Transcriptome and phenotypic analysis reveals Gata3-dependent signalling pathways in murine hair follicles

Abstract The transcription factor Gata3 is crucially involved in epidermis and hair follicle differentiation. Yet, little is known about how Gata3 co-ordinates stem cell lineage determination in skin, what pathways are involved and how Gata3 differentially regulates distinct cell populations within the hair follicle. Here, we describe a conditional Gata3-/- mouse (K14-Gata3-/-) in which Gata3 is specifically deleted in epidermis and hair follicles. K14-Gata3-/- mice show aberrant postnatal growth and development, delayed hair growth and maintenance, abnormal hair follicle organization and irregular pigmentation. After the first hair cycle, the germinative layer surrounding the dermal papilla was not restored; instead, proliferation was pronounced in basal epidermal cells. Transcriptome analysis of laser-dissected K14-Gata3-/- hair follicles revealed mitosis, epithelial differentiation and the Notch, Wnt and BMP signaling pathways to be significantly overrepresented. Elucidation of these pathways at the RNA and protein levels and physiologic endpoints suggests that Gata3 integrates diverse signaling networks to regulate the balance between hair follicle and epidermal cell fates

GATA3 haploinsufficiency causes a rapid deterioration of distortion product otoacoustic emissions (DPOAEs) in mice

Human HDR (hypoparathyroidism, deafness and renal dysplasia)-syndrome is caused by haploinsufficiency of zinc-finger transcription factor GATA3. The hearing loss due to GATA3 haploinsufficiency has been shown to be peripheral in origin, but it is unclear to what extent potential aberrations in the outer hair cells (OHCs) contribute to this disorder. To further elucidate the pathophysiological mechanism underlying the hearing defect in HDR-syndrome, we investigated the OHCs in heterozygous Gata3-knockout mice at both the functional and morphological level. While the signal-to-noise ratios of distortion product otoacoustic emissions (DPOAE) in wild type mice did not change significantly during the first half-year of live, those in the heterozygous Gata3 mice decreased dramatically. In addition, both light microscopic and transmission electron microscopic analyses showed that the number of OHCs containing vacuoles was increased in the mutants. Together, these findings indicate that outer hair cell malfunctioning plays a major role in the hearing loss in HDR-syndrome

GATA-3 is involved in the development of serotonergic neurons in the caudal raphe nuclei

Abstract The GATA-3 transcription factor shows a specific and restricted expression pattern in the developing and adult mouse brain. In the present study we investigated the role of GATA-3 in the caudal raphe system, which is known to operate as a modulator of motor activity. We demonstrate that virtually all neurons in the caudal raphe nuclei that express GATA-3 also produce serotonin. Absence of GATA-3, as analyzed in chimeric -/- mice, affects the cytoarchitecture of serotonergic neurons in the caudal raphe nuclei. As a result the chimeras show a serious defect in their locomotor performance on a rotating rod. In sum, we conclude that GATA-3 plays a major role in the development of the serotonergic neurons of the caudal raphe nuclei, and that it is crucial for their role in locomotion

Association between graft storage time and donor age with endothelial cell density and graft adherence after Descemet membrane endothelial keratoplasty

Importance After retrospectively evaluating the clinical outcome of 500 consecutive cases after Descemet membrane endothelial keratoplasty (DMEK), we extended the analysis in this study by assessing the effect of donor-related parameters on endothelial cell density (ECD) decline and detachment rate in this group. Observations This retrospective case series included 500 cases who had undergone DMEK from October 2007 to September 2012 at the Netherlands Institute for Innovative Ocular Surgery (NIIOS), Rotterdam, the Netherlands. Logistic regression analysis (n = 332 eyes) showed that donor age might be associated with a 3% increase in the risk for a detachment (odds ratio, 0.97; 95% CI, 0.94-1.00; P = .049) (ie, higher donor age seems to be associated with lower chances of a detachment). In addition, linear regression analysis indicated that graft storage time in medium was associated with ECD decrease (ie, the longer the storage time, the larger the decrease at 6 months after DMEK) (P = .01). Conclusions and Relevance We showed an association between graft storage time and ECD decline after DMEK and possibly between donor age and graft detachment. Therefore, donor storage times should be kept as short as possible to improve short-term ECDs. More research is needed to draw definite conclusions on the possible effect of donor age on the chance of a detachment after DMEK

Prognostic factors for recovery following acute lateral ankle ligament sprain: a systematic review.

