Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib.

Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877 C > T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

The Infarct-Limiting Effect of Remote Ischemic Conditioning in Rats Is Not Affected by Aspirin.

PURPOSE: Remote ischemic conditioning (RIC) has been shown to be a powerful cardioprotective therapy in animal models. However, a protective effect in patients presenting with acute myocardial infarction has failed to be confirmed. A recent pre-clinical study reported that aspirin which is routinely given to patients undergoing reperfusion therapy blocked the infarct-limiting effect of ischemic postconditioning. The present study was designed to test whether aspirin could also be blocking the infarct-limiting effect of RIC. METHODS: This was investigated in vivo using male Sprague Dawley rats (n = 5 to 6 per group) subjected to either 30 min of regional myocardial ischemia, followed by 120-min reperfusion, or additionally to a RIC protocol initiated after 20-min myocardial ischemia. The RIC protocol included four cycles of 5-min hind limb ischemia interspersed with 5-min reperfusion. Intravenous aspirin (30 mg/kg) or vehicle (saline) was administered after 15-min myocardial ischemia. RESULTS: RIC significantly reduced infarct size (IS) normalized to the area at risk, by 47%. Aspirin administration did not affect IS nor did it attenuate the infarct-limiting effect of RIC. CONCLUSION: Aspirin administration in the setting of myocardial infarction is not likely to interfere with the cardioprotective effect of RIC.

Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

Vaccine hesitancy educational tools for healthcare providers and trainees: A scoping review.

In the era of vaccine hesitancy, highlighted by the current SARS-CoV2 pandemic, there is an acute need to develop an approach to reduce and address apprehension towards vaccinations. We sought to map and present an overview of existing educational interventions for healthcare providers (HCPs) on strategies to engage in effective vaccine discussion. We applied the Joanna Briggs Institute methodology framework in this scoping review. We searched five relevant databases (MEDLINE, CINAHL, EMBASE, PsycInfo, and SCOPUS) and grey literature through the Google search engine using keywords and subject headings that were systematically identified. We identified 3384 citations in peer-reviewed literature and 41 citations in grey literature. After screening for our inclusion criteria, we included 28 citations from peer reviewed literature and 16 citations from grey literature for analysis. We identified a total of 41 unique education interventions. Interventions were available from multiple disciplines, training levels, clinical settings, and diseases/vaccines. Interventions predominantly centered around two foci: knowledge sharing and communication training. Most interventions identified from peer-reviewed literature were facilitated and were applied with multiple modes of delivery. Interventions from grey literature were more topical and generally self-directed. We identified several gaps in knowledge. Firstly, accessibility and generalizability of interventions was limited. Secondly, distribution of interventions did not adequately address nursing and pharmacy disciplines, and did not cover the breadth of medical specialties for whom vaccine discussions apply. Thirdly, no interventions addressed self monitoring and the clinicians' recognition and management of emotions during difficult conversations. There is a need to address this gap and provide available, credible and comprehensive educational interventions that will support our healthcare providers in effective communication with vaccine hesitant patients.

Contactless skin perfusion monitoring with video cameras: tracking pharmacological vasoconstriction and vasodilation using photoplethysmographic changes.

