NBL1 Reduces Corneal Fibrosis and Scar Formation after Wounding.

Corneal scarring is a leading cause of blindness. Currently, there is no treatment to prevent and/or reduce corneal scar formation under pathological conditions. Our previous data showed that the NBL1 protein, also termed the DAN Family BMP (Bone morphogenetic protein) Antagonist, was highly expressed in corneal stromal cells upon wounding. Here, we examined the function of NBL1 in corneal wound healing. Mouse corneas were mechanically wounded, followed by a 2-week treatment using NBL1. Wounded corneas treated with vehicle or an Fc tag served as controls. Compared with the controls, NBL1 treatment facilitated wound re-epithelialization, partially restored the stromal thickness, and significantly reduced corneal scar formation. NBL1 treatment did not decrease immune cell infiltration, indicating that the anti-scarring effect was not dependent on immune suppression. We further examined the anti-fibrotic effect of NBL1 on human corneas. Pairs of human corneas were induced to form myofibroblasts (a key player in fibrosis and scarring) upon wounding and incubation in a medium containing TGF-ß1. The OS corneas were treated with Fc as a control, and the OD corneas were treated with NBL1. Compared with the control, human corneas treated with NBL1 had significantly fewer myofibroblasts, which was consistent with these mouse data. A further study revealed that NBL1 treatment inhibited BMP canonical (phospho-Smad1/5) and no-canonical (phospho-p38) pathways in human corneas. Data show that NBL1 reduced corneal fibrosis and scar formation in mice and cultured human corneas. The underlying molecular mechanism is not certain because both anti-fibrotic Smad1/5 and pro-fibrotic p38 pathways were inhibited upon NBL1 treatment. Whether the p38 pathway dominates the Smad1/5 pathway during corneal fibrosis, leading to the anti-fibrotic effect of NBL1, needs further investigation.

Exploring new-graduate physiotherapists' preparedness for, and experiences working within, Australian acute hospital settings.

BACKGROUND: New-graduate physiotherapists experience a steep learning curve when transitioning from student to clinician. The acute hospital setting is known to present unique challenges for health clinicians, however, the preparedness of new-graduate physiotherapists for working within this setting remains unclear. PURPOSE: The aim of this study was to investigate new-graduate physiotherapists' experiences of working in acute hospital settings and their perceptions toward how their pre-professional training prepared them for this setting. METHODS: A qualitative study with a general inductive approach was used. Semi-structured interviews with new-graduate physiotherapists working in acute hospital settings were undertaken (n = 14). Interview data were subject to thematic analysis. RESULTS: Four themes were generated from the data: 1) multifactorial and high-pressure nature; 2) managing relationships; 3) realizing responsibility; and 4) constructing realistic experiences. CONCLUSION: The acute hospital setting presents unique obstacles and additional challenges when transitioning from student to clinician. New-graduates value the role of pre-professional training in their preparation for this context, however, new-graduates reflected on being sheltered from some areas of practice as students. Recommendations are suggested for education providers to adapt pre-professional training, and for employers to implement workplace strategies, which may support new-graduate physiotherapists in the acute hospital setting.

Differentiation Trajectory of Limbal Stem and Progenitor Cells under Normal Homeostasis and upon Corneal Wounding.

Limbal stem cells (LSCs) reside discretely at limbus surrounded by niche cells and progenitor cells. The aim of this study is to identify the heterogeneous cell populations at limbus under normal homeostasis and upon wounding using single-cell RNA sequencing in a mouse model. Two putative LSC types were identified which showed a differentiation trajectory into limbal progenitor cell (LPC) types under normal homeostasis and during wound healing. They were designated as "putative active LSCs" and "putative quiescent LSCs", respectively, because the former type actively divided upon wounding while the later type stayed at a quiescent status upon wounding. The "putative quiescent LSCs" might contribute to a barrier function due to their characteristic markers regulating vascular and epithelial barrier and growth. Different types of LPCs at different proliferative statuses were identified in unwounded and wounded corneas with distinctive markers. Four maturation markers (Aldh3, Slurp1, Tkt, and Krt12) were screened out for corneal epithelium, which showed an increased expression along the differentiation trajectory during corneal epithelial maturation. In conclusion, our study identified two different types of putative LSCs and several types of putative LPCs under normal homeostasis and upon wounding, which will facilitate the understanding of corneal epithelial regeneration and wound healing.

