Stefan Hajdu

Elevated transforming growth factor-beta 1 (TGF-β1) levels in human fracture healing

Introduction Transforming growth factor-beta 1(TGF-β1) is a regulatory protein, involved in bone fracture healing. Circulating TGF-β1 levels have been reported to be a predictor of delayed bone healing and non-union, suggesting active relationship between tissue and circulating TGF-β1 in fracture healing. The purpose of this study was to analyse TGF-β1 local and serum concentrations in fracture healing to further contribute to the understanding of molecular regulation of fracture healing. Patients and methods Serum samples of 113 patients with long bone fractures were collected over a period of 6 months following a standardised time schedule. TGF-β1 serum concentrations were measured using ELISA. Patients were assigned to 2 groups: Group 1 contained 103 patients with physiological healing. Group 2 contained 10 patients with impaired healing. Patients in both groups were matched. One patient of the group 2 had to be excluded because of missing match partner. In addition, fracture haematoma from 11 patients of group 1 was obtained to analyse local TGF-β1 concentrations. 33 volunteers donated serum which served as control. Results TGF-β1 serum concentrations increased during the early healing period and were significantly higher in patients with physiological healing compared to controls (P = 0.04). Thereafter, it decreased continuously between weeks 2 and 8 and fell again after week 8. TGF-β1 serum concentrations in patients with physiological healing were significantly higher at week 24 compared to controls (P = 0.05). In non-unions, serum concentrations differed significantly from those of controls at week 6 (P = 0.01). No significant difference in between patients with physiological and impaired fracture healing was observed. Fracture haematoma contained significantly higher TGF-β1 concentrations than peripheral serum of the patients (P = 0.017). Conclusion Elevated levels of TGF-β1 in haematoma and in serum after bone fracture especially during the entire healing process indicate its importance for fracture healing.

Invasive fungal infections and (1,3)-β-d-glucan serum concentrations in long-term intensive care patients

OBJECTIVE Invasive fungal infections are associated with high morbidity and increased mortality. This study was performed to assess the epidemiology of fungal infections and to determine (1,3)-beta-D-glucan serum concentrations in patients admitted to intensive care units (ICUs). PATIENTS AND METHODS Overall 197 patients were admitted to nine medical and surgical intensive care units (ICUs) at a 2200-bed university hospital during a 3-month period. Retrospectively, the patients were split into three groups: group A comprised 24 patients with proven invasive fungal infections admitted for a median of 40 days. Group B comprised 58 patients who were admitted to the ICU for 30 days but without fungal infection. One hundred and fifteen post-operative patients served as controls (group C). The levels of (1,3)-beta-D-glucan were monitored in all patients twice weekly during their ICU admittance. RESULTS Average (1,3)-beta-D-glucan concentrations were significantly higher in the patients with fungal infections compared to group B and group C (median 44 vs. 22 and 12.9 pg/ml, respectively; p<0.001). For a serum (1,3)-beta-D-glucan level of 40 pg/ml, the sensitivity, the specificity, the positive predictive value, the negative predictive value, the area under the curve of the receiver operating characteristics (AUC ROC) curve, the likelihood ratio (LR)+ and LR- were 52.2, 75.9, 46.2, 80, 0.7, 2.16, and 0.63, respectively, on day 7. Patients in group A had bacterial infections significantly more often than patients in group B (p=0.003). The hospitalization before ICU admittance for group A was significantly longer than for groups B and C (median 19 (group A) vs. 6 (group B) vs. 10 (group C) days; p<0.05). CONCLUSIONS Longer hospitalization and multiple bacterial infections were found to be the main risk factors for invasive fungal infections. Long-term ICU patients have elevated (1,3)-beta-D-glucan levels, not only due to invasive fungal infections, but also due to the serious underlying diseases and conditions, inter-current complications, and intensive care measures. Yet, persistently high serum levels of (1,3)-beta-D-glucan in ICU patients may be indicative of invasive fungal infections and warrant additional diagnostic efforts.

