Background:Renal cystic disease arising from various etiologies results in fluid-filled cavities within the kidneys.Moreover,preexisting renal dysfunction has been shown to exacerbate multiple pathologies.While swine ...Background:Renal cystic disease arising from various etiologies results in fluid-filled cavities within the kidneys.Moreover,preexisting renal dysfunction has been shown to exacerbate multiple pathologies.While swine bred for biomedical research are often clinically inspected for illness/parasites,more advanced diagnostics may aid in uncovering underlying renal abnormalities.Methods:Computed tomography was performed in 54 female prepubertal Yorkshire swine to characterize renal cysts;urine and blood chemistry,and histology of cysts were also performed.Results:Digital reconstruction of right and left kidneys demonstrated that roughly one-third of the animals(17/54;31%)had one or more renal cyst.Circulating biomarkers of renal function were not different between animals that had cysts and those that did not.Alternatively,urinary glucose(P=.03)was higher and sodium(P=.07)tended to be lower in animals with cysts compared to animals without,with no differences in protein(P=.14)or potassium(P=.20).Aspiration of cystic fluid was feasible in two animals,which revealed that the cystic fluid urea nitrogen(97.6±28.7 vs 911.3±468.2 mg/dL),potassium(29.8±14.4 vs 148.2±24.85 mmol/L),uric acid(2.55±1.35 vs 11.4±5.65 mg/dL),and creatinine(60.34±17.26 vs 268.99±95.79 mg/dL)were much lower than in the urine.Histology demonstrated a cyst that markedly compresses the adjacent cortex and is lined by a single layer of flattened epithelium,bounded by fibrous connective tissue which extends into the parenchyma.There is tubular atrophy and loss in these areas.Conclusion:This study provides valuable insight for future studies focusing on kidney function in swine bred for biomedical research.展开更多
AIM: To assess the effect of our novel cell-permeable nuclear factor-kappaB (NF-κB) inhibitor peptide PN50 in an experimental model of acute pancreatitis. PN50 was produced by conjugating the cell-penetrating penetra...AIM: To assess the effect of our novel cell-permeable nuclear factor-kappaB (NF-κB) inhibitor peptide PN50 in an experimental model of acute pancreatitis. PN50 was produced by conjugating the cell-penetrating penetratin peptide with the nuclear localization signal of the NF-κB p50 subunit.METHODS: Pancreatitis was induced in male Wistar rats by administering 2×100 μg/kg body weight of cholecystokininoctapeptide (CCK) intraperitoneally (IP) at an interval of 1 h. PN50-treated animals received 1 mg/kg of PN50 IP 30 min before or after the CCK injections. The animals were sacrificed 4 h after the first injection of CCK.RESULTS: All the examined laboratory (the pancreatic weight/body weight ratio, serum amylase activity,pancreatic levels of TNF-α and IL-6, degree of lipid peroxidation, reduced glutathione levels, NF-κB binding activity, pancreatic and lung myeloperoxidase activity) and morphological parameters of the disease were improved before and after treatment with the PN50 peptide.According to the histological findings, PN50 protected the animals against acute pancreatitis by favoring the induction of apoptotic, as opposed to necrotic acinar cell death associated with severe acute pancreatitis.CONCLUSION: Our study implies that reversible inhibitors of stress-responsive transcription factors like NF-κB might be clinically useful for the suppression of the severity of acute pancreatitis.展开更多
AIM To compare the effects of the four most commonly used preservation solutions on the outcome of liver transplantations.METHODS A systematic literature search was performed using MEDLINE, Scopus, EMBASE and the Coch...AIM To compare the effects of the four most commonly used preservation solutions on the outcome of liver transplantations.METHODS A systematic literature search was performed using MEDLINE, Scopus, EMBASE and the Cochrane Library databases up to January 31^(st), 2017. The inclusion criteria were comparative, randomized controlled trials(RCTs) for deceased donor liver(DDL) allografts with adult and pediatric donors using the gold standard University of Wisconsin(UW) solution or histidinetryptophan-ketoglutarate(HTK), Celsior(CS) and Institut Georges Lopez(IGL-1) solutions. Fifteen RCTs(1830 livers) were included; the primary outcomes were primary non-function(PNF) and one-year posttransplant graft survival(OGS-1). RESULTS All trials were homogenous with respect to donor and recipient characteristics. There was no statistical difference in the incidence of PNF with the use of UW, HTK, CS and IGL-1(RR = 0.02, 95%CI: 0.01-0.03, P = 0.356). Comparing OGS-1 also failed to reveal any difference between UW, HTK, CS and IGL-1(RR = 0.80, 95%CI: 0.80-0.80, P = 0.369). Two trials demonstrated higher PNF levels for UW in comparison with the HTK group, and individual studies described higher rates of biliary complications where HTK and CS were used compared to the UW and IGL-1 solutions. However, the meta-analysis of the data did not prove a statistically significant difference: the UW, CS, HTK and IGL-1 solutions were associated with nearly equivalent outcomes.CONCLUSION Alternative solutions for UW yield the same degree of safety and effectiveness for the preservation of DDLs, but further well-designed clinical trials are warranted.展开更多
