Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula.

Fistula is a representative devastating complication in Crohn's patients due to refractory to conventional therapy and high recurrence. In our phase I clinical trial, adipose tissue-derived stem cells (ASCs) demonstrated their safety and therapeutic potential for healing fistulae associated with Crohn's disease. This study was carried out to evaluate the efficacy and safety of ASCs in patients with Crohn's fistulae. In this phase II study, forty-three patients were treated with ASCs. The amount of ASCs was proportioned to fistula size and fistula tract was filled with ASCs in combination with fibrin glue after intralesional injection of ASCs. Patients without complete closure of fistula at 8 weeks received a second injection of ASCs containing 1.5 times more cells than the first injection. Fistula healing at week 8 after final dose injection and its sustainability for 1-year were evaluated. Healing was defined as a complete closure of external opening without any sign of drainage and inflammation. A modified per-protocol analysis showed that complete fistula healing was observed in 27/33 patients (82%) by 8 weeks after ASC injection. Of 27 patients with fistula healing, 26 patients completed additional observation study for 1-year and 23 patients (88%) sustained complete closure. There were no adverse events related to ASC administration. ASC treatment for patients with Crohn's fistulae was well tolerated, with a favorable therapeutic outcome. Furthermore, complete closure was well sustained. These results strongly suggest that autologous ASC could be a novel treatment option for the Crohn's fistula with high-risk of recurrence.

Benefits of Urban Forest Healing Program on Depression and Anxiety Symptoms in Depressive Patients.

Depression is considered a widespread mental health problem worldwide. Moreover, anxiety symptoms are very closely related to depression in patients, and it is known that the coexistence rate of depression and anxiety diagnosed simultaneously is high. Treatment and preventive management of depression and anxiety are essential for public health. Forest healing is attracting attention as a form of low-cost preventive medicine that is safe and has no side effects. However, although the physiological and psychological effects have been scientifically proven, it is insufficient to reveal a direct relationship between forest healing and depression. This study investigated the benefits of an urban forest healing program on depression and anxiety symptoms in depressive disorders. We employed a randomized controlled trial design. Forty-seven depressive patients were randomly divided into an urban forest healing program group and a control group. Measures included the Montgomery-Asberg depression rating scale (MADRS), the Hamilton Anxiety Rating Scale (HARS), and the State-Trait Anxiety Inventory (STAI) questionnaires. Our results revealed that the combination of general treatment and forest healing programs for patients with depression is more effective in improving depression and anxiety than routine treatment alone. We expect our work to serve as a starting point for more sophisticated research discussing the availability of non-pharmacological treatments in forest healing.

Effects of Mobile-Based Forest-Therapy Programs Using Urban Forests for Symptoms of Depressed Patients.

This study investigated the effect of mobile-based forest therapy programs on relieving depression to advance non-pharmaceutical treatments for patients with depression. The effects of depression, sleep quality, and physical symptoms were analyzed as measurement indicators to determine the effectiveness of symptom relief in patients with depression. This study used a randomized controlled experiment design. Participants were randomly assigned, and a total of 44 people participated, including 23 in the experimental group and 21 in the control group. The experimental group participated in a mobile-based forest therapy program (participating once a week) for six sessions. As a result of this study, depression patients who participated in the mobile-based forest therapy program conducted in urban forests showed a significant reduction in MADRS (from 21.48 ± 4.05 to 7.13 ± 7.00). In addition, PSQI (from 19.78 ± 7.69 to 14.48 ± 8.11) and PHQ-15 (from 9.87 ± 5.08 to 7.57 ± 5.03) were also found to significantly improve symptoms. This suggests that forest-therapy programs using mobile applications can be applied as non-pharmaceutical interventions to relieve symptoms in patients with depression.

The clinical course and outcomes of post-transplantation diabetes mellitus after heart transplantation.

