The impact of robotic rectal cancer surgery at a Canadian regional cancer centre: a retrospective cohort study.

BACKGROUND: Although robotic surgery has several advantages over other minimally invasive surgery (MIS) techniques for rectal cancer surgery, the uptake in Canada has been limited owing to a perceived increase in cost and lack of training. The objective of this study was to determine the impact of access to robotic surgery in a Canadian setting. METHODS: We conducted a retrospective cohort study involving consecutive adults undergoing surgical resection for rectal cancer between 2017 and 2020. The primary exposure was access to robotic surgery. Outcomes included MIS utilization, short-term outcomes, total cost of care, and quality of surgical resection. We completed univariate and multivariate analyses. RESULTS: We included 171 individuals in this cohort study (85 in the prerobotic period and 86 in the robotic period). The 2 groups had similar baseline characteristics. A higher proportion of individuals underwent successful MIS in the robotic phase (86% v. 46%, p < 0.001). Other benefits included a shorter mean length of hospital stay (5.1 d v. 9.2 d, p < 0.001). The quality of surgical resection was similar between groups. The total cost of care was $16 746 in the robotic period and $18 808 in the prerobotic period (mean difference -$1262, 95% confidence interval -$4308 to $1783; p = 0.4). CONCLUSION: Access to robotic rectal cancer surgery increased successful completion of MIS and shortened hospital stay, with a similar total cost of care. Robotic rectal cancer surgery can enhance patient outcomes in the Canadian setting.

Infestation rates of lice Lepeophtheirus salmonis and Caligus elongatus on Atlantic salmon in fixed and towed sentinel cages.

Sea lice are a key limitation to sustainable salmon aquaculture, and effective monitoring strategies are critical for the management of these parasites. Sentinel cages are an established means of assessing infestation pressure at fixed locations, but as smolts move through systems they will be exposed to varying lice densities. As a means of assessing infestation pressure along trajectories, we describe the development and application of towed sentinel cages (TSCs) in a Scottish sea loch containing salmonid aquaculture. Trial deployments took place over 3 yr (2016-2018), and levels of sea lice infestation were compared between methodologies. Oceanographic data was collected alongside TSCs to put the results into the environmental context that smolts and sea lice experienced during the tows. The sea lice infestation rates found from TSCs were comparable to those on contemporaneously deployed fixed sentinel cages. Thus, due to their practicability and consistency with other surveillance methods, TSCs could be used to improve the assessment of exposure risk along wild salmonid smolt migration trajectories, where these are known.

The impact of robotic surgery on a tertiary care colorectal surgery program, an assessment of costs and short term outcomes: A Canadian perspective.

BACKGROUND: Robotic surgery for colorectal pathology has gained interest as it can overcome technical challenges and limitations of traditional laparoscopic surgery. A lack of training and costs have been cited as reasons for limiting its use in Canada. The objective of this paper was to assess the impact of robotic surgery on outcomes and costs in a Canadian setting. METHODS: This is a retrospective study of consecutive patients undergoing left sided colorectal surgery ("Pre-Robotic Phase" n = 145 vs. "Post Robotic Phase" n = 150) and a single tertiary care centre in Ontario, Canada. Utilization and success of minimally invasive surgery (MIS), length of stay, complications and hospital costs were compared. Univariate and Multivariate analysis was used for these comparisons. RESULTS: Characteristics, diagnosis and type of resection were similar between groups. Robotic Implementation resulted in higher rates of successful MIS (i.e. attempt at MIS without conversion) (85% vs. 47%, P < 0.001), shorter mean length of stay (4.7 days vs. 8.4 days, P < 0.001), and similar mean operative times (3.9 h vs. 3.9 h, P = 0.93). Emergency Department visits were fewer in the Robotic Phase (24% vs. 34%, P = 0.04), with no difference in readmission, anastomotic leak or unplanned reoperation. After robotic implementation, the mean total hospital costs decreased, but this was not statistically significant (-$1453, 95% CI -$3974 to +$1068, P = 0.25). Regression analysis, adjusting for age, gender, obesity, ASA and procedure showed similar findings (Robotic Phase -$657, 95% CI -$3038 to +$1724, vs Pre Robotic Phase [Reference], P = 0.59). INTERPRETATION: Implementation of a robotic colorectal surgery program in a Canadian tertiary care centre showed improved clinical outcomes, without a significant increase in the cost of care. Although this study is from a single institution, we have demonstrated that robotic colorectal surgery is feasible and can be cost effective in the right setting.

