Biomedical subjects

Philip F Stahel

Publications and source records attributed to Philip F Stahel.

16 recordsLinked to original sources

PubMed2006

Activation of caspase-1 dependent interleukins in developmental brain trauma.

Focal mechanical cortical trauma triggers diffuse apoptotic neurodegeneration in the developing rat brain which is associated with invasion of brain tissue with inflammatory mediators. We hypothesized that caspase-1 and the two caspase-1-processed cytokines, interleukin (IL)-1beta and IL-18, are involved in trauma-induced neuronal cell death in the developing brain. 7-day-old Wistar rats or C57/BL6 mice were subjected to head trauma using a weight drop device. Animals were sacrificed at defined time points following trauma and brains were processed for histology and molecular analyses. Neuronal cell death in the immature brain peaked at 12-24 h and was accompanied by a marked increase of mRNA and protein levels for caspase-1, IL-1beta and IL-18 within 2 to 12 h following the injury. Caspase-1 levels were elevated for 72 h, whereas IL-1beta decreased earlier at 48 h. IL-18 remained high over a period of 3 days and decreased to normal levels by day 7 after the injury. Intraperitoneal injection of recombinant human IL-18-binding protein (IL-18BP), a specific inhibitor of IL-18, attenuated traumatic brain injury. Mice deficient in IL-18 (IL-18-/-) were protected against trauma-induced brain damage. These findings indicate that IL-18 is involved in trauma-induced neuronal cell death in the immature rodent brain and might serve as a potential therapeutic target.

Animals↗

PubMed2006

Fatigue behavior of Ilizarov frame versus tibial interlocking nail in a comminuted tibial fracture model: a biomechanical study.

BACKGROUND: Treatment options for comminuted tibial shaft fractures include plating, intramedullary nailing, and external fixation. No biomechanical comparison between an interlocking tibia nail with external fixation by an Ilizarov frame has been reported to date. In the present study, we compared the fatigue behaviour of Ilizarov frames to interlocking intramedullary nails in a comminuted tibial fracture model under a combined loading of axial compression, bending and torsion. Our goal was to determine the biomechanical characteristics, stability and durability for each device over a clinically relevant three month testing period. The study hypothesis was that differences in the mechanical properties may account for differing clinical results and provide information applicable to clinical decision making for comminuted tibia shaft fractures. METHODS: In this biomechanical study, 12 composite tibial bone models with a comminuted fracture and a 25 mm diaphyseal gap were investigated. Of these, six models were stabilized with a 180-mm four-ring Ilizarov frame, and six models were minimally reamed and stabilized with a 10 mm statically locked Russell-Taylor Delta tibial nail. After measuring the pre-fatigue axial compression bending and torsion stiffness, each model was loaded under a sinusoidal cyclic combined loading of axial compression (2.8/28 lbf; 12.46/124.6 N) and torque (1.7/17 lbf-in; 0.19/1.92 Nm) at a frequency of 3 Hz. The test was performed until failure (implant breakage or >or= 5 degrees angulations and/or 2 cm shortening) occurred or until 252,000 cycles were completed, which corresponds to approximately three months testing period. RESULTS: In all 12 models, both the Ilizarov frame and the interlocking tibia nail were able to maintain fracture stability of the tibial defect and to complete the full 252,000 cycles during the entire study period of three months. A significantly higher stiffness to axial compression and torsion was demonstrated by the tibial interlocking nail model, while the Ilizarov frame provided a significantly increased range of axial micromotion. CONCLUSION: This is the first study, to our knowledge, which compares the biomechanical properties of an intramedullary nail to an external Ilizarov frame to cyclic axial loading and torsion in a comminuted tibia shaft fracture model. Prospective, randomized trials comparing Ilizarov frames and interlocked tibial nails are needed to clarify the clinical impact of these biomechanical findings.

Journal Article↗

PubMed2006

Metabolic changes after polytrauma: an imperative for early nutritional support.

Major trauma induces marked metabolic changes which contribute to the systemic immune suppression in severely injured patients and increase the risk of infection and posttraumatic organ failure. The hypercatabolic state of polytrauma patients must be recognized early and treated by an appropriate nutritional management in order to avoid late complications. Clinical studies in recent years have supported the concept of "immunonutrition" for severely injured patients, which takes into account the supplementation of Omega-3 fatty acids and essential aminoacids, such as glutamine. Yet many aspects of the nutritional strategies for polytrauma patients remain controversial, including the exact timing, caloric and protein amount of nutrition, choice of enteral versus parenteral route, and duration. The present review will provide an outline of the pathophysiological metabolic changes after major trauma that endorse the current basis for early immunonutrition of polytrauma patients.