Objectives.Clinical assessment of skin perfusion informs prognosis in critically ill patients. Video camera monitoring could provide an objective, continuous method to monitor skin perfusion. In this prospective, interventional study of healthy volunteers, we tested whether video camera-derived photoplethysmography imaging and colour measurements could detect drug-induced skin perfusion changes.Approach.We monitored the lower limbs of 30 volunteers using video cameras while administering phenylephrine (a vasoconstrictor) and glyceryl trinitrate (a vasodilator). We report relative pixel intensity changes from baseline, as absolute values are sensitive to environmental factors. The primary outcome was the pre- to peak- infusion green channel amplitude change in the pulsatile PPGi waveform component. Secondary outcomes were pre-to-peak changes in the photoplethysmographic imaging waveform baseline, skin colour hue and skin colour saturation.Main results.The 30 participants had a median age of 29 years (IQR 25-34), sixteen (53%) were male. A 34.7% (p= 0.0001) mean decrease in the amplitude of the pulsatile photoplethysmographic imaging waveform occurred following phenylephrine infusion. A 30.7% (p= 0.000004) mean increase occurred following glyceryl trinitrate infusion. The photoplethysmographic imaging baseline decreased with phenylephrine by 2.1% (p= 0.000 02) and increased with glyceryl trinitrate by 0.5% (p= 0.026). Skin colour hue changed in opposite direction with phenylephrine (-0.0013,p= 0.0002) and glyceryl trinitrate (+0.0006,p= 0.019). Skin colour saturation decreased with phenylephrine by 0.0022 (p= 0.0002), with no significant change observed with glyceryl trinitrate (+0.0005,p= 0.21).Significance.Drug-induced vasoconstriction and vasodilation are associated with detectable changes in photoplethysmographic imaging waveform parameters and skin hue. Our findings suggest video cameras have great potential for continuous, contactless skin perfusion monitoring.

Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop.

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

The impact of cultural stress and gender norms on alcohol use severity among Latino immigrant men.

Alcohol misuse affects 15 million people in the United States. Compared to White men, Latino men have disproportionately higher rates of both alcohol misuse and negative alcohol-related consequences (e.g. drunk driving, liver disease, alcohol dependence, HIV/AIDS). This cross sectional study examined how cultural stressors [immigration stress and negative context of reception (NCR)] coupled with traditional Latino male gender norms (machismo and caballerismo) influences alcohol use severity (AUS) among adult Latino immigrant men. Data for the present study was collected between 2017 and 2018 from 279 Cuban, Central American, and South American adult Latino men who immigrated to the US approximately 10 years prior. Results from hierarchical multiple regression analysis revealed higher levels of perceived NCR (ß = 0.15, p = .01), and machismo (ß = 0.16, p = .02) were associated with greater AUS. Significant interaction effects were found between both cultural stressors and machismo [immigration stress x machismo (ß = 0.22, p < .001); NCR x machismo (ß = 0.22, p < .001)] whereby higher levels of machismo strengthened the association between cultural stress and AUS. Findings from the present study can inform culturally appropriate interventions aimed at mitigating alcohol use among Latino immigrant men.

[Purpura in a young woman with hyperthyroidism]. / Purpura chez une jeune femme hyperthyroïdienne.

INTRODUCTION: Propylthiouracil (PTU) is a synthetic antithyroid drug that can induce ANCA-associated vasculitis. OBSERVATION: A 27-year-old woman diagnosed with Graves' disease was on PTU for the past 10 years. She developed purpuric lesions of the legs and on the tip of the nose diagnosed as vasculitis. ANCAs were positive, with anti-MPO and anti-PR3 on blood ELISA. After discontinuation of PTU, she was able to fully recover. CONCLUSION: All synthetic antithyroid drugs can induce ANCA-associated vasculitis, more often PTU. In most cases, antibodies are directed against MPO. Dual anti-MPO and anti-PR3 positivity is possible, but rare. The mechanism could be through an accumulation of PTU in neutrophils, altering the structure of MPO and making it immunogenic. PTU can also induce ANCA-free or lupus vasculitis, maculopapular rashes or urticaria. Many other drugs can induce ANCA-associated vasculitis.

Cigarette-smoking characteristics and interest in cessation in patients with head-and-neck cancer.

Purpose: Many patients diagnosed with head-and-neck cancer are current or former smokers. Despite the well-known adverse effects of smoking, continuation of smoking during cancer treatment is associated with reduced efficacy of that treatment and with cancer recurrence. In the present study, we examined smoking characteristics in patients with head-and-neck cancer near the time of cancer treatment. Methods: A prospective cohort of patients with head-and-neck cancer who attended a dental oncology clinic before receiving cancer treatment at a regional cancer centre were invited to participate in a study that involved completing an interviewer-administered questionnaire to assess smoking characteristics, intention to quit, motivation to quit, and strategies perceived to potentially aid in successful cessation. Results: The study enrolled 493 ever-smokers, with a response rate of 96.1% and a self-reported current smoker rate of 37.1% (n = 183). Most of the current smokers reported high nicotine dependence, with 84.7% (n = 155) indicating a time to first cigarette of 30 minutes or less. Most had previously attempted to quit smoking (77.0%), and many had prior unsuccessful quit attempts before resuming smoking again. Most were interested in quitting smoking (85.8%), and many (70.5%) were seriously considering quitting smoking within the subsequent 30 days. Conclusions: Patients with head-and-neck cancer reported high nicotine dependence and high interest in cessation opportunities near the time of treatment for cancer. Those results might provide support for provision of smoking cessation opportunities.

