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Michael Kremer

Publications and source records attributed to Michael Kremer.

13 recordsLinked to original sources
PubMed2006

Graft tumor necrosis factor receptor-1 protects after mouse liver transplantation whereas host tumor necrosis factor receptor-1 promotes injury.

BACKGROUND: Tumor necrosis factor (TNF)-alpha is a cytokine with pleiotropic effects on the liver. The predominant hepatic receptor for TNFalpha is TNF receptor-1 (TNFR1). TNFR1 mediates liver injury after ischemia/reperfusion but is also mitogenic during hepatic regeneration. This study investigated the role of graft and host TNFR1 in early graft injury after liver transplantation in mice. METHODS: Livers from TNFR1 deficient (TNFR1-/-) and wild type (WT) mice were transplanted into either TNFR1-/- or WT recipients in all four possible combinations after 12 hours of cold storage. After eight hours, alanine transferase (ALT), necrosis, TdT-mediated dUTP-digoxigenin nick-end labeling (TUNEL) staining, caspase-3 activation, and myeloperoxidase were determined. RESULTS: When TNFR1-/- livers were transplanted into either WT or TNFR1-/- recipients, ALT was twofold greater than when WT donor livers were used. Necrosis and TUNEL staining also increased twofold and sevenfold, respectively, after transplantation of TNFR1-/- donor livers compared to WT. By contrast, ALT and necrosis decreased when WT or TNFR1-/- livers were transplanted into TNFR1-/- hosts compared to WT, which was associated with decreased neutrophil infiltration. CONCLUSION: In conclusion, graft and recipient TNFR1 has opposing effects. Graft TNFR1 decreases graft injury, whereas recipient TNFR1 mediates an increase of injury associated with enhanced neutrophil infiltration. Cross-transplanting of knockout and wild-type livers provides a new means to investigate graft-host interactions during hepatic injury.

Alanine Transaminase↗
PubMed2006

Differentially expressed genes in postperfusion biopsies predict early graft dysfunction after liver transplantation.

BACKGROUND: Preservation induced injury is a major contributing factor to early graft dysfunction in liver allograft recipients. We hypothesized that changes in gene expression represent the earliest indicator of ischemia/reperfusion-related injuries measurable in the graft and could be used as prognostic marker for the occurrence of graft-related complications. METHODS: We studied the expression of 67 genes, known to play a role in acute inflammatory processes by real-time polymerase chain reaction in 59 postperfusion biopsies. The level of expression was correlated with the occurrence of graft-related complications. RESULTS: We identified six genes that were significantly correlated with the occurrence of early graft dysfunction (Spearman test, two-tailed; P<0.05). High C-reactive protein (CRP) gene expression levels correlated significantly with the need of therapeutic interventions due to graft-related complications (P=0,011). Furthermore, five genes related to vascular endothelial cell physiology (CTGF, WWP2, CD274, VEGF. and its receptor FLT1) showed significantly reduced expression in the postperfusion biopsies of patients with need of therapeutic interventions due to graft-related complications in the first month (P<0.05). Using a risk score based on the expression of these five genes, complications could be predicted with 96% sensitivity (ROC analysis, specificity: 74%, positive predictive value: 72%, negative predictive value: 96%). CONCLUSION: Quantitative gene expression analysis in postperfusion biopsies may be a valuable tool to prospectively identify patients at risk for early clinical allograft dysfunction after liver transplantation.

Acute Disease↗
PubMed2006

LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice.

Although it is clear that bile acid accumulation is the major initiator of fibrosis caused by cholestatic liver disease, endotoxemia is a common side effect. However, the depletion of hepatic macrophages with gadolinium chloride blunts hepatic fibrosis. Because endotoxin is a key activator of hepatic macrophages, this study was designed to test the hypothesis that LPS signaling through CD14 contributes to hepatic fibrosis caused by experimental cholestasis. Wild-type mice and CD14 knockout mice (CD14(-/-)) underwent sham operation or bile duct ligation and were killed 3 wk later. Measures of liver injury, such as focal necrosis, biliary cell proliferation, and inflammatory cell influx, were not significantly different among the strains 3 wk after bile duct ligation. Markers of liver fibrosis such as Sirius red staining, liver hydroxyproline, and alpha-smooth muscle actin expression were blunted in CD14(-/-) mice compared with wild-type mice after bile duct ligation. Despite no difference in lymphocyte infiltration, the macrophage/monocyte activation marker OX42 (CD11b) and the oxidative stress/lipid peroxidation marker 4-hydroxynonenal were significantly upregulated in wild-type mice after bile duct ligation but not in CD14(-/-) mice. Increased profibrogenic cytokine mRNA expression in the liver after bile duct ligation was significantly blunted in CD14(-/-) mice compared with the wild type. The hypothesis that LPS was involved in experimental cholestatic liver fibrosis was tested using mice deficient in LPS-binding protein (LBP(-/-)). LBP(-/-) mice had less liver injury and fibrosis (Siruis red staining and hydroxyproline content) compared with wild-type mice after bile duct ligation. In conclusion, these data demonstrate that endotoxin in a CD14-dependent manner exacerbates hepatic fibrogenesis and macrophage activation to produce oxidants and cytokines after bile duct ligation.