Journal Article↗

PubMed2006

Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation.

BACKGROUND: Neuroprotective strategies for prevention of the neuropathological sequelae of traumatic brain injury (TBI) have largely failed in translation to clinical treatment. Thus, there is a substantial need for further understanding the molecular mechanisms and pathways which lead to secondary neuronal cell death in the injured brain. The intracerebral activation of the complement cascade was shown to mediate inflammation and tissue destruction after TBI. However, the exact pathways of complement activation involved in the induction of posttraumatic neurodegeneration have not yet been assessed. In the present study, we investigated the role of the alternative complement activation pathway in contributing to neuronal cell death, based on a standardized TBI model in mice with targeted deletion of the factor B gene (fB-/-), a "key" component required for activation of the alternative complement pathway. RESULTS: After experimental TBI in wild-type (fB+/+) mice, there was a massive time-dependent systemic complement activation, as determined by enhanced C5a serum levels for up to 7 days. In contrast, the extent of systemic complement activation was significantly attenuated in fB-/- mice (P < 0.05,fB-/- vs. fB+/+; t = 4 h, 24 h, and 7 days after TBI). TUNEL histochemistry experiments revealed that posttraumatic neuronal cell death was clearly reduced for up to 7 days in the injured brain hemispheres of fB-/- mice, compared to fB+/+ littermates. Furthermore, a strong upregulation of the anti-apoptotic mediator Bcl-2 and downregulation of the pro-apoptotic Fas receptor was detected in brain homogenates of head-injured fB-/- vs. fB+/+ mice by Western blot analysis. CONCLUSION: The alternative pathway of complement activation appears to play a more crucial role in the pathophysiology of TBI than previously appreciated. This notion is based on the findings of (a) the significant attenuation of overall complement activation in head-injured fB-/- mice, as determined by a reduction of serum C5a concentrations to constitutive levels in normal mice, and (b) by a dramatic reduction of TUNEL-positive neurons in conjunction with an upregulation of Bcl-2 and downregulation of the Fas receptor in head-injured fB-/- mice, compared to fB+/+ littermates. Pharmacological targeting of the alternative complement pathway during the "time-window of opportunity" after TBI may represent a promising new strategy to be pursued in future studies.

Animals↗

PubMed2006

Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury.

The complement system represents an important mediator of neuroinflammation in traumatic brain injury. We have previously shown that transgenic mice with central nervous system-targeted overexpression of Crry, a potent murine complement inhibitor at the level of C3 convertases, are protected from complement-mediated neuropathological sequelae in brain-injured mice. This knowledge was expanded in the present study to a pharmacological approach by the use of a recombinant Crry molecule (termed Crry-Ig) which was recently made available in a chimeric form fused to the non-complement fixing mouse IgG1 Fc region. In a standardized model of closed head injury in mice, the systemic injection of 1 mg Crry-Ig at 1 h and 24 h after trauma resulted in a significant neurological improvement for up to 7 days, as compared to vehicle-injected control mice (P < 0.05, repeated measures ANOVA). Furthermore, the extensive neuronal destruction seen in the hippocampal CA3/CA4 sublayers in head-injured mice with vehicle injection only was shown to be preserved - to a similar extent as in "sham"-operated mice - by the posttraumatic injection of Crry-Ig. Real-time RT-PCR analysis revealed that the post-treatment with Crry-Ig resulted in a significant up-regulation of candidate neuroprotective genes in the injured hemisphere (Bcl-2, C1-Inh, CD55, CD59), as compared to the vehicle control group (P < 0.01, unpaired Student's t test). Increased intracerebral Bcl-2 expression by Crry-Ig treatment was furthermore confirmed at the protein level by Western blot analysis. These data suggest that pharmacological complement inhibition represents a promising approach for attenuation of neuroinflammation and secondary neurodegeneration after head injury.

Animals↗

PubMed2006

Key issues in advanced bleeding care in trauma.