A framework for role allocation in education, research and leadership services in Canadian academic divisions of general surgery: a modified Delphi consensus.

BACKGROUND: Moving toward a funding standard similar to that for clinical services for roles essential to the functioning of education, research and leadership services within divisions of general surgery is necessary to strengthen divisional resilience. We aimed to identify roles and underlying tasks in these services central to sustainable functioning of Canadian academic divisions of general surgery. METHODS: Between June 2018 and October 2020, we used a 4-step modified Delphi method (online survey, face-to-face nominal group technique [n = 12], semistructured telephone interview [n = 8] and nominal group technique [n = 12]) to achieve national consensus from an expert panel of all 17 heads of academic divisions of general surgery in Canada on the roles and accompanying tasks essential to education, research and leadership services within an academic division of general surgery. We used 70% agreement to determine consensus. RESULTS: The expert panel agreed that a framework for role allocation in education, research and leadership services was relevant and necessary. Consensus was reached for 7 roles within the educational service, 3 roles within the research service and 5 roles within the leadership service. CONCLUSION: Our framework represents a national consensus that defines role standards for education, research and leadership services in Canadian academic divisions of general surgery. The framework can help divisions build resiliency, and enable sustained and deliberate advances in these services.

Vascular Access Complications and Clinical Outcomes of Vascular Surgical Repairs Following Transcatheter Aortic Valve Implantation (TAVI).

BACKGROUND: Transcatheter aortic valve implantation (TAVI) procedures have revolutionized the treatment of aortic stenosis. However, due to large sheaths, improperly deployed closure devices, and the comorbidities and challenges innate to this population, vascular access complications can be devastating. The objective of this study is to evaluate vascular access complications in one of the largest TAVI sites in North America. METHODS: This was a retrospective single center review between January 2014 and December 2018 of vascular access complications necessitating operative intervention by vascular surgery. Patient demographics and preoperative comorbidities were collected. Type of vascular access complication, types of repair, closure device used, and postoperative outcomes were analyzed. RESULTS: A total of 37 cases out of a total of 985 TAVI procedures were identified. TAVI was carried out in the operating suite (70%) or the catheterization lab (30%). Consults to vascular surgery were requested intraoperatively (60%), immediately postoperative (14%), later in the day of the TAVI (20%), and on postoperative day 1 (6%). The location of injury included common femoral artery (49%), superficial femoral artery (11%) and external iliac artery (41%), with some cases injuring multiple vessels. Closure devices were found in the subcutaneous tissue (26%), anterior wall (37%), posterior wall (11%), intra-arterial (11%), closing the anterior to the posterior wall (16%), and in the inguinal ligament (5%). Injuries included tears (11%), dissections (38%), and vessel rupture (19%). The majority of repairs were done primarily (64%), with patch (28%) and bypass (8%) less frequently. Four patients died perioperatively (11%), 2 from hemorrhage, 1 from cardiac arrest, and 1 from progressive respiratory disease. CONCLUSIONS: Access complications during TAVI procedures predispose complex patients to increased risk of morbidity and mortality. Careful patient selection, proper access techniques, and performing high risk patients in the operating suite with vascular surgery are fundamental in minimizing complications.

Endothelin receptor antagonist improves donor lung function in an ex vivo perfusion system.

BACKGROUND: A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). METHODS: After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). RESULTS: Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin-eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. CONCLUSIONS: These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for ß-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures. METHODS: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes. DISCUSSION: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

Assessment of chicken breast meat quality after freeze/thaw abuse using magnetic resonance imaging techniques.

