GPR55 inhibits the pro-adipogenic activity of anandamide in human adipose stromal cells.

The endocannabinoid anandamide (AEA) stimulates adipogenesis via the cannabinoid receptor CB1 in adipose stromal cells (ASCs). However, AEA interacts also with nonclassical cannabinoid receptors, including transient receptor potential cation channel (TRPV)1 and G protein-coupled receptor (GPR)55. Their roles in AEA mediated adipogenesis of human ASCs have not been investigated. We examined the receptor-expressions by immunostaining on human ASCs and tested their functionality by measuring the expression of immediate early genes (IEGs) related to the transcription factor-complex AP-1 upon exposition to receptor agonists. Cells were stimulated with increasing concentrations of specific ligands to investigate the effects on ASC viability (proliferation and metabolic activity), secretory activity, and AEA mediated differentiation. ASCs expressed both receptors, and their activation suppressed IEG expression. TRPV1 did not affect viability or cytokine secretion. GPR55 decreased proliferation, and it inhibited the release of hepatocyte growth factor. Blocking GPR55 increased the pro-adipogenic activity of AEA. These data suggest that GPR55 functions as negative regulator of cannabinoid mediated pro-adipogenic capacity in ASCs.

Evaluation of the Effect of Botulinum Toxin A on the Lymphatic Endothelial Cells.

INTRODUCTION: Botulinum toxin A (BoTA) is a neurotoxin formed by Clostridium botulinum, with a broad medical application spectrum. While the primary effect of BoTA is on the muscles, the effects of BoTA in other systems including the blood vasculature have already been examined, revealing unexpected actions. However, no studies exist to the best of our knowledge regarding the potential effects of BoTA on the lymphatic vascular system, possessing a critical role in health and disease. Isolated human lymphatic endothelial cells (LECs) were cultured in dedicated in vitro culture systems. The analysis including imaging and cell culture approaches as well as molecular biology techniques is performed to examine the LEC alterations occurring upon exposure to different concentrations of BoTA. MATERIALS AND METHODS: Human LECs were cultured and expanded on collagen-coated petri dishes using endothelial basal medium and the commercial product Botox from Allergan as used for all our experiments. Harvested cells were used in various in vitro functional tests to assess the morphologic and functional properties of the BoTA-treated LECs. Gene expression analysis was performed to assess the most important lymphatic system-related genes and pathways. RESULTS: Concentrations of 1, 5 or 10 U of BoTA did not demonstrate a significant effect regarding the proliferation and migration capacity of the LECs versus untreated controls. Interestingly, even the smallest BoTA dose was found to significantly decrease the cord-like-structure formation capacity of the seeded LECs. Gene expression analysis was used to underpin possible molecular alterations, suggesting no significant effect of BoTA in the modification of gene expression versus the starvation medium control. CONCLUSION: LECs appear largely unaffected to BoTA treatment, with an isolated effect on the cord-like-structure formation capacity. Further work needs to assess the effect of BoTA on the smooth-muscle-cell-covered collecting lymphatic vessels and the possible aesthetic implications of such an effect, due to edema formation. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Surgical Management of Breast Capsular Contracture-A Multi-institutional Data Analysis of Risk Factors for Early Complications.

BACKGROUND: Capsular contracture (CC) is a common complication following implant-based breast surgery, often requiring surgical intervention. Yet, little is known about risk factors and outcomes following CC surgery. METHODS: We reviewed the American College of Surgeons National Surgical Quality Improvement Program database (2008-2021) to identify female patients diagnosed with CC and treated surgically. Outcomes of interest included the incidence of surgical and medical complications at 30-days, reoperations, and readmissions. Confounder-adjusted multivariable analyses were performed to establish risk factors. RESULTS: 5,057 patients with CC were identified (mean age: 55 ± 12 years and mean body mass index [BMI]: 26 ± 6 kg/m2). While 2,841 (65%) women underwent capsulectomy, capsulotomy was performed in 742 patients (15%). Implant removal and replacement were recorded in 1,160 (23%) and 315 (6.2%) cases, respectively. 319 (6.3%) patients experienced postoperative complications, with 155 (3.1%) reoperations and 99 (2.0%) readmissions. While surgical adverse events were recorded in 139 (2.7%) cases, 86 (1.7%) medical complications occurred during the 30 day follow-up. In multivariate analyses, increased BMI (OR: 1.04; p = 0.009), preoperative diagnosis of hypertension (OR: 1.48; p = 0.004), and inpatient setting (OR: 4.15; p < 0.001) were identified as risk factors of complication occurrence. CONCLUSION: Based on 14 years of multi-institutional data, we calculated a net 30 day complication rate of 6.3% after the surgical treatment of CC. We identified higher BMI, hypertension, and inpatient setting as independent risk factors of postoperative complications. Plastic surgeons may wish to integrate these findings into their perioperative workflows, thus optimizing patient counseling and determining candidates' eligibility for CC surgery. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The Angiopoietin-2/Angiopoietin-1 ratio increases early in burn patients and predicts mortality.