The aim of this study was to describe in more detail the predisposition, natural course, and clinical impact of post-transplantation diabetes mellitus (PTDM) after heart transplantation (HT). The characteristics and clinical outcomes of 54 patients with PTDM were compared with those of 140 patients without PTDM. The mean age of PTDM patients was significantly higher than controls (48.9 ± 9.3 vs 38.6 ± 13.3 yr, respectively, P = 0.001), and ischemic heart disease was a more common indication of HT (20.4% [11/54] vs 7.1% [10/140], respectively, P = 0.008). In multivariate analysis, only recipient age (odds ratio, 1.80; 95% confidence interval, 1.35-2.40; P = 0.001) was associated with PTDM development. In 18 patients (33%), PTDM was reversed during the follow-up period, and the reversal of PTDM was critically dependent on the time taken to develop PTDM (1.9 ± 1.0 months in the reversed group vs 14.5 ± 25.3 months in the maintained group, P = 0.005). The 5-yr incidence of late infection (after 6 months) was higher in the PTDM group than in the control group (30.4% ± 7.1% vs 15.4% ± 3.3%, respectively, P = 0.031). However, the 5-yr overall survival rate was not different (92.9% ± 4.1% vs 85.8% ± 3.2%, respectively, P = 0.220). In conclusion, PTDM after HT is reversible in one-third of patients and is not a critical factor in patient survival after HT.

Quantitative Benefit-Risk Assessment of COVID-19 Vaccines Using the Multi-Criteria Decision Analysis.

In the early SARS-CoV-2 (COVID-19) pandemic, four major vaccines were approved despite limited efficacy and safety data through short regulatory review periods. Thus, it is necessary to assess the benefit-risk (BR) profiles of the COVID-19 vaccines. We conducted a quantitative BR assessment for four COVID-19 vaccines (mRNA-based: mRNA-1273 and BNT162b2; viral vector-based: Ad26.COV.2 and ChAdOx1-S) using multi-criteria decision analysis. Three benefit criteria and two risk criteria were considered: preventing COVID-19 infection for (1) adults aged ≥18 years; (2) seniors aged 60 years or older; and (3) severe COVID-19, adverse events (AEs), and serious AEs. Data were retrieved from clinical trials, observational studies, and county-specific AE monitoring reports. Based on the collected data, vaccines were scored for each criterion. 22 professionals weighted each criterion. The overall BR score was calculated using scores and weights. mRNA-1273 was the most preferred vaccine in pre-authorization and BNT162b2 in post-authorization. We found that the mRNA vaccine had a good balance between the benefits and risks. Using this BR assessment, the benefit-risk profile of COVID-19 vaccines can be updated with cumulated data. It will contribute to building evidence for decision making by policy makers and health professionals.

Effects of Urban Forest Therapy Program on Depression Patients.

Depression is a common serious mental health condition that can have negative personal and social consequences, and managing it is critical for treating depression patients. Forest therapy is emerging as a promising non-pharmacological intervention to improve mental health. However, although the effectiveness of forest therapy programs using forests far from the city has been proven, it is not well known that urban forests can be easily accessed in daily life. Therefore, this study aimed to examine the effects of an urban forest therapy program on depression symptoms, sleep quality, and somatization symptoms of depression patients. To evaluate this, a randomized controlled trial (RCT) design was employed. A total of 47 depression patients participated in this study (22 in the urban forest therapy program group and 25 in the control group). The Beck Depression Inventory (BDI), the Hamilton Rating Scale for Depression (HRSD), the Pittsburgh Sleep Quality Index (PSQI), and the Patient Health Questionnaire-15 (PHQ-15) were administered to each participant to assess the effects of the urban forest therapy program. The results of this study revealed that depression patients in the urban forest therapy program had significantly alleviated depression symptoms and improved sleep quality and somatization symptoms compared to the control group. In conclusion, this study demonstrates the possibility that the urban forest therapy program could be used as an effective non-pharmacological treatment to alleviate depression disorder.

Clinical trial of autologous differentiated adipocytes from stem cells derived from human adipose tissue.

