Philip Gierer

Angular stable multiple screw fixation (Targon FN) versus standard SHS for the fixation of femoral neck fractures

OBJECTIVE Head-preserving fracture care especially for the elderly may be complicated by acetabular screw penetration, cut out, delayed union or femoral head necrosis. The following comparative study analyses whether a new angular stable device may overcome these shortcomings. MATERIAL AND METHODS The Targon FN plate (BBraun/Aesculap, Germany) employs up to four angular stable telescoping screws for the fixation of the head fragment. In a prospective study patients with displaced and undisplaced intracapsular femoral neck fractures where treated by closed reduction and fracture fixation using either the Targon FN implant or a standard sliding hip screw (SHS). Patients were followed up clinically, radiographically and via telephone at a mean of follow-up time of 15.5 months. RESULTS Fifty-two patients (mean age: 67 years) with femoral neck fractures were treated with either Targon FN (27 patients) or SHS (25 patients). Time for surgery did not differ within the two groups (56 min Targon FN vs. 55 min SHS). Eight patients with SHS (32%) and four patients (15%) with Targon FN experienced cut out of the lag screw and received hip replacement (p<0.05). Implant failure occurred after a mean of 1.8 months after SHS and 6.0 months after Targon FN implantation. Final radiographs revealed substantial subsidence in both groups (5.0mm Targon FN; 9.8mm SHS, p=0.055) with a clear trend to less subsidence for the Targon FN group. Furthermore, asymmetrical telescoping of the lag screws occurred in 30% (n=8), complete depletion of telescoping distance in 11% (n=3) in the Targon FN group. Functional assessment using the HHS assessment tool, however, presented with slightly better results for the SHS treatment (87.7 ± 13.9) when compared to Targon FN fixation (69.5 ± 14.5). CONCLUSIONS The study revealed less subsidence of the head fragment, lower cut out rate and a lower rate of conversion to hemiarthroplasty after Targon FN fixation in comparison to a standard SHS fixation in a small number of patients with hip fractures. However, this was not accompanied by functional limitations in the SHS group.

Selective cyclooxygenase-2 inhibition reverses microcirculatory and inflammatory sequelae of closed soft-tissue trauma in an animal model.

BACKGROUND Despite the common use of nonsteroidal anti-inflammatory drugs in the treatment of closed soft-tissue injuries, our understanding of the effect of these medications on tissue healing is incomplete. Using high-resolution multifluorescence microscopy, we investigated the efficiency of preinjury and postinjury treatment with the selective cyclooxygenase (COX)-2 inhibitor parecoxib to improve compromised perfusion of traumatized muscle tissue and to minimize secondary tissue damage. METHODS With use of a pneumatically driven and computer-controlled impact device, closed soft-tissue trauma of the left hindlimb was induced in anesthetized rats that had had intravenous administration of 10 mg/kg of either parecoxib sodium (seven rats) or an equal volume of saline solution (seven rats). Seven additional animals received parecoxib two hours after the trauma, and seven animals without trauma served as controls. RESULTS Time-course studies with use of both Western blot protein analysis and immunohistochemistry demonstrated a transient upregulation of COX-2 protein expression with peak levels eight to twelve hours after trauma and a return to near baseline level at eighteen hours. Regardless of whether parecoxib was administered before or after the injury, it completely restored microcirculatory impairment within the injured muscle. This was indicated by the mean values (and standard error of the mean) for nutritive perfusion (434 +/- 15 cm/cm(2) in animals treated before the injury and 399 +/- 8 cm/cm(2) in those treated after injury), nicotinamide adenine dinucleotide (NADH) levels (73 +/- 2 aU and 74 +/- 1 aU, respectively), and inflammatory cell interaction (184 +/- 36 and 186 +/- 32 n/mm(2), respectively, for leukocytes, and 1.0 +/-0.1 and 0.8 +/- 0.1 n/mm(2), respectively, for platelets) at eighteen hours after trauma, which were not different from those found in noninjured muscle tissue of controls. In contrast, skeletal muscle in saline solution-treated animals revealed persistent perfusion failure (296 +/-30 cm/cm(2)) with tissue hypoxia (NADH, 100 +/- 4 aU), and enhanced endothelial interaction of both leukocytes (854 +/- 73 mm(-2)) and platelets (2.3 +/- 0.5 n/mm(2)) at eighteen hours after trauma. CONCLUSIONS AND CLINICAL RELEVANCE Treatment of skeletal muscle soft-tissue trauma with parecoxib before as well as after injury is highly effective in restoring disturbed microcirculation. Moreover, a reduced inflammatory cell response helps to prevent leukocyte or platelet-dependent secondary tissue injury. These results deserve further investigation to prove that selective COX-2 inhibitors improve performance and promote healing following closed soft-tissue injury.