BACKGROUND: One-third of individuals who sustain an acute lateral ankle ligament sprain suffer significant disability due to pain, functional instability, mechanical instability or recurrent sprain after recovery plateaus at 1 to 5 years post injury. The identification of early prognostic factors associated with poor recovery may provide an opportunity for early-targeted intervention and improve outcome. METHODS: We performed a comprehensive search of AMED, EMBASE, Psych Info, CINAHL, SportDiscus, PubMed, CENTRAL, PEDro, OpenGrey, abstracts and conference proceedings from inception to September 2016. Prospective studies investigating the association between baseline prognostic factors and recovery over time were included. Two independent assessors performed the study selection, data extraction and quality assessment of the studies. A narrative synthesis is presented due to inability to meta-analyse results due to clinical and statistical heterogeneity. RESULTS: The search strategy yielded 3396 titles/abstracts after duplicates were removed. Thirty-six full text articles were then assessed, nine of which met the study inclusion criteria. Six were prospective cohorts, and three were secondary analyses of randomised controlled trials. Results are presented for nine studies that presented baseline prognostic factors for recovery after an acute ankle sprain. Age, female gender, swelling, restricted range of motion, limited weight bearing ability, pain (at the medial joint line and on weight-bearing dorsi-flexion at 4 weeks, and pain at rest at 3 months), higher injury severity rating, palpation/stress score, non-inversion mechanism injury, lower self-reported recovery, re-sprain within 3 months, MRI determined number of sprained ligaments, severity and bone bruise were found to be independent predictors of poor recovery. Age was one prognostic factor that demonstrated a consistent association with outcome in three studies, however cautious interpretation is advised. CONCLUSIONS: The associations between prognostic factors and poor recovery after an acute lateral ankle sprain are largely inconclusive. At present, there is insufficient evidence to recommend any factor as an independent predictor of outcome. There is a need for well-conducted prospective cohort studies with adequate sample size and long-term follow-up to provide robust evidence on prognostic factors of recovery following an acute lateral ankle sprain. TRIAL REGISTRATION: Prospero registration: CRD42014014471

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Reply to: Stewart, Rosalind M. K.; Hiscott, Paul S. and Kaye, Stephen B. "Correspondence : Endothelial Migration and New Descemet Membrane after Endothelial Keratoplasty"2 page(s

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Reply to: Price Jr., Francis W. and Price, Marianne O. "Correspondence : Spontaneous Corneal Clearance Despite Graft Detachment after Descemet Membrane Endothelial Keratoplasty"2 page(s

Visual rehabilitation rate after isolated descemet membrane transplantation : Descemet membrane endothelial keratoplasty

Objective: To evaluate visual rehabilitation after Descemet membrane endothelial keratoplasty (DMEK) in the management of corneal endothelial disorders. Methods: In this prospective, nonrandomized, clinical study, DMEK was performed in a first group of 35 consecutive patients with either Fuchs endothelial dystrophy or bullous keratopathy. The Descemet membrane was stripped from the recipient posterior stroma with the anterior chamber completely filled with air. Using a 3.0-mm clear corneal incision, an organ-cultured donor Descemet roll 9 to 10 mm in diameter was inserted into the recipient anterior chamber, positioned on the posterior stroma, and secured by completely filling the anterior chamber with air for 45 to 60 minutes. Resutls: Ten eyes had preexisting ocular disease or an early graft detachment. In the remaining 25 DMEK-treated eyes, best-corrected visual acuity was 20/40 (Snellen notation, 0.5) or more in 18 eyes (72%) within 1 month. At 3 months, best-corrected visual acuity was 20/40 (0.5) or more in 23 of 25 eyes (92%) and 20/25 (0.8) or more in 15 of 25 eyes (60%). Conclusions: In most cases, DMEK results in functional visual rehabilitation within 1 to 3 months. Overall, visual recovery after DMEK may be faster and more complete than with other techniques for (lamellar) keratoplasty for treatment of corneal endothelial disorders.4 page(s