The incidence of hemostatic abnormalities in the early hours after traumatic incident is high and represents an independent predictor of mortality. Key factors in the development of traumatic coagulopathy include the severity of injury, hypothermia, acidosis, hemorrhagic shock, hemodilution, clotting factor consumption, and fibrinolysis. Assessment of bleeding includes evaluation of the mechanism of injury, vital signs, biochemistry, detection of external and internal bleeding sources, injuries found upon secondary investigation, and response to treatment. Priority in treating the bleeding trauma patient should be given to prevention of further bleeding, hypothermia, acidosis, coagulopathy, and maintenance of tissue oxygenation, achieved by careful physical handling, damage control surgery, analgesia, maintenance of normothermia, correction of coagulopathy, control of blood pH, and serum calcium. Priority during initial treatment is to restore tissue perfusion and achieve hemostasis in vital functions; other nonvital procedures may generally be delayed. This state-of-the-art review aims to address key issues in acute control of bleeding in the trauma patient.

Hemorrhage↗

PubMed2006

Concepts of transtibial amputation: Burgess technique versus modified Brückner procedure.

The technique of a long posterior myocutaneous flap described by Ernest M. Burgess in the late 1960s is one of the most frequent procedures for below-knee amputations worldwide. To account for some potential problems associated with this procedure in patients with occlusive arterial disease, Lutz Brückner developed a modified amputation technique for transtibial amputation in the 1980s. Although this new standardized procedure has been widely used in Germany, it is not well known outside central Europe, secondary to its lack of description in English published work. In this review article, we describe a comparison of the technical aspects of the Burgess procedure with the modified Brückner technique for transtibial amputations. In addition, the charts of 69 consecutive patients with end-stage occlusive arterial disease undergoing below-knee amputation by either of the two standardized procedures (Burgess, n = 29; Brückner, n = 40) were reviewed. The clinical results of the two procedures are reported and compared. Review of the German published work suggests that the two techniques for transtibial amputation in patients with occlusive arterial disease appear to have similar results. This is further supported by data from our own 10-year experience with 69 patients undergoing below-knee amputation by either of the two standardized procedures. This suggests that the Brückner technique is at least equivalent to the Burgess procedure with regard to the clinical outcome in patients with occlusive arterial disease. The potential advantages of the standardized modified Brückner procedure compared with the 'classical' Burgess technique for transtibial amputation remain to be assessed in prospective multicentre trials.

Amputation, Surgical↗

PubMed2005

Closed head injury--an inflammatory disease?

Closed head injury (CHI) remains the leading cause of death and persisting neurological impairment in young individuals in industrialized nations. Research efforts in the past years have brought evidence that the intracranial inflammatory response in the injured brain contributes to the neuropathological sequelae which are, in large part, responsible for the adverse outcome after head injury. The presence of hypoxia and hypotension in the early resuscitative period of brain-injured patients further aggravates the inflammatory response in the brain due to ischemia/reperfusion-mediated injuries. The profound endogenous neuroinflammatory response after CHI, which is phylogenetically aimed at defending the intrathecal compartment from invading pathogens and repairing lesioned brain tissue, contributes to the development of cerebral edema, breakdown of the blood-brain barrier, and ultimately to delayed neuronal cell death. However, aside from these deleterious effects, neuroinflammation has been recently shown to mediate neuroreparative mechanisms after brain injury as well. This "dual effect" of neuroinflammation was the focus of extensive experimental and clinical research in the past years and has lead to an expanded basic knowledge on the cellular and molecular mechanisms which regulate the intracranial inflammatory response after CHI. Thus, head injury has recently evolved as an inflammatory and immunological disease much more than a pure traumatological, neurological, or neurosurgical entity. The present review will summarize the so far known mechanisms of posttraumatic neuroinflammation after CHI, based on data from clinical and experimental studies, with a special focus on the role of pro-inflammatory cytokines, chemokines, and the complement system.

Animals↗

PubMed2005

IL-18: a key player in neuroinflammation and neurodegeneration?

Interleukin (IL)-18 is a potent inflammatory cytokine of the IL-1 family. It is synthesized as an inactive precursor (pro-IL-18), which is cleaved into its functionally active form by caspase-1. Resident cells of the CNS express IL-18 and caspase-1 constitutively, thus providing a local IL-18-dependent immune response. Recent studies have highlighted a crucial role for IL-18 in mediating neuroinflammation and neurodegeneration in the CNS under pathological conditions, such as bacterial and viral infection, autoimmune demyelinating disease, and hypoxic-ischemic, hyperoxic and traumatic brain injuries. This review provides a synopsis of the current knowledge of IL-18-dependent mechanisms of action during acute neurodegeneration in immature and adult brains.

Animals↗

PubMed2004

Tumor necrosis factor-mediated inhibition of interleukin-18 in the brain: a clinical and experimental study in head-injured patients and in a murine model of closed head injury.