Background:Junctional hemorrhage surpassed extremity hemorrhage as the leading cause of preventable death after the resurgence of limb tourniquets during the recent conflicts in Afghanistan and Iraq.Junctional tourniq...Background:Junctional hemorrhage surpassed extremity hemorrhage as the leading cause of preventable death after the resurgence of limb tourniquets during the recent conflicts in Afghanistan and Iraq.Junctional tourniquets(JTQs)were developed in response to this injury pattern.Published data for JTQ efficacy are limited and do not incorporate nonmedical,military first responders.We compared the time for effective placement and scores for device satisfaction between two different JTQs,stratified by combat lifesaver(CLS)and combat medics.Methods:We performed a prospective,randomized,crossover trial utilizing the SAM ’ Medical Junctional Tourniquet(SJT)and Junctional Emergency Treatment Tool(JETTTM).Investigators simple randomized CLS and combat medics to SJT or JETT for their first JTQ application on mannequins with penetrating inguinal injuries.Then,participants immediately placed the other JTQ on another casualty with the same injury.The primary outcome measured was time of successful applicatio n.Success was defined as proper JTQ placement and a pressu re reading of at least 180 mmHg.We compared outcomes between CLS and combat medics.Unsuccessful JTQ applications were excluded from the comparative analysis.Results:From June 2015 to August 2015,a total of 227 personnel(133 CLS and 94 combat medics)at Fort Hood,Texas,USA volunteered to participate in the study.Twenty-eight percent(38 of 133)of CLS and 40%(38 of 94)of combat medics placed both JTQs successfully,for a total of 152 applications(76 SJTs and 76 JETTs).We found a significant difference between applications of the JETT between the CLS and combat medics(92.0±37.7 s versus70.5±20.5 s,P=0.004).No other subg roup analyses,whether by device or user,demonstrated a sig nifica nt difference in application time.Both groups preferred the SJT over the JETT.CLS disagreed with combat medics that the JETT could be easily applied by one person(median 3.0[2.0,4.0]versus median 4.0[3.0,5.0];P=0.006).Conclusions:Overall,success rates for both the SJT and JETT were low.Improved training is needed to increase successful application of junctional tourniquets before widespread implementation.Combat lifesavers and combat medics prefer the SJT over the JETT.展开更多
Background: In combat operations, patients with traumatic injuries require expeditious evacuation to improve survival. Studies have shown that long transport times are associated with increased morbidity and mortality...Background: In combat operations, patients with traumatic injuries require expeditious evacuation to improve survival. Studies have shown that long transport times are associated with increased morbidity and mortality. Limited data exist on the influence of transport time on patient outcomes with specific injury types. The objective of this study was to determine the impact of the duration of time from the initial request for medical evacuation to arrival at a medical treatment facility on morbidity and mortality in casualties with traumatic extremity amputation and noncompressible torso injury(NCTI).Methods: We completed a retrospective review of MEDEVAC patient care records for United States military personnel who sustained traumatic amputations and NCTI during Operation Enduring Freedom between January 2011 and March 2014. We grouped patients as traumatic amputation and NCTI(AMP+NCTI), traumatic amputation only(AMP),and neither AMP nor NCTI(Non-AMP/NCTI). Analysis was performed using chi-squared tests, Fisher's exact tests,Cochran-Armitage Trend tests, Shapiro-Wilks tests, Wilcoxon and Kruskal-Wallis techniques and Cox proportional hazards regression modeling.Results: We reviewed 1267 records, of which 669 had an injury severity score(ISS) of 10 or greater and were included in the analysis. In the study population, 15.5% sustained only amputation injuries(n=104, AMP only), 10.8% sustained amputation and NCTI(n=72, AMP+NCTI), and 73.7% did not sustain either an amputation or an NCTI(n=493,Non-AMP/NCTI). AMP+NCTI had the highest mortality(16.7%) with transport time greater than 60 min. While the AMP+NCTI group had decreasing survival with longer transport times, AMP and Non-AMP/NCTI did not exhibit the same trend.Conclusions: A decreased transport time from the point of injury to a medical treatment facility was associated with decreased mortality in patients who suffered a combination of amputation injury and NCTI. No significant association between transport time and outcomes was found in patients who did not sustain NCTI. Priority for rapid evacuation of combat casualties should be given to those with NCTI.展开更多
Background: Pediatric casualties account for a notable proportion of encounters in the deployed setting based on the humanitarian medical care mission. Previously published data demonstrates that an age-adjust shock i...Background: Pediatric casualties account for a notable proportion of encounters in the deployed setting based on the humanitarian medical care mission. Previously published data demonstrates that an age-adjust shock index may be a useful tool in predicting massive transfusion and death in children. We seek to determine if those previous findings are applicable to the deployed, combat trauma setting.Methods: We queried the Department of Defense Trauma Registry(DODTR) for all pediatric subjects admitted to US and Coalition fixed-facility hospitals in Iraq and Afghanistan from January 2007 to January 2016. This was a secondary analysis of casualties seeking to validate previously published data using the shock index, pediatric age adjusted. We then used previously published thresholds to determine patients outcome for validation by age grouping, 1–3 years(1.2), 4–6 years(1.2), 7–12 years(1.0), 13–17 years(0.9).Results: From January 2007 through January 2016 there were 3439 pediatric casualties of which 3145 had a documented heart rate and systolic pressure. Of those 502(16.0%) underwent massive transfusion and 226(7.2%) died prior to hospital discharge. Receiver operating characteristic(ROC) thresholds were inconsistent across age groups ranging from 1.0 to 1.9 with generally limited area under the curve(AUC) values for both massive transfusion and death prediction characteristics. Using the previously defined thresholds for validation, we reported sensitivity and specificity for the massive transfusion by age-group: 1–3(0.73, 0.35), 4–6(0.63, 0.60), 7–12(0.80, 0.57), 13–17(0.77, 0.62). For death, 1–3(0.75, 0.34), 4–6(0.66–0.59), 7–12(0.64, 0.52), 13–17(0.70, 0.57). However, negative predictive values(NPV) were generally high with all greater than 0.87.Conclusions: Within the combat setting, the age-adjusted pediatric shock index had moderate sensitivity and relatively poor specificity for predicting massive transfusion and death. Better scoring systems are needed to predict resource needs prior to arrival, that perhaps include other physiologic metrics. We were unable to validate the previously published findings within the combat trauma population.展开更多
