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1.  Deficiency of complement receptors CR2/CR1 in Cr2-/- mice reduces the extent of secondary brain damage after closed head injury 
Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2 -/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2 -/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2 -/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2 -/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2 -/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2 -/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury.
PMCID: PMC4050415  PMID: 24885042
Closed head injury; Neuroinflammation; Complement receptor; Cr2 -/- mice; Secondary brain injury
2.  Challenging the Role of Adaptive Immunity in Neurotrauma: Rag1−/− Mice Lacking Mature B and T Cells Do Not Show Neuroprotection after Closed Head Injury 
Journal of Neurotrauma  2012;29(6):1233-1242.
The role of adaptive immunity in contributing to post-traumatic neuroinflammation and neuropathology after head injury remains largely unexplored. The present study was designed to investigate the pathophysiological sequelae of closed head injury in Rag1−/− mice devoid of mature B and T lymphocytes. C57BL/6 wild-type and Rag1−/− mice were subjected to experimental closed head injury, using a standardized weight-drop device. Outcome parameters consisted of neurological scoring, quantification of blood–brain barrier (BBB) function, measurement of inflammatory markers and mediators of apoptosis in serum and brain tissue, and assessment of neuronal cell death, astrogliosis, and tissue destruction. There was no difference between wild-type and Rag1−/− mice with regard to injury severity and neurological impairment for up to 7 days after head injury. The extent of BBB dysfunction was in a similar range for both groups. Quantification of complement activation fragments in serum revealed significantly attenuated C3a levels in Rag1−/− mice compared to wild-type animals. In contrast, the levels of pro- and anti-inflammatory cytokines and pro-apoptotic and anti-apoptotic mediators remained in a similar range for both groups, and the histological analysis of brain sections did not reveal a difference in reactive astrogliosis, tissue destruction, and neuronal cell death in Rag1−/− compared to wild-type mice. These findings suggest that adaptive immunity is not of crucial importance for initiating and sustaining the inflammatory neuropathology after closed head injury. The attenuated extent of post-traumatic complement activation seen in Rag1−/− mice implies a cross-talk between innate and adaptive immune responses, which requires further investigation in future studies.
PMCID: PMC3325549  PMID: 22335783
adaptive immunity; closed head injury; complement system; natural antibodies; Rag1
3.  Mechanical Quantification of Local Bone Quality in the Humeral Head: A Feasibility Study 
Surgical treatment of proximal humerus fractures can be challenging due to osteoporosis. The weak bone stock makes stable implant anchorage difficult, which can result in low primary stability. Accordingly, significant failure rates, even with modern locking plates, are reported in the literature. Intraoperative knowledge of local bone quality could be helpful in improving results. This study evaluates the feasibility of local bone quality quantification using breakaway torque measurements.
Materials and Methods:
A torque measurement tool (DensiProbe™) was developed to determine local resistance to breakaway offered by the cancellous bone in the humeral head to quantify local bone quality. The tool was adapted to a standard locking plate (PHILOS, Synthes), allowing measurement in the positions of the six humeral head screws, as provided by the aiming device of the plate. Two hundred and seventy measurements were performed in 44 fresh cadaveric human humeri.
Handling of the tool was straight forward and provided reproducible results for the six different positions. The method allows discrimination between the respective positions with statistical significance, and thus provides reliable information on the local distribution of bone quality within the humeral head.
This study introduces a new method using breakaway torque to determine local bone quality within the humeral head in real time. Because DensiProbe is adapted to a standard locking plate, there is the potential for intraoperative application. The information provided could enable the surgeon to improve fixation of osteoporotic proximal humerus fractures.
PMCID: PMC3664459  PMID: 23730382
Bone quality; DensiProbe; fracture; osteoporosis; proximal humerus.
4.  Radiation dose reduction in CT-guided periradicular injections in lumbar spine: Feasibility of a new institutional protocol for improved patient safety 
Image guided spinal injections are successfully used in the management of low back pain and sciatica. The main benefit of CT-guided injections is the safe, fast and precise needle placement, but the radiation exposure remains a serious concern. The purpose of the study was to test a new institutional low-dose protocol for CT-guided periradicular injections in lumbar spine to reduce radiation exposure while increasing accuracy and safety for the patients.