BACKGROUND: Angiopoietin-2 (Angpt-2) is involved in the pathogenesis of the capillary leak syndrome in sepsis and has been shown to be associated with worse outcomes in diverse critical illnesses. It is however unclear whether Angpt-2 plays a similar role in severely burned patients during the early phase characterized by massive capillary leakage. Our aim was to analyze the Angiopoietin-2/Angiopoietin-1 ratio (Angpt-2/Angpt-1 ratio) over the first two days in critically ill burn patients and examine its association with survival and further clinical parameters. METHODS: Adult burn patients with a total burn surface area (TBSA) ≥ 20% treated in the burn intensive care unit (ICU) of the University Hospital of Zurich, Switzerland, were included. Serum samples were collected prospectively and serum Angpt-1 and Angpt-2 were measured by enzyme-linked immunosorbent assay (ELISA) over the first two days after burn insult and stratified according to survival status, TBSA and the abbreviated burn severity index (ABSI). Due to hemodilution in the initial resuscitation phase, the Angpt-2/Angpt-1 ratio was normalized to albumin. RESULTS: Fifty-six patients were included with a median age of 51.5 years. Overall mortality was 14.3% (8/56 patients). The total amount of infused crystalloids was 12́902 ml (IQR 9́362-16́770 ml) at 24 h and 18́461 ml (IQR 13́024-23́766 ml) at 48 h. The amount of substituted albumin was 20 g (IQR 10-50 g) at 24 h and 50 g (IQR 20-60 g) at 48 h. The albumin-corrected Angpt-2/Angpt-1 ratios increased over the first 48 h after the burn insult (d0: 0.5 pg*l/ml*g [IQR 0.24 - 0.80 pg*l/ml*g]; d1: 0.83 pg*l/ml*g [IQR 0.29 - 1.98 pg*l/ml*g]; d2: 1.76 pg*l/ml*g [IQR 0.70 - 3.23 pg*l/ml*g]; p < 0.001) and were significantly higher in eventual ICU non-survivors (p = 0.005), in patients with a higher TBSA (p = 0.001) and in patients with a higher ABSI (p = 0.001). CONCLUSIONS: In analogy to the pathological host response in sepsis, the Angpt-2/Angpt-1 ratio steadily increases in the first two days in critically ill burn patients, suggesting a putative involvement in the pathogenesis of capillary leakage in burns. A higher Angpt-2/Angpt-1 ratio is associated with mortality, total burn surface area and burn scores.

Acromegaly and the long-term fracture risk of the vertebra and hip: a national cohort study.

In this national cohort study, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58-2.78]) and hip (HR 2.52 [1.61-3.95]) fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up. PURPOSE: Acromegaly is characterized by the overproduction of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), both play important roles in regulating bone metabolism. We investigated the risk of vertebral and hip fractures in patients with acromegaly compared to age- and sex-matched controls. METHODS: This nationwide population-based cohort study included 1,777 patients with acromegaly aged 40 years or older in 2006-2016 and 8,885 age- and sex-matched controls. A Cox proportional hazards model was used to estimate the adjusted hazard ratio (HR) [95% confidence interval]. RESULTS: The mean age was 54.3 years and 58.9% were female. For approximately 8.5 years of follow-up, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58-2.78]) and hip (HR 2.52 [1.61-3.95]) fractures than the controls in the multivariate analyses. There were significant differences in the risks of clinical vertebral (P < 0.0001) and hip (P < 0.0001) fractures between the patients with acromegaly and the controls in the Kaplan-Meier survival analysis. The multivariable-adjusted HRs for clinical vertebral fractures comparing the patients with acromegaly with controls during and excluding the first 7 years of observation were 1.69 [1.15-2.49] and 2.70 [1.75-4.17], respectively. The HRs for hip fractures during and excluding the first 7 years of observation were 2.29 [1.25-4.18] and 3.36 [1.63-6.92], respectively. CONCLUSIONS: The patients with acromegaly had a higher risk of hip fractures as well as clinical vertebral fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up.