Continuous delivery of local anesthetics might be useful for management of localized and chronic pain. Controlled release injectable anesthetics have been developed but they can deliver the drug for only few days and ...Continuous delivery of local anesthetics might be useful for management of localized and chronic pain. Controlled release injectable anesthetics have been developed but they can deliver the drug for only few days and the release is not zero-order. A drug delivery system (DDS) consisting of a perforated reservoir for drug containment and release and its potential for management of chronic pain is described. Proof of principle is detailed for long-term zero order delivery of butamben. In this study, the DDS was a polyimide tube with a 0.20 mm hole and butamben release was evaluated in vitro. It is envisioned that the DDS could be implanted in proximity to a nerve, enervating the pain source, for long-term control of chronic pain.展开更多
Stress can be associated with many physiologicalchanges resulting in significant decrements in human performance.Due to growing interests in alternative and complementary medicine by Westerners,many of the traditions ...Stress can be associated with many physiologicalchanges resulting in significant decrements in human performance.Due to growing interests in alternative and complementary medicine by Westerners,many of the traditions and holistic yogic breathing practices today are being utilized as a measure for healthier lifestyles.These state-of-the-art practices can have a significant impact on common mental health conditions such as depression and generalized anxiety disorder.However,the potential of yogic breathing on optimizing human performance and overall well-being is not well known.Breathing techniques such as alternate nostril,Sudarshan Kriya and bhastrika utilizes rhythmic breathing to guide practitioners into a deep meditative state of relaxation and promote self-awareness.Furthermore,yogic breathing is physiologically stimulating and can be described as a natural"technological"solution to optimize human performance which can be categorized into:(1)cognitive function(i.e.,mind,vigilance);and(2)physical performance(i.e.,cardiorespiratory,metabolism,exercise,whole body).Based on previous studies,we postulate that daily practice of breathing meditation techniques play a significant role in preserving the compensatory mechanisms available to sustain physiological function.This preservation of physiological function may help to offset the time associated with reaching a threshold for clinical expression of chronic state(i.e.,hypertension,depression,dementia)or acute state(i.e.,massive hemorrhage,panic attic)of medical conditions.However,additional rigorous biomedical research is needed to evaluate the physiological mechanisms of various forms of meditation(i.e.,breath-based,mantra,mindfulness)on human performance.These efforts will help to define how compensatory reserve mechanisms of cardiovascular and immune systems are modulated by breath-based meditation.While it has been suggested that breath-based meditation is easier for beginning practitioners when compared to other forms of meditation more research is needed to elucidate these observations.A breath-based meditation sequence suchas Sudarshan Kriya has the potential to help develop an individual’s self-awareness and support better integration of the brain(i.e.,mind)with other organ systems(i.e.,body)for enhanced human performance.展开更多
Traumatic injury is one of the leading causes of death, with uncontrolled hemorrhage from coagulation dysfunction as one of the main potentially preventable causes of the mortality. Hypothermia, acidosis, and resuscit...Traumatic injury is one of the leading causes of death, with uncontrolled hemorrhage from coagulation dysfunction as one of the main potentially preventable causes of the mortality. Hypothermia, acidosis, and resuscitative hemodilution have been considered as the significant contributors to coagulation manifestations following trauma, known as the lethal triad. Over the past decade, clinical observations showed that coagulopathy may be present as early as hospital admission in some severely injured trauma patients. The hemostatic dysfunction is associated with higher blood transfusion requirements, longer hospital stay, and higher mortality. The recognition of this early coagulopathy has initiated tremendous interest and effort in the trauma community to expand our understanding of the underlying pathophysiology and improve clinical treatments. This review discusses the current knowledge of coagulation complications following trauma.展开更多
AIM: To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.METHODS: Pancreatitis was indu...AIM: To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.METHODS: Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 x 100 μg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.RESULTS: Administering the proteasome inhibitor MG132 (at a dose of 10 mg/kg, ip) 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein (HSP72) and decreased DNA-binding of nuclear factor-kB (NF-kB). Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress.CONCLUSION: Our findings suggest that proteasome inhibition might be beneficial not only for the prevention, but also for the therapy of acute pancreatitis.展开更多