BACKGROUND: Adipose tissue-derived stem cells (ASCs) are considered to be a reliable cell source for the generation of adipose tissue because they can be differentiated into adipocytes. Previous data have indicated that adipogenic differentiation of ASCs before transplantation can enhance the regeneration of adipose tissue. OBJECTIVE: To evaluate the efficacy and safety of the use of autologous differentiated adipocytes for the treatment of depressed scars. METHODS: Autologous differentiated adipocytes were produced using well-established techniques, including the harvesting of stromal vascular fraction cells from lipoaspirates, expansion of ASCs, and differentiation into adipocytes. This was an open-label, dose-escalation study. Patients were given a subcutaneous injection of differentiated adipocytes and followed for 12 weeks. RESULTS: Thirty-one patients were injected with differentiated adipocytes. When the differentiated adipocytes were injected subcutaneously into depressed scars, the average recovery in volume was 74.6% at 12 weeks. Of 17 patients who completed the follow-up after determination of dose, seven were willing to enroll for extended follow-up. Long-term follow-up revealed that the recovery in volume at 12 weeks was maintained well for at least 1 year. There were no significant adverse events. CONCLUSIONS: The use of autologous differentiated adipocytes can be a safe and effective treatment for soft tissue defects, with relatively long-term maintenance of volume. The authors have indicated no significant interest with commercial supporters.

An analysis of the number of liver and kidney transplantations during COVID-19 pandemic in Korea.

Background: The severity of the coronavirus disease 2019 (COVID-19) pandemic has discouraged organ donation. However, the prevalence of COVID-19 in Korea was much lower in comparison to Western countries. With this, the authors decided to determine the real-world impact of COVID-19 on organ donation and transplantation in Korea. Methods: The number of kidney transplantations (KTs) and liver transplantations (LTs) performed in 2020 were compared with those in 2019 using the Korean Network for Organ Sharing database and Asan Medical Center (AMC) database. Results: The annual number of deceased donors (DDs) was 450 in 2019 compared to 478 in 2020. Monthly DD number was 37.5±5.9 in 2019 and 39.8±4.4 in 2020 (P=0.284). Annual number of DD kidney transplant (DDKT) was 794 in 2019 and 848 in 2020, and monthly number was 66.1±10.4 in 2019 and 70.7±9.8 in 2020 (P=0.285). The annual number of DDLT was 391 in 2019 and 395 in 2020, and the monthly number was 32.6±5.7, 2019 and 32.9±4.7 in 2020 (P=0.877). The annual number of living donor (LD) KT was 2,293 in 2019 and 1,432 in 2020, and the monthly number was 191.1±19.5 in 2019 and 119.3±11.7 in 2020 (P<0.001). Annual number of living donor LDLT was 1,577 in 2019 and 1,146 in 2020, and monthly number was 131.4±18.1 in 2019 and 95.5±8.0 in 2020 (P<0.001). In the AMC, not all types of KT and LT changed significantly. Conclusions: The results of this study indicate that the number of DD organ transplantations remained stable in Korea in 2020, but the number of LD organ transplantations was significantly reduced. However, the number of organ transplantations did not change in the AMC.

Corrigendum to: Deceased donor liver transplantation under the Korean model for end-stage liver disease score-based liver allocation system: 2-year allocation results at a high-volume transplantation center.

[This corrects the article on p. 112 in vol. 33.].

Adipogenic differentiation of human adipose tissue-derived stem cells obtained from cryopreserved adipose aspirates.

BACKGROUND: Although frozen adipose tissue is frequently used for soft tissue augmentation, the viability of frozen fat remains a controversy. The cryopreservation of adipose tissue is important for the future use of adipose-derived stem cells (ASCs) and adipocytes. OBJECTIVE: To determine whether optimal cryopreservation techniques with regard to the addition of cryopreservative agents and preservation temperature is essential for the long-term storage of adipose tissue and whether ASCs from cryopreserved adipose aspirates are reliable for use in adipogenic differentiation. MATERIALS AND METHODS: Adipose tissue was frozen directly or with cryoprotectant at -20 degrees C or -80 degrees C for 1 year. The viability of adipose aspirates and the differentiation of ASCs isolated from adipose tissue were evaluated. RESULTS: The viability of adipose aspirates frozen with dimethyl sulfoxide at -80 degrees C was approximately 87% after 2 months of storage. Moreover, ASCs from adipose tissue stored with cryoprotectant survived successfully for 1 year and differentiated into adipocytes, although ASCs were not detected in the directly frozen adipose tissue. CONCLUSION: Adipose tissue cryopreserved with cryoprotectant and stored at optimal temperature might prove to be a reliable source of human ASCs and adipocytes.

Simultaneous liver-kidney transplantation: A single-center experience in Korea.

BACKGROUNDS/AIMS: Simultaneous liver and kidney transplantation (SLKT) has been established as the treatment of choice for patients with concurrent end-stage liver and end-stage kidney diseases. The objective of this study was to analyze the nationwide incidence of SLKT in Korea and the outcomes of SLKT in a high-volume transplant center. METHODS: Databases of the Korean Network for Organ Sharing (KONOS) and Asan Medical Center from 2000 to 2019 were retrospectively reviewed to determine the incidence of SLKT. RESULTS: During 20 years from 2000 to 2019, deceased donor SLKT was performed for 38 cases in the KONOS database. The proportion of deceased donor SLKT was 0.6% (20 of 3333) before adoption of MELD score, which was significantly increased to 1.2% (18 of 1524) after the adoption of MELD score (p=0.034). In our institution, there were 11 cases of SLKT (2 cases with deceased donors and 9 cases with living donors). SLKT accounted for 0.2% (11 of 6468) of total liver transplantation volume. During follow-up, five patients died due to hepatocellular carcinoma recurrence (n=2), infection (n=2), or unknown cause (n=1). The 1-year and 10-year overall patient survival rates were 90.9% and 81.8%, respectively. CONCLUSIONS: Results of this study revealed that the incidence of deceased donor SLKT was very low. An increase of such incidence is not anticipated unless the number of deceased donors is markedly increased. Currently, sequential living donor liver transplantation and kidney transplantation with deceased or living donors are mainstays of transplantation rather than SLKT in our institution.

Deceased donor liver transplantation under the Korean model for end-stage liver disease score-based liver allocation system: 2-year allocation results at a high-volume transplantation center.

Background: The Korean model for end-stage liver disease (MELD) score-based liver allocation system was started in June 2016 in Korea. Methods: This study analyzed the detailed allocation results of deceased donor liver transplantation (DDLT) during the first 2 years after the MELD score-based liver allocation system implementation at a high-volume liver transplantation (LT) center in Korea. Results: This study included 174 patients with age above 12 years. The patient ABO blood groups were A (n=65, 37.4%), B (n=51, 29.3%), O (n=28, 16.1%), and AB (n=30, 17.2%). The LT types were primary LT in 141 patients (81.0%) and retransplantation in 33 (19.0%). The Korean Network for Organ Sharing status categories at LT were as follows: status 1 (n=11, 6.3%), status 2 (n=82, 47.1%), status 3 (n=63, 36.2%), and status 4 (n=18, 10.3%). The mean MELD score at LT and waiting period were 36.6±4.6 and 62.1±98.2 days in blood group A; 37.6±3.6 and 25.7±38.1 days in blood group B; 38.8±2.7 and 26.0±30.5 days in blood group O; and 34.8±5.5 and 68.4±110.5 days in blood group AB (P<0.001 and P=0.012), respectively. Patients with blood group O and AB had the highest and lowest mean MELD scores at LT allocation, respectively. Conclusions: Serious deceased organ donor shortage resulted in very high MELD score cutoffs for DDLT allocation. Additionally, a significant inequality was observed in the possibility for DDLT according to blood group compatibility. Nationwide follow-up studies are necessary to precisely determine the allocation status of DDLT.

Assessment of patient safety and the efficiency of facility utilization following simplified ultra-rapid intravenous infusion of hepatitis B immunoglobulin in a high-volume liver transplantation center.

BACKGROUNDS/AIMS: This study intended to evaluate patient safety and efficiency of facility utilization following simplified ultra-rapid intravenous infusion of hepatitis B immunoglobulin (HBIG) in recipients of hepatitis B virus-associated adult liver transplantation (LT), who visited our outpatient clinic. METHODS: Our simplified ultra-rapid infusion protocol was to directly infuse 50 ml volume of 10,000 IU HBIG for 20-25 minutes on an ambulatory basis. The incidence of adverse side-effects and the efficiency of facility utilization were assessed retrospectively. RESULTS: A total of 1,513 patients received 12,472 sessions of HBIG infusion according to simplified ultra-rapid infusion method. Of these, 1,172 patients were converted from conventional ultra-rapid infusion method, and received 8,352 sessions of HBIG infusion for 18 months (mean 7.1 times; 4.8 times per year). The remaining 341 de novo patients received 4,120 sessions of HBIG infusion for 18 months (mean 12.1 times; 8.1 times per year). None of these patients experienced any adverse side-effects following the simplified ultra-rapid infusion. The maximal capacity of HBIG infusion sessions at the injection facility of our outpatient clinic was increased from 65-70 sessions to 80 sessions, after introduction of simplified ultra-rapid infusion method. Mean trough anti-HBs titer was lower, and mean interval of HBIG infusion was longer in the combination therapy group compared with HBIG monotherapy group. CONCLUSIONS: Our high-volume study indicates that in nearly all LT recipients, rapid infusion of highly purified HBIG within 30 minutes was well-tolerated. This suggests that it would be reasonable to perform simplified ultra-rapid infusion protocol widely for patient convenience.

Functional and expression analyses of mgl-1, a mouse orthologue of lethal giant larvae recessive oncogene.

We recently isolated a few mammalian homologue of Drosophila lethal giant larvae (lgl) recessive oncogene, suggesting that there is functional conservation among proteins of this family. The comparison of amino acid sequence for mgl-1 with other lgl family members using the clustal method showed that they are highly homologous. Therefore, we investigated the biological function of mgl-1, a mouse orthologue of lgl, in the absence of Saccharomyces cerevisiae Sop1 and Sop2, the yeast homologues of the lgl recessive oncogene. Functional analysis showed that the expression of mgl-1 cDNA partially restored salt tolerance in yeast, indicating the evolutionary conservation of lgl family members. Since the developmental expression profile of mgl-1 has not been elucidated, the temporal and spatial expression patterns of mouse mgl-1 during early embryonic development were analyzed. The temporal expression analysis revealed that mgl-1 is expressed throughout embryonic development from days E4.5 to E18.5 with the strong expression at E10.5. The analysis of spatial expression showed that mgl-1 mRNA is detected in CNS, craniofacial region, eyes, limbs, and the gut.

Clinical implication of allogenic implantation of adipogenic differentiated adipose-derived stem cells.

We recently reported that autologous adipogenic differentiated adipose-derived stem cells (ASCs) can potentially be used as an effective and safe therapy for soft-tissue regeneration. In the present study, we investigated whether adipogenic differentiated ASCs can be used for allogenic applications to enlarge their therapeutic use. The allogenic immune response of adipogenic differentiated ASCs was investigated by flow cytometry and mixed lymphocyte culture. To determine whether adipogenic differentiated ASCs can form new adipose tissue without immune rejection, these cells were implanted subcutaneously into allo- or xenogenic recipient mice. In addition, the safety of the allogenic implantation of adipogenic differentiated ASCs was explored in a phase I clinical study. Adipogenic differentiated ASCs do not express major histocompatibility complex (MHC) class II molecules and costimulatory molecules, and the expression levels of MHC class I decreased after differentiation. In addition, these cells do not elicit an immune response against MHC-mismatched allogenic lymphocytes and formed new adipose tissue without immune rejection in the subcutaneous region of MHC-mismatched mice. Moreover, these cells did not induce clinically significant local and systemic immune responses or adverse events in the subcutaneous region of donor-independent healthy subjects. These results suggest that adipogenic differentiated ASCs can be used as a "universal donor" for soft-tissue engineering in MHC-mismatched recipients.

Fibrin glue improves the therapeutic effect of MSCs by sustaining survival and paracrine function.

Fibrin glue has been widely investigated as a cell delivery vehicle for improving the therapeutic effects of mesenchymal stem cells (MSCs). Implanted MSCs produce their therapeutic effects by secreting paracrine factors and by replacing damaged tissues after differentiation. While the influence of fibrin glue on the differentiation potential of MSCs has been well documented, its effect on paracrine function of MSCs is largely unknown. Herein we investigated the influence of fibrin glue on the paracrine effects of MSCs. MSCs were isolated from human adipose tissue. The effects of fibrin glue on survival, migration, secretion of growth factors, and immune suppression of MSCs were investigated in vitro. MSCs in fibrin glue survived and secreted growth factors such as the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) over 14 days. VEGF and immune modulators, including the transforming growth factor (TGF)-ß1 and prostaglandin E2, secreted from MSCs in fibrin glue significantly increased under inflammatory conditions. Thus, MSCs in fibrin glue effectively suppressed immune reactions. In addition, fibrin glue protected the MSCs from oxidative stress and prevented human dermal fibroblast death induced by exposure to extreme stress. In contrast, MSCs within fibrin glue hardly migrated. These results suggest that fibrin glue may sustain survival of implanted MSCs and their paracrine function. Our results provide a mechanistic data to allow further development of MSCs with fibrin glue as a clinical treatment.

Peroxiredoxin 3 is a key molecule regulating adipocyte oxidative stress, mitochondrial biogenesis, and adipokine expression.

AIMS: Increased oxidative stress and mitochondrial dysfunction in obese adipocytes contribute to adipokine dysregulation, inflammation, and insulin resistance. RESULTS: Through an advanced proteomic analysis, we found that peroxiredoxin 3 (Prx3), a thioredoxin-dependent mitochondrial peroxidase, is highly expressed in 3T3-L1 adipocytes compared to preadipocytes. Interestingly, in obese db/db mice and human subjects, adipose Prx3 levels were significantly decreased, indicating its association with obesity. We therefore employed Prx3 knockout (KO) mice and transfected 3T3-L1 cells to examine the role of endogenous Prx3 in adipocyte metabolism. Prx3 KO mice had increased fat mass compared to wild-type due to adipocyte hypertrophy. Increased adipogenic transcription factors and lipogenic gene expression during differentiation of adipose tissue-derived stem cells from Prx3-deficient mice confirmed that these adipocytes are likely to accumulate fat. Mitochondrial protein carbonylation in Prx3 KO adipose tissue and mitochondrial superoxide level in Prx3 knockdown 3T3-L1 cells were increased showing aberrant regulation of oxidative stress. Proteomic analysis and gene expression analysis of Prx3 KO mice adipocytes also showed defect in mitochondria biogenesis along with enzymes involved in glucose/lipid metabolism and oxidative phosphorylation. In addition, expression level of adiponectin was downregulated and plasminogen activator inhibitor-1 was upregulated in Prx3 KO adipocytes. Impaired glucose tolerance and insulin resistance further implied metabolic dysregulation in Prx3 KO mice. INNOVATION AND CONCLUSION: These data suggest that endogenous Prx3 may play an essential role in maintaining normal characteristics of adipocytes and that defect in Prx3 alters mitochondrial redox state and function, and adipokine expression in adipocytes leading to metabolic alteration.

Enhancement of adipose tissue formation by implantation of adipogenic-differentiated preadipocytes.

Engineered adipose tissue could be used for the reconstruction or augmentation of soft tissues lost due to mastectomy or lumpectomy in plastic and reconstructive surgery. Preadipocytes are a feasible cell source for adipose tissue regeneration. However, the enhancement of the in vivo adipogenic conversion of preadipocytes remains a major task. In vitro, the adipogenic differentiation of preadipocytes prior to implantation might enhance the adipose tissue regeneration. In the present study, we investigated whether implantation of adipogenic-differentiated preadipocytes enhances the adipose tissue formation compared with implantation of undifferentiated preadipocytes. We also investigated whether basic fibroblast growth factor (bFGF) further enhances the adipose tissue formation mediated by the implantation of adipogenic-differentiated preadipocytes. A fibrin matrix containing human preadipocytes cultured in adipogenic differentiation-inducing conditions with (group 1) or without (group 2) bFGF was injected into the subcutaneous spaces of athymic mice. Fibrin matrices containing undifferentiated human preadipocytes with (group 3) or without (group 4) bFGF were also implanted. Six weeks after implantation, the implanted cells formed new tissues in all groups. Importantly, the implantation of adipogenic-differentiated preadipocytes resulted in more extensive adipogenesis than the implantation of undifferentiated preadipocytes, as evaluated by adipose tissue area and human adipocyte-specific gene expression in the newly formed tissues. In addition, bFGF enhanced neovascularization in the newly formed tissues and further enhanced the adipogenesis mediated by the adipogenic-differentiated preadipocytes. The present study demonstrates that the implantation of adipogenic-differentiated preadipocytes enhances adipose tissue regeneration, as compared with the implantation of undifferentiated preadipocytes, and that cell transplantation-mediated adipogenesis can be further enhanced by the delivery of bFGF.