Fractures of the manubrium sterni: treatment options and a possible classification of different types of fractures.

BACKGROUND: Sternum fractures are mostly located on the sternal corpus, seldom on the manubrium. Fractures of the sternal manubrium are, however, more frequently associated with severe concomitant injuries of thoracic organs, and therefore deserve special attention. In addition, in its function as a capstone in between the anterior chest wall and the shoulder girdle, it is exposed to a multiplicity of forces. Therefore the questions arise what types of fractures are observed in today's clinical practice, how to classify them and which treatment options are available. This study reports on different types of fractures which involve the manubrium sterni. METHODS: Between January 2012 and October 2014, data was collected from all severely injured patients (ISS ≥16), which received a CT scan of the thorax in our Level-I-Trauma Center and retrospectively analyzed concerning sternal fractures. Fracture type, collateral injuries, age, and information about the circumstances of the accident were noted. RESULTS: Of 890 evaluable patients, 154 (17.3%) had a fracture of the sternum and 23 (2.6%) of the manubrium. Fractures of the manubrium appeared in following types: A-type-transverse fracture (n=11) in 1st intercostal space by direct blunt trauma or flexion of the torso with sagittal instability; B-type-oblique fracture (n=9) by seat belt injury with rotatory instability; C-type-combined, more fragmentary fracture (n=3) by direct blunt trauma with simultaneous flexion of the torso and multi directional instability. Fractures only little dislocation were treated conservatively, and unstable fractures were surgically stabilized (n=10). CONCLUSIONS: In summary, three main types of fractures could be found. A-type fractures were stabilized with a longitudinal plate osteosynthesis and B-type fractures with transverse positioned plates. To treat complex C-type fractures, plates with a T- or H-form could be a good solution. Level of evidence: Level III retrospective prognostic cohort study.

Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway.

Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.

Reduced invasive and muscle-sparing operative approaches to the posterolateral chest wall provide an excellent accessibility for the operative stabilization! : Minimized approaches to the posterolateral chest wall.

PURPOSE: Stabilizing techniques for flail chest injuries are described through wide surgical approaches to the chest wall, especially in the most affected posterior and lateral regions. Severe morbidity due to these invasive approaches needs to be considered due to dissection of the scapular guiding muscles and the risk of injuries to neurovascular bundles. This study discusses possibilities for minimized approaches to the posterior and lateral regions. METHOD: Ten fresh-frozen cadavers in lateral decubitus position were observed on both sides. Each surgical arm was kept mobile during the procedure. Approaches were performed following a standard protocol with muscle-sparing incisions starting with 5 cm in length and extending to 10 and 15 cm. The accessible surface comparing the extensions was measured. Visible ribs were counted. In a next step, MatrixRib® Plates were fixed to those ribs to prove the feasibility of rib stabilization through limited approaches. RESULTS: Combinations of the posterior and lateral minimized approaches allow surgical fixation of 6-9 and 7-11 ribs through 5 and 10 cm incisions, respectively. In the case of an extreme expansion of a rib fracture series, an access extension can be made to 15 cm to be able to adequately supply the entire hemithorax using two approaches. CONCLUSION: Extensive invasive surgical approaches to the thoracic wall can be replaced by reduced invasive and muscle-sparing access combinations. A free-moving positioning of the arm and an accurate preoperative plan for minimizing approaches are essential. Minimally invasive plate techniques are very helpful adjuncts.

Analysis on the Age Distribution of Sternum Fractures.

BACKGROUND: Sternum fractures (SFs) are described as a rare entity of bony fractures. Various accident mechanisms may cause SF such as the direct impact of traffic accidents and also by indirect mechanisms within the framework of falls. Osteoporotic fractures also play an increasing role in SF, but no reliable data on the age distribution of SF in a representative collective have been published so far. MATERIAL AND METHODS: The age distribution of all inpatients treated with SF (S22.2) in Germany from 2005 to 2012 using diagnosis-related group-based routine data was evaluated. Various accident statistics are included in the interpretation of age peaks. RESULTS: A total of 47,893 patients (24,960 as main diagnosis and 22,933 as secondary diagnosis) were included in the study. SF is a rarity in childhood, with a share of 1.83% before the age of 16 years, followed by a sudden increase in the frequency up to the age of 20 years. A decrease in the frequency is observed up to the age of 35 years before it increases again to the age of 75 years. Three age peaks can be observed at 18, 55, and 75 years. Those who are older than 65 years account for 43.3% of total SF. DISCUSSION AND CONCLUSION: The first age summit after the age of 16 years shows an identical course to the frequency of traffic accidents of this age group, as well as the decline to the fourth decade and the subsequent resurgence up to the fifth decade. After 65 years, the incidence of accidents increases, in particular, the risk of falling in elderly people. In the context of a weaker bone structure, low falls are a common course for fragility fractures. The present analysis of routines shows for the first time the age distribution of the SF taking into account all hospital cases of the observation period.