In vivo evidence for apoptosis, but not inflammation in the hindlimb muscle of neuropathic rats

Abstract Loose ligation of the rat sciatic nerve (chronic constriction injury (CCI) model) provokes signs and symptoms like those observed in complex regional pain syndrome (CRPS) patients. Neurogenic inflammation is a purported cause of neuropathic pain despite inconsistent evidence to support this hypothesis. To clarify this issue, we examined effects of CCI on microcirculation, inflammatory cell–cell interaction and cell integrity in muscle tissue using intravital fluorescence microscopic, molecular and immunohistochemical techniques. CCI‐rats, but not sham‐operated animals developed symptoms of neuropathic pain and oedema on the ipsilateral hindpaw. Despite signs of neuropathic pain, high resolution in vivo multifluorescence microscopy revealed physiological values for functional capillary density, leukocyte–endothelial cell interaction and microvascular permeability in muscle tissue of CCI‐animals, similarly as found in controls, indicating absence of perfusion failure and inflammatory cell reaction. However, CCI‐animals represented with marked apoptosis of bisbenzimide‐stained muscle tissue cells, as given by in vivo fluorescence microscopic assessment of cell death‐associated condensation, fragmentation and/or crescent‐shaped formation of their nuclear chromatin. Apoptosis was further confirmed by increased caspase 3 protein levels and positive terminal deoxyuridine nick end labeling histochemistry. The present study demonstrates that sciatic nerve ligation‐induced neuropathy causes cell apoptosis without concomitant inflammation‐associated microcirculatory dysfunction in muscle tissue. Beside the well‐known pattern of neuropathic pain, the CCI‐model has now additionally been shown to reflect the response of muscle tissue to impaired innervation, i.e. prompting muscle cells to undergo non‐inflammatory apoptotic cell death. This finding deserves further investigation in that apoptosis may contribute to neuropathic pain conditions like CRPS.

Intramedullary nail versus volar plate fixation of extra-articular distal radius fractures. Two year results of a prospective randomized trial

BACKGROUND Intramedullary techniques for stabilization of displaced distal radius fractures are now available. Purported benefits include limited soft tissue dissection while affording sufficient stability to allow early wrist motion. The primary null hypothesis of this randomized trial is that there is no significant difference with respect to functional outcome, pain and disability between patients treated with either 2.4-mm volar locking plate fixation or intramedullary nail fixation of unstable dorsally displaced extra-articular fractures of the distal radius. METHODS We conducted a single-centre, parallel-group trial, with unrestricted randomization. Patients with dorsally displaced extra-articular distal radius fractures were randomized to receive volar locking plate (n=72) fixation or intramedullary nailing (n=80). The outcome was measured on the basis of the Gartland and Werley and Castaing score; the pain level; the range of wrist motion; the rate of complications; and radiographic measurements including volar tilt and ulnar variance. Clinical and radiographic assessment was performed at 8 weeks, 6 months, 1 year and 2 years after the operation. RESULTS There were no significant differences between groups in terms of range of motion, grip strength or the level of pain during the entire follow-up period (p>0.05). There was no significant difference between treatment groups with respect to volar tilt or ulnar variance (p>0.05). There was no significant difference in the complication rate between groups (p>0.05). CONCLUSIONS The present study supports the view that intramedullary nail fixation and volar plate fixation for the treatment of displaced extra-articular distal radius fractures have equivalent radiographic and functional outcomes. LEVEL OF EVIDENCE Level I therapeutic study.

Gene expression profile and synovial microcirculation at early stages of collagen-induced arthritis

A better understanding of the initial mechanisms that lead to arthritic disease could facilitate development of improved therapeutic strategies. We characterized the synovial microcirculation of knee joints in susceptible mouse strains undergoing intradermal immunization with bovine collagen II in complete Freunds adjuvant to induce arthritis (i.e. collagen-induced arthritis [CIA]). Susceptible DBA1/J and collagen II T-cell receptor transgenic mice were compared with CIA-resistant FVB/NJ mice. Before onset of clinical symptoms of arthritis, in vivo fluorescence microscopy of knee joints revealed marked leucocyte activation and interaction with the endothelial lining of synovial microvessels. This initial inflammatory cell response correlated with the gene expression profile at this disease stage. The majority of the 655 differentially expressed genes belonged to classes of genes that are involved in cell movement and structure, cell cycle and signal transduction, as well as transcription, protein synthesis and metabolism. However, 24 adhesion molecules and chemokine/cytokine genes were identified, some of which are known to contribute to arthritis (e.g. CD44 and neutrophil cytosolic factor 1) and some of which are novel in this respect (e.g. CC chemokine ligand-27 and IL-13 receptor α1). Online in vivo data on synovial tissue microcirculation, together with gene expression profiling, emphasize the potential role played by early inflammatory events in the development of arthritis.

