Summary
Background
Chronic wounds, a common morbidity in recessive dystrophic epidermolysis bullosa (RDEB), lack definitive therapies.
Objectives
To assess allogeneic epidermal skin grafts in terms ...of wound healing and durability over time.
Methods
In a prospective, open‐label clinical trial for postallogeneic haematopoietic cell transplantation (post‐alloHCT) patients with RDEB, up to nine chronic wounds per patient were grafted over 1 year. Epidermal grafts measuring 5 cm2 were obtained from related alloHCT donors in the outpatient setting using the CELLUTOMETM Epidermal Harvesting System. Wounds were photographed and symptom inventories completed at baseline and 6, 12 and 52 weeks after grafting. The trial was registered at ClinicalTrials.gov (NCT02670837).
Results
Between August 2016 and January 2019, eight patients with RDEB received a total of 35 epidermal allografts at a median of 1157 days (range 548–2884) post‐alloHCT. The median (interquartile range) percentage reductions in wound surface area were 75% (52–94), 95% (72–100) and 100% (97–100) at 6, 12 and 52 weeks postgraft, respectively, each significantly reduced from baseline (P < 0·001). Donor harvest sites healed quickly without scarring. Biopsy evaluation at 1 year of an epidermal allograft site revealed wildtype type VII collagen (immunofluorescence), anchoring fibrils (electron microscopy), and full‐thickness skin whole‐DNA donor chimerism of 42% (compared with 16% in concurrently biopsied native skin). This strategy subsequently supported release of RDEB pseudosyndactyly.
Conclusions
The immune tolerance established by alloHCT supports successful adoptive transfer of donor epidermal grafts. Persistence of donor grafts in a single patient beyond 1 year and observed migration of donor‐grafted cells into adjacent wound suggest that epidermal allografts include nonterminally differentiated cells and/or trigger recruitment of donor bone‐marrow‐derived cells to mediate wound healing.
What is already known about this topic?
Chronic nonhealing wounds cause great morbidity in patients with recessive dystrophic epidermolysis bullosa (RDEB) including pain, itch and loss of local barrier/thermoregulatory skin function, and serve as a nidus for infection and squamous cell carcinoma development.
The standard of care for chronic RDEB wounds is supportive, with local cleansing, emollient and dressing application.
Skin grafts from healthy allogeneic (nonself) donors provide only transient benefit as genetic differences drive immune rejection of transplanted tissue.
What does this study add?
Successful allogeneic haematopoietic cell transplantation establishes immune tolerance for secondary tissue grafts from the same donor, herein demonstrated with skin grafts.
Persistence of epidermal allografts beyond the keratinocyte lifespan and outgrowth into the adjacent wound suggest inclusion of nonterminally differentiated cells in the graft.
Epidermal allografting can be completed in a minimally invasive manner in the outpatient setting, with tolerability to the donor allowing for repeat sessions over time.
Linked Comment: Bauer. Br J Dermatol 2021; 184:1002–1003.
Summary
Background
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe systemic genodermatosis lacking therapies beyond supportive care for its extensive, life‐limiting manifestations.
...Objectives
To report the safety and preliminary responses of 10 patients with RDEB to bone marrow transplant (BMT) with post‐transplant cyclophosphamide (PTCy BMT) after reduced‐intensity conditioning with infusions of immunomodulatory donor‐derived mesenchymal stromal cells (median follow‐up 16 months).
Methods
BMT toxicities, donor blood and skin engraftment, skin biopsies, photographic and dynamic assessments of RDEB disease activity were obtained at intervals from pre‐BMT to 1 year post‐BMT.