Animals↗
PubMed2006

Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis.

Steatohepatitis enhances the severity of liver injury caused by acute inflammation. The purpose of this study was to test the hypothesis that fatty liver due to chronic choline-deficient diet exacerbates concanavalin A (ConA)-induced liver hepatitis, which is predominantly facilitated by T cells. Male C57BL/6 mice were fed either control choline-sufficient diet (CSD) or choline-deficient diet (CDD) for 6 weeks before ConA administration. Mice were sacrificed 3, 9, and 24 hours after ConA injection. Liver injury measured by aspartate aminotransferase (AST), alanine aminotransferase (ALT), pathology, and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) staining was minimal in mice fed either diet before ConA exposure. However, ConA-induced liver injury was significantly greater in CDD-fed mice compared with control-fed mice. Liver cytokines were assessed by quantitative real-time polymerase chain reaction (PCR). The expression of T helper (Th) 1 cytokines tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), and interferon gamma (IFN-gamma) were dramatically elevated after ConA in CDD-fed mice compared with control-fed mice. CDD also enhanced ConA-induced STAT4 activation, but not STAT6. Notably, regulators of T-cell differentiation were strongly shifted toward a predominant Th1 profile. T-bet, regulator of the Th1 response, was up-regulated in CDD-fed mice, whereas Th2 regulator GATA-3 was significantly suppressed in CDD-fed mice after ConA. Moreover, the expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3, and repressor of GATA-3 (ROG) favored a predominant Th1 cytokine response in CDD-fed mice. In conclusion, these data support the hypothesis that hepatosteatosis caused by CDD is associated with more severe ConA-induced hepatitis due to a predominant shift toward Th1 response.

Alanine Transaminase↗
PubMed2005

Identification of differentially expressed genes after partial rat liver ischemia/reperfusion by suppression subtractive hybridization.

AIM: To identify potential diagnostic target genes in early reperfusion periods following warm liver ischemia before irreversible liver damage occurs. METHODS: We used two strategies (SSH suppression subtractive hybridization and hybridization of cDNA arrays) to determine early changes in gene expression profiles in a rat model of partial WI/R, comparing postischemic and adjacent nonischemic liver lobes. Differential gene expression was verified (WI/R; 1 h/2 h) and analyzed in more detail after warm ischemia (1 h) in a reperfusion time kinetics (0, 1, 2 and 6 h) and compared to untreated livers by Northern blot hybridizations. Protein expression was examined on Western blots and by immunohistochemistry for four differentially expressed target genes (Hsp70, Hsp27, Gadd45a and IL-1rI). RESULTS: Thirty-two individual WI/R target genes showing altered RNA levels after confirmation by Northern blot analyzes were identified. Among them, six functionally uncharacteristic expressed sequences and 26 known genes (12 induced in postischemic liver lobes, 14 with higher transcriptional expression in adjacent nonischemic liver lobes). Functional categories of the verified marker genes indicate on the one hand cellular stress and tissue damage but otherwise activation of protective cellular reactions (AP-1 transcription factors, apoptosis related genes, heat shock genes). In order to assign the transcriptional status to the biological relevant protein level we demonstrated that Hsp70, Hsp27, Gadd45a and IL-1rI were clearly up-regulated comparing postischemic and untreated rat livers, suggesting their involvement in the WI/R context. CONCLUSION: This study unveils a WI/R response gene set that will help to explore molecular pathways involved in the tissue damage after WI/R. In addition, these genes especially Hsp70 and Gadd45a might represent promising new candidates indicating WI/R liver damage.

Animals↗
PubMed2005

Peer effects in drug use and sex among college students.

Past research suggests that congregating delinquent youth increases their likelihood of problem behavior. We test for analogous peer effects in the drug use and sexual behavior of male (n = 279) and female (n = 435) college students, using data on the characteristics of first-year roommates to whom they were randomly assigned. We find that males who reported binge drinking in high school drink much more in college if assigned a roommate who also binge drank in high school than if assigned a nonbinge-drinking roommate. No such multiplier effect is observed for females, nor are multiplier effects observed for marijuana use or sexual behavior for either males or females. Students who did not engage in these behaviors in high school do not appear to be affected by their roommates' high school behavior.

Adolescent↗
PubMed2005

Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver.

