Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsCFL conceived the study, participated in data collection, performed statistical analysis, interpreted results, and wrote the manuscript. VCW, TMH, YFL, YJJ, CTC, and CCS participated in data collection and manuscript revision. YCY, KCW, YYH, PRT, and NKC participated in data collection. FCH performed statistical analysis, participated in data interpretation and manuscript writing. WJK and KDW conceived the study and participated in manuscript revision. All authors read and approved the final manuscript.Supplementary MaterialAdditional file 1:A table showing the demographic and clinical characteristics of survivors stratified by follow-up duration.Click here for file(80K, DOC)NotesPlease see related letter by Lopes and Jorge, http://ccforum.com/content/16/6/467AcknowledgementsThis study was supported by the Ta-Tung Kidney Foundation, Mrs Hsiu-Chin Lee Kidney Research Fund, Taiwan National Science Council (grant NSC 96-2314-B-002-033-MY2, NSC 97-2314-B-002-155-MY2), and National Taiwan University Hospital (NTUH 098-001177, NTUH 100-001667). The authors would like to thank the all participants of the NSARF.
Shock states are defined by an acute circulatory failure leading to prolonged and intense tissue hypoxia that may lead to death. Tissue hypoxia is accompanied by a decreased production of ATP in the mitochondria. Hypoxia-inducible factor-1 (HIF1) is a heterodimer made of two sub-units (�� and ��) [1,2]. The gene coding for HIF1�� is on chromosome 14 (14q21-q24) [3]. HIF1�� protein concentration is correlated to cellular oxygen concentration [4]. In hypoxemic conditions, HIF1�� is not degraded and accumulates in the cellular nucleus [5]. The effects of HIF1�� are stimulation of erythropoiesis, glycolysis, angiogenesis, and vasodilation [1]. In normoxic conditions, HIF1�� and its messenger RNA (mRNA) have a very short half-life of five minutes [6,7]. This suggests that HIF1�� is an immediate surrogate marker of cellular oxygenation.In human shock states, plasma lactate is routinely used as a marker of tissue hypoxia. This marker has been validated for the detection of shock states as well as the prediction of patient outcomes [8,9]. However, plasma lactate concentrations are influenced by both the production and clearance of lactate.

However, the effects of metformin on mitochondria likely depend on dose, in vivo just as in vitro. Patients enrolled in this present study had an average serum drug level of 32 �� 14 mg/L, much lower than that of severely intoxicated patients (61 �� 25 mg/L in our previous series) [7]. in vitro, metformin was added to plasma to obtain an initial (toxic) concentration of 166 mg/L, or higher. Even if final drug levels were probably lower, due to cellular uptake [13], they likely exceeded 32 �� 14 mg/L. In other words, overdose severity was high (or very high) in vitro, but only moderate in vivo. We cannot exclude that a 24- to 48-hour delay in evaluating platelet mitochondrial function further contributed to diminish our capacity to detect early larger alterations.The constant decrease in platelet complex IV activity was totally unexpected, as it never occurred in vitro, not even at the highest drug dose. Underlying mechanisms were not specifically investigated so that we can only speculate on them. Only some of the patients received sedation, catecholamines and/or mechanical ventilation, so that these factors likely had no major role. Conversely, all patients had undergone renal replacement therapy by the time their platelet mitochondrial function was assessed. Whether renal failure per se or extra-corporeal support can inhibit human platelet complex IV is currently unknown.All patients enrolled in this study had a favourable outcome, despite signs of mitochondrial inhibition in platelets (and possibly other tissues). This may suggest that prognosis does not depend on the effects of metformin on the respiratory chain. However, it may also indicate that the rate of survival will be unexpectedly high if mitochondrial dysfunction is due to a compound that can be easily removed from the body (using renal replacement therapy, for instance) [32].ConclusionsSevere metformin overdose can alter mitochondrial function and increase lactate production of human platelets, in vitro and, possibly, ex vivo. If analogue changes also occur in other organs, they will likely contribute to the pathogenesis of metformin-induced lactic acidosis.Key messages? In pigs, severe metformin intoxication causes mitochondrial dysfunction in platelets as well as in other more vital organs, including the heart, kidney and skeletal muscle.? Human platelets exposed to a toxic dose of metformin, either in vitro or in vivo, have clear signs of mitochondrial dysfunction.? If mitochondrial dysfunction is a generalized phenomenon even in humans, it will likely contribute to the development of lactic acidosis (possibly by augmenting tissue lactate production).