Results
Related donors varied from haploidentical (n = 6) to human leucocyte antigen (HLA)‐matched (n = 3), with one HLA‐matched unrelated donor. Transplant complications included graft failure (n = 3; two pursued a second PTCy BMT), veno‐occlusive disease (n = 2), posterior reversible encephalopathy (n = 1) and chronic graft‐versus‐host disease (n = 1; this patient died). In the nine ultimately engrafted patients, median donor chimerism at 180 days after transplant was 100% in peripheral blood and 27% in skin. Skin biopsies showed stable (n = 7) to improved (n = 2) type VII collagen protein expression by immunofluorescence and gain of anchoring fibril components (n = 3) by transmission electron microscopy. Early signs of clinical response include trends toward reduced body surface area of blisters/erosions from a median of 49·5% to 27·5% at 100 days after BMT (P = 0·05), with parental measures indicating stable quality of life.
Conclusions
PTCy BMT in RDEB provides a means of attaining immunotolerance for future donor‐derived cellular grafts (ClinicalTrials.gov identifier NCT02582775).
What's already known about this topic?
Severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) is marked by great morbidity and early death.
No cure currently exists for RDEB.
Bone marrow transplant (BMT) is the only described systemic therapy for RDEB.
What does this study add?
The first description of post‐transplant cyclophosphamide (PTCy) BMT for RDEB.
PTCy was well tolerated and provided excellent graft‐versus‐host disease prophylaxis, replacing long courses of calcineurin inhibitors in patients receiving human leucocyte antigen‐matched sibling BMT.
What is the translational message?
The PTCy BMT platform permits identification of a suitable related donor for most patients and for subsequent adoptive transfer of donor nonhaematopoietic cells after establishment of immunological tolerance.
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Under Wisconsin state law, the greater prairie chicken (GRPC; Tympanuchus cupido pinnatus) has been listed as a threatened species since 1976. In 2014-15, we conducted a pilot study to determine the ...prevalence and intensity of gapeworms (Syngamus spp.) in female Wisconsin GRPCs collected from 2 monitored populations. We captured 62 female GRPCs using walk-in-style traps for females and night lighting for juveniles ≥45 days of age. From these individuals, we collected 15 carcasses of radio-marked birds, most of whom died due to predation events. Through dissection, we identified gapeworm in 20% of examined carcasses and report an intensity ranging between 4 and 74 worms.
The purpose of this study was to assess the follow-up of patients with vaccinia-associated myocarditis.
With the threat of biological warfare, the U.S. Department of Defense resumed a program for ...widespread smallpox vaccinations on December 13, 2002. One-year afterwards, there has been a significant increase in the occurrence of myocarditis and pericarditis among those vaccinated.
Cases were identified through sentinel reporting to military headquarters, systematic surveillance, and spontaneous reports.
A total of 540,824 military personnel were vaccinated with a New York City Board of Health strain of vaccinia from December 2002 through December 2003. Of these, 67 developed myopericarditis at 10.4 +/- 3.6 days after vaccination. The ST-segment elevation was noted in 57%, mean troponin on admission was 11.3+/- 22.7 ng/dl, and peak cardiac enzymes were noted within 8 h of presentation. On follow-up of 64 patients (96%) at a mean of 32 +/- 16 weeks, all patients had objective normalization of echocardiography, electrocardiography, laboratory testing, graded exercise testing, and functional status; 8 (13%) reported atypical, non-limiting persistent chest discomfort.
Post-vaccinial myopericarditis should be considered in patients with chest pain within 30 days after smallpox vaccination. Normalization of echocardiography, electrocardiography, and treadmill testing is expected, and nearly all patients have resolution of chest pain on follow-up.
Bone formation and remodeling occurs throughout life and requires the sustained activity of osteoblasts and osteoclasts, particularly during periods of rapid bone growth. Despite increasing evidence ...linking bone cell activity to global energy homeostasis, little is known about the relative energy requirements or substrate utilization of bone cells. In these studies, we measured the uptake and distribution of glucose in the skeleton in vivo using positron-emitting 18F-fluorodeoxyglucose （lSF-FDG） and non-invasive, high-resolution positron emission tomography/computed tomography （PE~/CT） imaging and ex vivo autoradiography. Assessment of ~SF-FDG uptake demonstrated that relative to other tissues bone accumulated a significant fraction of the total dose of the glucose analog..Skeletal accumulation was greatest in young mice undergoing the rapid bone formation that characterizes early development. PET/CT imaging revealed that lSF-FDG uptake was greatest in the epiphyseal and metaphyseal regions of long bones, which accords with the increased osteoblast numbers and activity at this skeletal site. Insulin administration significantly increased skeletal accumulation of lSF-FDG, while uptake was reduced in mice lacking the insulin receptor specifically in osteoblasts or fed a high-fat diet. Our results indicated that the skeleton is a site of significant glucose uptake and that its consumption by bone cells is subject to regulation by insulin and disturbances in whole-body metabolism.