Predictive value of neuromarkers supported by a set of clinical criteria in patients with mild traumatic brain injury: S100B protein and neuron-specific enolase on trial: Clinical article

OBJECT The role of the neuromarkers S100B protein and neuron-specific enolase (NSE) in minor head injury is well established. Moreover, there are sensitive decision rules available in the literature to identify clinically important brain lesions. However, it is not clear if using the biomarkers has an influence on the predictability of the decision rule. The purpose of this study was to determine if a set of preclinical and clinical parameters combined with 2 neuromarker levels could serve as reliable guidance for accurate diagnosis. METHODS Prospective evaluation of a cohort of head trauma patients with Glasgow Coma Scale scores of 13-15 was performed at an academic, Level I trauma center. Blood samples and cranial CT studies were obtained for all patients within 3 hours after injury. The hypothesis of the study was whether the combination of an increase of S100B and NSE levels in serum and other defined risk factors are associated with a pathological finding on CT. A forward stepwise logistic regression model was used. RESULTS The study included 107 head trauma patients with a mean age of 59 ± 23 years. Twenty-five patients (23.4%) had traumatic lesions on CT. Eight patients underwent craniotomy. The analysis provided a model with good overall accuracy for discriminating cases with clinically important brain injury, including the 6 variables of S100B, NSE, nausea, amnesia, vomiting, and loss of consciousness. The area under the curve (AUC) was 0.88 (0.83-0.93). The receiver operating characteristic curve plots detecting clinically important brain injury for the single variables of S100B and NSE showed an AUC of 0.63 and 0.64, respectively. Conclusions The integration of the neuromarker panel as part of a diagnostic rule including the high-risk factors of nausea, vomiting, amnesia, and loss of consciousness is safe and reliable in determining a diagnosis, pending the availability of more brain-specific neuromarkers. CLINICAL TRIAL REGISTRATION NO.: NCT00622778 (ClinicalTrials.gov).

Effects of Vancomycin, Daptomycin, Fosfomycin, Tigecycline, and Ceftriaxone on Staphylococcus epidermidis Biofilms

Infection of medical implanted material is associated with considerable morbidity and costs. In the following work, we investigated the effects of vancomycin, daptomycin, fosfomycin, tigecycline, and ceftriaxone on biofilms formed by Staphylococcus epidermidis isolates causative for implant infection and catheter‐associated bacteremia. Biofilms were studied using the static microtiter plate model and incubated with the antibiotics increasing the concentration from 1× to 128× the minimal inhibitory concentration (MIC) of the respective isolate tested. To quantify the reduction of the biomass, the optical density ratio (ODr) of stained biofilms and the number of growing bacteria were determined. Incubation of the staphylococcal biofilms with the antibiotics decreased the biofilm ODr (at baseline = 1) for ceftriaxone (0.83 ± 0.48) but minimally only for fosfomycin (0.96 ± 0.64), daptomycin (1.05 ± 0.59), tigecycline (1.18 ± 0.66), and vancomycin (0.98 ± 0.44) at exceedingly high concentrations of 128 × MIC. The significant reduction of the bacterial growth was not achieved for all antibiotics, not even at the highest concentrations tested. Using higher doses of the antibiotics may be of some value in the treatment of biofilm‐associated infections, although effects are seen only at clinically unachievable doses. However, to eradicate the staphylococcal biofilm, additional measures like debridement and/or removal of the implant are needed.

Invasive mycoses following trauma.

Invasive fungal infection may afflict people with trauma in two ways: either by entry into tissue via penetrating trauma or by haematogenous spread in critically ill people with polytrauma. Penetrating injury allows the advance of ubiquitously present fungi into the human body. Miniscule foreign material fosters the establishment and growth of fungi within the traumatically changed tissue. The seriousness of the infection depends upon the type of injury, the body area and the persons general condition. Usually, the infection is confined to the cutis and subcutis; the fascia, muscles and bones are rarely affected. In the presence of immunocompromise, however, the fungus may spread rapidly and cause systemic disease. The following overview will focus on fungal infection associated with open wounds and fractures, particularly eye injury and with near-drowning, tropical mycetoma and nosocomial conditions. Post-traumatic invasive fungal infections are rare, but the surgeon should be alert to this possibility in cases with chronic inflammation and deferred healing of injuries, with or without systemic inflammatory response.