The Operative Management of Flail Chest Injuries with Concomitant Sternal Fracture.

Background: Flail Chest Injuries (FCI) are one of the most severe thoracic injuries. Moreover, an additional sternal fracture (SF) even worsens the outcome, such as the duration of mechanical ventilation, therefore an surgical fixation of the fractures could be considered in certain cases to improve the weaning from the ventilator. This paper aims to emphasize on the management of different types of SF in FCI. Methods: All surgically treated cases (2012-2016) that showed the combination of FCI and SF have been evaluated for their clinical details, the morphology of the fractures and the technical aspects of the surgical procedure in a retrospective investigation. Results: All of the SF (n=15) had been fixed by locked plate osteosynthesis through a median approach in a supine position. Three main regions of the sternum showed the need for different fixation strategies: the upper manubrium, central and lower corpus sterni. Concomitant rib fractures were addressed either through the same approach or through additional limited incisions. Conclusions: Combinations of SF and FCI are high risc injuries with high demand on surgical skills. They can be properly fixed with a locking plate osteosynthesis through a combination of limited incisions employing different types of plates depending on the type of SF.

Surgical Stabilization of Costoclavicular Injuries - A Combination of Flail Chest Injuries and a Clavicula Fracture.

Background: Flail chest injuries (FCI) are associated with a high morbidity and mortality rate. As a concomitant clavicle fracture in FCI even worsens the outcome, the question is how can those costoclavicular injuries (CCI) be managed surgically. Methods: 11 patients with CCI were surgically treated by a locked plate osteosynthesis of the Clavicle and the underlying ribs through limited surgical approaches under general anesthesia. Patients were followed up after 2, 6, 12, 26 and 52 weeks. Results: All patients showed severe chest wall deformity due to severely displaced fractures of the ribs and the clavicle. They were suffering from pain and restriction of respiratory movements. The chest wall could be restored to normal shape in all cases with uneventful bone healing and a high patient convenience. Fractures of the clavicle and the second rib were managed through an innovative clavipectoral approach, the others through standard approaches to the anterolateral and the posterolateral chest wall. Two patients complained about numbness around the lateral approach and lasting periscapular pain. Conclusions: Surgical stabilization might be the appropriate therapy in CCI with dislocated fractures since they would cause severe deformity and loss of function of the chest wall and the shoulder.

Comparative studies of different types of osteosynthesis on the human corpse preparation in bilateral antero-lateral flail chest.

INTRODUCTION: Bilateral flail chest injuries are challenging in treatment and comparatively often require an operative stabilization of the anterior chest wall to re-establish normal physiological conditions of the chest wall in shape and statics. Various procedures have been described which are technically sophisticated for the surgeon. Consequently there is an increasing interest in potentials of operative care and their effectiveness on the anterolateral chest wall. MATERIALS AND METHODS: 12 Human cadavers were prepared and the natural Sternum Position (NP) was marked. A digital probe was fixed to the sternum at the height of the 4th intercostal space in order to measure and compare the stability of the thorax. Readings were taken of the sternal displacement at 1-5cm sagittal distance from NP in starting conditions and from every combination of materials. Serial osteotomies were performed on 2 locations on ribs 2-8 to induce bilateral flail chest. Afterwards the stabilization was achieved with different implants: RESULTS: The osteotomies lead to a subsidence of the sternum occurred to almost 75 mm from NP which corresponds to a maximal unstable situation. The unstable chest wall showed substantially more stabilization through the use of locking plates. Our materialcombinations showed a stability of up to 60% of normal. The more ribs were treated osteosynthetically, the higher the stability of the chest wall. DISCUSSION AND CONCLUSIONS: Locking plate fixation offers anatomically realignment of the ribs whereas metal strut support only lifts up the chest wall, but could not provide realignment of the dislocated ribs.

Do low profile implants provide reliable stability in fixing the sternal fractures as a "fourth vertebral column" in sternovertebral injuries?

BACKGROUND: Flexion and compression forces to the trunk can cause severe instability of the vertebral column and the anterior chest wall, mostly associated with an unstable fracture of the sternum. In combination, the worst case would be a complete disruption of the trunk. Some authors consider the sternum-rib-complex to be the fourth vertebral column. This study discusses the possibilities to treat instable trunk injuries with sternal fractures concomitant to vertebral spine fractures through anterior sternal plating employing a locked plate osteosynthesis in a low profile design instead of the use of bulky implants. METHODS: 11 Patients suffering from at least one fracture of a vertebral body in combination with an unstable sternum fracture were stabilized through a locked plate osteosynthesis in low profile design at the sternum between November 2011 and October 2014. The vertebral spine injury was stabilized as well, if necessary. Patients were followed up with a look at the consolidation of the fractures and the question if any failure of the implants occurred. RESULTS: Anterior sternal plating was uneventful in all cases. All Sternal fractures showed sufficient consolidation. No failure of implants has been seen during follow up over two years.. CONCLUSIONS: A locked plate osteosynthesis of a sternal fracture in low profile design seem to be an appropriate option for stabilization of the sternum in combined sternovertebral injuries.

Concomitant Sternal Fracture in Flail Chest: An Analysis of 21,741 Polytrauma Patients from the TraumaRegister DGU®.

Background Isolated sternal fractures (SFs) rarely show complications, but their influence in a thorax trauma of the seriously injured still remains unclear. Methods A retrospective analysis of the TraumaRegister DGU® was performed involving the years 2009 to 2013 (Injury Severity Score [ISS] ≥ 16, primary admission to a trauma center). Cohort formation: Unilateral and bilateral flail chest (FC) injuries with and without a concomitant SF, respectively. Results In total, 21,741 patients (25% female) met the inclusion criteria, with 3,492 (16.1%) showing SF. Unilateral FC patients were on average 53.6 ± 18.4 years old, and bilateral FC patients were on average 55.2 ± 17.7 years old. The ISS in unilateral FC and bilateral FC amounted to 31.2 ± 13.0 and 43.4 ± 13.1 points, respectively. FC with an SF occurred more frequently as an injury to car occupants and less frequently as an injury to motorcyclists or in injuries due to falls. Conclusion Patients with an SF additional to an FC had longer hospital and intensive care unit stays and were longer artificially respirated than those patients without an SF. SF indicates possible cardiac and thoracic spine injuries.

A multimodal approach to ankle instability: Interrelations between subjective and objective assessments of ankle status in athletes.

The aim of this retrospective cohort study is to investigate the association between different subjective and objective assessments of ankle function in a population of athletes with or without functional ankle instability (FAI). 29 athletes with a history of ankle spraining were divided into two groups according to their ankle status: 16 with FAI (initial ankle sprain with residual functional instability) (age 24.6 ± 3.1 years), and 13 COPERS (initial ankle sprain without residual instability) (age 25.3 ± 4.4 years). The assessment of each individual's ankle function was based on three approaches: The "functional-ankle-ability-measure" (FAAM) assessing subjective ankle functionality, measures of sensorimotor control as objective functional measurements and MRI-based T2-mapping as a quantitative marker of compositional joint status. Pearson's product-moment-correlation coefficient, student's t-test and analysis-of-variance were used for statistical analysis. Significant group differences existed for subjective ankle function (FAAM, p = 0.04) and MRI-data mainly in the medial compartment of the ankle joint (p ≤ 0.05). We found unique associations between T2-mapping results and sensorimotor scores in the COPER (r = -0.756-0.849), and "FAI"-group (r = 0.630-0.657). The location and magnitude differed between groups. No correlations existed between these measures and the FAAM. This exploratory study provides preliminary evidence for potential interrelations between various diagnostic measures of ankle function and structure in individuals with and without FAI. We found associations between MRI-results and selected measures of sensorimotor control, indicating a potential link between loss of ankle function and early joint degeneration. Despite these interrelations, each of the different assessment options appears to contain unique information on ankle functionality important in a clinical assessment.

Surgical fixation of sternal fractures: preoperative planning and a safe surgical technique using locked titanium plates and depth limited drilling.

Different ways to stabilize a sternal fracture are described in literature. Respecting different mechanisms of trauma such as the direct impact to the anterior chest wall or the flexion-compression injury of the trunk, there is a need to retain each sternal fragment in the correct position while neutralizing shearing forces to the sternum. Anterior sternal plating provides the best stability and is therefore increasingly used in most cases. However, many surgeons are reluctant to perform sternal osteosynthesis due to possible complications such as difficulties in preoperative planning, severe injuries to mediastinal organs, or failure of the performed method. This manuscript describes one possible safe way to stabilize different types of sternal fractures in a step by step guidance for anterior sternal plating using low profile locking titanium plates. Before surgical treatment, a detailed survey of the patient and a three dimensional reconstructed computed tomography is taken out to get detailed information of the fracture's morphology. The surgical approach is usually a midline incision. Its position can be described by measuring the distance from upper sternal edge to the fracture and its length can be approximated by the summation of 60 mm for the basis incision, the thickness of presternal soft tissue and the greatest distance between the fragments in case of multiple fractures. Performing subperiosteal dissection along the sternum while reducing the fracture, using depth limited drilling, and fixing the plates prevents injuries to mediastinal organs and vessels. Transverse fractures and oblique fractures at the corpus sterni are plated longitudinally, whereas oblique fractures of manubrium, sternocostal separation and any longitudinally fracture needs to be stabilized by a transverse plate from rib to sternum to rib. Usually the high convenience of a patient is seen during follow up as well as a precise reconstruction of the sternal morphology.

Limited integrative repair capacity of native cartilage autografts within cartilage defects in a sheep model.

The purpose of this study was to investigate integration and cellular outgrowth of native cartilage autografts transplanted into articular cartilage defects. Native cartilage autografts were applied into chondral defects in the femoral condyle of adult sheep. Within the defects, the calcified cartilage layer was either left intact or perforated to induce bone marrow stimulation. Empty defects served as controls. The joints were analyzed after 6 and 26 weeks by macroscopic and histological analysis using the ICRS II Score and Modified O'Driscoll Scores. Non-treated defects did not show any endogenous regenerative response and bone marrow stimulation induced fibrous repair tissue. Transplanted native cartilage grafts only insufficiently integrated with the defect borders. Cell death and loss of proteoglycans were present at the margins of the grafts at 6 weeks, which was only partially restored at 26 weeks. Significant cellular outgrowth from the grafts or defect borders could not be observed. Bonding of the grafts could be improved by additional bone marrow stimulation providing ingrowing cells that formed a fibrous interface predominantly composed of type I collagen. Transplanted native cartilage grafts remain as inert structures within cartilage defects and fail to induce integrative cartilage repair which rather demands additional cells provided by additional bone marrow stimulation.

Surgical fixation of sternal fractures: locked plate fixation by low-profile titanium plates--surgical safety through depth limited drilling.

PURPOSE: Operative treatment of sternal fractures has become a matter of increasing interest. Anterior plating seems to be the most appropriate method for fixing sternal fractures. However, there are several concerns in relation to the operative procedure such as severe injuries to mediastinal organs, patient comfort and proper stabilisation, for example. This paper describes a safe method of anterior sternal plating using locked plate fixation with limited depth drilling. METHODS: Ten patients with sternal fractures were included in this cohort study and were treated by anterior plating using one or two plates in parallel through a median approach to the sternum. Follow up was performed after six weeks, 12 weeks and six months. RESULTS: Follow up revealed no serious complications. One patient suffered from postoperative wound seroma. No problems were caused by the plates. CONCLUSIONS: Sternal plating using low profile locked titanium plates seems to be a safe and stable method with a high level of patient comfort.

The Transient Chondrocyte Phenotype in Human Osteophytic Cartilage: A Role of Pigment Epithelium-Derived Factor?

OBJECTIVE: To identify factors that are responsible for the phenotypic differences between transient chondrocytes within human osteophytes prone to endochondral ossification and permanent chondrocytes within articular cartilage persisting for decades. METHODS: Differential gene expression of chondrocytes from human osteophytes or from articular cartilage was detected by cDNA microarray analysis. The expression of pigment epithelium-derived factor (PEDF), one of the most impressively differentially expressed genes, was validated by quantitative reverse transcriptase polymerase chain reaction as well as immunohistochemistry. The mode of action of PEDF was explored by cell viability assays and by detecting target genes. RESULTS: PEDF mRNA expression was upregulated by 118.5-fold (P = 0.01) in human osteophytic cartilage compared with articular cartilage, which was reflected by strong immunostaining for PEDF in the cartilaginous layer of osteophytes but largely negative staining in articular cartilage. Elevated levels of PEDF in osteophytes were associated with enhanced apoptosis. PEDF increased the expression of the proapoptotic factor FasL and induced cell death in cell culture. Osteochondral progenitor cells were more responsive to PEDF than differentiated articular chondrocytes. CONCLUSIONS: The induction of the proapoptotic factor PEDF within the osteophyte cartilage suggests a molecular concept for the transient chondrocyte phenotype that arises from progenitor cells and is prone to terminal differentiation and cell death.

Thrombospondin-1 prevents excessive ossification in cartilage repair tissue induced by osteogenic protein-1.

This study investigated the effect of thrombospondin-1 (TSP-1) on the formation of cartilage repair tissue in combination with stimulation by osteogenic protein-1 (OP-1). In miniature pigs, articular cartilage lesions in the femoral trochlea were treated by the microfracture technique and either received no further treatment (MFX), or were treated by additional application of recombinant osteogenic protein-1 (MFX+OP-1), recombinant TSP-1 (MFX+TSP-1), or a combination of both proteins (MFX+TSP-1+OP-1). Six and 26 weeks after surgery, the repair tissue and the degree of endochondral ossification were assessed by histochemical and immunohistochemical methods detecting collagen types I, II, X, TSP-1, and CD31. Microfracture treatment merely induced the formation of inferior fibrocartilaginous repair tissue. OP-1 stimulated chondrogenesis, but also induced chondrocyte hypertrophy, characterized by synthesis of collagen type X, and excessive bone formation. Application of TSP-1 inhibited inadvertant endochondral ossification, but failed to induce chondrogenesis. In contrast, the simultaneous application of both TSP-1 and OP-1 induced and maintained a permanent, nonhypertrophic chondrocyte-like phenotype within cartilage repair tissue. The data of this study demonstrate that OP-1 and TSP-1 complement each other in a functional manner. While OP-1 induces chondrogenesis of the ingrowing cells, TSP-1 prevents their further hypertrophic differentiation and prevents excessive endochondral ossification within the lesions.

Chondromodulin 1 stabilizes the chondrocyte phenotype and inhibits endochondral ossification of porcine cartilage repair tissue.

OBJECTIVE: To investigate the effect of chondromodulin 1 on the phenotype of osteochondral progenitor cells in cartilage repair tissue. METHODS: Self-complementary adeno-associated virus (AAV) vectors carrying chondromodulin 1 complementary DNA (AAV-Chm-1) were applied to cartilage lesions in the knee joints of miniature pigs that were treated by the microfracture technique. Alternatively, isolated porcine osteochondral progenitor cells were infected with AAV-Chm-1 or with AAV-GFP control vectors ex vivo prior to being transplanted into cartilage lesions in which the subchondral bone plate was left intact. The quality of the repair tissue and the degree of endochondral ossification were assessed by histochemical and immunohistochemical methods. The effects of chondromodulin 1 overexpression were also analyzed by angiogenesis assays and quantitative reverse transcriptase-polymerase chain reaction. RESULTS: AAV-Chm-1-infected cells efficiently produced chondromodulin 1, which had strong antiangiogenic effects, as verified by the inhibition of tube formation of endothelial cells. Gene expression analyses in vitro revealed the cell cycle inhibitor p21WAF1/Cip1 as one target up-regulated by AAV-Chm-1. Direct application of AAV-Chm-1 vectors into microfractured porcine cartilage lesions stimulated chondrogenic differentiation of ingrowing progenitor cells, but significantly inhibited terminal chondrocyte hypertrophy, the invasion of vessel structures, and excessive endochondral ossification, which were otherwise observed in untreated lesions. Indirect gene transfer, with infection of porcine osteochondral progenitor cells by AAV-Chm-1 ex vivo, also supported chondrogenic differentiation of these transplanted cells. AAV-Chm-1-infected cells maintained a chondrocyte-like phenotype and formed a hyaline-like matrix that was superior to that formed by uninfected or AAV-GFP-infected cells. CONCLUSION: Our findings indicate that the antiangiogenic factor chondromodulin 1 stabilizes the chondrocyte phenotype by supporting chondrogenesis but inhibiting chondrocyte hypertrophy and endochondral ossification.

Deletion of the oxygen-dependent degradation domain results in impaired transcriptional activity of hypoxia-inducible factors.

Hypoxia-inducible factors (HIF1α/HIF2α) are key transcription factors that promote angiogenesis. The overexpression of degradation-resistant HIF mutants is considered a promising pro-angiogenic therapeutic tool. We compared the transcriptional activity of HIF1α/HIF2α mutants that obtained their resistance to oxygen-dependent degradation either by deletion of their entire oxygen-dependent degradation (ODD) domain or by replacement of prolyl residues that are crucial for oxygen-dependent degradation. Although all HIF mutants translocated into the nucleus, HIF1α and HIF2α mutants inclosing the point mutations were significantly more effective in trans-activating the target gene VEGF and in inducing tube formation of endothelial cells than mutants lacking the complete ODD domain.

Stop of loss of cognitive performance during rehabilitation after total hip arthroplasty-prospective controlled study.

Prolonged hospitalization is known to be associated with a loss of cognitive performance. Does playing video games (VGs) developed to improve cognitive properties delay this loss or even lead to an increase in cognitive performance? We performed a 10-day longitudinal study of patients who received total hip arthroplasty. We compared 16 patients (6 male) aged 66 ± 9 years (mean ± standard deviation) who played Dr. Kawashima's Brain Training: How Old Is Your Brain? (Nintendo; Redmond, Washington) on a Nintendo DS handheld console with 16 control patients (6 male) aged 69 ± 14 years. We measured cognitive performance 1 day preoperation, as well as on days 2 and 9 postoperation. With the daily exercise of a specific VG by the play group, the patients' fluid intelligence (median intelligence quotient 99-106), working memory capacity, and rate of information processing significantly improved over the course of 7 postoperative days. The cognitive performance of the control group did not increase. However, the memory spans of both groups did not systematically change. Exercise with VGs can prevent the loss of cognitive performance during prolonged hospitalization.

Early repolarization, left ventricular diastolic function, and left atrial size in professional soccer players.

Recent data have suggested a relation among long-term endurance sport practice, left atrial remodeling, and atrial fibrillation. We investigated the influence of an increased vagal tone, represented by the early repolarization (ER) pattern, on diastolic function and left atrial size in professional soccer players. Fifty-four consecutive athletes underwent electrocardiography, echocardiography, and exercise testing as part of their preparticipation screening. Athletes were divided into 2 groups according to presence or absence of an ER pattern, defined as a ST-segment elevation at the J-point (STE) > or =0.1 mm in 2 leads. For linear comparisons average STE was calculated. Mean age was 24 +/- 4 years. Twenty-five athletes (46%) showed an ER pattern. Athletes with an ER pattern had a significant lower heart rate (54 +/- 9 vs 62 +/- 11 beats/min, p = 0.024), an increased E/e' ratio (6.1 +/- 1.2 vs 5.1 +/- 1.0, p = 0.002), and larger volumes of the left atrium (25.6 +/- 7.3 vs 21.8 +/- 5.0 ml/m(2), p = 0.031) compared to athletes without an ER pattern. There were no significant differences concerning maximum workload, left ventricular dimensions, and systolic function. Univariate regression analysis revealed significant correlations among age, STE, and left atrial volume. In a stepwise multivariate regression analysis age, STE and e' contributed independently to left atrial size (r = 0.659, p <0.001). In conclusion, athletes with an ER pattern had an increased E/e' ratio, reflecting a higher left atrial filling pressure, contributing to left atrial remodeling over time.

Bone penetration of amoxicillin and clavulanic acid evaluated by population pharmacokinetics and Monte Carlo simulation.

Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for > or = 50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (> or = 90%) probabilities of target attainment (PTAs) for MICs of < or = 12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.