BACKGROUND: Freezing/thawing meat can result in quality losses as a result of the formation, melting and reformation of ice. These changes in water state can result in alterations in texture, water holding and other key quality attributes. It was hypothesized that magnetic resonance imaging (MRI) could quantify changes in mobility and localization of water as a function of freezing/thawing, which could be correlated with quality measurements. RESULTS: Drip loss increased significantly for unbrined samples by over 100% after each freeze/thaw cycle (1.5% to 3.3% to 5.3% drip loss). Brine uptake decreased 50% after 2 cycles (from 53% to 28% mass uptake). Drip loss for brined samples increased after 2 cycles; other attributes were not significantly affected. MRI showed brined samples had less change in both proton density and T2 distributions. High-field nuclear magnetic resonance (NMR) imaging showed greater change in T2 distributions. CONCLUSION: As freeze/thaw damage increased, meat quality was reduced in both brined and unbrined chicken breasts, with more prominent changes in unbrined meat. These decreases in quality correlated with changes, albeit small, in water mobility and localization as measured by MRI. High-field NMR micro-imaging showed more dramatic changes in T2 distributions in unbrined samples. These MRI techniques are shown to be useful in the assessment of meat quality after freeze/thaw abuse. © 2018 Society of Chemical Industry.

'Diabulima' through the lens of social media: a qualitative review and analysis of online blogs by people with Type 1 diabetes mellitus and eating disorders.

AIMS: To perform a qualitative review of online blogs authored by people self-identifying as having Type 1 diabetes and an eating disorder or 'diabulimia', a term used by people with Type 1 diabetes to describe an eating disorder that is characterized by deliberate restriction of insulin to control weight. METHODS: We conducted a structured qualitative review of online blogs published between 2012 and 2017 authored by people who report having Type 1 diabetes and an eating disorder or diabulimia. The subsequent thematic analysis followed a six-phase process and was conducted by two independent researchers. RESULTS: From 147 000 search results, 11 blogs (304 posts) matched criteria for further analyses. Three key themes and 18 subthemes emerged: 1) different aspects of bloggers' relationship with insulin, including motives for omitting insulin, secrecy of insulin omission and perception of control; 2) bloggers' experiences of diabetes complications, and diabetes ketoacidosis in particular, as well as their worries about future complications; 3) strategies for recovery and triggers for relapse, which involved diabetes self-management and setting up a support system. CONCLUSIONS: Qualitative analyses of blogs authored by people with Type 1 diabetes and an eating disorder or diabulimia have identified high levels of diabetes distress and provided insight into different motives for insulin omission and strategies for recovery. Considering the limited evidence for effective interventions, these findings may help the development of complex interventions to improve biomedical and psychological outcomes in this group.

Eating disorders in people with Type 1 diabetes: experiential perspectives of both clients and healthcare professionals.

AIMS: To explore the experiential perspective of people with Type 1 diabetes mellitus and eating disorders and that of the healthcare professionals treating them, and to understand the experience of both sides to inform future development of healthcare services. METHODS: Participants were recruited from Diabetics with Eating Disorders (a national UK charity), and through professional networks. Nine partially/fully recovered individuals with Type 1 diabetes and eating disorders and eight healthcare professionals participated in semi-structured interviews carried out by medically trained researchers. Data were transcribed and coded using a six-stage framework of thematic analysis. RESULTS: Four superordinate themes and several subordinate themes emerged from the Type 1 diabetes and eating disorders dataset: (1) perceptions surrounding service provision; (2) reflections on the recovery process; (3) the experiential perspective of living with Type 1 diabetes and an eating disorder; and (4) support mechanisms. Healthcare professional data elicited three superordinate themes and several subordinate themes: (1) service provision; (2) personal insight and reflection of professional role; and (3) challenges of working with dual diagnoses. CONCLUSION: People with Type 1 diabetes and eating disorders and their healthcare professionals provided insight into healthcare services from the patient and care delivery perspectives. There was general agreement from both groups that a multidisciplinary, collaborative (family inclusive), clinical approach to treatment is important, as well as adequate training opportunities for service providers. These findings may help to inform development strategies for multidisciplinary care approaches to Type 1 diabetes complicated by eating disorders.

Standard vs. intensified management of heart failure to reduce healthcare costs: results of a multicentre, randomized controlled trial.