AIM To investigate genetic factors that might help define which Crohn's disease(CD) patients are likely to benefit from anti-tumor necrosis factor(TNF) therapy. METHODS This was a prospective cohort study. Patient...AIM To investigate genetic factors that might help define which Crohn's disease(CD) patients are likely to benefit from anti-tumor necrosis factor(TNF) therapy. METHODS This was a prospective cohort study. Patients wererecruited from a university digestive disease practice database. We included CD patients who received antiTNF therapy,had available medical records(with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood,and 7 single nucleotide polymorphisms(SNPs) were assessed. The main outcome measure(following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age,gender,race,and socioeconomic status disease,as well as disease characteristics(such as Montreal criteria). RESULTS121 patients were included. Twenty-one were nonresponders,and 100 were ever-responders. Fas ligand SNP(rs763110) genotype frequencies,TNF gene-308 SNP(rs1800629) genotype frequencies,and their combination,were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype(P = 0.009,OR = 4.30,95%CI: 1.45-12.80). The presence of the A(minor) TNF gene-308 allele correlated with three-fold higher odds of being a non-responder(P = 0.049,OR = 2.88,95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF-308 A allele had nearly five-fold higher odds of being a non-responder(P = 0.015,OR = 4.76,95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.CONCLUSION The Fas-ligand SNP and TNF gene-308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.展开更多
Background: Dietary supplement use(protein/amino acids, weight-loss supplements, performance enhancers) is common among U.S. military members. Reported dietary supplement use in deployed troops is limited and is of co...Background: Dietary supplement use(protein/amino acids, weight-loss supplements, performance enhancers) is common among U.S. military members. Reported dietary supplement use in deployed troops is limited and is of concern in settings where troops are exposed to high ambient temperatures, increased physical demands, and dehydration. Our objective was to describe dietary supplement use and adverse events(AEs) among deployed U.S. service members compared with their pre-deployment use.Methods: We conducted an institutional review board(IRB) approved, descriptive study in Afghanistan using a written questionnaire and collected demographic information, dietary supplement use before and during deployment, AEs associated with supplement use, and physical workout routines. Participants were U.S. military personnel of all branches of service deployed to Afghanistan. They were recruited in high-traffic areas in the combat theater. We analyzed the data with descriptive statistics. Paired t-test/Wilcoxon signed-rank test was conducted to examine the before/during deployment changes for continuous data, and Mc Nemar's chi-square test was conducted for categorical data. We constructed separate logistic regression models to determine the best predictors of increases or decreases in dietary supplement use, with demographic information, reasons for using supplements, and education requested/received as covariates in each model. All statistical tests were two-sided at a significance level of 5%(P<0.05).Results: Data were collected on 1685 participants. Ninety-seven of the participants were in the Army or Air Force. The participants were more likely to work out daily or more than once a day during deployment. Thirty-five percent of the participants reported no supplement use before or during deployment. The remaining 65% of participants reported increased use and increased frequency of use of supplements(e.g., daily) during deployment compared with predeployment. Additionally, more people followed label instructions strictly during deployment vs. predeployment. Overall, the frequency of self-reported AEs among supplement users remained consistent before and during deployment. The only significant difference noted was in problems falling or staying asleep, which increased during deployment. In the adjusted logistic regression models, the level of formal education, military branch, occupational specialty, education about dietary supplements, and certain reasons for using supplements(to boost energy, lose weight, gain muscle strength and mass, and as a meal replacement) were significant predictors of changes in supplement use.Conclusion: Deployed U.S. service members were more likely to use dietary supplements, use more than one supplement and use supplements more frequently during deployment than pre-deployment. No serious AEs were reported, but problems falling or staying asleep increased during deployment.展开更多
Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(...Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(CEPO),regulates innate and adaptive immune cells and affects renal allograft survival,we utilized a rat model of fully MHC-mismatched kidney transplantation.CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group.This therapeutic effect was inhibited when the recipients were given LY294002,a selective inhibitor of the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway or anti-EPO receptor(EPOR)antibody,in addition to CEPO.In vitro,CEPO inhibited the differentiation and function of dendritic cells and modulated their production of proinflammatory and anti-inflammatory cytokines,along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells.Moreover,after CD4^(+)T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell(Treg)/Th17 ratio increased.These effects were abolished by LY294002 or anti-EPOR antibody,suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner.The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.展开更多