Kupffer cells and liver sinusoidal endothelial cells (LSEC) clear portal venous blood from gut-derived bacterial degradation products such as lipopolysaccharide (LPS) without inducing a local inflammatory reaction. LPS tolerance was reported for Kupffer cells, but little is known whether sensitivity of LSEC toward LPS is dynamically regulated. Here, we demonstrate that LSEC react to LPS directly as a function of constitutive Toll-like receptor 4 (TLR4)/CD14 expression but gain a LPS-refractory state upon repetitive stimulation without loss of scavenger activity. LPS tolerance in LSEC is characterized by reduced nuclear localization of nuclear factor-kappaB upon LPS rechallenge. In contrast to monocytes, however, TLR4 surface expression of LSEC is not altered by LPS stimulation and thus does not account for LPS tolerance. Mechanistically, LPS tolerance in LSEC is linked to prostanoid production and may account for cross-tolerance of LPS-treated LSEC to interferon-gamma stimulation. Functionally, LPS tolerance in LSEC results in reduced leukocyte adhesion following LPS rechallenge as a consequence of decreased CD54 surface expression. Furthermore, LPS tolerance is operative in vivo, as we observed by intravital microscopy-reduced leukocyte adhesion to LSEC and improved sinusoidal microcirculation in the liver after repetitive LPS challenges. Our results support the notion that LPS tolerance in organ-resident scavenger LSEC contributes to local hepatic control of inflammation.

Animals↗
PubMed2003

The AANA Foundation Closed Malpractice Claims Study on nerve injuries during anesthesia care.

Anesthesia-associated nerve injury is a common cause of patient morbidity and litigation. To identify factors associated with perioperative nerve injuries and rationalize preventive strategies, 44 cases from the American Association of Nurse Anesthetists (AANA) Foundation Closed Malpractice Claims Database pertaining to nerve injuries in which nurse anesthetists provided care were analyzed. Emerging patterns and themes related to the development of injury were identified. The database is a collection of medical liability claims filed against CRNAs insured by the St Paul Fire and Marine Insurance Company; 44 claims of anesthesia-related nerve injury were analyzed. The most common injury was to the brachial plexus (15 [34%]), followed by ulnar nerve injury (7 [16%]), radial nerve injury (5 [11%]), peroneal nerve injury (4 [9%]), paraplegia (4 [9%]), lumbosacral injury (3[7%]), and a variety of "other" injuries (8[18%]). These numbers and percentages total more than 44 (100%) as some patients incurred multiple injuries. Documentation on the anesthesia record of the use of intraoperative protective padding and patient position was lacking or inadequate in a majority of the claims. Effective strategies for the prevention of nerve injury during anesthesia are reviewed. Abnormal body habitus, several disease states, anesthesia technique, improper positioning, lack of adequate padding, and tourniquet use have been implicated as risk factors.

Adolescent↗
PubMed2002

A synthesis of the Australian Patient Safety Foundation Anesthesia Incident Monitoring Study, the American Society of Anesthesiologists Closed Claims Project, and the American Association of Nurse Anesthetists Closed Claims Study.

The study of anesthesia risk is fraught with methodological challenges and the epidemiological uncertainty peculiar to anesthesia: the true frequency of anesthetic mortality is unknown. If anesthesia mortality is as rare as 1 in 200,000 cases, the sample needed to study this phenomenon would be enormous. Existing studies provide insights to the genesis of damaging events and adverse outcomes in anesthesia. We examined research design, methodology, and findings to date in 3 studies of anesthesia risk. Limitations include self-report by providers in the Australian study and the retrospective nature of closed claims research in American studies. Respiratory events were the largest class of injury in all 3 studies; substandard care frequently was involved. Australian investigators noted a high rate of human error and equipment issues. American physician investigators found that death or brain damage occurred in 85% of respiratory cases, 72% of which were deemed preventable. Nurse anesthetist investigators had similar findings for respiratory claims. Patient acuity and procedure complexity may be less significant contributory factors to anesthesia risk than are provider vigilance and clinical decision making. Prospective multicenter studies conducted politically may be the only type of research that definitively addresses the myriad issues in anesthesia risk research.

Anesthesia↗
PubMed1997

Quantitative Tissue Doppler Echocardiography: Physiological Nonuniformity of Left Ventricular Transmural Myocardial Wall-Motion Velocities and Gradients.

Tissue Doppler echocardiography (TDE) is a new method by which transmural myocardial function can be studied noninvasively. In order to investigate physiology and reproducibility, 24 young, healthy volunteers were examined by M-mode TDE. Nonuniformity of transmural tissue layer velocities became apparent: Subendocardial and subepicardial velocities of the anteroseptal myocardial wall (AW) were 3.5 +/- 0.7 and 1.3 +/- 0.5 cm/sec (P < 0.0001, t-test), whereas in the posterolateral wall (PW) values of 3.6 +/- 0.6 and 1.2 +/- 0.4 cm/sec (P < 0.0001, t-test), respectively, were revealed. The ratios, termed "myocardial velocity gradients" as a new indicator of left ventricular performance, were 3.1 +/- 1.0 and 3.4 +/- 1.1, respectively. AW and PW did not differ (N.S.). Tolerance borders did not overlap, and intraobserver variability did not reach intersubject variability (P < 0.0001, F-ratio test). TDE provides new and more sophisticated insights into left ventricular performance. It seems to be accurate and reliable and therefore worth introducing into the clinical arena.

Journal Article↗