Hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia (ED), which encompasses a large group of syndromes that share several phenotypic features such as missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. X-linked hypohidrotic ectodermal dysplasia (XL-HED) is associated with mutations in ectodysplasin (EDA1). Hypohidrosis due to hypoplastic sweat glands and thin, sparse hair are phenotypic features that significantly affect the daily lives of XL-HED individuals and therefore require systematic analysis. We sought to determine the quality of life of individuals with XL-HED and to quantify sweat duct and hair phenotypes using confocal imaging, pilocarpine iontophoresis, and phototrichogram analysis. Using these highly sensitive and non-invasive techniques, we demonstrated that 11/12 XL-HED individuals presented with a complete absence of sweat ducts and that none produced sweat. We determined that the thin hair phenotype observed in XL-HED was due to multiple factors, such as fewer terminal hairs with decreased thickness and slower growth rate, as well as fewer follicular units and fewer hairs per unit. The precise characterization of XL-HED phenotypes using sensitive and non-invasive techniques presented in our study will improve upon larger genotype-phenotype studies and in the assessment of future therapies in XL-HED.
A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin ( N = 8) or placebo ( N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years ( P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group ( n = 7) than in the placebo ( n = 3) group ( P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT ( P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov
As the field of medicine shifts from a paternalistic to a more patientcentered orientation, the dynamics of shared decision making become increasingly complicated. International globalization and national socioeconomic differences have added unintended difficulties to culturally sensitive communication between physician and patient, which can contribute to the growing erosion of clinician empathy. This article offers a strategy for teaching students how to enter into conversations about shared decision making by bolstering their empathy as a result of exposing them to the many variables outside of their patients' control. Patients' historical and cultural context, gender identity, sexual orientation, and common assumptions about clinicians as well as institutional biases can severely limit students' ability to integrate patients' value-laden preferences into shared decision making about health care.
A mutation's effect on craniofacial phenotype is modulated by genetic background, but associated developmental interactions are not well understood. Our objective was to quantify the influence of three inbred backgrounds (FVB, 129, BL6) on the expression of craniofacial dysmorphology associated with Sprouty (Spry) 1, 2, and 4 deletions in mice. We quantified adult morphology with landmarks placed on micro‐computed tomography derived surfaces of heterozygote and homozygote knockouts, and unaffected littermates of each background. Within a background strain, mice with two deletions differ strongly from controls, including a visually identifiable rounded cranium and shortened face in Spry 2 homozygotes. Although not as extreme, heterozygotes significantly differ in shape from controls in many cases. Deletion effects are significantly different between background strains after correcting for shape differences in background controls, including a larger reduction of the nasal aperture associated with Spry1 deletion on 129 background versus FVB. Spry 4 deletion on FVB results in a more projected upper face associated with diastema teeth, while the effect of it on C57 is minimal. There are significant background effects on expression of craniofacial dysmorphology associated with Spry deletions, patterns of which can help illuminate how modifier genes can influence the effects of major genetic perturbations.Grant Funding Source: NIH (1R01‐DE021708, DP2‐OD007191, RO1‐DE021420, F30‐DE022482); NSERC (238992‐12); CIHR fellowship through ACHRI to CJP
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