文摘Background:Renal cystic disease arising from various etiologies results in fluid-filled cavities within the kidneys.Moreover,preexisting renal dysfunction has been shown to exacerbate multiple pathologies.While swine bred for biomedical research are often clinically inspected for illness/parasites,more advanced diagnostics may aid in uncovering underlying renal abnormalities.Methods:Computed tomography was performed in 54 female prepubertal Yorkshire swine to characterize renal cysts;urine and blood chemistry,and histology of cysts were also performed.Results:Digital reconstruction of right and left kidneys demonstrated that roughly one-third of the animals(17/54;31%)had one or more renal cyst.Circulating biomarkers of renal function were not different between animals that had cysts and those that did not.Alternatively,urinary glucose(P=.03)was higher and sodium(P=.07)tended to be lower in animals with cysts compared to animals without,with no differences in protein(P=.14)or potassium(P=.20).Aspiration of cystic fluid was feasible in two animals,which revealed that the cystic fluid urea nitrogen(97.6±28.7 vs 911.3±468.2 mg/dL),potassium(29.8±14.4 vs 148.2±24.85 mmol/L),uric acid(2.55±1.35 vs 11.4±5.65 mg/dL),and creatinine(60.34±17.26 vs 268.99±95.79 mg/dL)were much lower than in the urine.Histology demonstrated a cyst that markedly compresses the adjacent cortex and is lined by a single layer of flattened epithelium,bounded by fibrous connective tissue which extends into the parenchyma.There is tubular atrophy and loss in these areas.Conclusion:This study provides valuable insight for future studies focusing on kidney function in swine bred for biomedical research.
基金Supported by the National Research Foundation (OTKA) T30735 and T042589
文摘AIM: To assess the effect of our novel cell-permeable nuclear factor-kappaB (NF-κB) inhibitor peptide PN50 in an experimental model of acute pancreatitis. PN50 was produced by conjugating the cell-penetrating penetratin peptide with the nuclear localization signal of the NF-κB p50 subunit.METHODS: Pancreatitis was induced in male Wistar rats by administering 2×100 μg/kg body weight of cholecystokininoctapeptide (CCK) intraperitoneally (IP) at an interval of 1 h. PN50-treated animals received 1 mg/kg of PN50 IP 30 min before or after the CCK injections. The animals were sacrificed 4 h after the first injection of CCK.RESULTS: All the examined laboratory (the pancreatic weight/body weight ratio, serum amylase activity,pancreatic levels of TNF-α and IL-6, degree of lipid peroxidation, reduced glutathione levels, NF-κB binding activity, pancreatic and lung myeloperoxidase activity) and morphological parameters of the disease were improved before and after treatment with the PN50 peptide.According to the histological findings, PN50 protected the animals against acute pancreatitis by favoring the induction of apoptotic, as opposed to necrotic acinar cell death associated with severe acute pancreatitis.CONCLUSION: Our study implies that reversible inhibitors of stress-responsive transcription factors like NF-κB might be clinically useful for the suppression of the severity of acute pancreatitis.
基金We thank Dr Ramin Shiekhattar (Wistar Institute, USA) for the baculoviruses expressing Flag-LSD1 and Drs Jianguo Song and Degui Chen (Shanghai Institute of Biochemistry and Cell Biol- ogy, China) for anti-HDAC1 antibody and H3K36me2 antibody, respectively. This study was partially supported by grants from the National Natural Science Foundation of China (90919025, 30871381), the Ministry of Science and Technology of China (2009CB918402, 2009CB825601) and the Research Platform for Cell Signaling Networks from the Science and Technology Com- mission of Shanghai Municipality (06DZ22923).
基金Supported by grants from the National Research Development and Innovation Office,NKFI K120232Hungarian Science Research Fund,No.GINOP 2.3.2-15-2016-00015 and No.EFOP-3.6.2-16-2017-00006New National Excellence Program of the Ministry of Human Capacities,No.UNKP-17-4
文摘AIM To compare the effects of the four most commonly used preservation solutions on the outcome of liver transplantations.METHODS A systematic literature search was performed using MEDLINE, Scopus, EMBASE and the Cochrane Library databases up to January 31^(st), 2017. The inclusion criteria were comparative, randomized controlled trials(RCTs) for deceased donor liver(DDL) allografts with adult and pediatric donors using the gold standard University of Wisconsin(UW) solution or histidinetryptophan-ketoglutarate(HTK), Celsior(CS) and Institut Georges Lopez(IGL-1) solutions. Fifteen RCTs(1830 livers) were included; the primary outcomes were primary non-function(PNF) and one-year posttransplant graft survival(OGS-1). RESULTS All trials were homogenous with respect to donor and recipient characteristics. There was no statistical difference in the incidence of PNF with the use of UW, HTK, CS and IGL-1(RR = 0.02, 95%CI: 0.01-0.03, P = 0.356). Comparing OGS-1 also failed to reveal any difference between UW, HTK, CS and IGL-1(RR = 0.80, 95%CI: 0.80-0.80, P = 0.369). Two trials demonstrated higher PNF levels for UW in comparison with the HTK group, and individual studies described higher rates of biliary complications where HTK and CS were used compared to the UW and IGL-1 solutions. However, the meta-analysis of the data did not prove a statistically significant difference: the UW, CS, HTK and IGL-1 solutions were associated with nearly equivalent outcomes.CONCLUSION Alternative solutions for UW yield the same degree of safety and effectiveness for the preservation of DDLs, but further well-designed clinical trials are warranted.
