Safe Pathway Research Articles

Long-term impact of postnatal nutritional programming on cardiac sensitivity to ischemia-reperfusion injury in vivo and on cardio-protective pathways in mice

Nutritional disturbances during the postnatal period may be responsible for a predisposition, or “programming”, to increased cardio-metabolic risk and to a progressive alteration of left ventricular contractility in adulthood. Our aim was to evaluate in mice the impact of postnatal overfeeding (PNOF) on cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo and on the myocardial expression of genes involved in heart protection against ischemia. PNOF was induced by the reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) was composed of 9 male pups/mother and overfed group (OF) of 3 pups/mother. In vivo I-R injury was induced by the ligation of the anterior interventricular artery for 45 minutes followed by 24h of reperfusion in hearts from 6-months aged mice. The gene expressions of proteins of interest composing the cardioprotective pathways (RISK pathway: Akt, ERK; SAFE pathway: JAK/STAT3; Sirtuins: SIRT1) were measured by RT-qPCR in mice aged 4 and 6 months. PNOF induced in OF group an early and permanent increase in body weight (+ 23%, P < 0.01, N = 11) and a significant increase of infarct size (+ 32%, P < 0.05, N = 11) at 6 months. Hearts OF mice aged 4 months showed a decreased expression of cardioprotective pathways, represented by a reduction in the gene expression of ERK1, Akt, PI3K, STAT3 and SIRT1. At 6 months, the expression of cardioprotective pathways was also reduced in OF group, with the diminution of the gene expression of STAT3, Akt and Erk1. Nutritional programming through short-term PNOF induced a long-lasting decrease in the expression of signaling pathways involved in cardiac cellular protection, which could explain why 6-months old mice show increased susceptibility to myocardial I-R injury in vivo. The mechanism of these alterations needs further exploration, but could involve alterations in cardiomyocyte's balance between apoptotic and regenerative pathways.

Electrocardiographic parameters of Sapajus libidinosus (SPIX, 1823) after chemical immobilization with tiletamine-zolazepam.

Tiletamine-zolazepam is a widely used as an alternative chemical immobilization method in non-human primates, with a safe application pathway and necessary relaxation. In order to determine the electrocardiographic parameters of Sapajus libidinosus after intramuscular tiletamine-zolazepam administration at the dose of 5mg/kg, nine animals were submitted to anesthesia. The interpretation of the electrocardiogram determined: heart rate in bpm and heart rhythm, P wave, P-R interval, R wave, QRS complex, T wave, Q-T interval, corrected QT interval and electrical axis. The mean HR was 206±32bpm. The majority of the monkeys showed normal sinus rhythm, but one animal showed sinus tachycardia. The most commonly observed electrical axis was between +30° and +90°. Two animals presented bigger alterations in the tracing such as low amplitude QRS and T wave bigger than 1/4 of the R wave. The administration of tiletamine-zolazepam was safe and efficacious, with minimal cardiovascular effects.

Kcne4 deletion sex dependently inhibits the RISK pathway response and exacerbates hepatic ischemia-reperfusion injury in mice.

Activation of antiapoptotic signaling cascades, such as the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways, is protective in a variety of tissues in the context of ischemia-reperfusion (IR) injury. Hepatic IR injury causes clinically significant hepatocellular damage in surgical procedures, including liver transplantation and hepatic resection, increasing associated morbidity and mortality. We previously found that the cardiovascular-expressed K+ voltage-gated channel ancillary subunit KCNE4 sex specifically influences the cardiac RISK/SAFE pathway response to IR and that Kcne4 deletion testosterone dependently exacerbates cardiac IR injury. Here, we discovered that germline Kcne4 deletion exacerbates hepatic IR injury damage in 13-mo-old male mice, despite a lack of Kcne4 expression in male mouse liver. Examining RISK/SAFE pathway induction, we found that Kcne4 deletion prevents the hepatic ERK1/2 phosphorylation response to IR injury. Conversely, in 13-mo-old female mice, Kcne4 deletion increased both baseline and post-IR GSK-3β inhibitory phosphorylation, and pharmacological GSK-3β inhibition was hepatoprotective. Finally, castration of male mice restored normal hepatic RISK/SAFE pathway responses in Kcne4-/- mice, eliminated Kcne4 deletion-dependent serum alanine aminotransferase elevation, and genotype independently augmented the hepatic post-IR GSK-3β phosphorylation response. These findings support a role for KCNE4 as a systemic modulator of IR injury response and uncover hormonally influenced, sex-specific, KCNE4-dependent and -independent RISK/SAFE pathway induction.

