Biomedical subjects

Mark Lehnert

Publications and source records attributed to Mark Lehnert.

10 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

Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation.

Hemorrhagic shock and resuscitation cause endotoxemia and hepatocellular damage. Because lipopolysaccharide-binding protein (LBP) enhances cellular responses to endotoxin, our aim was to determine whether LBP contributes to hemorrhage/resuscitation-induced injury by comparing LBP knockout and wild-type mice. Under pentobarbital anaesthesia, wild-type and LBP-deficient mice were hemorrhaged to 30 mmHg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer solution. Serum alanine aminotransferase (ALT) necrosis, neutrophil infiltration, and 4-hydroxynonenal by histology/cytochemistry and stress kinase activation by immunoblot analysis were then determined. ALT in wild-type mice was 2,461 +/- 383 and 1,418 +/- 194 IU/l (means +/- SE), respectively, at 2 and 6 h after resuscitation versus sham ALT of 102 +/- 6 IU/l. In LBP-deficient mice, ALT was blunted at both time points to 1,108 +/- 340 and 619 +/- 171 IU/l (P < 0.05). Liver necrosis after 6 h was also attenuated from 3.5 +/- 0.8% in wild-type mice to 1.3 +/- 0.5% in LBP-deficient mice (P < 0.05). After hemorrhage/resuscitation, neutrophil infiltration increased 71% more in wild-type than LBP knockout mice. Similarly, hepatic 4-hydroxynonenal staining, indicative of lipid peroxidation, decreased from 33.8 +/- 4.5% in wild-type mice to 11.6 +/- 1.9% in knockout mice (P < 0.05). After hemorrhage/resuscitation, activation of MAPKs, JNK and ERK, occurred in wild-type mice, which was largely blocked in LBP-deficient mice. However, endotoxin in portal blood after resuscitation was not significantly different between wild-type and knockout mice. In conclusion, hemorrhagic shock and resuscitation to mice cause severe, LBP-mediated hepatocellular damage. An absence of LBP blunts hepatocellular injury with decreased neutrophil infiltration, oxidative stress, and c-Jun and ERK activation.

Acute-Phase Proteins↗

PubMed2006

A prospective study comparing operative time in conventional laparoscopic and robotically assisted Thal semifundoplication in children.

BACKGROUND: It is not clear if robotically assisted surgery (providing articulating instruments, 3-dimensional vision, intuitive ergonomics) performed in pediatric patients offers the same advantages over conventional surgery as in adult patients. In the laboratory setting, robots require less time to perform certain tasks. Accordingly, we tested the hypothesis that the time required to perform a robotically assisted laparoscopic Thal semifundoplication is different compared with a conventional laparoscopic procedure in children. METHODS: The time required to perform single operative steps was prospectively recorded in 10 consecutively performed Thal semifundoplications with the use of a robot (da Vinci) and in 10 consecutively performed operations done by conventional laparoscopy. RESULTS: No conversion to an open operation was necessary, and there were no intraoperative complications throughout the study and no postoperative complications up to 14 months after surgery. Total operative time was similar in both groups. In the robotically assisted group, time for setup was significantly longer (20.8 +/- 7.5 vs 34.6 +/- 9.2 minutes, P < .05), but dissection of the hiatal region as the most challenging operative step was accomplished 34% faster in the robotically assisted group (30.8 +/- 8.7 vs 20.2 +/- 5.3 minutes, P < .05). CONCLUSION: At the current level of technology, the robotic system is superior compared with established standard laparoscopic techniques requiring tissue preparation; however, the potential benefit in operating time is counterbalanced by the increased complexity of setting up the system.

Adolescent↗

PubMed2006

Delayed elevation of soluble tumor necrosis factor receptors p75 and p55 in cerebrospinal fluid and plasma after traumatic brain injury.

Recent studies have reported a significant inflammatory reaction in the brain and the systemic circulation after traumatic brain injury (TBI). Although there is growing knowledge and understanding of the mechanisms and mediators involved in the proinflammatory reaction, little is known about the anti-inflammatory mediators in the brain. As tumor necrosis factor alpha (TNF-alpha) plays a detrimental role in the initiation and promotion of the proinflammatory reactions after TBI, the endogenous scavenger system, represented by the soluble TNF receptors (sTNFRs) p55 and p75, seems to have an important anti-inflammatory capacity by binding to circulating TNF-alpha. To evaluate this potentially anti-inflammatory response to trauma, we analyzed sTNFR p55 and p75 in paired plasma/cerebrospinal fluid (CSF) samples of 29 patients who encountered TBI. Values were compared with reference values obtained from healthy volunteers (n = 91). Patients with TBI showed significantly (P < 0.001) elevated sTNFR p55 and p75 values starting from day 2 and lasting until day 10 if compared with reference values. In contrast to the early increased plasma values p55 and p75 showed slowly increasing CSF values starting on day 4 and 3, respectively. Significantly (P < 0.001) increased CSF values of p 55 were determined on days 4 to 6 and day 9. p75 showed significantly (P < 0.001) elevated values if compared with control values on days 7 and 9. The sTNFR p55 and p75 show a distinct and long-lasting elevation in plasma of patients after TBI. In contrast, CSF values display a delayed and less intense elevation of both receptors in patients with TBI. These findings are suggestive of an imbalance of the proinflammatory and anti-inflammatory reactions of the central nervous system after trauma, with an emphasis on the proinflammatory mechanisms and a slow increase of potentially anti-inflammatory mediators such as the soluble TNFRs after TBI.