Targeting myocardial ischaemic injury in the absence of reperfusion.

Sudden myocardial ischaemia causes an acute coronary syndrome. In the case of ST-elevation myocardial infarction (STEMI), this is usually caused by the acute rupture of atherosclerotic plaque and obstruction of a coronary artery. Timely restoration of blood flow can reduce infarct size, but ischaemic regions of myocardium remain in up to two-thirds of patients due to microvascular obstruction (MVO). Experimentally, cardioprotective strategies can limit infarct size, but these are primarily intended to target reperfusion injury. Here, we address the question of whether it is possible to specifically prevent ischaemic injury, for example in models of chronic coronary artery occlusion. Two main types of intervention are identified: those that preserve ATP levels by reducing myocardial oxygen consumption, (e.g. hypothermia; cardiac unloading; a reduction in heart rate or contractility; or ischaemic preconditioning), and those that increase myocardial oxygen/blood supply (e.g. collateral vessel dilation). An important consideration in these studies is the method used to assess infarct size, which is not straightforward in the absence of reperfusion. After several hours, most of the ischaemic area is likely to become infarcted, unless it is supplied by pre-formed collateral vessels. Therefore, therapies that stimulate the formation of new collaterals can potentially limit injury during subsequent exposure to ischaemia. After a prolonged period of ischaemia, the heart undergoes a remodelling process. Interventions, such as those targeting inflammation, may prevent adverse remodelling. Finally, harnessing of the endogenous process of myocardial regeneration has the potential to restore cardiomyocytes lost during infarction.

Juvenile cataract in association with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by benign hamartomas occurring in multiple organ systems including the brain, kidneys, heart, lungs, liver, skin, and the eyes. Typical retinal findings associated with TSC include astrocytic hamartoma and achromic patch. While rare cases of cataract occurring in the setting of TSC have been reported, this is the first analysis of a large series of individuals with TSC that aims to quantify the frequency of this finding and to describe its clinical and genetic associations. MATERIALS AND METHODS: This is a retrospective chart review of 244 patients from the Herscot Center for Tuberous Sclerosis Complex at the Massachusetts General Hospital who underwent complete ophthalmic examination. We describe the clinical and genetic findings in five individuals with TSC and juvenile cataract. RESULTS: Four of five cases (80%) were unilateral. The cataract was described as having an anterior subcapsular component in 3 of 5 cases (60%). Three individuals (60%) underwent lensectomy with intraocular lens (IOL) implant and two individuals (40%) were observed. Genetic testing revealed a known disease-causing mutation in TSC2 in 100% of cases. CONCLUSIONS: Recent evidence suggests that mTOR signaling may play a role in cataract formation which could explain the relatively high incidence of juvenile cataract in this population. Juvenile cataract is a potentially under-recognized ocular manifestation of TSC.

Effect of Remote Glucose Monitoring Utilizing Computerized Insulin Dose Adjustment Algorithms: A Pilot Project.