Arterial Embolism After Facial Fat Grafting: A Systematic Literature Review.

BACKGROUND: While autologous fat grafting of the face is considered a generally safe procedure, severe complications such as arterial embolism (AE) have been reported. OBJECTIVE: To summarize data on injection-related visual compromise, stroke, and death caused by arterial embolism after facial fat transplantation. MATERIALS AND METHODS: Plastic surgery societies were contacted for reports on AE after autologous facial fat injection. In addition, a systematic literature review was performed. Data extracted included study design, injection site/technique, symptoms, management, outcome, and etiology. RESULTS: 61 patients with a mean age of 33.56 ± 11.45 years were reported. Injections targeted the glabella or multiple facial regions (both n = 16/61, 26.2%) most commonly, followed by injections in the temples (n = 10/61, 16.4%) and the forehead (n = 9/61, 14.8%). The mean volume injected was 21.5 ± 21.5 ml. Visual symptoms were described most frequently (n = 24/58, 41.4%) followed by neurological symptoms (n = 20/58, 34.5%), or both (n = 13/58, 22.4%). Ophthalmic artery (OA, n = 26/60, 43.3%), anterior or middle cerebral artery (CA, n = 11/60, 18.3%) or both (n = 14/60, 23.3%) were most frequently occluded. Outcome analysis revealed permanent vision loss in all patients with OA occlusion (n = 26/26, 100%), neurological impairment in most patients with CA occlusion (n = 8/10, 80%), and vision loss in most patients suffering from both OA and CA occlusion (n = 7/11, 63.6%). Six patients died following embolisms. CONCLUSIONS: AE causes severe complications such as blindness, stroke, and death. Due to a lack of high-quality data, no evidence-based treatment algorithms exist. To increase patient safety, a database collecting cases and complications should be established. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Methacrylated Gelatin as a Scaffold for Mechanically Isolated Stromal Vascular Fraction for Cutaneous Wound Repair.

Mechanically processed stromal vascular fraction (mSVF) is a highly interesting cell source for regenerative purposes, including wound healing, and a practical alternative to enzymatically isolated SVF. In the clinical context, SVF benefits from scaffolds that facilitate viability and other cellular properties. In the present work, the feasibility of methacrylated gelatin (GelMA), a stiffness-tunable, light-inducible hydrogel with high biocompatibility is investigated as a scaffold for SVF in an in vitro setting. Lipoaspirates from elective surgical procedures were collected and processed to mSVF and mixed with GelMA precursor solutions. Non-encapsulated mSVF served as a control. Viability was measured over 21 days. Secreted basic fibroblast growth factor (bFGF) levels were measured on days 1, 7 and 21 by ELISA. IHC was performed to detect VEGF-A, perilipin-2, and CD73 expression on days 7 and 21. The impact of GelMA-mSVF on human dermal fibroblasts was measured in a co-culture assay by the same viability assay. The viability of cultured GelMA-mSVF was significantly higher after 21 days (p < 0.01) when compared to mSVF alone. Also, GelMA-mSVF secreted stable levels of bFGF over 21 days. While VEGF-A was primarily expressed on day 21, perilipin-2 and CD73-positive cells were observed on days 7 and 21. Finally, GelMA-mSVF significantly improved fibroblast viability as compared with GelMA alone (p < 0.01). GelMA may be a promising scaffold for mSVF as it maintains cell viability and proliferation with the release of growth factors while facilitating adipogenic differentiation, stromal cell marker expression and fibroblast proliferation.

Impact of a High-Fat Diet at a Young Age on Wound Healing in Mice.