We performed a retrospective analysis of a prospective database during a 4-month period (Oct-Dec 2011) at a German University hospital using a newly established low-dose-CT-protocol for periradicular injections in patients suffering from lumbar disc herniation and nerve root entrapment. Inclusion criteria were acute or chronic nerve root irritation due to lumbar disc hernia, age over 18, compliance and informed consent. Excluded were patients suffering from severe obesity (BMI > 30), coagulopathy, allergy to injected substances, infection and non-compliant patients. Outcome parameters consisted of the measured dose length product (mGycm2), the amount of scans, age, gender, BMI and the peri-interventional complications. The results were compared to 50 patients, treated in the standard-interventional CT-protocol for spinal injections, performed in June-Oct 2011, who met the above mentioned inclusion criteria.
A total amount of 100 patients were enrolled in the study. A significant radiation dose reduction (average 85.31%) was achieved using the institutional low-dose protocol compared to standard intervention mode in CT-guided periradicular injections in lumbar spine. Using the low-dose protocol did not increase the complications rate in the analyzed cohort.
Low-dose-CT-protocols for lumbar perineural injections significantly reduce the exposure to radiation of non-obese patients without an increase of complications. This increases long-time patient safety of stochastic radiation effects.
PMCID: PMC3482608  PMID: 22888796
CT-Guided spinal injections; Periradicular injection; Computed tomography; Lumbar spine; Low dose protocol
5.  Alteration of complement hemolytic activity in different trauma and sepsis models 
Complement activation is involved in various diseases in which innate immunity plays a crucial role. However, its pathophysiological relevance is not clearly understood. Experimental models have been widely used to characterize the role of complement activation under different pathological conditions, such as hypoxemia, ischemia and reperfusion, tissue damage, and polymicrobial invasion. Screening of the complement status and function is, however, strongly dependent on the laboratory-specific techniques being used to sample and measure complement, making it difficult to compare the results found in different laboratories. Therefore, we evaluated complement function by measuring complement hemolytic activity (CH50) in various animal models of isolated ischemia reperfusion (I/R: kidney, liver, gut), hemorrhagic traumatic shock (HTS), endotoxic shock (LPS), and sepsis (CLP). Complement activation was less pronounced in isolated models of ischemia and reperfusion, whereas a strong complement response was observed early after HTS, CLP, and LPS. In summary, CH50 is a well-established, quick, and cost-effective screening method of complement function. However, because we obtained different results in clinically relevant animal models, further differentiation using specific complement factor analysis is necessary.
PMCID: PMC3413207  PMID: 22879778
CH50; complement; hemorrhagic shock; inflammation; ischemia/reperfusion; sepsis
6.  Introducing standardized “readbacks” to improve patient safety in surgery: a prospective survey in 92 providers at a public safety-net hospital 
BMC Surgery  2012;12:8.
Communication breakdowns represent the main root cause of preventable complications which lead to harm to surgical patients. Standardized readbacks have been successfully implemented as a main pillar of professional aviation safety for decades, to ensure a safe closed-loop communication between air traffic control and individual pilots. The present study was designed to determine the perception of staff in perioperative services regarding the role of standardized readbacks for improving patient safety in surgery at a single public safety-net hospital and level 1 trauma center.
A 12-item questionnaire was sent to 180 providers in perioperative services at Denver Health Medical Center. The survey was designed to determine the individual participants’ perception of (1) appropriateness of current readback processes; (2) willingness to attend a future training module on this topic; (3) specific scenarios in which readbacks may be effective; and (4) perceived major barriers to the implementation of standardized readbacks. Survey results were compared between departments (surgery versus anesthesia) and between specific staff roles (attending or midlevel provider, resident physician, nursing staff), using non-parametric tests.
The response rate to the survey was 50.1 % (n = 92). Respondents overwhelmingly recognized the role of readbacks in reducing communication errors and improving patient safety. There was a strong agreement among respondents to support participation in a readbacks training program. There was no difference in the responses between the surgery and anesthesia departments.
There was a statistically significant difference in the healthcare providers willingness to attend a short training module on readbacks (p < 0.001). Resident physicians were less likely to endorse the importance of readbacks in reducing communication errors (p = 0.01) and less willing to attend a short training module on readbacks (p < 0.001), as compared to staff providers and nursing staff.
The main challenge for respondents, which emanated from their responses, appeared to relate to determining the ideal scenarios in which readbacks may be most appropriately used. Overall, respondents strongly felt that readbacks had an important role in patient handoffs, patient orders regarding critical results, counting and verifying surgical instruments, and delegating multiple perioperative tasks.