Tumor necrosis factor (TNF) and interleukin-(IL)-18 are important mediators of neuroinflammation after closed head injury (CHI). Both mediators have been previously found to be significantly elevated in the intracranial compartment after brain injury, both in patients as well as in experimental model systems. However, the interrelation and regulation of these crucial cytokines within the injured brain has not yet been investigated. The present study was designed to assess a potential regulation of intracranial IL-18 levels by TNF based on a clinical study in head-injured patients and an experimental model in mice. In the first part, we investigated the interrelationship between the daily TNF and IL-18 cerebrospinal fluid levels in 10 patients with severe CHI for up to 14 days after trauma. In the second part of the study, the potential TNF-dependent regulation of intracerebral IL-18 levels was further characterized in an experimental set-up in mice: (1) in a standardized model of CHI in TNF/lymphotoxin-alpha gene-deficient mice and wild-type (WT) littermates, and (2) by intracerebro-ventricular injection of mouse recombinant TNF in WT C57BL/6 mice. The results demonstrate an inverse correlation of intrathecal TNF and IL-18 levels in head-injured patients and a TNF-dependent inhibition of IL-18 after intracerebral injection in mice. These findings imply a potential new anti-inflammatory mechanism of TNF by attenuation of IL-18, thus confirming the proposed "dual" function of this cytokine in the pathophysiology of traumatic brain injury.

Journal Article↗

PubMed2003

Cefepime tissue penetration in experimental acute pancreatitis.

INTRODUCTION: Antibiotic treatment represents a cornerstone in the management of severe acute pancreatitis. However, different antibiotic substances are currently used. In this study, we analyzed penetration of cefepime into pancreatic tissue in two models of acute pancreatitis. AIMS AND METHODOLOGY: Following induction of acute pancreatitis, animals were treated with a single intravenous dose of cefepime (0.1 mg/g of body weight). At two different time points, blood and tissue samples were obtained for determination of cefepime concentration and microbiologic analysis. RESULTS: Mean pancreatic tissue concentrations +/- SEM 30 minutes after drug administration were significantly higher in animals with either mild acute pancreatitis (113 +/- 22 mg/kg) or severe acute pancreatitis (75 +/- 22 mg/kg) than in control animals (30 +/- 6 mg/kg) (p < 0.005). The minimal inhibitory concentrations (MIC90) for organisms usually isolated from infected pancreatic necrosis vary between 0.05 and 8 mg/L, which is between nine and 1,500 times lower than the mean peak concentration found in necrotic pancreatic tissue. Seven hours 30 minutes after antibiotic administration, pancreatic cefepime concentrations were still above the MIC90 in 100% and 83% of animals with mild and severe disease, respectively. The infection rate of pancreatic tissue was significantly lower after antibiotic treatment and was similar after imipenem/cilastatin or cefepime treatment. CONCLUSION: Because of its antibacterial coverage and proven tissue penetration in acute pancreatitis, cefepime should be studied in patients with severe acute pancreatitis.

Animals↗

PubMed2003

Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice.

The role of intracerebral complement activation after traumatic brain injury remains unclear. In this study, the authors demonstrate that transgenic mice with astrocyte-targeted expression of the soluble complement inhibitor sCrry have a significantly reduced neurologic impairment and improved blood-brain barrier function after closed head injury compared with wild-type C57BL/6 littermates. This work further implicates the complement system as a participant in secondary progression of brain damage after head trauma and provides a strong rationale for future studies of posttraumatic pharmacologic complement inhibition.

Animals↗

PubMed2002

1alpha,25-dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants.