Gender differences in prevalence and clinical correlates of anxiety symptoms in first-episode and drug-naïve patients with major depressive disorder.

AIM: Gender differences in major depressive disorder (MDD) are commonly reported; however, gender differences in first-episode and drug-naïve (FEDN) patients with major depressive disorder remain unclear. This study aimed to examine potential gender differences in the prevalence and clinical correlates of comorbid anxiety in FEDN patients with MDD. METHODS: A cross-sectional study was conducted with1718 FEDN patients with MDD. Patients' demographic and clinical data were collected and analyzed using standardized clinical evaluation forms. The Hamilton depression scale (HAMD), Hamilton anxiety scale (HAMA) and Positive and Negative Syndrome Scale (PANSS) were used to evaluate depression, anxiety and psychotic symptoms, respectively. RESULTS: There were no gender-based differences in the comorbidity rates of MDD and anxiety disorders (male: 10.2% vs. female:12.7%, P = 0.123). The prevalence of MDD with severe anxiety symptoms in male patients was similar to that of female patients (80.8%vs. 80.1%, P = 0.749). Male MDD patients were younger, had earlier age of onset, and were less likely to be married. In both the male and female groups, HAMD scores, HAMA scores, suicide attempts, and psychotic symptoms in patients with severe anxiety symptoms were higher than those patients without severe anxiety symptoms (all p ≤ 0.001). Furthermore, binary logistic regression analysis showed that psychotic symptoms and suicide attempts significantly predicted severe anxiety symptoms in both male and female patients with MDD, while body mass index(BMI)significantly predicted severe anxiety symptoms in MDD females only. CONCLUSION: Our study showed that there were no gender differences in the prevalence of comorbid anxiety in FEDN patients with MDD. Suicide attempts and psychiatric symptoms were associated with severe anxiety symptoms in both men and women with MDD, whereas BMI was only correlated with severe anxiety symptoms in women.

Velocity Vector Imaging to Assess Longitudinal Wall Motion of Adult Carotid Arteries.

OBJECTIVE: We aimed to assess longitudinal wall motion of the common carotid artery (CCA) using velocity vector imaging (VVI). METHODS: From October 2018 to July 2019, we prospectively performed VVI of 204 CCAs (102 adult volunteers, 57 men, 45 women) in young (n = 40, 20-44 y), mid-age (n = 30, 45-64 y), and senior (n = 32, ≥65 y) groups. VVI parameters of CCA included longitudinal motion pattern, motion parameters (strain, strain rate, displacement), and time-to-peak motion parameters (time-to-peak strain, time-to-peak strain rate, time-to-peak displacement). Statistical analyses included one-way ANOVA post-hoc testing to examine the difference in VVI parameters among the 3 age groups and in paired groups; unpaired t tests to examine the difference in VVI parameters between CCAs with and without atherosclerotic plaque, between hypertensive and normotensive subjects without atherosclerotic plaque; linear regression to analyze correlations of VVI parameters to age, carotid intima-media thickness; and intraclass correlation coefficient to test inter- and intra-observer reliability in performing VVI of the CCA. RESULTS: Differences in VVI parameters and patterns among the 3 age groups, between hypertensive and normotensive, and CCAs with and without plaque were significant (p < .01). CCA motion- and time-to-peak motion parameters were correlated to age (R2 = 0.63-0.56) and carotid intima-media thickness (R2 = 0.29-0.22). CCA wall motion dyssynchrony was remarkable in seniors. The repeatability and reproducibility for performing carotid artery VVI were good (intraclass correlation coefficient > 0.85). CONCLUSIONS: VVI is feasible to assess changes in longitudinal CCA wall mechanical properties and synchrony with aging, atherosclerosis, and hypertension.

Ultrasound shear wave elastography in assessment of skeletal muscle stiffness in senior volunteers.