End of life of fuel cells and hydrogen products: From technologies to strategies

End-of-Life (EoL) technologies and strategies are needed to support the deployment of fuel cells and hydrogen (FCH) products. This article explores current and novel EoL technologies to recover valuable materials from the stacks of proton exchange membrane fuel cells and water electrolysers, alkaline water electrolysers, and solid oxide fuel cells. Current EoL technologies are mainly based on hydrometallurgical and pyro-hydrometallurgical methods for the recovery of noble metals, while novel methods attempt to recover additional materials through efficient, safe and cost-competitive pathways. Strengths, weaknesses, opportunities and threats of the reviewed EoL technologies are identified under techno-economic, environmental and regulatory aspects. Beyond technologies, strategies for the EoL of FCH stacks are defined mainly based on the role of manufacturers and recovery centres in the short-, mid- and long-term. In this regard, a dual role manufacturer/recovery centre would characterise long-term scenarios within a potential context of a well-established hydrogen economy.

Clinical impact and cost-effectiveness of noncontrast MRI in the evaluation of suspected appendiceal abscesses in children.

Noncontrast MRI has been shown to be feasible in children with postappendectomy abscesses and helps guide clinical management, but its role in preoperative appendiceal abscesses is unclear. To determine the cost-effectiveness and impact on clinical management of noncontrast MRI in pediatric patients with suspected appendiceal abscess, both pre- and postappendectomy. Retrospective cohort study. In all, 82 children under the age of 18 years with suspected appendiceal abscess on ultrasound. Diffusion-weighted imaging and T2 -weighted single-shot fast spin-echo imaging of the abdomen and pelvis at 1.5T and 3T. The presence, location, size, and apparent diffusion coefficient (ADC) of fluid collections and the presence of a drainage path was noted by three pediatric radiologists. Imaging time, completeness of the exam, and impact on clinical management was recorded. The incremental cost-effectiveness ratio was calculated for MRI relative to CT, taking into account hospital charges, radiation exposure, and risk of adverse reaction to iodinated contrast. Descriptive statistics were used. Intraclass correlation coefficient and Fleiss' kappa were used to assess interobserver variation. Proportions were compared using Fisher's exact test (statistical significance at P < 0.05). MRI confirmed the presence of collections in most cases, with alternative diagnosis established in 10 patients (Tubo-ovarian abscess n = 7, Crohn's disease, ileal anastomotic leak, and Birkitts lymphoma each n = 1). MRI showed the presence of a safe drainage pathway in 92-97% of pelvic abscesses and 86-98% of abdominal abscesses compared with 7-10% and 75-81%, respectively, for ultrasound. MR was cost-effective compared with CT, taking into account the direct charges, risk of radiation induced cancer, and adverse reaction to iodinated contrast. Noncontrast MR is cost-effective and affects clinical management in a significant proportion of children with suspected appendiceal abscesses. 5 Technical Efficacy: Stage 6 J. Magn. Reson. Imaging 2019.

Derivations of Positive Pressure Condition for Development of Foldable Safe Pathway in Railway Tunnel Fires

Derivations of Positive Pressure Condition for Development of Foldable Safe Pathway in Railway Tunnel Fires

Patient-Specific Three-Dimensional Model for a Safe Surgical Pathway in Sacral Chondrosarcoma.

Sacral tumors are amongst the most challenging procedures to treat because of the complex anatomy. This study determined whether patient-specific models change preoperative planning decisions made in preparation for en bloc resection of complex sacral mass surgical procedures. Imaging showed a big encapsulated mass at the S2-3 level involving the neural foramina and obscuring the nerve roots. High-resolution images were acquired and utilized to generate a patient-specific 3D tumor model. The visual and tactile inspection of 3D models allowed the best anatomical understanding, with faster and clearer comprehension of the surgical anatomy. The 3D sacral model was for observation of previously unapparent anatomical details; with this new technology, surgeon can observe their planned surgical intervention, explore the patient-specific anatomy and extension of the tumor, and sharpen their procedure choices. Moreover, multiple planes showed how far the angles on the plane would extend for osteotomy of the sacrum. Another result was identifying correct guides and safe venture landmarks. The study helped to establish safe osteotomy line wherever the nerve roots were retained and enabled osteotomy by preserving bilaterally the S1 and S2 nerve roots for wide excision of wide excision of primary sacral tumor to get adequate bowel and bladder functions. Finally, it helped to determine whether or not the remaining bone in the sacrum is sufficient for spinopelvic stability and needed fixation. It was decided spinopelvic fixation was not necessary for this case. Surgical intervention of sacral tumors varies depending on the tumor, its size, extension, and location. Surgery can have profound risks including unnecessary nerve root resection spinopelvic instability and suboptimal oncological resection. 3D models help to transfer complex anatomical information to clinicians and provide guidance in the preoperative planning stage, for intraoperative navigation and for surgical training purposes.

