A Life Course Study of Early Childhood Height Growth and Adult Working Memory and Depression Outcomes

Evidence has been mounting that exposures during fetal development and early postnatal life are important determinants of many adult health outcomes including. diabetes, obesity and cardiovascular disease. Critical periods of early development have been identified for certain outcomes. Early life factors are suspected as having a role in cognitive and psychiatric outcomes, but research to date is limited. Birth weight, considered a marker for fetal development, has been positively associated with cognitive abilities. A few postnatal studies provide evidence that early childhood height growth, an indicator of overall development, is also positively associated with cognitive abilities in adults under age 25 years. There has been no research on early childhood height growth and cognitive outcomes in middle age adults. Low birth weight has also been associated with a spectrum of neuropsychiatric disorders, including, in one study, affective disorders. There are no known studies of early childhood height growth and neuropsychiatric disorders. With this background, I made two hypotheses. First, I hypothesized that early childhood height growth is positively associated with working memory ability in middle age adults. Second, I hypothesized that early childhood height growth is inversely associated with lifetime major depressive disorder in middle age adults. I also explored effect modification by sex and by small for gestational age status. I tested these hypotheses using data from the Early Determinants of Adult Health (EDAH) study and its sister study Fetal Antecedents of Major Depression and Cardiovascular Disease (MDCVD). These studies were adult follow-up studies of two birth cohorts recruited in the 1960’s: the Child Health and Development Studies (CHDS) and the New England Family Study (NEFS); both followed subjects from birth through childhood. Birth length and successive early childhood height measures were available enabling a study of three height growth periods, birth to 4 months, 4 months to 1 year and 1 to 4 years. The adult follow up study included 4 measures of different aspects of working memory ability as well as a structured interview that assessed neuropsychiatric outcomes including lifetime major depressive disorder. We found some evidence that early childhood height growth was positively associated with adult working memory ability in specific growth periods. Results of the analysis of early childhood height growth and adult lifetime MDD do not support the association between early childhood height growth and lifetime MDD

Eustachian tube symptoms are frequent in chronic rhinosinusitis and respond well to endoscopic sinus surgery

BACKGROUND: Symptoms of Eustachian tube (ET) dysfunction are seldom assessed in patients with chronic rhinosinusitis (CRS). The Sino-Nasal Outcome Test (SNOT-22) quality-of-life tool includes two questions that specifically screen for symptoms of ET dysfunction (Ear Fullness; Ear Pain). OBJECTIVE: The purpose of this study was to determine the extent to which these ET symptoms were present in patients with CRS, and whether these symptoms respond to endoscopic sinus surgery (ESS). METHODOLOGY: SNOT-22 data collected prospectively at time of recruitment into IRB-approved clinical trials or case-control studies in CRS was pooled to provide a cross section of the frequency and severity of ET dysfunction. When applicable to the trials, the SNOT-22 was repeated at least 3 months following ESS. RESULTS: Five trials rendering 131 patients were available for assessment. The control group comprised of 251 participants from two case-control studies. Ear Fullness of equal/greather than 1 was reported in 80/131 CRS patients compared to 45/251 control patients. Ear Pain of equal/greather than 1 was reported in 39/131 CRS patients compared to 33/251 control patients. Following ESS, mean Ear Fullness and Ear Pain scores decreased to 1.17 and 0.73, respectively. CONCLUSION: Symptoms suggestive of ET dysfunction are frequent in CRS, and for most patients the symptoms will decrease post-ESS to a level comparable with a non-CRS population. Patients whose ET symptoms do not respond to ESS may represent a target population for emerging therapeutic options for ET dysfunction

Optimisation of a suppression and replacement therapeutic strategy for animal models of rhodopsin-linked autosomal dominant Retinitis Pigmentosa

THESIS 10066The focus of research presented in this PhD thesis was optimising a therapeutic strategy for an inherited retinal disorder termed Retinitis Pigmentosa (RP). RP is a disease in which the photoreceptors progressively degenerate. This initiates with degeneration of rod cells and as the disease progresses typically the cone photoreceptors are also affected. At the end stage of the disease affected individuals are legally blind. RP can be inherited as an autosomal dominant (adRP), autosomal recessive or x-linked recessive condition, although digenic and mitochondrial inherited forms of the disease have also been characterised

Suppression and Replacement Gene Therapy for Autosomal Dominant Disease in a Murine Model of Dominant Retinitis Pigmentosa

For dominantly inherited disorders development of gene therapies, targeting the primary genetic lesion has been impeded by mutational heterogeneity. An example is rhodopsin-linked autosomal dominant retinitis pigmentosa with over 150 mutations in the rhodopsin gene. Validation of a mutation-independent suppression and replacement gene therapy for this disorder has been undertaken. The therapy provides a means of correcting the genetic defect in a mutation-independent manner thereby circumventing the mutational diversity. Separate adeno-associated virus (AAV) vectors were used to deliver an RNA interference (RNAi)-based rhodopsin suppressor and a codon-modified rhodopsin replacement gene resistant to suppression due to nucleotide alterations at degenerate positions over the RNAi target site. Viruses were subretinally coinjected into P347S mice, a model of dominant rhodopsin-linked retinitis pigmentosa. Benefit in retinal function and structure detected by electroretinography (ERG) and histology, respectively, was observed for at least 5 months. Notably, the photoreceptor cell layer, absent in 5-month-old untreated retinas, contained 3?4 layers of nuclei, whereas photoreceptor ultrastructure, assessed by transmission electron microscopy (TEM) improved significantly. The study provides compelling evidence that codelivered suppression and replacement is beneficial, representing a significant step toward the clinic. Additionally, dual-vector delivery of combined therapeutics represents an exciting approach, which is potentially applicable to other inherited disorders

Structure-activity relationship of a novel family of cysteinyl leukotriene receptor antagonist quinoline compounds with anti-angiogenic activity

Pharacology 2016, London, United Kingdom, 13-15 December 2016Introduction: Previously, we identified quininib (2-[(E)-2-(quinolin-2-yl)vinyl]phenol), a cysteinyl leukotriene receptor antagonist with anti-angiogenic and anti-permeable activity (1,2). Here, we report a structure activity relationship study to more comprehensively characterise features which confer anti-angiogenic activity