The Efficacy and Safety Profile of Netarsudil 0.02% in Glaucoma Treatment: Real-World Outcomes

Introduction: More effective glaucoma medications are necessary as medication intolerance and non-adherence remain problematic. Netarsudil is a newly FDA-approved Rho kinase inhibitor. We hypothesize that netarsudil will safely reduce intraocular pressure (IOP) compared to baseline even while other glaucoma medications are used. Methods: This retrospective observational study was conducted on glaucoma patients seen at the Wills Eye Hospital Glaucoma Service who received netarsudil 0.02% between March and September of 2018. Intraocular pressure (IOP, via Goldmann applanation tonometry) and best corrected visual acuity (BCVA, via Snellen visual acuity charts) comparisons between baseline and 1- and 3-month follow-up visits were performed using Student’s t-tests. Results: This study included 172 eyes of 108 patients. Compared to baseline, a mean±SD decrease in IOP of 3.67±4.91 and 3.91±4.83 mmHg was noted at 1- and 3-month follow-up visits, respectively (both p\u3c0.001). No statistically significant difference in IOP change between patients on ≥3 and \u3c3 glaucoma medications at month 1 was observed (p=0.667). Conjunctival hyperemia was the most common side effect at months 1 and 3 (15.7% and 23.0% of patients, respectively). Blurred vision was reported at 1- and 3-month follow-up (5.8% and 8.0% of patients, respectively), but no significant difference in BCVA was observed (p= 0.723 and 0.611, respectively). Discussion: With a mild side effect profile, netarsudil yielded a significant IOP reduction in glaucoma patients, including significant reductions in patients on ≥3 medications. Given its efficacy and unique mechanism of action, earlier-line use of netarsudil may be considered

Ahmed vs Baerveldt Glaucoma Drainage Device in Uveitic Glaucoma

Introduction: Uveitis is an inflammatory eye disorder which may elevate intraocular pressure (IOP), causing sight-threatening glaucoma. Treatment of refractory uveitic glaucoma involves implantation of a glaucoma drainage device (GDD). Uveitic glaucoma has been a minority diagnosis in prior studies comparing the valved Ahmed GDD and non-valved Baerveldt GDD. Here we compare the safety and efficacy of the Ahmed and Baerveldt GDD in uveitic glaucoma. Methods: This retrospective comparative study was conducted on patients with uveitic glaucoma (≥14 years old) who underwent Ahmed or Baerveldt GDD implantation between 2006–2018 with a minimum follow-up of 3 months. Success was defined as IOP of 6-21 mmHg with (complete success) or without (qualified success) medications, with at least light perception vision and no further glaucoma surgery. Pearson Chi-squared test, independent t test, and Kaplan-Meier survival model were utilized for statistical analysis. Results: 137 eyes of 122 patients (67 Ahmed and 70 Baerveldt) were included. Baseline characteristics were comparable in both groups. The Baerveldt group experienced greater IOP reduction (60.3% vs. 44.5%), higher complete success rate (28.6% vs. 10.4%), higher complication rate (44.3% vs. 20.9%), and higher hypotony rate (10% vs. 0%) than the Ahmed group (all p values \u3c0.05). Discussion: Our results are in line with pooled analysis of previous GDD comparison studies on various types of glaucoma. For patients with uveitic glaucoma, the Baerveldt implant provided a significantly higher success rate and greater IOP reduction with fewer medications, but was associated with a higher complication rate, compared to the Ahmed implant

Tyrosine Phosphorylation of Rac1: A Role in Regulation of Cell Spreading

Rac1 influences a multiplicity of vital cellular- and tissue-level control functions, making it an important candidate for targeted therapeutics. The activity of the Rho family member Cdc42 has been shown to be modulated by tyrosine phosphorylation at position 64. We therefore investigated consequences of the point mutations Y64F and Y64D in Rac1. Both mutations altered cell spreading from baseline in the settings of wild type, constitutively active, or dominant negative Rac1 expression, and were accompanied by differences in Rac1 targeting to focal adhesions. Rac1-Y64F displayed increased GTP-binding, increased association with βPIX, and reduced binding with RhoGDI as compared with wild type Rac1. Rac1-Y64D had less binding to PAK than Rac1-WT or Rac1-64F. In vitro assays demonstrated that Y64 in Rac1 is a target for FAK and Src. Taken together, these data suggest a mechanism for the regulation of Rac1 activity by non-receptor tyrosine kinases, with consequences for membrane extension

Transcriptomic Profiling of Virus-Host Cell Interactions following Chicken Anaemia Virus (CAV) Infection in an In Vivo Model.