How can we improve oncofertility care for patients? A systematic scoping review of current international practice and models of care.

BACKGROUNDFertility preservation (FP) is an important quality of life issue for cancer survivors of reproductive age. Despite the existence of broad international guidelines, the delivery of oncofertility care, particularly amongst paediatric, adolescent and young adult patients, remains a challenge for healthcare professionals (HCPs). The quality of oncofertility care is variable and the uptake and utilization of FP remains low. Available guidelines fall short in providing adequate detail on how oncofertility models of care (MOC) allow for the real-world application of guidelines by HCPs.OBJECTIVE AND RATIONALEThe aim of this study was to systematically review the literature on the components of oncofertility care as defined by patient and clinician representatives, and identify the barriers, facilitators and challenges, so as to improve the implementation of oncofertility services.SEARCH METHODSA systematic scoping review was conducted on oncofertility MOC literature published in English between 2007 and 2016, relating to 10 domains of care identified through consumer research: communication, oncofertility decision aids, age-appropriate care, referral pathways, documentation, training, supportive care during treatment, reproductive care after cancer treatment, psychosocial support and ethical practice of oncofertility care. A wide range of electronic databases (CINAHL, Embase, PsycINFO, PubMed, AEIPT, Education Research Complete, ProQuest and VOCED) were searched in order to synthesize the evidence around delivery of oncofertility care. Related citations and reference lists were searched. The review was undertaken following registration (International prospective register of systematic reviews (PROSPERO) registration number CRD42017055837) and guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).OUTCOMESA total of 846 potentially relevant studies were identified after the removal of duplicates. All titles and abstracts were screened by a single reviewer and the final 147 papers were screened by two reviewers. Ten papers on established MOC were identified amongst the included papers. Data were extracted from each paper and quality scores were then summarized in the oncofertility MOC summary matrix. The results identified a number of themes for improving MOC in each domain, which included: the importance of patients receiving communication that is of a higher quality and in different formats on their fertility risk and FP options; improving provision of oncofertility care in a timely manner; improving access to age-appropriate care; defining the role and scope of practice of all HCPs; and improving communication between different HCPs. Different forms of decision aids were found useful for assisting patients to understand FP options and weigh up choices.WIDER IMPLICATIONSThis analysis identifies core components for delivery of oncofertility MOC. The provision of oncofertility services requires planning to ensure services have safe and reliable referral pathways and that they are age-appropriate and include medical and psychological oncofertility care into the survivorship period. In order for this to happen, collaboration needs to occur between clinicians, allied HCPs and executives within paediatric and adult hospitals, as well as fertility clinics across both public and private services. Training of both cancer and non-cancer HCPs is needed to improve the knowledge of HCPs, the quality of care provided and the confidence of HCPs with these consultations.

Ischemic Stroke Increases Heart Vulnerability to Ischemia-Reperfusion and Alters Myocardial Cardioprotective Pathways.