As the prevalence of juvenile-onset obesity rises globally, the multitude of related health consequences gain significant importance. In this context, obesity is associated with impaired cutaneous wound healing. In experimental settings, mice are the most frequently used model for investigating the effect of high-fat diet (HFD) chow on wound healing in wild-type or genetically manipulated animals, e.g., diabetic ob/ob and db/db mice. However, these studies have mainly been performed on adult animals. Thus, in the present study, we introduced a mouse model for a juvenile onset of obesity. We exposed 4-week-old mice to an investigational feeding period of 9 weeks with an HFD compared to a regular diet (RD). At a mouse age of 13 weeks, we performed excisional and incisional wounding and measured the healing rate. Wound healing was examined by serial photographs with daily wound size measurements of the excisional wounds. Histology from incisional wounds was performed to quantify granulation tissue (thickness, quality) and angiogenesis (number of blood vessels per mm2). The expression of extracellular matrix proteins (collagen types I/III/IV, fibronectin 1, elastin), inflammatory cytokines (MIF, MIF-2, IL-6, TNF-α), myofibroblast differentiation (α-SMA) and macrophage polarization (CD11c, CD301b) in the incisional wounds were evaluated by RT-qPCR and by immunohistochemistry. There was a marked delay of wound closure in the HFD group with a decrease in granulation tissue quality and thickness. Additionally, inflammatory cytokines (MIF, IL-6, TNF-α) were significantly up-regulated in HFD- when compared to RD-fed mice measured at day 3. By contrast, MIF-2 and blood vessel expression were significantly reduced in the HFD animals, starting at day 1. No significant changes were observed in macrophage polarization, collagen expression, and levels of TGF-ß1 and PDGF-A. Our findings support that an early exposition to HFD resulted in juvenile obesity in mice with impaired wound repair mechanisms, which may be used as a murine model for obesity-related studies in the future.

Vascularized Lymph Node Transfer Improved Outcomes of Elderly Patients with Secondary Upper Extremity Lymphedema.

BACKGROUND: Secondary lymphedema is a debilitating morbidity. This study investigated the outcomes of vascularized lymph node transfer (VLNT) in elderly patients with secondary upper extremity lymphedema. METHODS: Between 2008 and 2018, elderly (≥65 years) patients with secondary upper extremity lymphedema who underwent VLNT were retrospectively reviewed. Cheng's Lymphedema Grading, Taiwan Lymphoscintigraphy Staging, and indocyanine green lymphography were used to select the procedures. Outcome measurements included complications, circumferential difference, episodes of cellulitis, and the Lymphedema-Specific Quality of Life questionnaire (LYMQoL). RESULTS: Eleven patients with a mean age of 70.2 ± 5.3 years (range 65-80 years) who underwent VLNT survived and no major complications were encountered. At a mean follow-up of 6.5 ± 3.6 years (range 2-13 years), the mean limb circumferential difference was significantly improved from 25.6 ± 11.5% to 8.3 ± 4.2% (p = 0.016), and the mean episode of cellulitis was statistically reduced from 2.4 ± 1.3 to 0.4 ± 0.9 times/year (p = 0.007). At a follow-up of 24 months, four domains of Function (from 30.6 ± 2.8 to 14.5 ± 2.5), Appearance (from 18.2 ± 1.9 to 8.5 ± 2.1), Symptoms (from 30.4 ± 5.9 to 10.9 ± 1.0) and Mood (from 29.2 ± 4.4 to 10.7 ± 1.0), as well as overall LYMQoL score (from 3.9 ± 1.1 to 7.4 ± 0.5), showed statistical improvement (all p < 0.05). CONCLUSIONS: VLNT for secondary upper extremity lymphedema in elderly patients significantly decreased the limb circumferential difference and frequency of cellulitis and improved quality of life without using compression garments postoperatively.

The associations of hepatic steatosis and fibrosis using fatty liver index and BARD score with cardiovascular outcomes and mortality in patients with new-onset type 2 diabetes: a nationwide cohort study.