AIMS: To determine if an intensified form of heart failure management programme (INT-HF-MP) based on individual profiling is superior to standard management (SM) in reducing health care costs during 12-month follow-up (primary endpoint). METHODS AND RESULTS: A multicentre randomized trial involving 787 patients (full analysis set) discharged from four tertiary hospitals with chronic HF who were randomized to SM (n = 391) or INT-HF-MP (n = 396). Mean age was 74 ± 12 years, 65% had HF with a reduced ejection fraction (31.4 ± 8.9%) and 14% were remote-dwelling. Study groups were well matched. According to Green, Amber, Red Delineation of rIsk And Need in HF (GARDIAN-HF) profiling, regardless of location, patients in the INT-HF-MP received a combination of face-to-face (home visits) and structured telephone support (STS); only 9% (`low risk') were designated to receive the same level of management as the SM group. The median cost in 2017 Australian dollars (A$1 equivalent to ∼EUR €0.7) of applying INT-HF-MP was significantly greater than SM ($152 vs. $121 per patient per month; P < 0.001), However, at 12 months, there was no difference in total health care costs for the INT-HF-MP vs. SM group (median $1579, IQR $644 to $3717 vs. $1450, IQR $564 to $3615 per patient per month, respectively). This reflected minimal differences in all-cause mortality (17.7% vs. 18.4%; P = 0.848) and recurrent hospital stay (18.6 ± 26.5 vs. 16.6 ± 24.8 days; P = 0.199) between the INT-HF-MP and SM groups, respectively. CONCLUSION: During 12-months follow-up, an INT-HF-MP did not reduce healthcare costs or improve health outcomes relative to SM.

Population-based study to re-evaluate optimal lymph node yield in colonic cancer.

BACKGROUND: It is well established that lymph node (LN) yield in colonic cancer resection has prognostic significance, although optimal numbers are not clear. Here, LN thresholds associated with both LN positivity and survival were evaluated in a single population-based data set. METHODS: Treatment records were linked to the Ontario Cancer Registry to identify a 25 per cent random sample of all patients with stage II/III colonic cancer between 2002 and 2008. Multivariable regression and Cox models evaluated factors associated with LN positivity and cancer-specific survival (CSS) respectively. Optimal thresholds were obtained using sequential regression analysis. RESULTS: On adjusted analysis of 5508 eligible patients, younger age (P < 0·001), left-sided tumours (P = 0·003), higher T category (P < 0·001) and greater LN yield (relative risk 0·89, 95 per cent c.i. 0·81 to 0·97; P = 0·007) were associated with a greater likelihood of LN positivity. Regression analyses with multiple thresholds suggested no substantial increase in LN positivity beyond 12-14 LNs. Cox analysis of stage II disease showed that lower LN yield was associated with a significant increase in the risk of death from cancer (CSS hazard ratio range 1·55-1·74; P < 0·001) compared with a greater LN yield, with no significant survival benefit beyond a yield of 20 LNs. Similarly, for stage III disease, a lower LN yield was associated with an increase in the risk of death from cancer (CSS hazard ratio range 1·49-2·20; P < 0·001) versus a large LN yield. In stage III disease, there was no observed LN threshold for survival benefit in the data set. CONCLUSION: There is incongruity in the optimal LN evaluation for colonic cancer. Although the historically stated threshold of 12 LNs may ensure accurate staging in colonic cancer, thresholds for optimal survival are associated with far greater yields.

Lymph node evaluation for colon cancer in routine clinical practice: a population-based study.