INTRODUCTION: Primary care physicians are often challenged to adjust insulin doses. To facilitate this process, we evaluated in a safety net clinic the work flow and glycemic effects of remote glucose monitoring utilizing Federal Drug Administration (FDA) cleared, Conformité Européenne (CE) registered software that contained computerized algorithms for insulin dose adjustments to help clinicians make dosing decisions for insulin-requiring patients. METHODS: Patients taking insulin for at least 6 months with HbA1c levels of at least 8.0% measured glucose levels with a meter attached to their smartphones. Readings were automatically transmitted to a secure, Health Insurance Portability and Accountability Act (HIPAA)-approved server. Values were analyzed every 2-3 weeks and reports, including recommendations for insulin dose changes, were sent to a clinic nurse practitioner (NP) who modified or accepted the recommendations. A staff person contacted patients with the new doses determined by the NP. RESULTS: Insulin regimens included basal alone (N = 11), basal/bolus (N = 14), and self-mixed/split (N = 3). Baseline HbA1 levels of 10.0% fell to 8.1% at 3 months (N = 28) and 7.6% at 6 months (N = 17) without any clinic visits for dose adjustments. There were 268 reports which allowed providers to see 268 other patients during these avoided clinic visits. The NP agreed with 82% of the recommendations. The total doses of insulin increased by 24%. No patient experienced severe hypoglycemia or visited an emergency department for hypoglycemia. CONCLUSION: Remote glucose monitoring utilizing computerized insulin dose adjustment algorithms saved time for both providers and patients while effectively improving glycemia. FUNDING: The Leonard M. Lipman Charitable Trust and Mellitus Health.

The risk of developing major depression among individuals with subthreshold depression: a systematic review and meta-analysis of longitudinal cohort studies.

BACKGROUND: Studies have consistently shown that subthreshold depression is associated with an increased risk of developing major depression. However, no study has yet calculated a pooled estimate that quantifies the magnitude of this risk across multiple studies. METHODS: We conducted a systematic review to identify longitudinal cohort studies containing data on the association between subthreshold depression and future major depression. A baseline meta-analysis was conducted using the inverse variance heterogeneity method to calculate the incidence rate ratio (IRR) of major depression among people with subthreshold depression relative to non-depressed controls. Subgroup analyses were conducted to investigate whether IRR estimates differed between studies categorised by age group or sample type. Sensitivity analyses were also conducted to test the robustness of baseline results to several sources of study heterogeneity, such as the case definition for subthreshold depression. RESULTS: Data from 16 studies (n = 67 318) revealed that people with subthreshold depression had an increased risk of developing major depression (IRR = 1.95, 95% confidence interval 1.28-2.97). Subgroup analyses estimated similar IRRs for different age groups (youth, adults and the elderly) and sample types (community-based and primary care). Sensitivity analyses demonstrated that baseline results were robust to different sources of study heterogeneity. CONCLUSION: The results of this study support the scaling up of effective indicated prevention interventions for people with subthreshold depression, regardless of age group or setting.

Centralized Clinical Trial Imaging Data Management: Practical Guidance from a Comprehensive Cancer Center's Experience.

Medical imaging is an integral part of clinical trial research and it must be managed properly to provide accurate data to the sponsor in a timely manner (Clune in Cancer Inform 4:33-56, 2007; Wang et al. in Proc SPIE Int Soc Opt Eng 7967, 2011). Standardized workflows for site qualification, protocol preparation, data storage, retrieval, de-identification, submission, and query resolution are paramount to achieve quality clinical trial data management such as reducing the number of imaging protocol deviations and avoiding delays in data transfer. Centralization of data management and implementation of relational databases and electronic workflows can help maintain consistency and accuracy of imaging data. This technical note aims at sharing the practical implementation of our centralized clinical trial imaging data management processes to avoid the fragmentation of tasks among various disease centers and research staff, and enable us to provide quality, accurate, and timely imaging data to clinical trial sponsors.

How can we better help cancer patients quit smoking? The London Regional Cancer Program experience with smoking cessation.