BACKGROUND: Although both type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are associated with increased risk of cardiovascular disease (CVD), evidence is lacking as to whether the presence of NAFLD confers an additional risk of CVD in patients with T2DM. We investigated the associations between hepatic steatosis and/or fibrosis and risk of myocardial infarction (MI), stroke, heart failure (HF), and mortality in patients with new-onset T2DM. METHODS: Using the Korean National Health Insurance dataset, we included 139,633 patients diagnosed with new-onset T2DM who underwent a national health screening from January 2009 to December 2012. Hepatic steatosis and advanced hepatic fibrosis were determined using cutoff values for fatty liver index (FLI) and BARD score. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards regression models. RESULTS: During the median follow-up of 7.7 years, there were 3,079 (2.2%) cases of MI, 4,238 (3.0%) cases of ischemic stroke, 4,303 (3.1%) cases of HF, and 8,465 (6.1%) all-cause deaths. Hepatic steatosis defined as FLI ≥ 60 was associated with increased risk for MI (HR [95% CI], 1.28 [1.14-1.44]), stroke (1.41 [1.25-1.56]), HF (1.17 [1.07-1.26]), and mortality (1.41 [1.32-1.51]) after adjusting for well-known risk factors. Compared to the group without steatosis, the group with steatosis and without fibrosis (BARD < 2) and the group with both steatosis and fibrosis (BARD ≥ 2) showed gradual increased risk for MI, stroke, HF, and mortality (all p for trends < 0.001). CONCLUSION: Hepatic steatosis and/or advanced fibrosis as assessed by FLI or BARD score were significantly associated with risk of CVD and mortality in new-onset T2DM.

Outcome Comparison of Different Reconstructive Approaches for Axillary Defects Secondary to Radical Excision of Hidradenitis Suppurativa.

BACKGROUND: Radical excision of debilitating hidradenitis suppurativa lesions is the only curative approach in the advanced stages of the disease. Different concepts for axillary reconstruction do exist, but data on their clinical outcome are scarce. METHODS: This is a retrospective cohort study of two reconstructive methods (posterior arm flap vs. vacuum-assisted closure [VAC] + split-thickness skin graft [STSG]) for axillary defects in patients with severe axillary hidradenitis suppurativa treated at the University Hospital Zurich between 2005 and 2020. RESULTS: A total of 35 patients (mean age 36 ± 10 years, mean BMI 29 ± 5 kg/m2, Hurley stage II-III) with 67 operated axillae were stratified according to their type of reconstruction. Median operation time in the flap group was 144 min (IQR 114-207) (cumulative 181 min [IQR 124-300]) and 50 min (IQR 40-81) in the VAC + STSG group (cumulative 151 min [IQR 94-194], p < 0.01; p = 0.20 [cumulative time]). The cumulative length of stay was 6 ± 3 days in the flap group and 14 ± 7 days in the VAC + STSG group (p < 0.01). Time to complete wound healing was 27 days (IQR 20-49) in the flap group and 62 days (IQR 41-75) in the VAC + STSG group (p < 0.01). Vancouver Scar Scale score was 6 (IQR 4-9) in the flap group and 11 (IQR 9-12) in the VAC + STSG group (p < 0.01). Protective sensory recovery was most satisfactory in the flap group (p < 0.01). Forty-four percent of patients of the VAC + STSG group demonstrated functional impairment of arm abduction. Time to return to work was less in group A with 42 days (IQR 27-57) needed as compared to group B with 48 days (IQR 34-55) needed (p = 0.32). The average cost saving was 25% higher for the flap group than for the VAC + STSG group. CONCLUSION: Despite an increased operation time, axillary reconstruction by the posterior arm flap yields a reduced length of stay, less time to complete wound healing along with restoration of a protective sensibility, and less axillary scarring avoiding functional deficits - eventually allowing earlier return to work.

Infections in Burn Patients: A Retrospective View over Seven Years.

Backgroundand objectives: Burn patients represent a challenging cohort because the injuries entail a vulnerability to colonisation by microorganisms. The ensuing infections can lead to serious complications and, in many cases, to the death of the burn patient. Surgical intervention and wound dressings, as well as antibiotic treatment, are crucial for optimising the treatment of the patient. Materialand Methods: In this retrospective analysis, we analysed the treatment course, antibiotic therapy, and general complications of 252 burn patients with second- or third-degree burns over a time span of 7 years. Results: Patients who developed infections tended to have, on average, a higher total body surface area (TBSA), higher abbreviated burn severity index (ABSI) scores, and longer hospital stays. Patients who were admitted to the burn unit after 2006 had significantly shorter stays in the burn unit. TBSA and ABSI scores were lower in the patient cohort admitted after 2006. Patients exhibiting a TBSA greater than 30% had significantly longer hospital stays and antibiotic treatment periods. TBSA and ABSI scores were significantly higher in patients who died. The results of binary logistic regression indicate that a higher ABSI score increases the odds ratio of developing an infection. Bacteria number had no significant effect on the odds of patient death but positively influenced the odds ratio of developing an infection. TBSA was negatively associated with the risk of developing an infection and was an insignificant predictor of mortality. Conclusions: To gauge the optimal treatment for a burn patient, it is crucial for practitioners to correctly select, dose, and time antibiotics for the patient. Monitoring bacterial colonisation is vital to nip rising infection in the bud and ensure the correct antibiotic selection. This will help prevent the development of multi-resistant bacteria.