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability ...attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Altering the balance of activity between the two eyes during the critical period for visual-system development profoundly affects competitive interactions among neurons in the lateral geniculate ...nucleus and primary visual cortex. Neurons in the lateral geniculate nucleus that are deprived of activity by closing or silencing one eye atrophy as a result of competition with non-deprived neurons for some critical factor(s) presumed to be present in the cortex. Based on their actions in the developing visual system, neurotrophins are attractive candidates for such factors. We tested whether neurotrophins mediate intracortical competition of afferents from the lateral geniculate nucleus by using monocular deprivation and a new method for highly localized, in vivo delivery of neurotrophins. This method allowed unambiguous identification of neurons that were exposed to neurotrophin. Here we report that only one neurotrophin, the TrkB ligand NT-4, rescued neurons in the lateral geniculate nucleus from the dystrophic effects of monocular deprivation.
Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive ...susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.
The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.
Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).
Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.
Primary graft failure is the major cause of mortality in infant HTx. The aim of this study was to characterize the indication and outcomes of infants requiring ECMO support due to primary graft ...failure after HTx. We performed a retrospective review of all infants (<1 yr) who underwent Htx from three institutions. From 1999 to 2008, 92 infants (<1 yr) received Htx. Sixteen children (17%) required ECMO after Htx due to low cardiac output syndrome. Eleven (69%) infants were successfully weaned off ECMO, and 9 (56%) infants were discharged with a mean follow‐up of 2.3 ± 2.5 yr. Mean duration of ECMO in survivors was 5.4 days (2–7 days) compared with eight days (2–10 days) in non‐survivors (p = NS). The five‐yr survival rate for all patients was 75%; however, the five‐yr survival rate was 40% in the ECMO cohort vs. 80% in the non‐ECMO cohort (p = 0.0001). Graft function within one month post‐Htx was similar and normal between ECMO and non‐ECMO groups (shortening fraction = 42 ± 3 vs. 40 ± 2, p = NS). For infants, ECMO support for primary graft failure had a lower short‐term and long‐term survival rate vs. non‐ECMO patients. Duration of ECMO did not adversely impact graft function and is an acceptable therapy for infants after HTx for low cardiac output syndrome.
A synergistic extraction solvent for the simultaneous removal of cesium and strontium from acidic solutions has been investigated. The extraction solvent consists of, ...4,4′,(5′)-di-(t-butyldicyclo-hexano)-18-crown-6 (DtBuCH18C6), calix4arene-bis-(tert-octylbenzo-crown-6) (BOBCalixC6), and 1-(2,2,3,3-tetrafluoropropoxy)-3-(4-sec-butylphenoxy)-2-propanol (Cs-7SB modifier) in a branched aliphatic kerosene (Isopar
®
L). Extraction synergy for strontium was observed when DtBuCH18C6 was combined with the BOBCalixC6 cesium extractant solvent and Cs-7SB modifier or if the Cs-7SB modifier was substituted into the SREX (Strontium Extraction) solvent in place of TBP. The novel process extracted both cesium and strontium simultaneously from 1 M nitric acid solutions with distribution ratios of 8.8 and 7.7 for strontium and cesium, respectively, at ambient temperature. Distribution coefficients for cesium and strontium as a function of nitric acid concentration and temperature were also obtained with 0.5 M<HNO
3
<2.5 M giving favorable distribution ratios. This new process utilizing the combined solvent has been named the Fission Product Extraction Process (FPEX).
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