Research Spotlight

Johannesson, L., A. Wall, J. M. Putman, L. Zhang, G. Testa and C. Diaz-Garcia (2019). “Rethinking the Time Interval to Embryo Transfer after Uterus Transplantation – Duets (Dallas Uterus Transplant Study).” BJOG 126(11): 1305-1309.

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Uterus transplant can allow women to carry their own pregnancy. Because of the transplant operation, infectious disease risks, and immunosuppressive medications, these pregnancies require careful planning. Conditions to achieve before ET include stable uterine graft function, absence of active rejection, stable immunosuppressive medication with agents with low teratogenic risk, and low‐risk status for harmful opportunistic infections. Our experience, the experience of other uterus transplant programmes, and results of successful pregnancies in other solid organ transplant recipients suggest ET could be considered as soon as 3 months after uterus transplantation if the above criteria are met. Given the unique characteristics of uterus transplantation and the recipient population, the transplant‐to‐ET interval should differ from recommendations in other organ and vascular allograft transplantations. The incentive of minimising the recipient‐graft time and concomitant exposure to immunosuppressants in this young, healthy patient population strongly supports shortening the transplant‐to‐ET time. (Excerpt from text, p. 1308; no abstract available.)

Jadavji, N. M., H. Mosnier, E. Kelly, K. Lawrence, S. Cruickshank, S. Stacey, A. McCall, S. Dhatt, E. Arning, T. Bottiglieri and P. D. Smith (2019). “One-Carbon Metabolism Supplementation Improves Outcome after Stroke in Aged Male Mthfr-Deficient Mice.” Neurobiol Dis Sep 13: 104613. [Epub ahead of print].

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The prevalence of stroke increases with age and the ability to absorb all nutrients from our diets decreases with age. Nutrition is a modifiable risk factor for stroke, which is a leading cause of death and disability in world-wide. Deficiencies in onecarbon metabolism, including in methyltetrahydrofolate reductase (MTHFR), have been linked to increased risk of stroke. The Mthfr(+/-) mice mouse model mimic the phenotype of the MTHFR677CT polymorphism, such as elevated levels of homocystine. Using this mouse model, the aim of this study was to investigate the impact of dietary supplementation with 5-methylTHF, vitamin B12, and choline after ischemic stroke. Male Mthfr(+/-) and wildtype littermate control mice were aged (~1.5-year-old) and were placed on control diet (CD) 4-weeks prior to sensorimotor cortex damage using photothrombosis (PT), a model for ischemic stroke. Post-operatively, one group of Mthfr(+/-) and wildtype littermate mice were placed on 5-methylTHF, vitamin B12, and choline supplemented diet (SD). Four weeks after PT and SD motor function was assessed using the accelerating rotarod, forepaw asymmetry, and ladder beam walking tasks. Total homocysteine and cysteine levels were measured in blood. Brain tissue was processed to assess lesion volume and investigate biochemical and molecular changes. After PT and SD, Mthfr(+/-) mice were able to stay on the accelerating rotarod longer and used their impaired forepaw to explore more when compared to CD animals. Furthermore, total homocysteine levels in plasma and lesion volume were reduced in Mthfr(+/+) and Mthfr(+/-) SD mice. Within the damage site, there were reduced levels of apoptotic cell death and increased neuroprotective cellular response in the brains of SD treated Mthfr(+/-) mice. This study reveals a critical role for onecarbon supplementation, with 5-methylTHF, vitamin B12, and choline, in supporting improvement after ischemic stroke damage.

Hasan, M. M., L. Thompson-Snipes, G. Klintmalm, A. J. Demetris, J. O’Leary, S. Oh and H. Joo (2019). “Cd24(Hi)Cd38(Hi) and Cd24(Hi)Cd27(+) Human Regulatory B Cells Display Common and Distinct Functional Characteristics.” J Immunol 203(8): 2110-2120.

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Although IL-10-producing regulatory B cells (Bregs) play important roles in immune regulation, their surface phenotypes and functional characteristics have not been fully investigated. In this study, we report that the frequency of IL-10-producing Bregs in human peripheral blood, spleens, and tonsils is similar, but they display heterogenous surface phenotypes. Nonetheless, CD24(hi)CD38(hi) transitional B cells (TBs) and CD24(hi)CD27(+) B cells (human equivalent of murine B10 cells) are the major IL-10-producing B cells. They both suppress CD4(+) T cell proliferation as well as IFN-gamma/IL-17 expression. However, CD24(hi)CD27(+) B cells were more efficient than TBs at suppressing CD4(+) T cell proliferation and IFN-gamma/IL-17 expression, whereas they both coexpress IL-10 and TNF-alpha. TGF-beta1 and granzyme B expression were also enriched within CD24(hi)CD27(+) B cells, when compared with TBs. Additionally, CD24(hi)CD27(+) B cells expressed increased levels of surface integrins (CD11a, CD11b, alpha1, alpha4, and beta1) and CD39 (an ecto-ATPase), suggesting that the in vivo mechanisms of action of the two Breg subsets are not the same. Lastly, we also report that liver allograft recipients with plasma cell hepatitis had significant decreases of both Breg subsets.

Gupta, A. K., R. P. Love, W. Abramovits and K. D. Vincent (2019). “Duobrii (Halobetasol Propionate and Tazarotene) Lotion for Topical Use: A Newly Approved Combination Corticosteroid and Retinoid Topical Treatment of Plaque Psoriasis in Adults.” Skinmed 17(3): 181-183.

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Filardo, G., B. da Graca, D. M. Sass, J. Hamilton, B. D. Pollock and J. R. Edgerton (2019). “Preoperative B-Blockers as a Coronary Surgery Quality Metric: The Lack of Evidence of Efficacy.” Ann Thorac Surg Sep 9. [Epub ahead of print].

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BACKGROUND: Two quality measures used in public-reporting and value-based payment programs require beta-blockers be administered <24 hours before isolated coronary artery bypass graft surgery (CABG) to prevent atrial fibrillation (AF) and mortality. Questions have arisen about continued use of these measures. METHODS: We conducted a systematic search for randomized controlled trials (RCTs) examining the impact of pre-operative beta-blockers on AF or mortality following isolated CABG to determine what evidence of efficacy supports the measures. RESULTS: We identified 11 RCTs. All continued B-blockers post-operatively, making it unfeasible to separate the benefits of pre- vs post-operative administration. Meta-analysis was precluded by methodological variation in beta-blocker utilized, timing and dosage, and supplemental and comparison treatments. Of the 8 comparisons of beta-blockers/beta-blocker+digoxin versus placebo (n=826 patients), 6 showed significant reductions in AF/supraventricular arrhythmias. Of the 3 comparisons (n=444) of beta-blockers versus amiodarone, 2 found no significant difference in AF; the third showed significantly lower incidence with amiodarone. One RCT compared beta-blocker+amiodarone versus each of those drugs separately; the combination reduced AF significantly better than the beta-blocker alone, but not amiodarone alone. 7 RCTs reported short-term mortality, but this outcome was too rare and the sample sizes too small to provide any meaningful comparisons. CONCLUSIONS: Existing RCT evidence does not support the structure of quality measures that require B-blocker administration specifically within 24 hours prior to CABG to prevent post-operative AF or short-term mortality. Quality measures should be revised to align with the evidence, and further studies conducted to determine optimal timing and method of prophylaxis.