Early mortality and cardiovascular disease, varied association with body mass index and its changes in insulin-treated diabetes: a nationwide study.

BACKGROUND/OBJECTIVES: We investigated the hazards of cardiovascular diseases (CVDs) and all-cause death during follow-up according to baseline body mass index (BMI) and percent change in BMI among adults with insulin-treated diabetes. SUBJECTS/METHODS: Using the Korean National Health Insurance Service datasets (2002-2017), the hazards of myocardial infarction (MI), stroke, and all-cause mortality during follow-up were analyzed according to baseline BMI and percent change in BMI among adults with insulin-treated diabetes and without baseline CVD and/or malignancy (N = 44,055). RESULTS: At baseline, 67.3% of total subjects were either obese or overweight. During a mean 3.8 years, 1,081 MI and 1,562 stroke cases developed; 2,847 deaths occurred over a mean 3.9 years. Compared with normal weight, overweight and obesity were associated with lower hazards of outcomes [hazard ratio (95% CI): 0.836 (0.712-0.981), 0.794 (0.687-0.917) for MI; 0.829 (0.726-0.946), 0.772 (0.684-0.870) for stroke; 0.740 (0.672-0.816), 0.666 (0.609-0.728) for death, respectively]. Underweight was associated with a higher hazard of all-cause death during follow-up [hazard ratio (95% CI): 2.035 (1.695-2.443)]. When the group with minimum absolute value for percent change in BMI was set as a reference, the relative reduction in BMI was associated with increased hazards of MI, stroke, and all-cause death, and relative increase in BMI was associated with increased hazards of stroke and all-cause death during follow-up. CONCLUSIONS: Among adults with insulin-treated diabetes, a high prevalence of overweight and obesity was observed, and baseline BMI category was inversely associated with CVD incidence and all-cause death during follow-up. Both weight loss and gain were associated with increased CVD incidence and all-cause death during follow-up, showing a U-shaped relationship between weight change and outcome. Stable body weight might be a predictor of a lower risk of CVDs and premature death among individuals with insulin-treated diabetes.

Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia.

Sepsis is a leading cause of death worldwide and recent studies have shown white adipose tissue (WAT) to be an important regulator in septic conditions. In the present study, the role of the inflammatory cytokine macrophage migration inhibitory factor (MIF) and its structural homolog D-dopachrome tautomerase (D-DT/MIF-2) were investigated in WAT in a murine endotoxemia model. Both MIF and MIF-2 levels were increased in the peritoneal fluid of LPS-challenged wild-type mice, yet, in visceral WAT, the proteins were differentially regulated, with elevated MIF but downregulated MIF-2 expression in adipocytes. Mif gene deletion polarized adipose tissue macrophages (ATM) toward an anti-inflammatory phenotype while Mif-2 gene knockout drove ATMs toward a pro-inflammatory phenotype and Mif-deficiency was found to increase fibroblast viability. Additionally, we observed the same differential regulation of these two MIF family proteins in human adipose tissue in septic vs healthy patients. Taken together, these data suggest an inverse relationship between adipocyte MIF and MIF-2 expression during systemic inflammation, with the downregulation of MIF-2 in fat tissue potentially increasing pro-inflammatory macrophage polarization to further drive adipose inflammation.

The endocannabinoid receptors CB1 and CB2 affect the regenerative potential of adipose tissue MSCs.