文摘Background:Junctional hemorrhage surpassed extremity hemorrhage as the leading cause of preventable death after the resurgence of limb tourniquets during the recent conflicts in Afghanistan and Iraq.Junctional tourniquets(JTQs)were developed in response to this injury pattern.Published data for JTQ efficacy are limited and do not incorporate nonmedical,military first responders.We compared the time for effective placement and scores for device satisfaction between two different JTQs,stratified by combat lifesaver(CLS)and combat medics.Methods:We performed a prospective,randomized,crossover trial utilizing the SAM ’ Medical Junctional Tourniquet(SJT)and Junctional Emergency Treatment Tool(JETTTM).Investigators simple randomized CLS and combat medics to SJT or JETT for their first JTQ application on mannequins with penetrating inguinal injuries.Then,participants immediately placed the other JTQ on another casualty with the same injury.The primary outcome measured was time of successful applicatio n.Success was defined as proper JTQ placement and a pressu re reading of at least 180 mmHg.We compared outcomes between CLS and combat medics.Unsuccessful JTQ applications were excluded from the comparative analysis.Results:From June 2015 to August 2015,a total of 227 personnel(133 CLS and 94 combat medics)at Fort Hood,Texas,USA volunteered to participate in the study.Twenty-eight percent(38 of 133)of CLS and 40%(38 of 94)of combat medics placed both JTQs successfully,for a total of 152 applications(76 SJTs and 76 JETTs).We found a significant difference between applications of the JETT between the CLS and combat medics(92.0±37.7 s versus70.5±20.5 s,P=0.004).No other subg roup analyses,whether by device or user,demonstrated a sig nifica nt difference in application time.Both groups preferred the SJT over the JETT.CLS disagreed with combat medics that the JETT could be easily applied by one person(median 3.0[2.0,4.0]versus median 4.0[3.0,5.0];P=0.006).Conclusions:Overall,success rates for both the SJT and JETT were low.Improved training is needed to increase successful application of junctional tourniquets before widespread implementation.Combat lifesavers and combat medics prefer the SJT over the JETT.
基金Department of Defense Joint Program Committee(JPC-6)
文摘Background: In combat operations, patients with traumatic injuries require expeditious evacuation to improve survival. Studies have shown that long transport times are associated with increased morbidity and mortality. Limited data exist on the influence of transport time on patient outcomes with specific injury types. The objective of this study was to determine the impact of the duration of time from the initial request for medical evacuation to arrival at a medical treatment facility on morbidity and mortality in casualties with traumatic extremity amputation and noncompressible torso injury(NCTI).Methods: We completed a retrospective review of MEDEVAC patient care records for United States military personnel who sustained traumatic amputations and NCTI during Operation Enduring Freedom between January 2011 and March 2014. We grouped patients as traumatic amputation and NCTI(AMP+NCTI), traumatic amputation only(AMP),and neither AMP nor NCTI(Non-AMP/NCTI). Analysis was performed using chi-squared tests, Fisher's exact tests,Cochran-Armitage Trend tests, Shapiro-Wilks tests, Wilcoxon and Kruskal-Wallis techniques and Cox proportional hazards regression modeling.Results: We reviewed 1267 records, of which 669 had an injury severity score(ISS) of 10 or greater and were included in the analysis. In the study population, 15.5% sustained only amputation injuries(n=104, AMP only), 10.8% sustained amputation and NCTI(n=72, AMP+NCTI), and 73.7% did not sustain either an amputation or an NCTI(n=493,Non-AMP/NCTI). AMP+NCTI had the highest mortality(16.7%) with transport time greater than 60 min. While the AMP+NCTI group had decreasing survival with longer transport times, AMP and Non-AMP/NCTI did not exhibit the same trend.Conclusions: A decreased transport time from the point of injury to a medical treatment facility was associated with decreased mortality in patients who suffered a combination of amputation injury and NCTI. No significant association between transport time and outcomes was found in patients who did not sustain NCTI. Priority for rapid evacuation of combat casualties should be given to those with NCTI.