However, fluid management itself may have an impact on lung and distal organ injury in ALI/ARDS [14,15]. Although fluid restriction may cause distal organ damage [14], selleck chemical MEK162 hypervolemia has been associated with increased lung injury [16,17].RMs seem to be more effective in extrapulmonary ALI/ARDS [9], caused mainly by sepsis [18], than in pulmonary ALI/ARDS. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. As the interaction between volemic status and RMs is not well established, we hypothesized that volemic status would potentiate possible deleterious effects of RMs on lung and distal organs in a model of extrapulmonary lung injury induced by sepsis.

Therefore, we compared the effects of RMs in the presence of hypovolemia, normovolemia, and hypervolemia on arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, IL-6, IL-1��, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis in an experimental model of sepsis-induced ALI.Materials and methodsAnimal preparation and experimental protocolThis study was approved by the Ethics Committee of the Health Sciences Center, Federal University of Rio de Janeiro. All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences, USA.

Sixty-six adult male Wistar rats (270 to 300 g) were kept under specific pathogen-free conditions in the animal care facility at the Laboratory of Pulmonary Investigation, Federal University of Rio de Janeiro. In 36 rats, Est,L, histology, and molecular biology were analyzed. The remaining 30 rats were used to evaluate lung W/D ratio. Animals were fasted for 16 hours before the surgical procedure. Following that, sepsis was induced by cecal ligation and puncture (CLP) as described in previous studies [19]. Briefly, animals were anesthetized with sevoflurane and a midline laparotomy (2 cm incision) was performed. The cecum was carefully isolated to avoid damage to blood vessels, and a 3.0 cotton ligature was placed below the ileocecal valve to prevent bowel obstruction. Finally, the cecum was punctured twice with an 18 gauge needle [20] and animals recovered from anesthesia. Soon after surgery, each rat received a subcutaneous injection of 1 ml of warm (37��C) normal saline with tramadol hydrochloride (20 Dacomitinib ��g/g body weight).Figure Figure11 depicts the time-course of interventions.

Currently, there is a global trend towards Graduate Entry Medicine with medical schools in the United Kingdom, Australia, Ireland, and Singapore conducting GEM programs solely or in parallel with schools leaver programs. Reports on the association between sociodemographic characteristics and emotional burnout among Ixazomib structure medical residents were subjective as the majority of the published work proposed weak or negative correlations [29, 30]. Our study findings were similar. With respect to working conditions, this study found a significant association between working hours and emotional burnout. This finding is similar to the results of a recent study among Turkish residents [31]. A significant association was seen between residents’ rotations and emotional burnout. Shanafelt et al. [28] had similar findings.

A myriad of stress factors was significantly associated with emotional burnout among medical residents in this study. Consistent with previous literature, various factors like work overload [4], work environment and available resources [7, 21], and remunerations and incentives [17] showed positive relationships with residents’ emotional burnout. A new observation found in this study was the significant association between resident-supervisor relationship and emotional burnout. This study postulates that appropriate mentorship, sufficient motivation, and fair assessments during resident-ship are key to preventing emotional burnout among medical residents.

The scientific literature has shown that t burnout prompted serious personal repercussions like substance abuse [32], family conflicts [19], and suicidal ideation [28]; much catastrophically compromising the efficacy of healthcare delivery system through increased medical errors [33]. This study found emotional burnout to significantly associate with residents’ personal and home Dacomitinib life. Previous studies found similar findings [30, 34].Another interesting new observation in this study is the association between residents’ emotional burnout and professional engagement through domains of the newly Graduate Medical Officer Flexi Timetable Work System Policy in Malaysia. Medical residents’ who were satisfied with the implementation of resident-supervisor-feedback/report system, reduction of work hours to 60�C72 hours with a ��two days off per week,�� and the introduction of Flexi-Work-Hours Policy exhibited a significantly lower level of emotional burnout compared to those not satisfied. Those who were unsatisfied with the increase of residency period from 1 year to 2 years exhibited a significantly higher level of emotional burnout in comparison to satisfied ones. An important finding in this study is having vocation (engagement) and avocation (leisure) is beneficial to professional behavior.