the potential to reduce the LOS and cost, with greater treatment benefit seen in malnourished patients; however, there is a need for additional research with greater patient numbers.

The potential for induction peptide receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal neuroendocrine tumours resectable.

AIMS: To assess the clinical utility of peptide receptor chemoradionuclide therapy (PRCRT) using (177)Lu-octreotate (LuTate) with concurrent 5FU chemotherapy in patients with inoperable primary pancreatic and duodenal neuroendocrine tumours (NETs). METHODS: Between December 2006 and October 2009, five patients with progressive inoperable pancreatic and duodenal NETs without distant metastatic disease or with a potentially resectable solitary distant metastasis were treated with PRCRT; in combination with external beam radiotherapy in one case. Patients were followed up three months post-treatment with somatostatin receptor scintigraphy, radiology, biochemical markers and clinical assessment. Radiological response classification was defined by Response Evaluation Criteria in Solid Tumours (RECIST) with the addition of a minor response (MR; 10-30% size reduction) classification. Long-term follow up was performed until July 2011. RESULTS: At three months post-treatment, all five patients had a scintigraphic response, four had a radiological response and three of the four symptomatic patients responded clinically. All five patients had an ongoing treatment response beyond three months including one where further tumour shrinkage facilitated curative surgery. All five patients are alive with 12-42 months of follow-up post-treatment. CONCLUSION: PRCRT can be effective in inoperable pancreatic and duodenal neuroendocrine tumours and may play a role as neoadjuvant therapy in this patient group.

Type 2 diabetes does not worsen prognosis in hepatocellular carcinoma.

INTRODUCTION: Type 2 diabetes (T2DM) is associated with liver inflammation and carcinogenesis. The prevalence of T2DM among patients with liver cirrhosis and hepatocellular carcinoma is increasing. However, the effect of T2DM on the natural history of hepatocellular carcinoma is not known. AIM: To examine the effect of T2DM on hepatocellular carcinoma (HCC) survival in treated and untreated disease. METHODS: Retrospective analysis was performed on HCC cases diagnosed during 2000-2005, and prospectively during 2006-August 2007. Demographics, HCC staging, response to treatment, and survival were collected. A comparison was made between patients with T2DM and without T2DM. RESULTS: One hundred and thirty-five patients were recruited in total; 58 (43%) had T2DM. Seventy (37 diabetic) patients were treated with percutaneous radiological therapies, with 168 treatments given. Treatment was determined by AASLD guidelines and patient tolerance, there was no randomisation. There was no significant difference in survival between diabetic and nondiabetic patients. There was a nonsignificant trend towards greater survival in diabetic patients (overall median survival diabetics 21 mths vs nondiabetics 5 mths, P=0.355). CONCLUSIONS: T2DM does not negatively impact on the natural history of treated or untreated HCC.

Prolactin acts on the hypothalamic-pituitary axis to modulate follicle-stimulating hormone gene expression in the female brushtail possum (Trichosurus vulpecula).

Brushtail possums exhibit a distinct preovulatory pattern of prolactin (Prl) secretion suggesting that Prl is involved in normal reproductive function. In some mammals, Prl is essential for corpus luteum (CL) function and/or modulation of steroidal effects on hypothalamic-pituitary activity. The aim of this study was to test the effects of biologically active recombinant possum Prl (recPosPrl) on both pituitary gland and CL function in possums. To confirm biological activity, administration of recPosPrl-N2C1 (10 µg) resulted in an 18-fold stimulation (P<0.05) of progesterone (P(4)) production by possum granulosa cells in vitro. Based on these findings, minipumps containing either recPosPrl-N2C1 (n=10) or saline (n=8) were inserted into lactating female possums. The expression levels of pituitary-derived PRL, LHB, FSHB and GNRHR and CL-derived LHR mRNA were quantified. Following a resumption of reproductive activity, no differences in ovulation incidence or plasma Prl concentrations were observed. Plasma Prl levels were less variable (P<0.001) in Prl-treated possums, confirming a self-regulatory role for Prl in this species. There was a marked down-regulation (P<0.001) of FSHB mRNA at the mid-luteal stage in Prl-treated possums, whereas mean PRL, LHB, GNRHR and LHR mRNA expression levels were not different between experimental groups. Plasma P(4) concentrations were not different (P=0.05) in Prl-treated possums, although tended to be higher in the peri-ovulatory and early-luteal phase. We conclude in the brushtail possum that Prl is self-regulated via a short-feedback loop common to all mammals studied and is able to modulate FSHB expression probably at the level of the hypothalamus and/or pituitary gland.

Estrogenic pyrethroid pesticides regulate expression of estrogen receptor transcripts in mouse Sertoli cells differently from 17beta-estradiol.

Studies suggested that exposure to agricultural pesticides may affect male fertility. Pyrethroids are widely used pesticides due to their insecticidal potency and low mammalian toxicity. A recombinant yeast assay system incorporating the human alpha-estrogen receptor was used to analyze the estrogenicity of a range of readily available pyrethroid pesticides. The commercial product Ripcord Plus showed estrogenic activity by this assay. To determine whether pyrethroid compounds might exert an effect on male fertility, mouse Sertoli cells were exposed in vitro to the endogenous estrogen, 17beta-estradiol, and selected estrogenic pyrethroids. Following exposure, transcript levels of the alpha- and beta-estrogen receptors were assessed. Exposure of Sertoli cells to the pyrethroid compounds, both at high and at low published serum concentrations, affected the expression of the two estrogen receptors; however, the influence on estrogen receptor gene expression was different from the effect from exposure to 17beta-estradiol. These results from our model systems suggest that (1) estrogenic pyrethroid pesticides affect the estrogen receptors, and therefore potentially the endocrine system, in a different manner from that of endogenous estrogen, and (2) should cells in the male testes be exposed to pyrethroid pesticides, male fertility may be affected through molecular mechanisms involving estrogen receptors.