Human adipose tissue includes large quantities of mesenchymal stromal cells (atMSCs), which represent an abundant cell source for therapeutic applications in the field of regenerative medicine. Adipose tissue secrets various soluble factors including endocannabinoids, and atMSCs express the cannabinoid receptors CB1 and CB2. This indicates that adipose tissue possesses an endocannabinoid system (ECS). The ECS is also ascribed great significance for wound repair, e.g. by modulating inflammation. However, the exact effects of CB1/CB2 activation in human atMSCs have not been investigated, yet. In the present study, we stimulated human atMSCs with increasing concentrations (1-30 µM) of the unspecific cannabinoid receptor ligand WIN55,212-2 and the specific CB2 agonist JWH-133, either alone or co-applied with the receptor antagonist Rimonabant (CB1) or AM 630 (CB2). We investigated the effects on metabolic activity, cell number, differentiation and cytokine release, which are important processes during tissue regeneration. WIN decreased metabolic activity and cell number, which was reversed by Rimonabant. This suggests a CB1 dependent mechanism, whereas the number of atMSCs was increased after CB2 ligation. WIN and JWH increased the release of VEGF, TGF-ß1 and HGF. Adipogenesis was enhanced by WIN, which could be reversed by blocking CB1. There was no effect on osteogenesis, and only WIN increased chondrogenic differentiation. Our results indicate that definite activation of the cannabinoid receptors exerted different effects in atMSCs, which could be of specific value in cell-based therapy for wound regeneration.

Adipose-Derived Stem/Stromal Cells in Kidney Transplantation: Status Quo and Future Perspectives.

Kidney transplantation (KT) is the gold standard treatment of end-stage renal disease. Despite progressive advances in organ preservation, surgical technique, intensive care, and immunosuppression, long-term allograft survival has not significantly improved. Among the many peri-operative complications that can jeopardize transplant outcomes, ischemia-reperfusion injury (IRI) deserves special consideration as it is associated with delayed graft function, acute rejection, and premature transplant loss. Over the years, several strategies have been proposed to mitigate the impact of IRI and favor tolerance, with rather disappointing results. There is mounting evidence that adipose stem/stromal cells (ASCs) possess specific characteristics that could help prevent, reduce, or reverse IRI. Immunomodulating and tolerogenic properties have also been suggested, thus leading to the development of ASC-based prophylactic and therapeutic strategies in pre-clinical and clinical models of renal IRI and allograft rejection. ASCs are copious, easy to harvest, and readily expandable in culture. Furthermore, ASCs can secrete extracellular vesicles (EV) which may act as powerful mediators of tissue repair and tolerance. In the present review, we discuss the current knowledge on the mechanisms of action and therapeutic opportunities offered by ASCs and ASC-derived EVs in the KT setting. Most relevant pre-clinical and clinical studies as well as actual limitations and future perspective are highlighted.

A Distinct Cytokine Profile and Stromal Vascular Fraction Metabolic Status without Significant Changes in the Lipid Composition Characterizes Lipedema.

Lipedema is an adipose tissue disorder characterized by the disproportionate increase of subcutaneous fat tissue in the lower and/or upper extremities. The underlying pathomechanism remains unclear and no molecular biomarkers to distinguish the disease exist, leading to a large number of undiagnosed and misdiagnosed patients. To unravel the distinct molecular characteristic of lipedema we performed lipidomic analysis of the adipose tissue and serum of lipedema versus anatomically- and body mass index (BMI)-matched control patients. Both tissue groups showed no significant changes regarding lipid composition. As hyperplastic adipose tissue represents low-grade inflammation, the potential systemic effects on circulating cytokines were evaluated in lipedema and control patients using the Multiplex immunoassay system. Interestingly, increased systemic levels of interleukin 11 (p = 0.03), interleukin 28A (p = 0.04) and interleukin 29 (p = 0.04) were observed. As cytokines can influence metabolic activity, the metabolic phenotype of the stromal vascular fraction was examined, revealing significantly increased mitochondrial respiration in lipedema. In conclusion, despite sharing a comparable lipid profile with healthy adipose tissue, lipedema is characterized by a distinct systemic cytokine profile and metabolic activity of the stromal vascular fraction.

Integrative Medicine and Plastic Surgery: A Synergy-Not an Antonym.