Background and Purpose- For years, the relationship between cardiac and neurological ischemic events has been limited to overlapping pathophysiological mechanisms and common risk factors. However, acute stroke may induce dramatic changes in cardiovascular function. The aim of this study was to evaluate how prior cerebrovascular lesions affect myocardial function and signaling in vivo and ex vivo and how they influence cardiac vulnerability to ischemia-reperfusion injury. Methods- Cerebral embolization was performed in adult Wistar male rats through the injection of microspheres into the left or right internal carotid artery. Stroke lesions were evaluated by microsphere counting, tissue staining, and assessment of neurological deficit 2 hours, 24 hours, and 7 days after surgery. Cardiac function was evaluated in vivo by echocardiography and ex vivo in isolated perfused hearts. Heart vulnerability to ischemia-reperfusion injury was investigated ex vivo at different times post-embolization and with varying degrees of myocardial ischemia. Left ventricles (LVs) were analyzed with Western blotting and quantitatve real-time polymerase chain reaction. Results- Our stroke model produced large cerebral infarcts with severe neurological deficit. Cardiac contractile dysfunction was observed with an early but persistent reduction of LV fractional shortening in vivo and of LV developed pressure ex vivo. Moreover, after 20 or 30 minutes of global cardiac ischemia, recovery of contractile function was poorer with impaired LV developed pressure and relaxation during reperfusion in both stroke groups. Following stroke, circulating levels of catecholamines and GDF15 (growth differentiation factor 15) increased. Cerebral embolization altered nitro-oxidative stress signaling and impaired the myocardial expression of ADRB1 (adrenoceptor β1) and cardioprotective Survivor Activating Factor Enhancement signaling pathways. Conclusions- Our findings indicate that stroke not only impairs cardiac contractility but also worsens myocardial vulnerability to ischemia. The underlying molecular mechanisms of stroke-induced myocardial alterations after cerebral embolization remain to be established, insofar as they may involve the sympathetic nervous system and nitro-oxidative stress.

Adult Congenital Heart Disease in Australia and New Zealand: A Call for Optimal Care

Adult congenital heart disease (ACHD) is a relatively new subspecialty in the cardiology field. The prevalence of ACHD is estimated at ∼ 3,000 per million adult population. The ACHD patient group is estimated to grow at ∼ 5% per year and in the next decade it is forecast that 1 in 150 young adults will carry some form of ACHD diagnosis. These estimates translate to ∼ 72,000 ACHD patients in Australia and ∼ 14,000 in New Zealand, although no current numbers are available. The Cardiac Society of Australia and New Zealand (CSANZ) has recently published Recommendations for Standards of Care for Adult Congenital Heart Disease (ACHD) in 2016. There is currently no long-term plan or proposal to address this huge health care burden within the federal government. This document details the size of the problem insofar as it is known and recommends solutions to be implemented. This document was developed by the Adult Congenital Heart Disease Working Group of the Paediatric and Congenital Council (the Congenital Heart Alliance of Australia and New Zealand) as a response to the chronic under resourcing in this area, the risk this poses to patients and clinicians, and the clear need for long-term planning to develop safe care pathways. These issues were raised with the CSANZ Board in December 2015 and the document was developed in response to the Board's request for more information. The current iteration was finalised on 14 November 2017. The authorship group comprised participants in the CSANZ adult CHD standards of care recommendations from 2013 with the inclusion of some newly trained ACHD cardiologists, who represented most states and territories across ANZ. None of the authors has any academic or professional conflict of interest.

Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways.

BackgroundIschemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI.Methods and ResultsAdult male Sprague‐Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff‐perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal‐regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin‐mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin‐mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes.ConclusionsThese results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.

Prevascularization of the Subcutaneous Space Improves Survival of Transplanted Mouse Islets

Introduction Beta cell replacement for the treatment of Type I diabetes has previously been limited by donor availability, invasive surgical techniques, and islet survival post-transplant. Transplantation into the subcutaneous space is ideal for graft accessibility and explant if necessary; however, prior investigations have shown that in comparison to other gold-standard sites (i.e., the kidney capsule), this location lacks the rich blood supply required to meet the high metabolic demands of islets. The aim of this study was to identify and demonstrate the efficacy of a novel prevascularization strategy to improve free islet graft survival in the subcutaneous space. Methods To investigate the ideal prevascularization device, four different materials were implanted into the subcutaneous space of B6 albino mice: polypropylene (PP) mesh, smooth PP, texturized polycaprolactone (PCL), and smooth PCL. Vascularity was assessed using indocyanine green fluorescence measurement at 1-week time points up to 6 weeks post implantation. At selected time points, mice were euthanized and specimens were examined using immunofluorescence histology. B6 mice that had been prevascularized for 2 weeks with textured PCL discs were made diabetic with intraperitoneal streptozosin injection (200 mg/kg). The prevascularization discs were removed, and the mice were then transplanted with 200, 400, 600, and 800 syngeneic mouse islets into the disc capsule. Blood glucose was measured for three weeks to monitor for diabetes cure. Intraperitoneal glucose tolerance test (IPGTT) was performed on transplant recipients to compare their function to diabetic and normal controls. Results When normalized to baseline fluorescence, the peak vascularity as measured by ICG fluorescence was determined for texturized PCL at the 2-week time point (Fig. 1). Histological analysis at 2 weeks (Fig. 2a) and 6 weeks (Fig. 2b) post-implantation demonstrated vascular ingrowth (vWF) and minimal foreign body reaction (macrophages, or F4/80). Diabetes reversal was not observed for 200- or 400-islet transplant recipients. 100% diabetes cure was seen with 800-islet transplants, and partial cure (50%) was seen with 600-islet transplants (Fig. 3). When subjected to IPGTT at 2 weeks post transplant, the 600-islet group showed similar blood glucose kinetics to non-diabetic control in cured mice and impaired glucose tolerance in partially cured and failed mice (Fig. 4).Conclusion Texturized PCL induces improved vascularity in the subcutaneous space of mice while inciting minimal foreign body reaction. Free islets transplanted in the subcutaneous space of mice have improved survival in the prevascularized implant capsule, and allow for comparable function to non-diabetic controls. This strategy may represent a safe and effective translational pathway for the application of subcutaneous islet transplant in human subjects in the near future. Research reported in this publication was supported in part by an NIAID T32 training grant from the National Institutes of Health under an award to the University of California, San Francisco (T32AI125222).