BACKGROUND: Guidelines recommend that 12 or more lymph nodes (lns) be evaluated during surgical resection of colon cancer. Here, we report ln yield and its association with survival in routine practice. METHODS: Electronic records of treatment were linked to the population-based Ontario Cancer Registry to identify all patients with colon cancer treated during 2002-2008. The study population (n = 5508) included a 25% random sample of patients with stage ii or iii disease. Modified Poisson regression was used to identify factors associated with ln yield; Cox models were used to explore the association between ln yield and overall (os) and cancer-specific survival (css). RESULTS: During 2002-2008, median ln yield increased to 17 from 11 nodes (p < 0.001), and the proportion of patients with 12 or more nodes evaluated increased to 86% from 45% (p < 0.001). Lymph node positivity did not change over time (to 53% from 54%, p = 0.357). Greater ln yield was associated with younger age (p < 0.001), less comorbidity (p = 0.004), higher socioeconomic status (p = 0.001), right-sided tumours (p < 0.001), and higher hospital volume (p < 0.001). In adjusted analyses, a ln yield of less than 12 nodes was associated with inferior os and css for stages ii and iii disease [stage ii os hazard ratio (hr): 1.36; 95% confidence interval (ci): 1.19 to 1.56; stage ii css hr: 1.52; 95% ci: 1.26 to 1.83; and stage iii os hr: 1.45; 95% ci: 1.30 to 1.61; stage iii css hr: 1.54; 95% ci: 1.36 to 1.75]. CONCLUSIONS: Despite a temporal increase in ln yield, the proportion of cases with ln positivity has not changed. Lymph node yield is associated with survival in patients with stages ii and iii colon cancer. The association between ln yield and survival is unlikely to be a result of stage migration.

Normothermic ex vivo perfusion provides superior organ preservation and enables viability assessment of hearts from DCD donors.

The shortage of donors in cardiac transplantation may be alleviated by the use of allografts from donation after circulatory death (DCD) donors. We have previously shown that hearts exposed to 30 min warm ischemic time and then flushed with Celsior supplemented with agents that activate ischemic postconditioning pathways, show complete recovery on a blood-perfused ex vivo working heart apparatus. In this study, these findings were assessed in a porcine orthotopic heart transplant model. DCD hearts were preserved with either normothermic ex vivo perfusion (NEVP) using a clinically approved device, or with standard cold storage (CS) for 4 h. Orthotopic transplantation into recipient animals was subsequently undertaken. Five of six hearts preserved with NEVP demonstrated favorable lactate profiles during NEVP and all five could be weaned off cardiopulmonary bypass posttransplant, compared with 0 of 3 hearts preserved with CS (p < 0.05, Fisher's exact test). In conclusion, DCD hearts flushed with supplemented Celsior solution and preserved with NEVP display viability before and after transplantation. Viability studies of human DCD hearts using NEVP are warranted.

Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis.

Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin-induced rhabdomyolysis.

Increasing the tolerance of DCD hearts to warm ischemia by pharmacological postconditioning.

Donation after circulatory death (DCD) offers a potential additional source of cardiac allografts. We used a porcine asphyxia model to evaluate viability of DCD hearts subjected to warm ischemic times (WIT) of 20­40 min prior to flushing with Celsior (C) solution. We then assessed potential benefits of supplementing C with erythropoietin, glyceryl trinitrate and zoniporide (Cs), a combination that we have shown previously to activate ischemic postconditioning pathways. Hearts flushed with C/Cs were assessed for functional, biochemical and metabolic recovery on an ex vivo working heart apparatus. Hearts exposed to 20-min WIT showed full recovery of functional and metabolic profiles compared with control hearts (no WIT). Hearts subjected to 30- or 40-min WIT prior to C solution showed partial and no recovery, respectively. Hearts exposed to 30-min WIT and Cs solution displayed complete recovery, while hearts exposed to 40-min WIT and Cs solution demonstrated partial recovery. We conclude that DCD hearts flushed with C solution demonstrate complete recovery up to 20-min WIT after which there is rapid loss of viability. Cs extends the limit of WIT tolerability to 30 min. DCD hearts with ≤30-min WIT may be suitable for transplantation and warrant assessment in a transplant model.

Fueling the public health workforce pipeline through student surge capacity response teams.

