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Blood Advances Jun 2024In utero hematopoietic cell transplantation (IUHCT) is an experimental non-myeloablative therapy with potential application to hematologic disorders including Sickle...
In utero hematopoietic cell transplantation (IUHCT) is an experimental non-myeloablative therapy with potential application to hematologic disorders including Sickle cell disease. Its clinical utility has been limited due to the early acquisition of T cell immunity beginning at approximately 14 weeks gestation, posing significant technical challenges and excluding from treatment fetuses evaluated after the first trimester. Using murine neonatal transplantation at 20 days post-coitum (DPC) as a model for late-gestation transplantation (LGT) in humans, we investigated whether immune modulation with anti-CD3 monoclonal antibody (mAb) could achieve donor-specific tolerance and sustained allogeneic engraftment comparable to the early-gestation fetal recipient at 14 DPC. In allogeneic wild-type strain combinations, administration of anti-CD3 mAb with transplantation resulted in transient T cell depletion followed by central tolerance induction confirmed by donor-specific clonal deletion and skin graft tolerance. Normal immune responses to third-party major histocompatibility complex and viral pathogens were preserved, and graft-versus-host disease did not occur. We further demonstrate successful application of this approach to the Townes mouse model of Sickle cell disease. These findings confirm the developing fetal T cell response as a barrier to LGT and support transient T cell depletion as a safe and effective immunomodulatory strategy by which to overcome it.
PubMed: 38941538
DOI: 10.1182/bloodadvances.2023012247 -
MSystems Jun 2024Skin ulceration syndrome (SUS) is currently the main disease threatening aquaculture due to its higher mortality rate and infectivity, which is caused by . Our previous...
Skin ulceration syndrome (SUS) is currently the main disease threatening aquaculture due to its higher mortality rate and infectivity, which is caused by . Our previous studies have demonstrated that SUS is accompanied by intestinal microbiota (IM) dysbiosis, alteration of short-chain fatty acids (SCFAs) content and the damage to the intestinal barrier. However, the mediating effect of IM on intestine dysfunction is largely unknown. Herein, we conducted comprehensive intestinal microbiota transplantation (IMT) to explore the link between IM and SUS development. Furthermore, we isolated and identified a strain with an ability to produce acetic acid from both healthy individual and SUS individual with IM from healthy donors. We found that dysbiotic IM and intestinal barrier function in SUS recipients could be restored by IM from healthy donors. The strain could restore IM community and intestinal barrier function. Consistently, acetate supply also restores intestinal homeostasis of SUS-diseased and -infected . Mechanically, acetate was found to specifically bind to its receptor-free fatty acid receptor 2 (FFAR2) to mediate IM structure community and intestinal barrier function. Knockdown of FFAR2 by transfection of specific FFAR2 siRNA could hamper acetate-mediated intestinal homeostasis . Furthermore, we confirmed that acetate/FFAR2 could inhibit -activated NF-κB-MLCK-MLC signaling pathway to restore intestinal epithelium integrity and upregulated the expression of ZO-1 and Occludin. Our findings provide the first evidence that restores pathogen-induced intestinal barrier dysfunction via acetate/FFAR2-NF-κB-MLCK-MLC axis, which provides new insights into the control and prevention of SUS outbreak from an ecological perspective.IMPORTANCESkin ulceration syndrome (SUS) as a main disease in aquaculture has severely restricted the developmental aquaculture industry. Intestinal microbiota (IM) has been studied extensively due to its immunomodulatory properties. Short-chain fatty acids (SCFAs) as an essential signal molecule for microbial regulation of host health also have attracted wide attention. Therefore, it is beneficial to explore the link between IM and SUS for prevention and control of SUS. In the study, the contribution of IM to SUS development has been examined. Additionally, our research further validated the restoration of SCFAs on intestinal barrier dysfunction caused by SUS via isolating SCFAs-producing bacteria. Notably, this restoration might be achieved by inhibition of NF-κB-MLCK-MLC signal pathway, which could be activated by . These findings may have important implications for exploration of the role of IM in SUS occurrence and provide insight into the SUS treatment.