文摘Background: Pediatric casualties account for a notable proportion of encounters in the deployed setting based on the humanitarian medical care mission. Previously published data demonstrates that an age-adjust shock index may be a useful tool in predicting massive transfusion and death in children. We seek to determine if those previous findings are applicable to the deployed, combat trauma setting.Methods: We queried the Department of Defense Trauma Registry(DODTR) for all pediatric subjects admitted to US and Coalition fixed-facility hospitals in Iraq and Afghanistan from January 2007 to January 2016. This was a secondary analysis of casualties seeking to validate previously published data using the shock index, pediatric age adjusted. We then used previously published thresholds to determine patients outcome for validation by age grouping, 1–3 years(1.2), 4–6 years(1.2), 7–12 years(1.0), 13–17 years(0.9).Results: From January 2007 through January 2016 there were 3439 pediatric casualties of which 3145 had a documented heart rate and systolic pressure. Of those 502(16.0%) underwent massive transfusion and 226(7.2%) died prior to hospital discharge. Receiver operating characteristic(ROC) thresholds were inconsistent across age groups ranging from 1.0 to 1.9 with generally limited area under the curve(AUC) values for both massive transfusion and death prediction characteristics. Using the previously defined thresholds for validation, we reported sensitivity and specificity for the massive transfusion by age-group: 1–3(0.73, 0.35), 4–6(0.63, 0.60), 7–12(0.80, 0.57), 13–17(0.77, 0.62). For death, 1–3(0.75, 0.34), 4–6(0.66–0.59), 7–12(0.64, 0.52), 13–17(0.70, 0.57). However, negative predictive values(NPV) were generally high with all greater than 0.87.Conclusions: Within the combat setting, the age-adjusted pediatric shock index had moderate sensitivity and relatively poor specificity for predicting massive transfusion and death. Better scoring systems are needed to predict resource needs prior to arrival, that perhaps include other physiologic metrics. We were unable to validate the previously published findings within the combat trauma population.
文摘Continuous delivery of local anesthetics might be useful for management of localized and chronic pain. Controlled release injectable anesthetics have been developed but they can deliver the drug for only few days and the release is not zero-order. A drug delivery system (DDS) consisting of a perforated reservoir for drug containment and release and its potential for management of chronic pain is described. Proof of principle is detailed for long-term zero order delivery of butamben. In this study, the DDS was a polyimide tube with a 0.20 mm hole and butamben release was evaluated in vitro. It is envisioned that the DDS could be implanted in proximity to a nerve, enervating the pain source, for long-term control of chronic pain.
文摘Stress can be associated with many physiologicalchanges resulting in significant decrements in human performance.Due to growing interests in alternative and complementary medicine by Westerners,many of the traditions and holistic yogic breathing practices today are being utilized as a measure for healthier lifestyles.These state-of-the-art practices can have a significant impact on common mental health conditions such as depression and generalized anxiety disorder.However,the potential of yogic breathing on optimizing human performance and overall well-being is not well known.Breathing techniques such as alternate nostril,Sudarshan Kriya and bhastrika utilizes rhythmic breathing to guide practitioners into a deep meditative state of relaxation and promote self-awareness.Furthermore,yogic breathing is physiologically stimulating and can be described as a natural"technological"solution to optimize human performance which can be categorized into:(1)cognitive function(i.e.,mind,vigilance);and(2)physical performance(i.e.,cardiorespiratory,metabolism,exercise,whole body).Based on previous studies,we postulate that daily practice of breathing meditation techniques play a significant role in preserving the compensatory mechanisms available to sustain physiological function.This preservation of physiological function may help to offset the time associated with reaching a threshold for clinical expression of chronic state(i.e.,hypertension,depression,dementia)or acute state(i.e.,massive hemorrhage,panic attic)of medical conditions.However,additional rigorous biomedical research is needed to evaluate the physiological mechanisms of various forms of meditation(i.e.,breath-based,mantra,mindfulness)on human performance.These efforts will help to define how compensatory reserve mechanisms of cardiovascular and immune systems are modulated by breath-based meditation.While it has been suggested that breath-based meditation is easier for beginning practitioners when compared to other forms of meditation more research is needed to elucidate these observations.A breath-based meditation sequence suchas Sudarshan Kriya has the potential to help develop an individual’s self-awareness and support better integration of the brain(i.e.,mind)with other organ systems(i.e.,body)for enhanced human performance.
文摘Traumatic injury is one of the leading causes of death, with uncontrolled hemorrhage from coagulation dysfunction as one of the main potentially preventable causes of the mortality. Hypothermia, acidosis, and resuscitative hemodilution have been considered as the significant contributors to coagulation manifestations following trauma, known as the lethal triad. Over the past decade, clinical observations showed that coagulopathy may be present as early as hospital admission in some severely injured trauma patients. The hemostatic dysfunction is associated with higher blood transfusion requirements, longer hospital stay, and higher mortality. The recognition of this early coagulopathy has initiated tremendous interest and effort in the trauma community to expand our understanding of the underlying pathophysiology and improve clinical treatments. This review discusses the current knowledge of coagulation complications following trauma.