The majority of all respondents appear to perceive standardized readbacks as an effective tool for reducing and/or preventing adverse events in the care of surgical patients, derived from a breakdown in communication among perioperative caregivers. Further work needs to be done to define the exact clinical scenarios in which readbacks may be most efficiently implemented, including the definition of a uniform set of scripted quotes and phrases, which should likely be standardized in concert with the aviation safety model.
PMCID: PMC3418160  PMID: 22713158
7.  New Insights into the Role of Peroxisome Proliferator-Activated Receptors in Regulating the Inflammatory Response after Tissue Injury 
PPAR Research  2012;2012:728461.
Major trauma results in a strong inflammatory response in injured tissue. This posttraumatic hyperinflammation has been implied in the adverse events leading to a breakdown of host defense mechanisms and ultimately to delayed organ failure. Ligands to peroxisome proliferator-activated receptors (PPARs) have recently been identified as potent modulators of inflammation in various acute and chronic inflammatory conditions. The main mechanism of action mediated by ligand binding to PPARs is the inhibition of the nuclear transcription factor NF-κB, leading to downregulation of downstream gene transcription, such as for genes encoding proinflammatory cytokines. Pharmacological PPAR agonists exert strong anti-inflammatory properties in various animal models of tissue injury, including central nervous system trauma, ischemia/reperfusion injury, sepsis, and shock. In addition, PPAR agonists have been shown to induce wound healing process after tissue trauma. The present review was designed to provide an up-to-date overview on the current understanding of the role of PPARs in the pathophysiology of the inflammatory response after major trauma. Therapeutic options for using recombinant PPAR agonists as pharmacological agents in the management of posttraumatic inflammation will be discussed.
PMCID: PMC3317007  PMID: 22481914
8.  A New Experimental Polytrauma Model in Rats: Molecular Characterization of the Early Inflammatory Response 
Mediators of Inflammation  2012;2012:890816.
Background. The molecular mechanisms of the immune response after polytrauma are highly complex and far from fully understood. In this paper, we characterize a new standardized polytrauma model in rats based on the early molecular inflammatory and apoptotic response. Methods. Male Wistar rats (250 g, 6–10/group) were anesthetized and exposed to chest trauma (ChT), closed head injury (CHI), or Tib/Fib fracture including a soft tissue trauma (Fx + STT) or to the following combination of injuries: (1) ChT; (2) ChT + Fx + STT; (3) ChT + CHI; (4) CHI; (5) polytrauma (PT = ChT + CHI + Fx + STT). Sham-operated rats served as negative controls. The inflammatory response was quantified at 2 hours and 4 hours after trauma by analysis of “key” inflammatory mediators, including selected cytokines and complement components, in serum and bronchoalveolar (BAL) fluid samples. Results. Polytraumatized (PT) rats showed a significant systemic and intrapulmonary release of cytokines, chemokines, and complement anaphylatoxins, compared to rats with isolated injuries or selected combinations of injuries. Conclusion. This new rat model appears to closely mimic the early immunological response of polytrauma observed in humans and may provide a valid basis for evaluation of the complex pathophysiology and future therapeutic immune modulatory approaches in experimental polytrauma.
PMCID: PMC3317068  PMID: 22481866
9.  Disturbances of the hypothalamic-pituitary-adrenal axis and plasma electrolytes during experimental sepsis 
Sepsis continues to be a poorly understood syndrome with a high mortality rate. While we are beginning to decipher the intricate interplay of the inflammatory response during sepsis, the precise regulation of the hypothalamic-pituitary-adrenal (HPA) axis and its impact on electrolyte homeostasis during sepsis remains incompletely understood.
Sepsis was induced in adult male Sprague-Dawley rats by cecal ligation and puncture (CLP). Plasma samples were obtained as a function of time (6-48 hrs) after CLP and compared with healthy animals (neg ctrl). Samples were analyzed for adrenocorticotropin (ACTH), corticosterone, and aldosterone levels, as well as concentrations of sodium (Na+), potassium (K+), chloride (Cl-), and magnesium (Mg2+).