PubMed: 38940521
DOI: 10.1128/msystems.00602-24 -
Frontiers in Bioscience (Landmark... Jun 2024Existing animal models for testing therapeutics in the skin are limited. Mouse and rat models lack similarity to human skin in structure and wound healing mechanism....
BACKGROUND
Existing animal models for testing therapeutics in the skin are limited. Mouse and rat models lack similarity to human skin in structure and wound healing mechanism. Pigs are regarded as the best model with regards to similarity to human skin; however, these studies are expensive, time-consuming, and only small numbers of biologic replicates can be obtained. In addition, local-regional effects of treating wounds that are closely adjacent to one-another with different treatments make assessment of treatment effectiveness difficult in pig models. Therefore, here, a novel nude mouse model of xenografted porcine hypertrophic scar (HTS) cells was developed. This model system was developed to test if supplying hypo-pigmented cells with exogenous alpha melanocyte stimulating hormone (α-MSH) will reverse pigment loss .
METHODS
Dyschromic HTSs were created in red Duroc pigs. Epidermal scar cells (keratinocytes and melanocytes) were derived from regions of hyper-, hypo-, or normally pigmented scar or skin and were cryopreserved. Dermal fibroblasts (DFs) were isolated separately. Excisional wounds were created on nude mice and a grafting dome was placed. DFs were seeded on day 0 and formed a dermis. On day 3, epidermal cells were seeded onto the dermis. The grafting dome was removed on day 7 and hypo-pigmented xenografts were treated with synthetic α-MSH delivered with microneedling. On day 10, the xenografts were excised and saved. Sections were stained using hematoxylin and eosin hematoxylin and eosin (H&E) to assess xenograft structure. RNA was isolated and quantitative real-time polymerase chain reaction (qRT-PCR) was performed for melanogenesis-related genes , , and .
RESULTS
The seeding of HTSDFs formed a dermis that is similar in structure and cellularity to HTS dermis from the porcine model. When hyper-, hypo-, and normally-pigmented epidermal cells were seeded, a fully stratified epithelium was formed by day 14. H&E staining and measurement of the epidermis showed the average thickness to be 0.11 ± 0.07 µm 0.06 ± 0.03 µm in normal pig skin. Hypo-pigmented xenografts that were treated with synthetic α-MSH showed increases in pigmentation and had increased gene expression of , , and compared to untreated controls (TYR: 2.7 ± 1.1 0.3 ± 1.1; TYRP1: 2.6 ± 0.6 0.3 ± 0.7; DCT 0.7 ± 0.9 0.3 ± 1-fold change from control; n = 3).
CONCLUSIONS
The developed nude mouse skin xenograft model can be used to study treatments for the skin. The cells that can be xenografted can be derived from patient samples or from pig samples and form a robust dual-skin layer containing epidermis and dermis that is responsive to treatment. Specifically, we found that hypo-pigmented regions of scar can be stimulated to make melanin by synthetic α-MSH .
Topics: Animals; Mice, Nude; Cicatrix, Hypertrophic; Mice; Disease Models, Animal; Swine; alpha-MSH; Humans; Skin; Fibroblasts; Melanocytes; Keratinocytes; Transplantation, Heterologous; Wound Healing; Skin Pigmentation
PubMed: 38940034
DOI: 10.31083/j.fbl2906230 -
Facial Plastic Surgery Clinics of North... Aug 2024Restoration of the beard region has become an important component of hair restoration surgery due to increased awareness of its natural-appearing results. In the... (Review)
Review
Restoration of the beard region has become an important component of hair restoration surgery due to increased awareness of its natural-appearing results. In the author's experience performing more than 700 primary beard hair transplants and tens of reparative procedures, key aesthetic steps include proper graft dissection so that one- and two-hair grafts contain a minimal cuff of surrounding skin, acute angulation and appropriate direction of recipient sites using the smallest possible recipient-site blades, and aesthetic design.
Topics: Humans; Hair; Alopecia; Esthetics; Scalp; Hair Follicle
PubMed: 38936998
DOI: 10.1016/j.fsc.2024.02.005 -
American Journal of Hematology Jun 2024Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label,...
Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7-97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan-Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46-90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90-8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0-51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.