In January 2003, the University of North Carolina Center for Public Health Preparedness established Team Epi-Aid to match graduate student volunteers with state and local health departments to assist with outbreaks and other applied public health projects. This study assessed whether Team Epi-Aid participation by full-time graduate students impacted post-graduation employment, particularly by influencing students to work in governmental public health upon graduation. In September 2010, 223 program alumni were contacted for an online survey and 10 selected for follow-up interviews. Eighty-three Team Epi-Aid alumni answered the survey (response rate = 37 %). Forty-one (49 %) reported participating in at least one activity, with 12/41 (29 %) indicating participation in Team Epi-Aid influenced their job choice following graduation. In 6 months prior to enrolling at UNC, 30 (36 %) reported employment in public health, with 16/30 (53 %) employed in governmental public health. In 6 months following graduation, 34 (41 %) reported employment in public health, with 27 (80 %) employed in governmental public health. Eight alumni completed telephone interviews (response rate = 80 %). Five credited Team Epi-Aid with influencing their post-graduation career. Experience in applied public health through a group such as Team Epi-Aid may influence job choice for public health graduates.

Distinct and opposing roles for the phosphatidylinositol 3-OH kinase catalytic subunits p110α and p110ß in the regulation of insulin secretion from rodent and human beta cells.

AIMS/HYPOTHESIS: Phosphatidylinositol 3-OH kinases (PI3Ks) regulate beta cell mass, gene transcription, and function, although the contribution of the specific isoforms is unknown. As reduced type 1A PI3K signalling is thought to contribute to impaired insulin secretion, we investigated the role of the type 1A PI3K catalytic subunits α and ß (p110α and -ß) in insulin granule recruitment and exocytosis in rodent and human islets. METHODS: The p110α and p110ß subunits were inhibited pharmacologically or by small hairpin (sh)RNA-mediated knockdown, and were directly infused or overexpressed in mouse and human islets, beta cells and INS-1 832/13 cells. Glucose-stimulated insulin secretion (GSIS), single-cell exocytosis, Ca(2+) signalling, plasma membrane granule localisation, and actin density were monitored. RESULTS: Inhibition or knockdown of p110α increased GSIS. This was not due to altered Ca(2+) responses, depolymerisation of cortical actin or increased cortical granule density, but to enhanced Ca(2+)-dependent exocytosis. Intracellular infusion of recombinant PI3Kα (p110α/p85ß) blocked exocytosis. Conversely, knockdown (but not pharmacological inhibition) of p110ß blunted GSIS, reduced cortical granule density and impaired exocytosis. Exocytosis was rescued by direct intracellular infusion of recombinant PI3Kß (p110ß/p85ß) even when p110ß catalytic activity was inhibited. Conversely, both the wild-type p110ß and a catalytically inactive mutant directly facilitated exocytosis. CONCLUSIONS/INTERPRETATION: Type 1A PI3K isoforms have distinct and opposing roles in the acute regulation of insulin secretion. While p110α acts as a negative regulator of beta cell exocytosis and insulin secretion, p110ß is a positive regulator of insulin secretion through a mechanism separate from its catalytic activity.

Enhanced preservation of pig cardiac allografts by combining erythropoietin with glyceryl trinitrate and zoniporide.

Erythropoietin has a tissue-protective effect independent of its erythropoietic effect that may be enhanced by combining it with the nitric oxide donor glyceryl trinitrate (GTN) and the sodium-hydrogen exchange inhibitor zoniporide in rat hearts stored with an extracellular-based preservation solution (EBPS). We thus sought to test this combination of agents in a porcine model of orthotopic heart transplantation incorporating donor brain death and total ischaemic time of approximately 260 min. Pig hearts were stored in one of four storage solutions: unmodified EBPS (CON), EBPS supplemented with GTN and zoniporide (GZ), EBPS supplemented with erythropoietin and zoniporide (EZ), or EBPS supplemented with all three agents (EGZ). A total of 4/5 EGZ hearts were successfully weaned from cardiopulmonary bypass compared with only 2/5 GZ hearts, 0/5 CON hearts and 0/5 EG hearts (p = 0.017). Following weaning from bypass EGZ hearts demonstrated superior contractility and haemodynamics than GZ hearts. All weaned hearts displayed impaired diastolic function. Release of troponin I from EGZ hearts was lower than all other groups. In conclusion, supplementation of EBPS with erythropoietin, glyceryl trinitrate and zoniporide provided superior donor heart preservation than all other strategies tested.

Diabetes and gout: efficacy and safety of febuxostat and allopurinol.

AIM: Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents. METHODS: Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ≥8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial. RESULTS: Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m²) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events. CONCLUSIONS: Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses.