Treatment of partial thickness burns of the face with Acticoat7™ : A retrospective single center study.

BACKGROUND: The face is affected in more than 50% of patients with extensive burn trauma. Effective treatment is of importance to avoid hypertrophic scarring, functional impairment and social stigmatization. MATERIAL AND METHODS: All patients treated with Acticoat7™ due to superficial and deep partial thickness burns of the face between 2008 and 2017 at the intensive care unit (ICU) for burn trauma at the Department for Plastic and Reconstructive Surgery of the Medical University of Vienna were retrospectively analyzed. Patients were evaluated for the number of required dressing changes until complete re-epithelialization, bacterial colonization, potential complications and the need for primary and secondary surgery. RESULTS: A total of 100 patients were analyzed. It took a median dressing change rate of 1 (range 0-5) in the superficial partial thickness and 3 (range 1-11) in the deep partial thickness group. Conservative treatment of deep partial thickness wounds was possible in 79% and 17% of these patients required secondary scar revision. Although bacterial colonization of the wounds frequently occurred, wound infections were rarely observed. CONCLUSION: Acticoat7™ is a valuable dressing for treating superficial and deep partial thickness burn wounds of the face in an intensive care unit setting. It enables extended time intervals between dressing changes without an increased risk for complications.

Air-fluidized therapy in the treatment of severe burns: A retrospective study from a burn intensive care unit in Austria.

INTRODUCTION: Air-fluidized therapy (AFT) has long been used in the treatment of severe burns. In patients with extensive burns involving the posterior trunk, we aim to keep affected posterior areas dry and to postpone their treatment, initially applying available split-thickness skin grafts in functionally more important regions. We retrospectively assessed the impact of AFT on the survival of patients treated in the burn intensive care unit (ICU) of the Medical University of Vienna, Austria, between 2003 and 2016. METHODS: This retrospective single-center study included patients aged ≥18 years with burned total body surface area (TBSA) ≥20% and IIb-III° thermal injuries on the posterior trunk who received AFT. Survival rates were compared with those predicted by the abbreviated burn severity index (ABSI). Demographic, clinical, and surgical data were analyzed. RESULTS: Seventy-five of 110 patients with posterior trunk burns received AFT. Their survival rate exceeded that predicted by the ABSI score (mean ABSI, 10.0 ± 2.0; 73.3% (95% CI: 62-83%) survival rate vs. 20-40% predicted; p < 0.0001); no such difference was observed in the non-AFT group (mean, 8.8 ± 1.9; 65.7% (95% CI: 48-81%) survival rate vs. 50-70% predicted). Patients receiving AFT had significantly greater TBSA (median, 50% (35-60) vs. 30% (25-45) and longer ICU stays (median, 63 (36-92) vs. 18 (9-52) days; both p < 0.0001). Fifty-one (68.0%) patients in the AFT group and 26 (74.3%) patients in the non-AFT group underwent posterior trunk surgery (p = 0.66) a median of 16 (10-26) and 5 (2.5-9.5) days, respectively, after admission (p < 0.0001). CONCLUSIONS: Patients receiving AFT had significantly better survival than predicted by ABSI score in contrast to patients not receiving AFT although burn injuries in this group were more severe (greater TBSA, higher ABSI). As intensive care was similar in these groups aside from AFT, the better survival could be attributed to this additional therapy.

Increased serum concentrations of soluble ST2 predict mortality after burn injury.

BACKGROUND: Large burn injuries induce a systemic response in affected patients. Soluble ST2 (sST2) acts as a decoy receptor for interleukin-33 (IL-33) and has immunosuppressive effects. sST2 has been described previously as a prognostic serum marker. Our aim was to evaluate serum concentrations of sST2 and IL-33 after thermal injury and elucidate whether sST2 is associated with mortality in these patients. METHODS: We included 32 burn patients (total body surface area [TBSA] >10%) admitted to our burn intensive care unit and compared them to eight healthy probands. Serum concentrations of sST2 and IL-33 were measured serially using an enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: The mean TBSA was 32.5%±19.6%. Six patients (18.8%) died during the hospital stay. Serum analyses showed significantly increased concentrations of sST2 and reduced concentrations of IL-33 in burn patients compared to healthy controls. In our study cohort, higher serum concentrations of sST2 were a strong independent predictor of mortality. CONCLUSIONS: Burn injuries cause an increment of sST2 serum concentrations with a concomitant reduction of IL-33. Higher concentrations of sST2 are associated with increased in-hospital mortality in burn patients.

Optimization of breast reconstruction results using TMG flap in 30 cases: Evaluation of several refinements addressing flap design, shaping techniques, and reduction of donor site morbidity.

BACKGROUND: The transverse myocutaneous gracilis (TMG) flap is a widely used alternative to abdominal flaps in autologous breast reconstruction. However, secondary procedures for aesthetic refinement are frequently necessary. Herein, we present our experience with an optimized approach in TMG breast reconstruction to enhance aesthetic outcome and to reduce the need for secondary refinements. METHODS: We retrospectively analyzed 37 immediate or delayed reconstructions with TMG flaps in 34 women, performed between 2009 and 2015. Four patients (5 flaps) constituted the conventional group (non-optimized approach). Thirty patients (32 flaps; modified group) underwent an optimized procedure consisting of modified flap harvesting and shaping techniques and methods utilized to reduce denting after rib resection and to diminish donor site morbidity. RESULTS: Statistically significant fewer secondary procedures (0.6 ± 0.9 versus 4.8 ± 2.2; P < .001) and fewer trips to the OR (0.4 ± 0.7 versus 2.3 ± 1.0 times; P = .001) for aesthetic refinement were needed in the modified group as compared to the conventional group. In the modified group, 4 patients (13.3%) required refinement of the reconstructed breast, 7 patients (23.3%) underwent mastopexy/mammoplasty or lipofilling of the contralateral breast, and 4 patients (13.3%) required refinement of the contralateral thigh. Total flap loss did not occur in any patient. Revision surgery was needed once. CONCLUSIONS: Compared to the conventional group, enhanced aesthetic results with consecutive reduction of secondary refinements could be achieved when using our modified flap harvesting and shaping techniques, as well as our methods for reducing contour deformities after rib resection and for overcoming donor site morbidities.

Venous Superdrainage in DIEP Flap Breast Reconstruction: The Impact of Superficial Inferior Epigastric Vein Dissection on Abdominal Seroma Formation.

BACKGROUND: Abdominal seroma formation after deep inferior epigastric perforator (DIEP) flap breast reconstruction is a common donor-site complication. Additional dissection of one or both of the superficial inferior epigastric veins (SIEVs) in DIEP flap breast reconstruction allows an additional anastomosis for venous superdrainage if venous congestion occurs. However, generally, SIEV dissection involves greater invasiveness into the inguinal region, which can traumatize lymphatic tissue and lead to lymph accumulation. The aim of this study was to evaluate the impact of SIEV dissection on the incidence of postoperative abdominal seroma. METHODS: A series of 100 consecutive cases performed by the Department of Plastic and Reconstructive Surgery at the Medical University of Vienna from 2001 to 2016 was analyzed. Patients were divided into three groups: unilateral, bilateral, and no SIEV dissection. Abdominal seroma rates, length of hospital stay, abdominal drainage duration, and drainage fluid volumes were compared retrospectively. RESULTS: Seromas were observed in 11.5 percent of patients without SIEV dissection, 17.2 percent of patients with unilateral SIEV dissection (p = 0.45 versus no SIEV), and 40 percent of patients with bilateral SIEV dissection (p = 0.02 versus no SIEV). The SIEV was anastomosed to salvage a congested DIEP flap twice. All seromas that developed could be treated with, on average, two fine-needle aspirations without any complications. CONCLUSIONS: Bilateral, but not unilateral, SIEV dissection increased abdominal seroma rates significantly. Venous congestion was observed rarely, but when it did occur, it endangered flap viability. Because an additional anastomosis of the SIEV can salvage a flap, unilateral SIEV dissection should be considered when raising a DIEP flap. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

First Experiences with Incisional Negative Pressure Wound Therapy in a High-Risk Poststernotomy Patient Population treated with Pectoralis Major Muscle Flap for Deep Sternal Wound Infection.

BACKGROUND: Radical debridement and wound closure with vascularized flaps has become a standard procedure in the treatment of deep sternal wound infections. Negative pressure incision management systems have been proven to diminish wound infections after sternotomy. In this study, the utility of Prevena Incision Management System (KCI Licensing Inc.) was evaluated in obese patients who received unilateral pectoralis major flap for the treatment of deep sternal wound infections. METHODS: The outcome and wound-related complication rates of 19 obese patients (mean body mass index, 33.7) treated for deep sternal wound infection with pectoralis major muscle flap in combination with Prevena between 2011 and 2016 were compared with 28 obese patients treated with conventional wound dressing only between 2000 and 2010. RESULTS: In patients additionally treated with Prevena, significantly fewer surgical revisions due to wound-related complications were necessary as compared with patients who received conventional wound dressing (5.3 vs. 32.1%, p = 0.034). A significantly shorter ICU length of stay (median 0 vs. 3.5 days, p < 0.001) and a trend toward shorter length of hospitalization (median 14 vs. 19.5 days after pectoralis major flap) could be observed. CONCLUSION: The application of Prevena significantly reduced revision surgery rates in obese patients treated with unilateral pectoralis major flap for deep sternal wound infections.

Management of the Nipple-Areola Complex in Selected Patients Undergoing Primary Breast Reconstruction: A Comparison of Immediate Replantation and Delayed Reconstruction.

BACKGROUND: Management of the nipple-areola complex is an important issue in primary breast reconstruction. When nipple-sparing mastectomy is not suitable, alternatives are immediate nipple-areola complex replantation and delayed reconstruction. The aim of this study was to examine whether patients benefit more from nipple-areola complex preservation by immediate replantation or delayed nipple-areola complex reconstruction. METHODS: Postoperative results and patient satisfaction after 54 primary breast reconstructions with immediate nipple-areola complex replantation or delayed nipple-areola complex reconstruction were retrospectively evaluated. RESULTS: The nipple-areola complex was replanted immediately in 37 cases and reconstructed later with nipple sharing and full-thickness skin grafting in 17 cases. Compared with immediate replantation, delayed reconstruction resulted in significantly better postoperative nipple projection (P = 0.01*, Mann-Whitney U test), greater similarity of color and projection with the contralateral side and greater patient satisfaction (Breast-Q). Complete loss of projection occurred in 4 of the 37 replanted nipple-areola complexes. No complete nipple-areola complex necrosis or tumor recurrence was observed in any patient. CONCLUSIONS: Immediate nipple-areola complex replantation is a safe and reliable procedure for selected patients with contraindications for nipple-sparing mastectomy who have a strong desire to maintain their own nipple-areola complexes, or in bilateral cases. However, drawbacks of this procedure include loss of projection and depigmentation. Delayed reconstruction with nipple sharing and full-thickness skin grafting is a good alternative, especially in unilateral cases; it leads to better postoperative results and greater patient satisfaction, but it involves a nipple-areola complex-free period.

Non-professional marathon running: RAGE axis and ST2 family changes in relation to open-window effect, inflammation and renal function.

Conflicting data exist on the relevance of marathon (M) and half marathon (HM) running for health. The number of non-professional athletes finishing M and HM events is steadily growing. In order to investigate molecular changes occurring in amateur athletes, we enrolled 70 non-professional runners finishing a single M (34) or HM (36) event at baseline, the finish line and during recovery, and 30 controls. The measurement of the Receptor for Advanced Glycation Endproducts, Interleukin 1 receptor antagonist, ST2 and cytokeratin 18 was combined with molecules measured during clinical routine. Results were analyzed in the light of blood cell analysis, lactate measurements, correction for changes in plasma volume and body composition assessments. There were intrinsic differences in body mass index, abdominal body fat percentage and training time between M and HM runners. C-reactive protein changes in M and HM runners. While soluble RAGE, AGEs and ST2 increased immediately after the race in HM runners, HMGB1 increased in HM and M after the race and declined to baseline after a recovery period. We give insights into the regulation of various molecules involved in physical stress reactions and their possible implications for the cardiovascular system or renal function.

Paracrine Factors from Irradiated Peripheral Blood Mononuclear Cells Improve Skin Regeneration and Angiogenesis in a Porcine Burn Model.

Burn wounds pose a serious threat to patients and often require surgical treatment. Skin grafting aims to achieve wound closure but requires a well-vascularized wound bed. The secretome of peripheral blood mononuclear cells (PBMCs) has been shown to improve wound healing and angiogenesis. We hypothesized that topical application of the PBMC secretome would improve the quality of regenerating skin, increase angiogenesis, and reduce scar formation after burn injury and skin grafting in a porcine model. Full-thickness burn injuries were created on the back of female pigs. Necrotic areas were excised and the wounds were covered with split-thickness mesh skin grafts. Wounds were treated repeatedly with either the secretome of cultured PBMCs (Sec(PBMC)), apoptotic PBMCs (Apo-Sec(PBMC)), or controls. The wounds treated with Apo-Sec(PBMC) had an increased epidermal thickness, higher number of rete ridges, and more advanced epidermal differentiation than controls. The samples treated with Apo-Sec(PBMC) had a two-fold increase in CD31+ cells, indicating more angiogenesis. These data suggest that the repeated application of Apo-Sec(PBMC) significantly improves epidermal thickness, angiogenesis, and skin quality in a porcine model of burn injury and skin grafting.

Early and Sustained Changes in Bone Metabolism After Severe Burn Injury.

CONTEXT: Severe burn injury causes a massive stress response, consecutively heightened serum levels of acute phase proteins, cortisol, and catecholamines with accompanying disturbance in calcium metabolism. OBJECTIVE: Evaluation of early and prolonged changes of serum bone turnover markers (BTMs) and regulators of bone metabolism. DESIGN: Longitudinal observational design. SETTING: University clinic. PATIENTS: A total of 32 male patients with a median age of 40.5 years and a median burned total body surface area of 40% (83% patients with full thickness burn injury). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Comparison of changes of BTM/regulators of bone metabolism in the early (d 2­7) and prolonged (d 7­56) phases after trauma. RESULTS: All investigated BTM/regulators significantly changed. During the early phase, pronounced increases were observed for serum type 1 collagen cross-linked C-telopeptide, intact N-terminal propeptide of type I procollagen, sclerostin, Dickkopf-1, bone-specific alkaline phosphatase, fibroblast growth factor 23, and intact parathyroid hormone levels, whereas 25-hydroxyvitamin D, albumin, serum, and ionized calcium levels decreased. Changes of osteoprotegerin, osteocalcin, and phosphate were less pronounced but remained significant. In the prolonged phase, changes of intact N-terminal propeptide of type I procollagen were most pronounced, followed by elevated sclerostin, osteocalcin, bone-specific alkaline phosphatase, and lesser changes for albumin levels. Calcium and ionized calcium levels tardily increased and remained within the limit of normal. In contrast, levels of intact parathyroid hormone, fibroblast growth factor 23, C-reactive protein, and to a lesser extent serum type 1 collagen cross-linked C-telopeptide and phosphate levels declined significantly during this phase of investigation. CONCLUSIONS: Ongoing changes of BTM and regulators of bone metabolism suggest alterations in bone metabolism with a likely adverse influence on bone quality and structure in male patients with severe burn injuries.

Wound Healing Effect of Conditioned Media Obtained From Adipose Tissue on Human Skin Cells: A Comparative in Vitro Study.

BACKGROUND: Split-thickness skin grafting is the gold standard to cover extensive acute and chronic wounds with a well-vascularized wound bed. Although some headway has been made in developing biological agents to speed up healing, there is still no treatment that sufficiently replaces skin grafts to date. The use of secretory factors of adipose tissue may be a feasible approach to developing topical wound applications for faster wound healing. METHODS: In this study, the effect of conditioned media (CMs) of human adipose-derived stem cells (ASCs), adipocytes, or adipose tissue on human skin cells was evaluated for viability, proliferation, and migration in vitro. Differentiation potential of stem cells treated with CM was monitored by AdipoRed staining and qualitative real-time polymerase chain reaction. Angiogenic potential of human endothelial cells treated with CM was tested via sprouting assay. RESULTS: The CM of adipose tissue significantly enhanced ASC proliferation (P < 0.01). Treatment with CM showed no inductive effect on ASC differentiation into adipocytes but, at the same time, significantly induced cell sprouting of endothelial cells (P < 0.001). We show for the first time that CM of adipose tissue is a potent inducer of proliferation of ASCs and angiogenesis, with comparable effects with those of stem cell-enriched CM. CONCLUSIONS: We suggest the use of the secretome of adipose tissue to produce CM for topical application on wounds, rather than working with adipose tissue or including the difficult process of enriching the patients' stem cells in vitro.

Acne inversa complicated by Actinomyces neuii.

INTRODUCTION: Acne inversa (AI) is a chronic and recurrent inflammatory skin disease. It occurs in intertriginous areas of the skin and causes pain, drainage, malodor and scar formation. While supposedly caused by an autoimmune reaction, bacterial superinfection is a secondary event in the disease process. METHODS: A unique case of a 43-year-old male patient suffering from a recurring AI lesion in the left axilla was retrospectively analysed. RESULTS: A swab revealed Actinomyces neuii as the only agent growing in the lesion. The patient was then treated with Amoxicillin/Clavulanic Acid 3 × 1 g until he was cleared for surgical excision. The intraoperative swab was negative for A. neuii. Antibiotics were prescribed for another 4 weeks and the patient has remained relapse free for more than 12 months now. CONCLUSION: Primary cutaneous Actinomycosis is a rare entity and the combination of AI and Actinomycosis has never been reported before. Failure to detect superinfections of AI lesions with slow-growing pathogens like Actinomyces spp. might contribute to high recurrence rates after immunosuppressive therapy of AI. The present case underlines the potentially multifactorial pathogenesis of the disease and the importance of considering and treating potential infections before initiating immunosuppressive regimens for AI patients.

Latissimus dorsi breast reconstruction: how much nerve resection is necessary to prevent postoperative muscle twitching?

BACKGROUND: The latissimus dorsi muscle flap represents a valuable option in breast reconstruction but can result in postoperative twitching and retraction, discomfort, arm movement limitations, and breast deformation. These complications can be avoided by denervation of the thoracodorsal nerve; however, the optimal method of nerve management is unknown. This study presents the authors' experience with the outcomes of latissimus dorsi flaps for breast reconstruction in the light of thoracodorsal nerve management strategies. METHODS: The authors retrospectively collected data from 74 patients who underwent partial or total breast reconstruction with a latissimus dorsi flap alone or with an implant between January of 1999 and October of 2011. Follow-up data were collected at 12 and 24 months postoperatively. RESULTS: In 56 patients (75.7 percent), the latissimus dorsi muscle was denervated at the time of surgery, whereas the thoracodorsal nerve remained intact in 18 patients (24.3 percent). No partial or total flap loss was observed. At 12 and 24 months' follow-up, all patients with an intact thoracodorsal nerve showed twitching of the muscle, and 50 percent and 67.9 percent, respectively, of the denervated patients showed twitching (p < 0.001). No patient had twitching if more than 4 cm of nerve was excised at 12 or 24 months postoperatively, and the length of nerve resection was predictive of the presence of twitching. CONCLUSION: Denervation of the latissimus dorsi is a safe and reliable procedure that should be performed at the time of breast reconstruction and should include more than 4 cm to achieve a nontwitching breast with a stable volume and shape.

Transient hypoxia leads to increased serum levels of heat shock protein-27, -70 and caspase-cleaved cytokeratin 18.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a worldwide burden. We have previously shown that elevated levels of heat shock protein-27 (HSP27), -70 (HSP70), and caspase-cleaved cytokeratin 18 (ccCK-18) were found in serum of COPD patients correlating with disease severity. We hypothesized that transient hypoxia triggers the release of HSPs and ccCK-18. METHODS: Fourteen healthy volunteers were subjected to transient normobaric hypoxia in an air-conditioned hypoxia chamber simulating an oxygen concentration at an altitude of up to 5500 meters. Serum samples were evaluated for HSP27, -70, and ccCK-18. RESULTS: Baseline concentrations were 2760 pg/mL +/- 517 SEM for HSP-27, 49 pg/mL +/- 22 SEM for HSP-70, and 226 U/L +/- 20 SEM for ccCK-18. After eight hours and an altitude equivalent of 5500 meters a significant increase was recorded, depicted by serum levels of 3737 pg/mL +/- 571 SEM for HSP-27, 202 pg/mL +/- 81 SEM for HSP-70, and 244 U/L +/- 20 SEM for ccCK-18 (p < 0.05). CONCLUSIONS: These results provide an explanation for the elevated serum levels of HSP-27, HSP-70, and ccCK-18 found in COPD patients, indicating that hypoxic conditions can trigger the release of the aforementioned factors.

Increased serum levels of HSP27 as a marker for incipient chronic obstructive pulmonary disease in young smokers.

BACKGROUND: Although chronic obstructive pulmonary disease (COPD) is amongst the leading causes of morbidity and mortality, no biomarkers for its early detection are known. We have recently demonstrated that COPD is accompanied by elevated serum heat shock protein (HSP) 27 levels as compared to a control population. OBJECTIVES: In an open prospective study, we investigated whether elevated HSP27 levels are associated with the early radiological signs of COPD, i.e., air trapping (AT), emphysema (E) and impaired lung function. METHODS: In total, 120 apparently healthy smokers underwent lung function testing and serum sampling. Serum levels of HSP27, phospho-HSP27, CXCR2 chemokines and proteins related to inflammation, tissue remodeling and apoptosis were evaluated by ELISA. Of these 120 subjects, 94 voluntarily underwent a high-resolution computed tomography scan. RESULTS: AT or AT and E were detected in 57.45%. Subjects with AT and E (n = 23) showed significantly higher HSP27 levels than those without any pathology [i.e., nothing abnormal detected (NAD)] (4,618 +/- 1,677 vs. 3,282 +/- 1,607 pg/ml; p = 0.0081). In a univariate logistic regression model including NAD and AT and E, the area under the curve of HSP27 in the receiver-operating-characteristic curve was 0.724, (0.594­0.854, 95% CI; p = 0.0033). Interestingly, proinflammatory IL-8 was elevated in those subjects with evidence of AT and E compared to those with AT and NAD. Lung function did not correlate with increased HSP27 levels or pathological radiological findings. CONCLUSIONS: HSP27 serum levels correlated with the early radiological signs of COPD, whereas lung function did not match with radiological findings or HSP27 serum levels. Serum HSP27 levels may serve as a potential marker to identify the early signs of COPD independent of lung function in young smokers.

Discrimination of clinical stages in non-small cell lung cancer patients by serum HSP27 and HSP70: a multi-institutional case-control study.

INTRODUCTION: Lung cancer represents a major healthcare problem. Accordingly, there is an urgent need to identify serum biomarkers for early diagnosis of lung pathology. We have recently described that patients with manifest COPD evidence elevated levels of heat shock proteins (HSPs). Based on these data, we speculated whether HSPs are also increased in patients with diagnosed lung cancer. METHODS: Serum levels of HSP27, phospho-HSP27 (pHSP27) and HSP70 in patients with non-small cell lung cancer (NSCLC) diagnosed at an early (stages I-II, n=37) or advanced (stages IIIA-IV, n=72) stage were determined by using ELISA. Healthy smokers (n=24), healthy never-smoker volunteers (n=33) and COPD patients (n=34) according to GOLD classification served as control population. RESULTS: Serum levels of HSP27 were elevated in patients with NSCLC diagnosed at an early or advanced stage when compared with both healthy control groups (P<0.005 and P<0.0001 respectively). Statistically significant differences were furthermore found between the groups of patients with early vs. advanced stage NSCLC (P=0.0021). Serum levels of HSP70 were also significantly elevated in patients with NSCLC diagnosed at an early or at an advanced stage when compared with either healthy control groups (P=0.0028 and P<0.0001 respectively). In univariate logistic regression models including healthy subjects and patients with NSCLC, HSP70 had an area under the curve (AUC) of 0.779 (P<0.0001) and HSP27 showed an AUC of 0.870 (P<0.0001). CONCLUSION: Our data suggest that serum HSP27 levels might serve as a possible tool to discriminate between early and advanced stages NSCLC.

The receptor for advanced glycation endproducts and its ligands in patients with myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is a T- and B-cell mediated autoimmune disorder affecting the neuromuscular junction. The receptor for advanced glycation endproducts (RAGE) plays a role in the amplification of chronic inflammatory disorders and autoimmune diseases. We sought to investigate the role of RAGE and its ligands in the pathophysiology of MG. METHODS: In this cross-sectional study we enrolled 42 patients with MG and 36 volunteers. We employed enzyme-linked immunosorbent assays to determine the concentration of soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1) in serum of patients and volunteers. In a subpopulation of patients we measured the serum levels of endogenous secretory (es) RAGE and various RAGE ligands, such as S100B, S100A8 and advanced glycation endproducts (AGE-CML). Reported are means and standard error mean. RESULTS: We found significantly reduced levels of the soluble receptors sRAGE and esRAGE in patients with MG compared to volunteers without MG (sRAGE [pg/ml] 927.2 ± 80.8 vs. 1400.1 ± 92.4; p<0.001; esRAGE [pg/ml] 273.5±24.6 vs. 449.0 ± 22.4; p<0.001). Further categorization of patients with MG according to the distribution of muscle involvement revealed the following sRAGE concentrations: generalized MG 999.4 ± 90.8 and ocular MG 696.1 ± 161.8 (vs. control; One-way ANOVA: p<0.001; Post hoc analysis: generalized vs. ocular MG: p=0.264, generalized MG vs. control: p=0.008, ocular MG vs. control: p=0.001). In patients with detectable antibodies specific for acetylcholine receptors (Anti-AChR positive) the sRAGE concentration was 970.0 ± 90.2 compared to those without (seronegative) 670.6 ± 133.1 (vs. control; One-way ANOVA: p<0.001; Post hoc analysis: Pos vs. Neg.: p=0.418, Pos vs. control: p=0.003, Neg. vs. control: p=0.008). We next investigated the role of RAGE ligands in MG. The concentrations of RAGE ligands in patients with MG and controls were as follows: (HMGB1 [ng/ml] 1.7 ± 0.1 vs. 2.1 ± 0.2; p=0.058; S100B [pg/ml] 22.5 ± 22.5 vs. 14.4 ± 9.2; p=0.698; S100A8 [pg/ml] 107.0 ± 59.3 vs. 242.5 ± 103.6; p=0.347; and AGE-CML [ng/ml] 1100.8 ± 175.1 vs. 1399.8 ± 132.8; p=0.179). CONCLUSIONS: Our data suggest a role for the RAGE pathway in the pathophysiology of MG. Further studies are warranted to elucidate more about this immunological axis in patients with MG.

Anti-thymocyte globulin induces neoangiogenesis and preserves cardiac function after experimental myocardial infarction.

RATIONALE: Acute myocardial infarction (AMI) followed by ventricular remodeling is the major cause of congestive heart failure and death in western world countries. OBJECTIVE: Of relevance are reports showing that infusion of apoptotic leucocytes or anti-lymphocyte serum after AMI reduces myocardial necrosis and preserves cardiac function. In order to corroborate this therapeutic mechanism, the utilization of an immunosuppressive agent with a comparable mechanism, such as anti-thymocyte globulin (ATG) was evaluated in this study. METHODS AND RESULTS: AMI was induced in rats by ligation of the left anterior descending artery. Initially after the onset of ischemia, rabbit ATG (10 mg/rat) was injected intravenously. In vitro and in vivo experiments showed that ATG induced a pronounced release of pro-angiogenic and chemotactic factors. Moreover, paracrine factors released from ATG co-incubated cell cultures conferred a down-regulation of p53 in cardiac myocytes. Rats that were injected with ATG evidenced higher numbers of CD68+ macrophages in the ischemic myocardium. Animals injected with ATG evidenced less myocardial necrosis, showed a significant reduction of infarct dimension and an improvement of post-AMI remodeling after six weeks (infarct dimension 24.9% vs. 11.4%, p<0.01). Moreover, a higher vessel density in the peri-infarct region indicated a better collateralization in rats that were injected with ATG. CONCLUSIONS: These data indicate that ATG, a therapeutic agent successfully applied in clinical transplant immunology, triggered cardioprotective effects after AMI that salvaged ischemic myocardium by down-regulation of p53. This might have raised the resistance against apoptotic cell death during ischemia. The combination of these mechanisms seems to be causative for improved cardiac function and less ventricular remodeling after experimental AMI.

Primary sources and immunological prerequisites for sST2 secretion in humans.

AIMS: Serum levels of the soluble growth stimulation gene-2 (sST2) are elevated in heart and pulmonary diseases. However, the relationship of the sST2/interleukin (IL)-33 axis and its triggers as well as its organ distribution is still not known. This study was thus designed to investigate the cellular origin and regulation of sST2 and IL-33 in vitro and in vivo. METHODS AND RESULTS: sST2 and IL-33 gene expression and protein secretion were analysed in pooled organ-specific cDNAs and in primary cell cultures, respectively, by RT-PCR and ELISA technology. The strongest sST2 mRNA expression was detected in heart and lung tissues, which correlated with spontaneous secretion of sST2 protein in vitro. The inflammatory cytokines IL-1alpha, IL-1beta, and tumour necrosis factor alpha as well as supernatants of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells led to an enhanced secretion of sST2 in cultured cardiac myocytes and lung alveolar epithelial cells. These cytokines enhanced sST2 secretion via an NFkappaB-dependent mechanism. In addition, LPS stimulation in humans in vivo induced a short-term inflammatory response that was followed by a massive enhancement of sST2 secretion. CONCLUSION: These results identify the primary sources and inflammatory triggers for the enhancement of sST2 secretion and demonstrate a relationship between inflammation and the secretion of a bioactive member of the IL-1R family, both in vitro and in vivo.