Microcirculatory sequelae of the rotator cuff after antegrade nailing in proximal humerus fracture

IntroductionAntegrade nailing allows a stable fixation and, thus, an early functional after treatment in proximal humerus fractures. Since the surgical procedure in antegrade humeral nailing requires a split of the supraspinatus tendon, the question arises whether the surgical approach causes microcirculatory dysfunction of the tendon.Materials and methodsA total of 15 consecutive patients suffering from proximal humerus fractures were enrolled. During the implantation of an antegrade humerus nail, microvascular perfusion of the supraspinatus tendon was directly visualized after the exposition and stabilization of the fracture using the OPS-imaging technique.ResultsImmediately after exposure, the nutritive perfusion showed physiological values of tendon microcirculation. After implanting antegrade humeral nails, the perfusion of the supraspinatus tendon reduced markedly. Capillary width was unaffected by the surgical procedure.ConclusionThe trauma leading to proximal humerus fracture causes no fundamental impairment of nutritive perfusion of the rotator cuff. Whereas the implantation of an antegrade humerus nail, which necessarily includes a splitting of the rotator cuff, nearly halves the functional capillary density of the supraspinatus tendon. Even though this effect seems to be reversible, the surgical dissection of the supraspinatus tendon should be performed in a soft tissue sparing way.

Activated protein C reduces tissue hypoxia, inflammation, and apoptosis in traumatized skeletal muscle during endotoxemia

Objective:Extensive surgical trauma leads to activation of the coagulation cascade and is often complicated by systemic inflammation and infection. Activated protein C, a natural coagulatory inhibitor, was recently shown to reduce mortality in septic patients. We herein report on the actions of activated protein C on skeletal muscle injury in experimental endotoxemia. Design:Prospective controlled animal study. Setting:University animal research facility. Subjects:Male Sprague-Dawley rats. Interventions:Closed soft tissue trauma was applied on the left hind limb of pentobarbital-anesthetized rats. Six hours later endotoxemia was induced by intraperitoneal injection of Escherichia coli lipopolysaccharide. An equivalent volume of physiologic saline was given in controls. At the same time point, treatment of animals was started by continuous intravenous application of activated protein C (24 &mgr;g/kg·hr) or vehicle solution over 18 hrs. Twenty-four hours after trauma, the extensor digitorum longus muscle was microsurgically exposed and analyzed by means of high-resolution multifluorescence microscopy. Measurements and Main Results:Endotoxemia aggravated traumatized muscle injury, as evidenced by reduced nutritive perfusion, increased tissue hypoxia, enhanced leukocyte-endothelial cell interaction, and apoptotic myocyte cells (249 ± 17 cm/cm2 vs. 298 ± 22 cm/cm2; reduced nicotinamide adenine dinucleotide [NADH], 149 ± 15 arbitrary units [AU] vs. 130 ± 13 AU; 417 ± 79 cells/mm2 vs. 344 ± 77 cells/mm2 and 62 ± 9 cells/mm2 vs. 31 ± 5 cells/mm2). Therapeutic intervention with activated protein C 6 hrs after trama protected nutritive perfusion and tissue oxygenation (341 ± 24 cm/cm2 and 115 ± 8 AU) and reduced inflammatory leukocyte adherence (185 ± 60 cells/mm2) and cellular apoptosis (15 ± 4 cells/mm2). Of note, the protection of traumatized muscle tissue by activated protein C was also maintained during endotoxemia, as indicated by a functional capillary density of 379 ± 10 cm/cm2, a NADH-fluorescence of 102 ± 6 AU, a leukocyte adherence of 82 ± 12 cells/mm2, and a myocyte apoptosis of 28 ± 4 cells/mm2. Conclusions:Microcirculatory injury of traumatized skeletal muscle tissue is enhanced by intravenous endotoxin application in this model of soft tissue trauma. Activated protein C ameliorates microcirculatory dysfunction and tissue injury, in particular in traumatized animals during endotoxemia.

Exaggeration of tissue trauma induces signs and symptoms of acute CRPS I, however displays distinct differences to experimental CRPS II.