PURPOSE: The aim of the study was to evaluate the reliability of ultrasound shear wave elastography (SWE) to assess biceps brachii muscle (BBM) and quadriceps muscle (QM) stiffness in senior volunteers. METHODS: Using a linear array ultrasound transducer (7 MHz), we prospectively measured shear wave velocity (SWV) of BBM and QM in passive joints (elbow and knee) flexion (90°) and extension (180°) in 19 senior volunteers by two operators. We developed SWV rate (SWVelbow-extension - SWVelbow-flexion)/SWVelbow-flexion to assess BBM contractibility. Statistical analysis included unpaired t-test to examine the difference in SWV of muscle between left vs right limbs, men vs women, and athletes vs nonathletes; Intraclass correlation coefficient (ICC) and violin plots for analyzing intra- and inter-observer reliability in performing SWE in muscles. RESULTS: There was no significant difference in SWV between left vs right (flexion or extension), male vs female (flexion or extension), for BBM and QM, and athlete vs nonathlete extension for QM (all p > 0.05). The difference in SWV of BBM in elbow extension and in SWV rate between athlete and nonathlete was significant (p < 0.05). The difference in muscle SWV between joint flexion and extension was also significant (p < 0.05). Reliability in performing SWE of BBM and QM was good (ICC > 0.75). CONCLUSIONS: Our results suggest that ultrasound SWE is feasible in estimating BBM and QM stiffness in seniors with good reproducibility. SWV rate and SWV of the extended BBM representing muscle contractibility in athlete were higher than in nonathlete.

Eculizumab for rescue of thrombotic microangiopathy in PM-Scl antibody-positive autoimmune overlap syndrome.

A 46-year-old female with interstitial lung disease presented with proximal muscle weakness, worsening hypertension, microangiopathic hemolysis, thrombocytopenia and deteriorating renal function. She had no sclerodactyly, but had abnormal capillaroscopy. She tested positive for PM-Scl antibodies, and a renal biopsy showed an acute thrombotic microangiopathy consistent with scleroderma renal crisis (SRC). She failed to respond to corticosteroids, plasmapheresis and renin-angiotensin pathway inhibitors. She recovered quickly with the anti-C5 antibody, eculizumab. She had no genetic abnormalities associated with atypical hemolytic uremic syndrome except a DNA variant of unknown significance in C3. This case suggests that eculizumab may be effective for SRC.

Myocardial ischemia-mediated excitatory reflexes: a new function for thromboxane A2?

Clinical and experimental evidence has shown that myocardial ischemia activates cardiac spinal afferents that mediate sympathoexcitatory reflex responses. During myocardial ischemia, thromboxane A2 (TxA2) is released in large quantities by activated platelets in the coronary circulation of patients with coronary artery disease. We hypothesized that endogenous TxA2 contributes to sympathoexcitatory reflexes during myocardial ischemia through stimulation of TxA2/prostaglandin endoperoxide (TP) receptors. Regional myocardial ischemia was induced by occlusion of a diagonal branch of left anterior descending coronary artery of anesthetized cats. Hemodynamic parameters and renal sympathetic nerve activity were recorded after sinoaortic denervation and bilateral vagotomy. Regional myocardial ischemia evoked significant increases in mean blood pressure (122+/-10 vs. 139+/-12 mmHg, before vs. ischemia), aortic flow (153+/-18 vs. 167+/-20 ml/min), first derivative of left ventricular pressure at 40-mmHg developed pressure (2,736+/-252 vs. 2,926+/-281 mmHg/s), systemic vascular resistance (0.6+/-0.1 vs. 0.9+/-0.12 peripheral resistance units), and renal sympathetic nerve activity (by 22%). The reflex nature of the excitatory responses was confirmed by observing its disappearance after blockade of cardiac nerve transmission with intrapericardial 2% procaine treatment. Moreover, application of U-46619 (2.5-10 microg), a TxA2 mimetic, on the heart caused graded increases in mean arterial pressure and renal nerve activity, responses that were abolished 3 min after local blockade of cardiac neural transmission with intrapericardial procaine. BM 13,177 (30 mg/kg iv), a selective TP receptor antagonist, eliminated the reflex responses to U-46619 and significantly attenuated the excitatory responses during brief (5 min) regional myocardial ischemia. The sympathoexcitatory reflex responses to U-46619 were unchanged by blockade of histamine H1 receptors with pyrilamine and serotonin 5-HT3 receptors with tropisetron, indicating specificity of this TP receptor agonist. These data indicate that endogenous TxA2 participates in myocardial ischemia-mediated sympathoexcitatory reflex responses through a TP receptor mechanism.