Background: Because continued cigarette smoking after a cancer diagnosis is associated with detrimental outcomes, supporting cancer patients with smoking cessation is imperative. We evaluated the effect of the Smoking Cessation Program at the London Regional Cancer Program (lrcp) over a 2-year period. Methods: The Smoking Cessation Program at the lrcp began in March 2014. New patients are screened for tobacco use. Tobacco users are counselled about the benefits of cessation and are offered referral to the program. If a patient accepts, a smoking cessation champion offers additional counselling. Follow-up is provided by interactive voice response (ivr) telephone system. Accrual data were collected monthly from January 2015 to December 2016 and were evaluated. Results: During 2015-2016, 10,341 patients were screened for tobacco use, and 18% identified themselves as current or recent tobacco users. In 2015, 84% of tobacco users were offered referral, but only 13% accepted, and 3% enrolled in ivr follow-up. At the lrcp in 2016, 77% of tobacco users were offered referral to the program, but only 9% of smokers accepted, and only 2% enrolled in ivr follow-up. Conclusions: The Smoking Cessation Program at the lrcp has had modest success, because multiple factors influence a patient's success with cessation. Limitations of the program include challenges in referral and counselling, limited access to nicotine replacement therapy (nrt), and minimal follow-up. To mitigate some of those challenges, a pilot project was launched in January 2017 in which patients receive free nrt and referral to the local health unit.

Comparison of Insulin Dose Adjustments by Primary Care Physicians and Endocrinologists.

IN BRIEF Insulin dose adjustment decisions in 20 simulated patients by nine primary care physicians (PCPs) and nine endocrinologists were compared to the algorithms used in a diabetes program in a large safety-net clinic. The number of dose changes was similar in the PCP and endocrinologist groups; however, the amounts of the dose changes in the PCP group were significantly closer to the diabetes program algorithms than the amounts in the endocrinologist group. Time constraints, rather than lack of ability, seem to be the major barrier to PCPs treating patients with insulin.

Unusually high illness severity and short incubation periods in two foodborne outbreaks of Salmonella Heidelberg infections with potential coincident Staphylococcus aureus intoxication.

We describe the investigation of two temporally coincident illness clusters involving salmonella and Staphylococcus aureus in two states. Cases were defined as gastrointestinal illness following two meal events. Investigators interviewed ill persons. Stool, food and environmental samples underwent pathogen testing. Alabama: Eighty cases were identified. Median time from meal to illness was 5·8 h. Salmonella Heidelberg was identified from 27 of 28 stool specimens tested, and coagulase-positive S. aureus was isolated from three of 16 ill persons. Environmental investigation indicated that food handling deficiencies occurred. Colorado: Seven cases were identified. Median time from meal to illness was 4·5 h. Five persons were hospitalised, four of whom were admitted to the intensive care unit. Salmonella Heidelberg was identified in six of seven stool specimens and coagulase-positive S. aureus in three of six tested. No single food item was implicated in either outbreak. These two outbreaks were linked to infection with Salmonella Heidelberg, but additional factors, such as dual aetiology that included S. aureus or the dose of salmonella ingested may have contributed to the short incubation periods and high illness severity. The outbreaks underscore the importance of measures to prevent foodborne illness through appropriate washing, handling, preparation and storage of food.

Does the Use of Volumetric Modulated Arc Therapy Reduce Gastrointestinal Symptoms after Pelvic Radiotherapy?

AIMS: Growing numbers of patients with cancer are surviving after treatment with pelvic radiotherapy. We evaluated the technique of volumetric modulated arc therapy (VMAT), which delivers a decreased dose to the organs at risk. We aimed to determine outcomes of this technique in terms of patient-reported acute toxicity and late effects and correlate the frequency of gastrointestinal symptoms with the volume of bowel receiving radiation dose. MATERIALS AND METHODS: Patients who were to receive VMAT for gynaecological malignancy completed patient-reported outcomes at baseline, the end of treatment, 8 weeks and 1 year. The rates of patient-reported toxicity were correlated with the volume of bowel irradiated. RESULTS: The frequencies of patient-reported gastrointestinal symptoms increased in the acute toxicity phase and tended to improve at 1 year, with the exception of faecal incontinence and rectal bleeding (P < 0.05). There was not a strong association between the volume of small bowel that was irradiated (P > 0.05 at all dose levels) and reported toxicity, suggesting that other factors are involved in the development of toxicity. CONCLUSION: Although VMAT decreases the dose delivered to the small bowel, this does not translate into a reduction in patient-reported toxicity.

Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning.

This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia-reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 µM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia-reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPCeff = 0.36 ± 0.03 µM vs C eff = 0.04 ± 0.04 µM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia-reperfusion injury (cell death = 45 ± 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors.

9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection.

In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.