As CRPS I frequently develops after tissue trauma, we proposed that an exaggerated inflammatory response to tissue trauma may underlie CRPS I. Therefore, we studied the vascular inflammatory, nociceptive and apoptotic sequelae of (i) soft tissue trauma and (ii) exaggerated soft tissue trauma in comparison to those of (iii) sciatic nerve chronic constriction injury, modeling CRPS II. Standardized soft tissue trauma (TR) was induced by means of a controlled impact injury technique in the hind limb of pentobarbital-anesthetized rats. Additional animals received soft tissue trauma and femoral arterial infusion of mediator-enriched supernatant achieved by homogenization and centrifugation of traumatized muscle tissue in order to provoke an exaggerated trauma response (ETR). Infusion of supernatant of non-traumatized muscle served as control intervention (STR, sham trauma response). Neuropathy was induced by chronic constriction injury of the sciatic nerve (CCI). Untreated animals served as controls (CO). Detailed nociceptive testing showed temporarily decreased mechanical pain thresholds in ETR animals that resolved within 14 days, while TR and STR animals, i.e. those with singular limb trauma, and controls remained free of pain. Neither cold- nor heat-evoked allodynia developed in post-traumatic animals, whereas CCI animals presented the well-known pattern of ongoing neuropathic pain. Using high-resolution in vivo multifluorescence microscopy, muscle tissue of traumatized animals revealed an enhanced inflammatory response that was found most pronounced in ETR animals. CCI of the sciatic nerve was not accompanied by tissue inflammation; however, induced myocyte apoptosis. Collectively, these data indicate that exaggeration of trauma response induces signs and symptoms of acute CRPS I. Pain perception displays differences to that in CRPS II. Apoptosis turns out to be a distinctive marker for CRPS, warranting further evaluation in clinical studies.

Modulation of granulocyte-endothelium interactions by antileukoproteinase: inhibition of anti-type II collagen antibody-induced leukocyte attachment to the synovial endothelium

Antileukoproteinase (ALP) is a physiological inhibitor of granulocytic serine proteases that has been shown to have anti-inflammatory properties in addition to its antiproteolytic activity. On the basis of its potential to block anti-collagen type II (CII) antibody-induced arthritis (CAIA) and to suppress the conformational activation of β2-integrins in leukocytes, the present study was undertaken to investigate its interference with leukocyte adherence to cytokine-activated endothelium. The potential of recombinant ALP to block the interactions of leukocytes with the endothelial lining was concomitantly investigated in vitro and in vivo. Thus, intravital fluorescence microscopic imaging of leukocyte rolling and firm adhesion to postcapillary venules were performed in the knee joints of DBA1/J mice after intravenous injection of anti-CII mAbs. An IL-1β-activated endothelial layer formed by a murine glomerular cell line (glEND.2) was used to assay the interaction with human leukocytes in vitro. Electromobility shift and luciferase reporter gene assays permitted the analysis of cytokine-induced activation of the NF-κB pathway. Fluorescence-activated cell sorting was applied to determine endothelial E-selectin expression. Leukocyte rolling and firm adhesion to the synovial endothelium in an early response to the anti-CII antibody transfer were significantly decreased in ALP-pretreated mice. Concomitantly, ALP suppressed the IL-1β-induced NF-κB activation and the upregulation of E-selectin expression in glEND.2 cells in vitro. These findings support the notion that the newly uncovered properties of ALP to interfere with cytokine signalling and upregulation of adhesion molecules in endothelial cells are likely to contribute to the therapeutic potential of ALP in immune-complex-induced tissue injury.

Supernatant of traumatized muscle induces inflammation and pain, but not microcirculatory perfusion failure and apoptotic cell death.

Soft tissue trauma induces an inflammatory response locally and in remote organs. Although remote organ failure is attributed to the systemic action of locally released mediators, it is so far unclear to what extent a direct cell injury and the consequences of ischemia or a secondary injury due to locally released mediators contribute to the manifestation of tissue damage at the primary site of trauma. Soft tissue trauma was induced by means of a controlled impact injury technique in the hind limb of pentobarbital-anesthetized rats. Additional animals received a femoral arterial infusion of supernatant of traumatized muscle tissue, of nontraumatized muscle, or 0.9% NaCl. Tissue injury was assessed by determining microcirculatory perfusion failure, inflammatory response, apoptotic cell death, and nociceptive pain behavior. Muscle tissue of traumatized animals revealed perfusion failure, tissue hypoxia, and inflammation. Nociceptive testing showed a decrease in mechanical pain thresholds of the affected hind paw. Infusion of supernatant of traumatized tissue induced local inflammation and pain comparable with that of directly traumatized tissue; however, it failed to cause nutritive perfusion failure. Supernatant of nontraumatized muscle did not affect muscle microcirculation and integrity. Only animals that underwent direct trauma presented with apoptotic cell death, as given by in vivo fluorescence microscopy, caspase 3 protein cleavage, and transferase-mediated dUTP nick-end labeling histology. Trauma-associated humoral factors cause post-traumatic hyperalgesia and inflammation, but not microvascular perfusion failure and apoptotic cell death. This finding may prompt future efforts in the therapy of closed soft tissue trauma to focus not only on antimediator strategies, but to add regimens targeting perfusion failure and tissue apoptosis.