PubMed: 38934629
DOI: 10.1002/ajh.27424 -
Medicina (Kaunas, Lithuania) Jun 2024The amniotic membrane is widely used in the treatment of chronic wounds, in toxic epidermal necrolysis (TEN), and in the treatment of burns. In our clinical practice,... (Comparative Study)
Comparative Study
The amniotic membrane is widely used in the treatment of chronic wounds, in toxic epidermal necrolysis (TEN), and in the treatment of burns. In our clinical practice, we use amniotic dressings on shallow skin wounds caused by burns. Counteracting infections is an important aspect of working with burn wounds. Therefore, the main goals of this work are to demonstrate the usefulness of amniotic membrane soaked in antiseptics for the prevention of wound infections and to compare the antibacterial efficacy of selected variants of allogeneic and xenogeneic amniotic membrane grafts soaked in specific antiseptic agents. The studied material consisted of human and pig placenta. The human and animal amnions were divided in two parts. The first part consisted of amniotic discs placed on rigid mesh discs and preparing the fresh amnion. The second part of the amnion was frozen at a temperature of -80 °C for 24 h. Then, it was radio-sterilized with a dose of 35 kGy. The amniotic discs were placed on rigid mesh to prepare the radiation-sterilized amnion. The amniotic discs were placed in a 12-well plate and immersed in 3 mL of the appropriate antiseptic solutions: Prontosan, Braunol, Borasol, Microdacyn, Octenilin, Sutrisept, and NaCl as a control. The amniotic discs were incubated in antiseptics for 3 h. The microbiological tests were conducted by placing the antiseptic-infused amniotic discs on microbiological media inoculated with hospital strains. The largest average zone of growth inhibition was observed in dressings soaked with Sutrisept, Braunol, and Prontosan. The greatest inhibition of bacterial growth was achieved for radiation-sterilized porcine amnion impregnated with Braunol and Sutrisept, as well as for radiation-sterilized human amnion impregnated with Braunol. Human and porcine amniotic membrane is effective in carrying antiseptics. Radiation-sterilized amnion seems to inhibit the growth of microorganisms better than fresh amnion.
Topics: Amnion; Humans; Anti-Infective Agents, Local; Burns; Animals; Swine; Female; Transplantation, Homologous; Transplantation, Heterologous
PubMed: 38929632
DOI: 10.3390/medicina60061015 -
Internal Medicine (Tokyo, Japan) Jun 2024A cholecystocutaneous fistula is a type of external biliary fistula that occurs when there is an abnormal connection between the gallbladder and skin. We report the...
A cholecystocutaneous fistula is a type of external biliary fistula that occurs when there is an abnormal connection between the gallbladder and skin. We report the first case of a cholecystocutaneous fistula that occurred in association with the development of lymphoma in the gallbladder. A 76-year-old woman who was under observation for follicular lymphoma with a low tumor burden presented with fatigue and abdominal pain. Imaging studies revealed cholecystitis associated with an abdominal subcutaneous abscess, and lymphoma transformation was confirmed by a lymph node biopsy. Edwardsiella tarda was cultured from both the abdominal subcutaneous abscess and percutaneous transhepatic gallbladder drainage, demonstrating cholecystocutaneous fistula, and open cholecystectomy revealed lymphoma cell infiltration into the gallbladder. Our case showed unique complications, and its successful management was associated with aggressive lymphoma development.
PubMed: 38925971
DOI: 10.2169/internalmedicine.3851-24 -
Antibodies (Basel, Switzerland) Jun 2024The proportion of patients with type I allergy in the world population has been increasing and with it the number of people suffering from allergic symptoms. Recently we...
The proportion of patients with type I allergy in the world population has been increasing and with it the number of people suffering from allergic symptoms. Recently we showed that prophylactic cell therapy employing allergen-expressing bone marrow (BM) cells or splenic B cells induced allergen-specific tolerance in naïve mice. Here we investigated if cell therapy can modulate an established secondary allergen-specific immune response in pre-immunized mice. We sensitized mice against the grass pollen allergen Phl p 5 and an unrelated control allergen, Bet v 1, from birch pollen before the transfer of Phl p 5-expressing BM cells. Mice were conditioned with several combinations of low-dose irradiation, costimulation blockade, rapamycin and T cell-depleting anti-thymocyte globulin (ATG). Levels of allergen-specific IgE and IgG1 in serum after cell transfer were measured via ELISA and alterations in cellular responses were measured via an in vitro proliferation assay and transplantation of Phl p 5 skin grafts. None of the tested treatment protocols impacted Phl p 5-specific antibody levels. Transient low-level chimerism of Phl p 5 leukocytes as well as a markedly prolonged skin graft survival were observed in mice conditioned with high numbers of Phl p 5 BMC or no sensitization events between the day of cell therapy and skin grafting. The data presented herein demonstrate that a pre-existing secondary allergen-specific immune response poses a substantial hurdle opposing tolerization through cell therapy and underscore the importance of prophylactic approaches for the prevention of IgE-mediated allergy.