Adolescent↗

PubMed2005

Hemodynamic and respiratory effects of robot-assisted laparoscopic fundoplication in children.

Laparoscopic fundoplication is increasingly used for treating gastro-esophageal reflux disease in children. Mechanical and pharmacological effects may contribute to hemodynamic and respiratory changes during carbon dioxide pneumoperitoneum. The aim of the present study was to evaluate the hemodynamic and respiratory effects of pneumoperitoneum (PP) with an intra-abdominal pressure (IAP) of 12 mmHg in children undergoing robot-assisted laparoscopic fundoplication during total intravenous anesthesia. Ten children, aged 8-16 years, American Society of Anesthesiologists physical status II-III, scheduled for robot-assisted laparoscopic fundoplication in the reverse Trendelenburg position were investigated. Minute ventilation (MV), peak inspiratory pressure (PIP), IAP, heart rate (HR), mean arterial blood pressure (MAP) were recorded, together with pH, base excess, HCO3-, P(et)CO2, PaCO2, and PaO2 at six time points: before insufflation, 10, 30, 60, 90 minutes after creating PP and after desufflation. The IAP was maintained at 12 mmHg. During insufflation MAP increased significantly from 70.6 (+/-9.0) to 84.8 (+/-10.4) mmHg, MV was increased from 4.6 (+/-0.8) to 5.5 (+/-0.9) l min(-1), PIP increased, PaO2 and pH decreased. P(et)CO2 increased from 33.1 (+/-1.6) to 36.6 (+/-1.6) mmHg together with PaCO2. Hemodynamic and respiratory effects due to the intra-abdominal insufflation of CO2 with an IAP of 12 mmHg are well tolerated, and anesthesia with remifentanil, propofol and mivacurium facilitates extubation immediately at the end of surgery.

Adolescent↗

PubMed2005

Free radical-dependent dysfunction of small-for-size rat liver grafts: prevention by plant polyphenols.

BACKGROUND & AIMS: The mechanisms by which small-for-size liver grafts decrease survival remain unclear. This study investigated the role of free radicals in injury to small-for-size grafts. METHODS: Rat liver explants were reduced in size ex vivo and transplanted into recipients of the same or greater body weight, resulting in a graft weight and standard liver weight of approximately 50% and 25%, respectively. A polyphenol extract from Camellia sinenesis (20 microg/mL) or an equivalent concentration of epicatechin was added to the storage solution and the lactated Ringer poststorage rinse solution. RESULTS: Serum alanine aminotransferase release increased from approximately 60 U/L before implantation to 750, 1410, and 2520 U/L after full-size, half-size, and quarter-size transplantation, respectively. Total bilirubin increased slightly after transplantation of full-size and half-size grafts but increased 104-fold in quarter-size grafts. In quarter-size grafts, histological changes included necrosis, leukocyte infiltration, and eosinophilic inclusion body formation. Polyphenol treatment ameliorated these effects by > or =67%. Survival was 30% after transplantation of small-for-size grafts. After polyphenol treatment, survival increased to 70%. Free radicals in bile assessed by spin trapping and 4-hydroxynonenal adducts measured by immunohistochemistry were also greater in reduced-size grafts, an effect ameliorated by polyphenols. Epicatechin, a major polyphenol from Camellia sinenesis, also improved graft function and decreased enzyme release, histopathologic changes, and free radical formation. CONCLUSIONS: Increased formation of free radicals occurs after transplantation of reduced-size livers, which contributes to graft dysfunction and failure. Plant polyphenols decrease liver graft injury and increase survival of small-for-size liver grafts, most likely by scavenging free radicals.

Alanine Transaminase↗

PubMed2005

Fracture and retrosternal dislocation of the medial clavicle in a 12-year-old child--case report, options for diagnosis, and treatment in children.

We report a retrosternally displaced epiphysiolysis in a 12-year-old child and discuss options for the most appropriate diagnostic and therapeutic approach. If a standard anteroposterior view of the shoulder girdle shows abnormalities or if appropriate clinical suspicion is present, we strongly favor an magnetic resonance imaging study for further workup instead of a computed tomographic scan, which is currently the diagnostic method of choice in clinical algorithms. Radiation exposure is thereby limited and maximum information about possible mediastinal soft tissue complications is obtained using a single diagnostic tool. If open reduction is indicated, retention of the joint or approximation of physeal fracture or treatment of ligamentous injury should be performed without metal devices. These suggestions for future management of these patients should further reduce the use of x-rays in children. In addition, applying a suture instead of using metal for stabilization can avoid the extensively described complications in literature that can potentially result from metal devices. In addition, sutures circumvent the need for a second operation for metal removal.

Accidental Falls↗

PubMed2003

Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats.