基金the postdoctoral fellowship of the Hungarian Ministry of Educationthe National Research Foundations (OTKA) grants T30735,T042589 and TS049817
文摘AIM: To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.METHODS: Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 x 100 μg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.RESULTS: Administering the proteasome inhibitor MG132 (at a dose of 10 mg/kg, ip) 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein (HSP72) and decreased DNA-binding of nuclear factor-kB (NF-kB). Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress.CONCLUSION: Our findings suggest that proteasome inhibition might be beneficial not only for the prevention, but also for the therapy of acute pancreatitis.
文摘AIM To investigate genetic factors that might help define which Crohn's disease(CD) patients are likely to benefit from anti-tumor necrosis factor(TNF) therapy. METHODS This was a prospective cohort study. Patients wererecruited from a university digestive disease practice database. We included CD patients who received antiTNF therapy,had available medical records(with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood,and 7 single nucleotide polymorphisms(SNPs) were assessed. The main outcome measure(following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age,gender,race,and socioeconomic status disease,as well as disease characteristics(such as Montreal criteria). RESULTS121 patients were included. Twenty-one were nonresponders,and 100 were ever-responders. Fas ligand SNP(rs763110) genotype frequencies,TNF gene-308 SNP(rs1800629) genotype frequencies,and their combination,were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype(P = 0.009,OR = 4.30,95%CI: 1.45-12.80). The presence of the A(minor) TNF gene-308 allele correlated with three-fold higher odds of being a non-responder(P = 0.049,OR = 2.88,95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF-308 A allele had nearly five-fold higher odds of being a non-responder(P = 0.015,OR = 4.76,95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.CONCLUSION The Fas-ligand SNP and TNF gene-308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.
文摘Background: Dietary supplement use(protein/amino acids, weight-loss supplements, performance enhancers) is common among U.S. military members. Reported dietary supplement use in deployed troops is limited and is of concern in settings where troops are exposed to high ambient temperatures, increased physical demands, and dehydration. Our objective was to describe dietary supplement use and adverse events(AEs) among deployed U.S. service members compared with their pre-deployment use.Methods: We conducted an institutional review board(IRB) approved, descriptive study in Afghanistan using a written questionnaire and collected demographic information, dietary supplement use before and during deployment, AEs associated with supplement use, and physical workout routines. Participants were U.S. military personnel of all branches of service deployed to Afghanistan. They were recruited in high-traffic areas in the combat theater. We analyzed the data with descriptive statistics. Paired t-test/Wilcoxon signed-rank test was conducted to examine the before/during deployment changes for continuous data, and Mc Nemar's chi-square test was conducted for categorical data. We constructed separate logistic regression models to determine the best predictors of increases or decreases in dietary supplement use, with demographic information, reasons for using supplements, and education requested/received as covariates in each model. All statistical tests were two-sided at a significance level of 5%(P<0.05).Results: Data were collected on 1685 participants. Ninety-seven of the participants were in the Army or Air Force. The participants were more likely to work out daily or more than once a day during deployment. Thirty-five percent of the participants reported no supplement use before or during deployment. The remaining 65% of participants reported increased use and increased frequency of use of supplements(e.g., daily) during deployment compared with predeployment. Additionally, more people followed label instructions strictly during deployment vs. predeployment. Overall, the frequency of self-reported AEs among supplement users remained consistent before and during deployment. The only significant difference noted was in problems falling or staying asleep, which increased during deployment. In the adjusted logistic regression models, the level of formal education, military branch, occupational specialty, education about dietary supplements, and certain reasons for using supplements(to boost energy, lose weight, gain muscle strength and mass, and as a meal replacement) were significant predictors of changes in supplement use.Conclusion: Deployed U.S. service members were more likely to use dietary supplements, use more than one supplement and use supplements more frequently during deployment than pre-deployment. No serious AEs were reported, but problems falling or staying asleep increased during deployment.
基金supported by the National Natural Science Foundation of China(No.81470977,No.81970652)the Guangdong Basic and Applied Basic Research Foundation(No.2019A1515011219)the Science and Technology Planning Project of Guangzhou(No.201803010016).S.Z.is supported by the National Institutes of Health grants R01 AR059103,Star Award and R61 AR073409.
文摘Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(CEPO),regulates innate and adaptive immune cells and affects renal allograft survival,we utilized a rat model of fully MHC-mismatched kidney transplantation.CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group.This therapeutic effect was inhibited when the recipients were given LY294002,a selective inhibitor of the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway or anti-EPO receptor(EPOR)antibody,in addition to CEPO.In vitro,CEPO inhibited the differentiation and function of dendritic cells and modulated their production of proinflammatory and anti-inflammatory cytokines,along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells.Moreover,after CD4^(+)T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell(Treg)/Th17 ratio increased.These effects were abolished by LY294002 or anti-EPOR antibody,suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner.The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.