Rapid Access Cardiology (RAC) Services Within a Large Tertiary Referral Centre—First Year in Review

Rapid Access Cardiology (RAC) services are hospital co-located cardiologist-led outpatient clinics providing prompt assessment and management of chest pain. This service model is part of chest pain management in the United Kingdom. However, little data exists on RAC services in Australia. Our aim was to describe the introduction of RAC services to an Australian tertiary centre (utility, safety, and acceptability). Referrals were accepted for low-intermediate risk chest pain. Referrer and patient clinical data was collected prospectively in the first year of RAC - 4 February 2015 to 4 February 2016. Data was linked to hospital presentations/admissions to identify readmissions/mortality data. Among 520 patients (55.0% male, mean age 55.2 years), 87.6% were referred from emergency and 68.4% assessed within 5 days. The final diagnosis was new coronary artery disease (CAD) in 7.9%, and 81.3% had ≥2 cardiovascular risk factors (diabetes, hyperlipidaemia, hypertension, overweight/obesity, smoker, pre-existing CAD, and chronic renal failure). On average, 0.8 cardiac tests were ordered per person. In total, 35 (6.7%) had invasive coronary angiograms, with 51.4% having obstructive CAD. Patients reported in surveys (82.8% response rate) that 93.0% "strongly agreed" RAC services were useful to the community. Referrers were also "very satisfied" with RAC (7/17) or "satisfied" (9/17). Furthermore, of 336 referrals, referrers reported without RAC they would admit the patient in 11.3% of cases. There were 4.8% (25/520) unplanned cardiovascular readmissions and 0.6% (3/520) of these were for acute coronary syndromes and no deaths. Outpatient RAC services are an accepted, effective and safe pathway for management of low-intermediate risk chest pain.

Roles of caveolin in ischemia postconditioning-induced cardioprotection

Background Ischemic postconditioning (IPO) refers to the treatment of multiple transient ischemia/reperfusion prior to continuous reperfusion following myocardial ischemia. A large number of studies have confirmed that caveolin (Cav), which plays an important role in signal integration, is involved in the process of IPO and has protective effects on myocardial ischemia/reperfusion injury(I/RI). Objective To review potential mechanisms underlying the protection of myocardia by IPO through identifying the role of Cav in I/RI. Content Cav is associated with multiple signal transduction pathways in IPO, including reperfusion injury salvage kinases (RISK) pathway, tumor necrosis factor-mediated survivor activating factor enhancement(SAFE) pathway, sphingosine kinase(SPK) pathway, nitric oxide/cyclic guanosine monophosphate/protein kinase G(NO/cGMP/PKG) pathway, bradykinin and adenosine′s signalling (BK/A2). These pathways, instead of functioning independently, may interact with each other or regulate the same targets, and as a consequence to confer protection of myocardia. Trend IPO has an important role in myocardial protection, but further research is needed to fully elucidate the complex underlying mechanisms. Key words: Caveolin; Postconditioning; Myocardial protection; Ischemia-reperfusion injury

Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice

Sudden cardiac death (SCD) is associated with both electrical and ischemic substrates, and is a major cause of ischemic heart disease mortality worldwide. Male sex predisposes to SCD but the underlying mechanisms are incompletely understood. KCNE4, a cardiac arrhythmia-associated potassium channel β-subunit, is upregulated by 5α-dihydrotestosterone (DHT). Thus, ventricular Kcne4 expression is low in young adult female mice, but high in males and postmenopausal (12+ months) females. Despite causing a sex-independent electrical substrate at 13 months of age (22% QT prolongation in both males and females; P < 0.01), Kcne4 deletion preferentially predisposed aged male mice to ischemia/reperfusion (IR)-provoked ventricular tachyarrhythmias. Interestingly, Kcne4 deletion caused baseline induction of cardioprotective RISK and SAFE pathways in 13-m-old female, but not male, mice. IR-invoked RISK/SAFE induction was also deficient in male but not female Kcne4−/− mice. Pharmacological inhibition of RISK/SAFE pathways in Kcne4−/− females eliminated sex-specific differences in IR-invoked tachyarrhythmia predisposition. Furthermore, castration of Kcne4−/− males eliminated sex-specific differences in both baseline and post-IR RISK/SAFE pathway induction, and tachyarrhythmia predisposition. Our results demonstrate for the first time that male sex can predispose in aged mice to dangerous ventricular tachyarrhythmias despite sex-independent electrical and ischemic substrates, because of testosterone-dependent impairment of RISK/SAFE pathway induction.

Solvent-salt synergy offers a safe pathway towards next generation high voltage Li-ion batteries

Solvent-salt synergy offers a safe pathway towards next generation high voltage Li-ion batteries

Diabetes Worsens Skeletal Muscle Mitochondrial Function, Oxidative Stress, and Apoptosis After Lower-Limb Ischemia-Reperfusion: Implication of the RISK and SAFE Pathways?

Objectives: Diabetic patients respond poorly to revascularization for peripheral arterial disease (PAD) but the underlying mechanisms are not well understood. We aimed to determine whether diabetes worsens ischemia-reperfusion (IR)-induced muscle dysfunction and the involvement of endogenous protective kinases in this process.Materials and Methods: Streptozotocin-induced diabetic and non-diabetic rats were randomized to control or to IR injury (3 h of aortic cross-clamping and 2 h of reperfusion). Mitochondrial respiration, reactive oxygen species (ROS) production, protein levels of superoxide dismutase (SOD2) and endogenous protective kinases (RISK and SAFE pathways) were investigated in rat gastrocnemius, together with upstream (GSK-3β) and downstream (cleaved caspase-3) effectors of apoptosis.Results: Although already impaired when compared to non-diabetic controls at baseline, the decline in mitochondrial respiration after IR was more severe in diabetic rats. In diabetic animals, IR-triggered oxidative stress (increased ROS production and reduced SOD2 levels) and effectors of apoptosis (reduced GSK-3β inactivation and higher cleaved caspase-3 levels) were increased to a higher level than in the non-diabetics. IR had no effect on the RISK pathway in non-diabetics and diabetic rats, but increased STAT 3 only in the latter.Conclusion: Type 1 diabetes worsens IR-induced skeletal muscle injury, endogenous protective pathways not being efficiently stimulated.

Remote ischemic preconditioning STAT3-dependently ameliorates pulmonary ischemia/reperfusion injury.

The lungs are highly susceptible to injury, including ischemia/reperfusion (I/R) injury. Pulmonary I/R injury can occur when correcting conditions such as primary pulmonary hypertension, and is also relatively common after lung transplantation or other cardiothoracic surgery. Methods to reduce pulmonary I/R injury are urgently needed to improve outcomes following procedures such as lung transplantation. Remote liver ischemic preconditioning (RLIPC) is an effective cardioprotective measure, reducing damage caused by subsequent cardiac I/R injury, but little is known about its potential role in pulmonary protection. Here, we analyzed the efficacy and mechanistic basis of RLIPC in a rat model of pulmonary I/R injury. RLIPC reduced lung I/R injury, lessening structural damage, inflammatory cytokine production and apoptosis. In addition, RLIPC preserved pulmonary function compared to controls following lung I/R injury. RLIPC stimulated phosphorylation of pulmonary STAT3, a component of the SAFE signaling pathway, but not phosphorylation of RISK pathway signaling proteins. Accordingly, STAT3 inhibition using AG490 eliminated the pulmonary protection afforded by RLIPC. Our data demonstrate for the first time that RLIPC protects against pulmonary I/R injury, via a signaling pathway requiring STAT3 phosphorylation.