BACKGROUND: Vitamin D3 and its metabolites have long been found to exert immunosuppressive effects both in vivo and in vitro. The present study investigated the effect of 1alpha,25-dihydroxycholecalciferol (1,25DHC) on vascularized renal allografts in rats. METHODS: Three days prior to transplantation, two groups of animals were subjected to 1,25DHC (1 microg/kg/day IP) and a low calcium diet, which was continued until the end of the experiments. Recipient organs were removed and single allografts were transplanted in a high responder strain combination (ACI --> Lewis). Following transplantation, low-dose cyclosporine A (3.2 mg/kg/day CsA) administration was started in two experimental groups of recipients (one group receiving 1,25 DHC additionally) whereas the control allograft recipients received no immunosuppression (control III). Graft survival and renal function was monitored until death or the end of experiments and allograft rejection was assessed histologically using the Banff classification. RESULTS: 1,25DHC significantly prolonged allograft survival in comparison to control III (9.6 +/- 1 vs. 5.7 +/- 0.2 days; P=0.009). In addition, a combination of 1,25DHC and low-dose CsA increased allograft survival compared to CsA administration alone (24 +/- 0.9 vs. 13 +/- 0.3 days; P=0.008). 1,25DHC preserved renal creatinine clearance and decreased proteinuria in comparison to control III, and the combination of 1,25DHC and low-dose CsA again showed an additive effect on preservation of renal function. 1,25DHC and low-dose CsA both decreased interleukin (IL)-2 and IL-12 expression levels in serum and allografts, and a combination treatment produced the strongest attenuation of IL-2 and IL-12 expression. In addition, 1,25DHC increased IL-4 and IL-10 expression levels in allografts, whereas CsA alone did not alter IL-4 and IL-10 expression. In contrast, combination of 1,25DHC and low-dose CsA showed a significant increase in IL-10 expression levels whereas IL-4 expression was not elevated. CONCLUSION: Monotherapy with 1,25DHC significantly prolongs survival of renal allografts and preserves graft function in rats. A combination of 1,25DHC and CsA caused an additive effect on graft survival with differential regulation of pro- and anti-inflammatory cytokines, as compared to 1,25DHC administration alone.

Adjuvants, Immunologic↗

PubMed2002

Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury.

Proinflammatory cytokines are important mediators of neuroinflammation after traumatic brain injury. The role of interleukin (IL)-18, a new member of the IL-1 family, in brain trauma has not been reported to date. The authors investigated the posttraumatic release of IL-18 in murine brains following experimental closed head injury (CHI) and in CSF of CHI patients. In the mouse model, intracerebral IL-18 was induced within 24 hours by ether anesthesia and sham operation. Significantly elevated levels of IL-18 were detected at 7 days after CHI and in human CSF up to 10 days after trauma. Published data imply that IL-18 may play a pathophysiological role in inflammatory CNS diseases; therefore its inhibition may ameliorate outcome after CHI. To evaluate the functional aspects of IL-18 in the injured brain, mice were injected systemically with IL-18-binding protein (IL-18BP), a specific inhibitor of IL-18, 1 hour after trauma. IL-18BP-treated mice showed a significantly improved neurological recovery by 7 days, accompanied by attenuated intracerebral IL-18 levels. This demonstrates that inhibition of IL-18 is associated with improved recovery. However, brain edema at 24 hours was not influenced by IL-18BP, suggesting that inflammatory mediators other than IL-18 induce the early detrimental effects of intracerebral inflammation.

Adult↗

PubMed2002

Inflammatory response in acute traumatic brain injury: a double-edged sword.

Inflammation is an important part of the pathophysiology of traumatic brain injury. Although the central nervous system differs from the other organs because of the almost complete isolation from the blood stream mediated by the blood-brain barrier, the main steps characterizing the immune activation within the brain follow a scenario similar to that in other organs. The key players in these processes are the numerous immune mediators released within minutes of the primary injury. They guide a sequence of events including expression of adhesion molecules, cellular infiltration, and additional secretion of inflammatory molecules and growth factors, resulting in either regeneration or cell death. The question is this: to what extent is inflammation beneficial for the injured brain tissue, and how does it contribute to secondary brain damage and progressive neuronal loss? This review briefly reports recent evidence supporting the dual, the beneficial, or the deleterious role of neuroinflammation after traumatic brain injury.

Animals↗

PubMedDate not supplied

Incidence and management of biliary pancreatitis in cholecystectomized patients. Results of a 7-year study.

Data are lacking concerning the frequency of biliary acute pancreatitis in the postcholecystectomy patient. The aim of this study was to identify patients at risk for biliary pancreatitis after cholecystectomy and to describe the therapeutic management of these patients, based on an analysis of 278 unselected patients with acute pancreatitis during a 7-year period. A biliary etiology was presumed in the presence of laboratory findings of cholestasis that could not be explained by another disease, together with the absence of any other known etiology of acute pancreatitis. A biliary cause of disease was found in 132 (47%) of 278 patients. Seventeen (13%) of 132 patients had a history of cholecystectomy. Endoscopic retrograde cholangiopancreatography was performed in all patients with a suspected biliary cause of acute pancreatitis. It showed bile duct stones, microlithiasis, or sludge in 14 patients, and was consistent with typical findings at the papilla of Vater after stone passage in another three patients. No surgical bile duct exploration was necessary. One patient with severe disease and infected pancreatic necrosis died of septic multiorgan failure.

Acute Disease↗