Physeal injuries of the distal tibia: long-term results in 376 patients

The aim of this study was to evaluate our treatment of distal tibial physeal injuries retrospectively and explain the relationship between the trauma mechanism, the radiographic injury pattern, the subsequent therapy and the functional outcome, as well as to further deduce and verify prognostic criteria. At the Department of Trauma Surgery, Vienna Medical University, 419 children and adolescent patients with physeal injuries of the distal tibia were treated from 1993 to 2007, of these 376 were included in our study and evaluated retrospectively. Seventy-seven displaced physeal fractures of the distal tibia were reconstructed anatomically by open or closed reduction and produced 95% excellent results. A perfect anatomical reduction, if necessary by open means, should be achieved to prevent a bone bridge with subsequent epiphysiodesis and post-traumatic deformities due to growth inhibition and/or retardation.

Clinical and functional outcome after anterior cruciate ligament reconstruction using the LARS™ system at a minimum follow-up of 10 years.

BACKGROUND Since the 1980s several artificial ligaments were used for reconstruction of the anterior cruciate ligament (ACL) serving different complications. The aim of this study was to assess the clinical and functional outcomes of primary ACL reconstruction using the Ligament Augmentation Reconstruction System (LARS™) with a minimum follow-up of 10-years. The LARS™ presents a synthetic material consisting of non-absorbing polyethylene terephthalate fibres used for ligament reconstruction. METHODS Outcomes of 18 patients who underwent arthroscopic ACL reconstruction using the LARS™ system between 2000 and 2004 with a minimum follow-up of 10 years were observed. The International Knee Documentation Committee score (IKDC), Visual Analog Scale (VAS), Lysholm score, and Tegner Activity Scale were assessed. Clinical assessment was performed by Lachman testing, assessment of side-to-side difference on KT-2000 testing and plain radiography evaluation of osteoarthritis. RESULTS There were seven males and 11 females, mean age 29 years (range, 18 to 44 years) and a mean follow-up of 151.5 months. Five patients (27.8%) sustained a re-rupture of the LARS™ system and underwent revision surgery after a mean time of 23 months and four patients (22.2%) presented with a re-rupture. The average IKDC score was 76.60 ± 18.18, the average Lysholm score was 88.00 ± 10.07 and the average Tegner activity score was five at final follow-up. CONCLUSION Our results indicate that the LARS™ system should currently not be suggested as a potential graft for primary reconstruction of the ACL. In special cases, however, the LARS™ system can serve as an alternative graft.

The skull unfolded: a cranial CT visualization algorithm for fast and easy detection of skull fractures.

PURPOSE To retrospectively assess the rate of detection of skull fractures at cranial computed tomography (CT) achieved with the use of curved maximum intensity projections (MIPs) compared with that achieved by reading transverse sections only. MATERIALS AND METHODS The institutional review board approved this research and waived informed consent. A curved thin (3-mm) MIP of the skull cap and a curved thick (50-mm) MIP of the skull base were obtained from the cranial CT data in 200 consecutive patients with head trauma. Four radiologists (two residents without experience in cranial CT and two consultants) independently evaluated all cases. Each radiologist reported findings in 100 patients by using transverse sections only and findings in the other 100 patients by using the unfolded view. The radiologists were blinded to patient names, and patient and group orders were randomized. The results were compared with a standard of reference established by two experts from all prior reading results, all reconstructions, and high-spatial-resolution multiplanar reformats. Logistic regression with repeated measurements was used for statistical analysis. RESULTS The experts found 63 fractures in 30 patients. When transverse sections only were used, the mean patient-based fracture detection rate was 43% (13 of 30) for inexperienced and 70% (21 of 30) for experienced readers; with curved MIPs, the rates were 80% (24 of 30) and 87% (26 of 30), respectively. Overall sensitivity was higher with curved MIPs (P < .001); specificity was higher with transverse sections (P < .001). CONCLUSION Curved MIPs enable a significantly higher fracture detection rate than transverse sections. They also considerably close the experience gap in fracture detection rate between residents and experts.