ACTH levels were found to be significantly reduced 6-24 hrs after CLP in comparison to baseline levels and displayed gradual recovery during the later course (24-48 hrs) of sepsis. Plasma corticosterone concentrations exhibited a bell-shaped response, peaking between 6 and 12 hrs followed by rapid decline and concentrations below negative control levels 48 hrs after injury. Aldosterone levels in septic animals were continuously elevated between 6 and 48 hrs. Whereas plasma Na+ levels were found to be persistently elevated following CLP, levels of K+, Cl- and Mg2+ were significantly reduced as a function of time and gradually recovered during the later course of sepsis.
CLP-induced sepsis resulted in dynamic changes of ACTH, corticosterone, and aldosterone levels. In addition, electrolyte levels showed significant disturbances after CLP. These electrolyte perturbations might be evoked by a downstream effect or a dysfunctional HPA-axis response during sepsis and contribute to severe complications during sepsis.
PMCID: PMC3264499  PMID: 22208725
10.  Molecular mechanisms of inflammation and tissue injury after major trauma-is complement the "bad guy"? 
Trauma represents the leading cause of death among young people in industrialized countries. Recent clinical and experimental studies have brought increasing evidence for activation of the innate immune system in contributing to the pathogenesis of trauma-induced sequelae and adverse outcome. As the "first line of defense", the complement system represents a potent effector arm of innate immunity, and has been implicated in mediating the early posttraumatic inflammatory response. Despite its generic beneficial functions, including pathogen elimination and immediate response to danger signals, complement activation may exert detrimental effects after trauma, in terms of mounting an "innocent bystander" attack on host tissue. Posttraumatic ischemia/reperfusion injuries represent the classic entity of complement-mediated tissue damage, adding to the "antigenic load" by exacerbation of local and systemic inflammation and release of toxic mediators. These pathophysiological sequelae have been shown to sustain the systemic inflammatory response syndrome after major trauma, and can ultimately contribute to remote organ injury and death. Numerous experimental models have been designed in recent years with the aim of mimicking the inflammatory reaction after trauma and to allow the testing of new pharmacological approaches, including the emergent concept of site-targeted complement inhibition. The present review provides an overview on the current understanding of the cellular and molecular mechanisms of complement activation after major trauma, with an emphasis of emerging therapeutic concepts which may provide the rationale for a "bench-to-bedside" approach in the design of future pharmacological strategies.
PMCID: PMC3247859  PMID: 22129197
11.  Survival following a vertical free fall from 300 feet: The crucial role of body position to impact surface 
We report the case of a 28-year old rock climber who survived an "unsurvivable" injury consisting of a vertical free fall from 300 feet onto a solid rock surface. The trauma mechanism and injury kinetics are analyzed, with a particular focus on the relevance of body positioning to ground surface at the time of impact. The role of early patient transfer to a level 1 trauma center, and "damage control" management protocols for avoiding delayed morbidity and mortality in this critically injured patient are discussed.
PMCID: PMC3212924  PMID: 22027092
12.  High-Energy Proximal Femur Fractures in Geriatric Patients 
Background: There is limited information in the literature on the outcomes and complications in elderly patients who sustain high-energy hip fractures. As the population ages, the incidence of high-energy geriatric hip fractures is expected to increase. The purpose of this study was to analyze the outcomes and complications in patients aged 65 years or older, who sustained a high-energy proximal femur fracture. Methods: Retrospective review of a prospective trauma database from January 2000 to April 2011 at a single US academic level-1 trauma center. Inclusion criteria consisted of all patients of age 65 years or older, who sustained a proximal femur fracture related to a high-energy trauma mechanism. Details concerning injury, acute treatment, and clinical course and outcome were obtained from medical records and radiographs. Results: We identified 509 proximal femur fractures in patients older than 65 years of age, of which 32 (6.3%) were related to a high-energy trauma mechanism. The mean age in the study group was 72.2 years (range 65-87), with a mean injury severity score of 20 points (range 9-57). Three patients died before discharge (9.4%), and 22 of 32 patients sustained at least one complication (68.8%). Blunt chest trauma represented the most frequently associated injury, and the main root cause of pulmonary complications. The patients' age and comorbidities did not significantly correlate with the rate of complications and the 1-year mortality. Conclusions: High-energy proximal femur fractures in elderly patients are not very common and are associated with a low in-hospital mortality rate of less than 10%, despite high rate of complications of nearly 70%. This selective cohort of patients requires a particular attention to respiratory management due to the high incidence of associated chest trauma.
PMCID: PMC3609398  PMID: 23569690
geriatric trauma; trauma surgery; fragility fractures; osteoporosis; anesthesia

Results 1-12 (12)