THE EXPRESSION PROFILE OF A GWAS DETECTED GENE (NINJ2) IN THE BRAIN OF A MOUSE MODEL OF ISCHEMIC STROKE

Stroke is the third leading cause of death and a major debilitating disease in the United States. Multiple factors, including genetic factors, contribute to the development of the disease. Genome-wide association studies (GWAS) have contributed to the identification of genetic loci influencing risk for complex diseases, such as stroke. In 2010, a GWAS of incident stroke was performed in four large prospective cohorts from the USA and Europe and identified an association of two Single Nucleotide Polymorphisms (SNPs) on chromosome 12p13 with a greater risk of ischemic stroke in individuals of European and African-American ancestry. These SNPs are located 11 Kb upstream of the nerve injury-induced gene 2, Ninjurin2 (NINJ2), suggesting that this gene may be involved in stroke pathogenesis. NINJ2 is a cell adhesion molecule induced in the distal glial cells from a sciatic-nerve injury at 7-days after injury. In an effort to ascribe a possible role of NINJ2 in stroke, we have assessed changes in the level of gene and protein expression of NINJ2 following a time-course from a transiently induced middle cerebral artery ischemic stroke in mice brains. We report an increase in the gene expression of NINJ2 in the ischemic and peri-infarct (ipsilateral) cortical tissues at 7 and 14-days after stroke. We also report an increase in the protein expression of NINJ2 in the cortex of both the ipsilateral and contralateral cortical tissues at the same time-points. We conclude that the expression of NINJ2 is regulated by an ischemic stroke in the cortex and is consistent with NINJ2 being involved in the recovery time-points of stroke.

Community health workers: The critical link to sustainable, healthy societies in low-resource settings---A model for the Baylor Shoulder to Shoulder Foundation

Community health workers (CHWs) can serve as a bridge between healthcare providers and communities to positively impact social determinants of health and, thus, the overall health of the population. The potential to effect lasting change is particularly significant within resource-poor settings with limited access to formally trained health care providers such as the small, rural village of Santa Ana Intibucá, Honduras and surrounding areas—located on the geographically and politically isolated border of Honduras and El Salvador. The Baylor Shoulder to Shoulder Foundation (BSTS) works in conjunction with Santa Ana's volunteer health committee to bring a health brigade that has provided health care and public health projects to the area at least twice a year since 2001. They have also hired a full-time Honduran physician, a Honduran in-country administrative director, and built a clinic; yet, no community health worker program exists. This CHW program model is the response to a clear need for a CHW program within the area served by BSTS and presents a CHW program model specific to Santa Ana Intibucá and surrounding areas to be implemented by BSTS. Methods used to develop this model include reviewing the literature for recommendations from leading authorities as well as successfully implemented CHW programs in comparable regions. This information was incorporated into existing knowledge and materials currently being used in the area. Using the CHW model proposed here, each brigade, in conjunction with the communities served, can help develop new modules to respond to the specific health priorities of the region at that time, incorporating consistent modes of contact with the local physician and the CHWs to provide refresher courses, training in new topics of interest, and to be reminded of the importance of community health workers' role as the critical link to healthy societies. With cooperation, effort, and support, the brigade can continue to help integrate a sustainable CHW system in which communities may be able to maximize the care they receive while also learning to care for their own health and the future of their communities.^

The two -state model of receptor activation: The agonist and the efficacy

The Two State model describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”. The beta 2 adrenergic receptor system is the model system which was used to formalize the concept of two states, and the mechanism of hormone agonist stimulation of this receptor is similar to ligand activation of other seven transmembrane receptors. Hormone binding to beta 2 adrenergic receptors stimulates the intracellular production of cyclic adenosine monophosphate (cAMP), which is mediated through the stimulatory guanyl nucleotide binding protein (Gs) interacting with the membrane bound enzyme adenylylcyclase (AC). ^ The effects of cAMP include protein phosphorylation, metabolic regulation and transcriptional regulation. The beta 2 adrenergic receptor system is the most well known of its family of G protein coupled receptors. Ligands have been scrutinized extensively in search of more effective therapeutic agents at this receptor as well as for insight into the biochemical mechanism of receptor activation. Hormone binding to receptor is thought to induce a conformational change in the receptor that increases its affinity for inactive Gs, catalyzes the release of GDP and subsequent binding of GTP and activation of Gs. ^ However, some beta 2 ligands are more efficient at this transformation than others, and the underlying mechanism for this drug specificity is not fully understood. The central problem in pharmacology is the characterization of drugs in their effect on physiological systems, and consequently, the search for a rational scale of drug effectiveness has been the effort of many investigators, which continues to the present time as models are proposed, tested and modified. ^ The major results of this thesis show that for many b2 -adrenergic ligands, the Two State model is quite adequate to explain their activity, but dobutamine (+/−3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methylpropyl]- b -phenethylamine) fails to conform to the predictions of the Two State model. It is a weak partial agonist, but it forms a large amount of high affinity complexes, and these complexes are formed at low concentrations much better than at higher concentrations. Finally, dobutamine causes the beta 2 adrenergic receptor to form high affinity complexes at a much faster rate than can be accounted for by its low efficiency activating AC. Because the Two State model fails to predict the activity of dobutamine in three different ways, it has been disproven in its strictest form. ^