Chicken Anaemia Virus (CAV) is an economically important virus that targets lymphoid and erythroblastoid progenitor cells leading to immunosuppression. This study aimed to investigate the interplay between viral infection and the host's immune response to better understand the pathways that lead to CAV-induced immunosuppression. To mimic vertical transmission of CAV in the absence of maternally-derived antibody, day-old chicks were infected and their responses measured at various time-points post-infection by qRT-PCR and gene expression microarrays. The kinetics of mRNA expression levels of signature cytokines of innate and adaptive immune responses were determined by qRT-PCR. The global gene expression profiles of mock-infected (control) and CAV-infected chickens at 14 dpi were also compared using a chicken immune-related 5K microarray. Although in the thymus there was evidence of induction of an innate immune response following CAV infection, this was limited in magnitude. There was little evidence of a Th1 adaptive immune response in any lymphoid tissue, as would normally be expected in response to viral infection. Most cytokines associated with Th1, Th2 or Treg subsets were down-regulated, except IL-2, IL-13, IL-10 and IFNγ, which were all up-regulated in thymus and bone marrow. From the microarray studies, genes that exhibited significant (greater than 1.5-fold, false discovery rate <0.05) changes in expression in thymus and bone marrow on CAV infection were mainly associated with T-cell receptor signalling, immune response, transcriptional regulation, intracellular signalling and regulation of apoptosis. Expression levels of a number of adaptor proteins, such as src-like adaptor protein (SLA), a negative regulator of T-cell receptor signalling and the transcription factor Special AT-rich Binding Protein 1 (SATB1), were significantly down-regulated by CAV infection, suggesting potential roles for these genes as regulators of viral infection or cell defence. These results extend our understanding of CAV-induced immunosuppression and suggest a global immune dysregulation following CAV infection

Parent perceptions of the quality of life of pet dogs living with neuro-typically developing and neuro-atypically developing children: an exploratory study

There is growing scientific and societal recognition of the role that pet dogs can play in healthy development of children; both those who are neuro-typically developing and those who live with a neuro-developmental disorder, such as autism or attention deficit hyperactivity disorder. However, little attention has been paid to how living with children positively and negatively affects quality of life of a pet dog. In this exploratory study we conducted semi-structured interviews with parents of neuro-typically developing children (n = 18) and those with a neuro-developmental disorder (n = 18) who owned a pet dog, until no new factors were identified. Living with children brought potentially positive benefits to the dog’s life including: imposition of a routine, participation in recreational activities and the development of a strong bond between the child and the dog. The importance of maintaining a routine was particularly prevalent in families with children with neuro-developmental disorders. Potential negative factors included having to cope with child meltdowns and tantrums, over stimulation from child visitors, harsh contact and rough and tumble play with the child. The regularity and intensity of meltdowns and tantrums was particularly evident in responses from parents with children with a neuro-developmental disorder. However, child visitors and rough play and contact were mentioned similarly across the groups. Protective factors included having a safe haven for the dog to escape to, parent’s awareness of stress signs and child education in dog-interaction. Parents were also asked to complete a stress response scale to provide an initial quantitative comparison of stress responses between dogs living with the two family-types. Parents with neuro-typically developing children more frequently observed their dog rapidly running away from a situation and less frequently observed their dog widening their eyes, than parents with children with a neuro-developmental disorder. We propose the development of a stress audit based on the findings reported here, to prevent potential dangerous situations, which may lead to dog bites and dog relinquishment and allow owners to maximise the benefits of dog ownership

Feeding mice with diets containing mercury-contaminated fish flesh from French Guiana: a model for the mercurial intoxication of the Wayana Amerindians

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Genetic Signatures of Exceptional Longevity in Humans

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity

Impact of inactivity and exercise on the vasculature in humans

The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct “vascular deconditioning and conditioning” effects which likely modify cardiovascular risk