PubMed: 38920972
DOI: 10.3390/antib13020048 -
Annals of Vascular Diseases Jun 2024Lymphedema is caused by dysfunction of the lymphatic system. It is divided into primary edema with no apparent cause and secondary edema with an exogenous cause. The... (Review)
Review
Lymphedema is caused by dysfunction of the lymphatic system. It is divided into primary edema with no apparent cause and secondary edema with an exogenous cause. The main symptoms are edema and heaviness, skin changes such as skin hardening, lymphocysts, lymphorrhoea, papillomas, and recurrent cellulitis. They are often irreversible and progressive, thus greatly reducing quality of life of the patients. Diagnosis is made by image examinations that can evaluate lymphatic flow and functions such as lymphoscintigraphy and indocyanine green fluorescence lymphangiography. Linear pattern and dermal backflow are the main findings. Conservative treatment consists of four components: compression therapy with elastic garments, exercise therapy, manual lymphatic drainage, and skin care, which is called complex physical therapy (CPT). Although CPT has become the gold standard of treatment, with evidence of efficacy reported in terms of volume reduction, maintenance, and prevention of cellulitis, it is a symptomatic treatment and does not improve impaired lymphatic flow. On the other hand, surgical treatment, such as lymphaticovenous anastomosis and vascularized lymph node transplantation, can create new lymphatic flow and improve lymphatic dysfunctions. Although these techniques are expected to be effective in volume reduction, cellulitis prevention, and improving quality of life, there is a need for more studies with a higher level of evidence in the future. In Japan, lymphedema is treated with a combination of conservative and surgical therapies, but lymphedema is intractable and few cases are completely cured. Therefore, how to improve the outcome of treatment is an important issue to be addressed in the future. (This is a translation of Jpn J Vasc Surg 2023; 32: 141-146.).
PubMed: 38919315
DOI: 10.3400/avd.ra.24-00011 -
European Journal of Dermatology : EJD Jun 2024Seborrheic Dermatitis of the scalp (SSD) is a chronic and relapsing inflammatory skin condition. Current SSD treatments mainly consist of topical applications of... (Review)
Review
Seborrheic Dermatitis of the scalp (SSD) is a chronic and relapsing inflammatory skin condition. Current SSD treatments mainly consist of topical applications of anti-fungals and anti-inflammatory agents. to review information about SSD and to provide dermatologists with practical recommendations for managing adult SSD. Material and methods: Between September and December 2023, an international group of experts in dermatology and hair and scalp disorders met to discuss published data about SD, SSD, dandruff, and management options. A total of 131 manuscripts available from PubMed were analysed, discussed and used for the present consensus. Each author was asked to complete a table listing currently used treatments to treat SSD according to the literature and to their own experience. The authors confirmed their use and regimen and commented on local treatment exceptions. They then agreed on prescription practices and proposed a general treatment approach. Currently, approved therapies to manage moderate and severe forms of SSD do not exist and there is a need for adapted and approved medications that treat efficiently and safely the disease. We propose a treatment algorithm that allows for the treatment of all severity grades of SSD. This algorithm may be completed with local treatment specifications. Despite the lack of approved therapies to manage moderate forms of SSD, a treatment algorithm is proposed and may help prescribers to manage SSD more efficiently.
Topics: Dermatitis, Seborrheic; Humans; Scalp Dermatoses; Adult; Consensus; Algorithms; Antifungal Agents; Dermatologic Agents; Anti-Inflammatory Agents; Severity of Illness Index
PubMed: 38919137
DOI: 10.1684/ejd.2024.4703