Accumulation of hydrophobic bile acids during cholestasis leads to generation of oxygen free radicals in the liver. Accordingly, this study investigated whether polyphenols from green tea Camellia sinenesis, which are potent free radical scavengers, decrease hepatic injury caused by experimental cholestasis. Rats were fed a standard chow or a diet containing 0.1% polyphenolic extracts from C. sinenesis starting 3 days before bile duct ligation. After bile duct ligation, serum alanine transaminase increased to 760 U/l after 1 day in rats fed a control diet. Focal necrosis and bile duct proliferation were also observed after 1-2 days, and fibrosis developed 2-3 wk after bile duct ligation. Additionally, procollagen-alpha1(I) mRNA increased 30-fold 3 wk after bile duct ligation, accompanied by increased expression of alpha-smooth muscle actin and transforming growth factor-beta and the accumulation of 4-hydroxynenonal, an end product of lipid peroxidation. Polyphenol feeding blocked or blunted all of these bile duct ligation-dependent changes by 45-73%. Together, the results indicate that cholestasis due to bile duct ligation causes liver injury by mechanisms involving oxidative stress. Polyphenols from C. sinenesis scavenge oxygen radicals and prevent activation of stellate cells, thereby minimizing liver fibrosis.

Actins↗

PubMed2003

Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver.

Recent evidence indicates that angiotensin II (ANG II) plays an important role in liver fibrogenesis. However, the underlying mechanisms are largely unknown. In advanced chronic liver diseases, circulating levels of ANG II are frequently elevated. We investigated the hepatic effects of prolonged systemic infusion of ANG II in normal rats. Saline or ANG II at subpressor and pressor doses (15 and 50 ng.kg-1.min-1, respectively) were infused to normal rats for 4 wk through a subcutaneous osmotic pump. Infusion of ANG II resulted in liver injury, as assessed by elevated serum liver enzymes. Livers from ANG II-perfused rats showed activation of JNK and ERK as well as increased NF-kappaB and activating protein-1 DNA-binding activity. Moreover, ANG II perfusion induced oxidative stress, increased concentration of proinflammatory cytokines, and upregulated the inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2. Histological examination of the livers from ANG II-infused rats showed mild portal inflammation as well as thickening and thrombosis of small hepatic vessels. ANG II-treated livers showed accumulation of CD43-positive inflammatory cells and activated hepatic stellate cells (HSCs) at the pericentral areas. A slight increase in collagen synthesis was observed, as assessed by Sirius red staining and hepatic hydroxyproline. All of these effects were observed when ANG II was perfused at subpressor and pressor doses. ANG II also accelerated the activation of primary cultured rat HSCs. In conclusion, increased systemic ANG II can induce liver injury by promoting proinflammatory events and vascular damage. ANG II-induced hepatic effects are not dependent on increase in arterial pressure.

Angiotensin II↗

PubMed2003

Dependence of liver injury after hemorrhage/resuscitation in mice on NADPH oxidase-derived superoxide.

Hemorrhagic shock and resuscitation cause hepatocellular damage by mechanisms involving oxidative stress. However, the sources of free radicals mediating hepatocellular injury remain controversial. Thus, this study tested the hypothesis that NADPH oxidase plays a role in producing hepatocellular injury after hemorrhagic shock and resuscitation. Both wild-type and NADPH oxidase-deficient mice (p47(phox) knockout mice) were subjected to hemorrhagic shock (3 h at 30 mmHg). The mice were resuscitated over 30 min with the shed blood and additional lactated Ringer's solution (50% of the shed blood volume). Serum alanine aminotransferase (ALT) levels increased at 1 and 6 h postresuscitation in wild-type animals to 4735 +/- 1017 IU/L and 1450 +/- 275 IU/L (mean +/- SE), respectively, whereas in knockout mice, this ALT increase was blunted at both time points (732 +/- 241 IU/L and 328 +/- 69 IU/L, P < 0.05). Liver necrosis assessed histologically 6 h after the end of reperfusion was also attenuated in the knockout mice (3.5% +/- 0.95% of area vs. 0.9% +/- 0.26%, P < 0.05). In hemorrhaged wild-type mice, infiltrating neutrophils were twice as numerous compared with hemorrhaged NADPH oxidase-deficient animals 6 h after reperfusion. In knockout animals, hepatic 4-hydroxynonenal content, indicative of lipid peroxidation from reactive oxygen species, was blunted (6.7% +/- 0.6% vs. 26.4% +/- 2.3% of stained area, P < 0.05), as shown by immunohistochemistry. Immunohistochemical staining for 3-nitrotyrosine, indicative of reactive nitrogen species formation, was also blunted in the livers of knockout mice (11.6% +/- 2.8% vs. 37.4% +/- 3.4, P < 0.05). In conclusion, hemorrhagic shock and resuscitation cause hepatocellular damage via NADPH oxidase-mediated oxidative stress. The absence of NADPH oxidase substantially attenuates hepatocellular injury after hemorrhagic shock and resuscitation, blunts neutrophil infiltration, and decreases formation of reactive oxygen and reactive nitrogen species.

Alanine Transaminase↗