Effects of Azithromycin in Combination with Vancomycin, Daptomycin, Fosfomycin, Tigecycline, and Ceftriaxone on Staphylococcus epidermidis Biofilms

ABSTRACT Staphylococcal biofilms on surgical implants are the underlying cause of a lack of response to antimicrobial treatment. We investigated the effects of vancomycin (VAN), daptomycin (DAP), fosfomycin (FOS), tigecycline (TGC), and ceftriaxone (CRX), alone and in combination with azithromycin (AZI), on established biofilms of Staphylococcus epidermidis. Biofilms were studied using the static microtiter plate model with established S. epidermidis biofilms, with an initial inoculum of 106/ml in 96-well polystyrene flat-bottom microtiter plates. Biofilms were inoculated with VAN, DAP, FOS, TGC, or CRX at two concentrations, alone or in combination with AZI (2, 512, or 1,024 mg/liter). To assess the reduction in biomass, the optical density ratio (ODr), calculated as (optical density [OD] of the treated biofilm)/(OD of the untreated biofilm, taken as 1), was used. For antibacterial efficacy, the viable bacterial count was used. Reductions in the biofilm ODr were observed for VAN (15 and 40 mg/liter) and FOS (200 mg/liter) only (ODr [mean ± standard deviation] for VAN at 15 and 40 mg/liter, 0.77 ± 0.32 and 0.8 ± 0.35, respectively; ODr for FOS at 200 mg/liter, 0.78 ± 0.26; P < 0.05), but not for DAP (2 and 5 mg/liter), TGC (0.2 and 2 mg/liter), or CRX (600 and 2,400 mg/liter). The addition of AZI had no further effect on the ODr, but a significant reduction of bacterial growth was achieved with high doses of AZI plus TGC or AZI plus CRX (a 3-log count reduction for AZI at 1,024 mg/liter plus CRX at 600 mg/liter and for AZI at 512 or 1,024 mg/liter plus CRX at 2,400 mg/liter; a 2-log count reduction for AZI at 512 or 1,024 mg/liter plus TGC at 2 mg/liter [P < 0.05]). No significant reduction in bacterial growth was observed for FOS (50 and 200 mg/liter), DAP (2 and 5 mg/liter), or TGC (0.2 mg/liter) in combination with AZI. None of the antibiotics at either concentration reduced the bacterial count of the biofilms when used alone. Thus, the use of a combination of AZI plus TGC, FOS, or CRX at high concentrations has little effect on biofilm density but significantly reduces bacterial growth.

Clinical and Functional Outcome of All-Inside Anterior Cruciate Ligament Reconstruction at a Minimum of 2 Years’ Follow-up

PURPOSE To evaluate the clinical and functional outcomes for anatomic anterior cruciate ligament (ACL) reconstruction using the all-inside technique with a minimum follow-up of 24 months. METHODS Patients undergoing anatomic ACL reconstruction via the all-inside technique between January 2011 and October 2012 were reviewed for inclusion in this study. Functional outcome measures, including the Lysholm score, International Knee Documentation Committee score, visual analog scale score, and Tegner Activity Scale, were used to evaluate outcomes before surgery and at 3, 6, 12, and > 24 months. At final follow-up, anteroposterior knee stability was assessed with KT-2000 (MEDmetric, San Diego, CA) measurements. RESULTS Of the 92 patients who underwent primary all-inside ACL reconstruction, 79 patients returned to final follow-up with a minimum of 2 years. There were 53 men and 26 women with a mean age of 29 years (range, 18 to 54 years) and a mean follow-up of 29 months (range, 24 to 45 months). The International Knee Documentation Committee score (44.6 v 89.7, P < .0001), Lysholm score (53.4 v 93.1, P < .001), visual analog scale score (5 v 0.1, P < .001), and Tegner activity score (2 v 6, P < .001) showed a significant improvement between baseline and final clinical follow-up. The mean side-to-side KT-2000 difference at final follow-up was 1.7 mm (range; 0 to 6 mm). Overall 10 patients (12.7%) sustained an ACL graft rerupture after a mean of 17.6 months (range, 6.9 to 28.6 months). CONCLUSIONS The current data support our first hypothesis that primary anatomic ACL reconstruction using the all-inside technique leads to improved functional outcomes between baseline and clinical follow-up at 24 months. Further, there was no difference in knee stability between the ACL reconstructed- and the contralateral normal knee at 24 months, which confirms our second hypothesis.