BACKGROUND: Integrative medicine focuses on the human being as a whole-on the body, mind, and spirit-to achieve optimal health and healing. As a synthesis of conventional and complementary treatment options, integrative medicine combines the pathological with the salutogenetic approach of therapy. The aim is to create a holistic system of medicine for the individual. So far, little is known about its role in plastic surgery. HYPOTHESIS: We hypothesize that integrative medicine based on a conventional therapy with additional anthroposophic therapies is very potent and beneficial for plastic surgery patients. Evaluation and consequence of the hypothesis: Additional anthroposophic pharmacological and non-pharmacological treatments are promising for all areas of plastic surgery. We are convinced that our specific approach will induce further clinical trials to underline its therapeutic potential.

Trochanteric Femur Fractures: Application of Skeletal Traction during Surgery Does Not Alter Soft-Tissue Microcirculation.

Background and Objectives: Wound infections provoked by alterations in microcirculation are major complications in the treatment of trochanteric femur fractures. Surgical fracture fixation on a traction table is the gold standard for treatment, but the effect on tissue microcirculation is unknown. Microcirculation could be impaired by the pull on the soft-tissue or by a release of vasoactive factors. We hypothesized that intraoperative traction impairs soft-tissue microcirculation. Materials and Methods: In 22 patients (14 women, eight men), average age 78 years (range 36-96 ± 14), with trochanteric femur fractures, non-invasive laser-Doppler spectrophotometry was used to assess oxygen saturation, hemoglobin content, and blood flow in the skin and subcutaneous tissue before and after application of traction. Measurements were recorded in nine locations around the greater trochanter at a depth of 2, 8, and 15 mm before and after fracture reduction by traction. Results: No differences were found in any depth with traction compared to without (oxygen saturation: p = 0.751, p = 0.308, and p = 0.955, haemoglobin content: p = 0.651, p = 0.928, and p = 0.926, blood flow: p = 0.829, p = 0.866, and p = 0.411). Conclusion: In this pilot study, the application of traction does not affect skin and subcutaneous microcirculation in the surgery of proximal femur fractures.

Risk of early mortality and cardiovascular disease in type 1 diabetes: a comparison with type 2 diabetes, a nationwide study.

BACKGROUND: Both type 1 and type 2 diabetes are well-established risk factors for cardiovascular disease and early mortality. However, few studies have directly compared the hazards of cardiovascular outcomes and premature death among people with type 1 diabetes to those among people with type 2 diabetes and subjects without diabetes. Furthermore, information about the hazard of cardiovascular disease and early mortality among Asians with type 1 diabetes is sparse, although the clinical and epidemiological characteristics of Asians with type 1 diabetes are unlike those of Europeans. We estimated the hazard of myocardial infarction (MI), hospitalization for heart failure (HF), atrial fibrillation (AF), and mortality during follow-up in Korean adults with type 1 diabetes compared with those without diabetes and those with type 2 diabetes. METHODS: We used Korean National Health Insurance Service datasets of preventive health check-ups from 2009 to 2016 in this retrospective longitudinal study. The hazard ratios of MI, HF, AF, and mortality during follow-up were analyzed using the Cox regression analyses according to the presence and type of diabetes in ≥ 20-year-old individuals without baseline cardiovascular disease (N = 20,423,051). The presence and type of diabetes was determined based on the presence of type 1 or type 2 diabetes at baseline. RESULTS: During more than 93,300,000 person-years of follow-up, there were 116,649 MIs, 135,532 AF cases, 125,997 hospitalizations for HF, and 344,516 deaths. The fully-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MI, hospitalized HF, AF, and all-cause death within the mean follow-up of 4.6 years were higher in the type 1 diabetes group than the type 2 diabetes [HR (95% CI) 1.679 (1.490-1.893) for MI; 2.105 (1.901-2.330) for HF; 1.608 (1.411-1.833) for AF; 1.884 (1.762-2.013) for death] and non-diabetes groups [HR (95% CI) 2.411 (2.138-2.718) for MI; 3.024 (2.730-3.350) for HF; 1.748 (1.534-1.993) for AF; 2.874 (2.689-3.073) for death]. CONCLUSIONS: In Korea, the presence of diabetes was associated with a higher hazard of cardiovascular disease and all-cause death. Specifically, people with type 1 diabetes had a higher hazard of cardiovascular disease and all-cause mortality compared to people with type 2 diabetes.