Cost-effectiveness development for the postoperative care of craniotomy patients: a safe transitions pathway in neurological surgery.

OBJECTIVE The authors' institution is in the top 5th percentile for hospital cost in the nation, and the neurointensive care unit (NICU) is one of the costliest units. The NICU is more expensive than other units because of lower staff/patient ratio and because of the equipment necessary to monitor patient care. The cost differential between the NICU and Neuro transitional care unit (NTCU) is $1504 per day. The goal of this study was to evaluate and to pilot a program to improve efficiency and lower cost by modifying the postoperative care of patients who have undergone a craniotomy, sending them to the NTCU as opposed to the NICU. Implementation of the pilot will expand and utilize neurosurgery beds available on the NTCU and reduce the burden on NICU beds for critically ill patient admissions. METHODS Ten patients who underwent craniotomy to treat supratentorial brain tumors were included. Prior to implementation of the pilot, inclusion criteria were designed for patient selection. Patients included were less than 65 years of age, had no comorbid conditions requiring postoperative intensive care unit (ICU) care, had a supratentorial meningioma less than 3 cm in size, had no intraoperative events, had routine extubation, and underwent surgery lasting fewer than 5 hours and had blood loss less than 500 ml. The Safe Transitions Pathway (STP) was started in August 2016. RESULTS Ten tumor patients have utilized the STP (5 convexity meningiomas, 2 metastatic tumors, 3 gliomas). Patients' ages ranged from 29 to 75 years (median 49 years; an exception to the age limit of 65 years was made for one 75-year-old patient). Discharge from the hospital averaged 2.2 days postoperative, with 1 discharged on postoperative day (POD) 1, 7 discharged on POD 2, 1 discharged on POD 3, and 1 discharged on POD 4. Preliminary data indicate that quality and safety for patients following the STP (moving from the operating room [OR] to the neuro transitional care unit [OR-NTCU]) are no different from those of patients following the traditional OR-NICU pathway. No patients required escalation in level of nursing care, and there were no readmissions. This group has been followed for greater than 1 month, and there were no morbidities. CONCLUSIONS The STP is a new and efficient pathway for the postoperative care of neurosurgery patients. The STP has reduced hospital cost by $22,560 for the first 10 patients, and there were no morbidities. Since this pilot, the authors have expanded the pathway to include other surgical cases and now routinely schedule craniotomy patients for the (OR-NTCU) pathway. The potential cost reduction in one year could reach $500,000 if we reach our potential of 20 patients per month.

Catestatin: A Master Regulator of Cardiovascular Functions

Cardiovascular disease (CVD), the most common cause of death globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor to morbidity and mortality from CVD. The plasma concentration of chromogranin A (CgA) is elevated in patients with CVD as well as patients with established human essential hypertension and heart failure (HF). In contrast, the plasma level of the CgA-derived peptide catestatin (CST) is diminished in human essential hypertension. Low conversion of CgA-to-CST has been associated with increased mortality in patients hospitalized with acute HF. Consistent with human findings, the lack of CST in CgA knockout (Chga-KO) mice eventuates in the development of hypertension and supplementation of CST to Chga-KO mice restores blood pressure, implicating CST as a key player in regulating hypertension. In the peripheral system, CST decreases blood pressure by stimulating histamine release, inhibiting catecholamine secretion, or causing vasodilation. Centrally, CST improves baroreflex sensitivity (BRS) and heart rate variability (HRV) by exciting GABAergic neurons in the caudal ventrolateral medulla (CVLM) and pyramidal neurons of the central amygdala; CST also decreases BRS by exciting glutamatergic rostral ventrolateral medulla (RVLM) neurons. In addition, CST provides cardioprotection by inhibiting inotropy and lusitropy; activating mitochondrial KATP channels, and stimulating reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways and consequent inhibition of mitochondrial permeability transition pore (mPTP). CST modulates cardiomyocyte Ca2+ levels by direct inhibition of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) activity and consequent reduction in phosphorylation of phospholamban and ryanodine receptor 2, thereby providing support for a direct functional role of CST in the failing myocardium. These multitude of effects establish CST as a master regulator of cardiovascular functions.