A Role for Cilia in Endocardial Cushion Development

Congenital heart defects due to the aberrant development of the atrioventricular (AV) valves and septum are among the most common developmental abnormality in newborns and cause significant neonatal morbidity and mortality. A key point in cardiac morphogenesis occurs when cells within the endocardial cushions (ECCs), the precursors for the AV valvoseptal complex, delaminate and undergo an epithelial-to-mesenchymal transformation (EMT). The mesenchymal cells then proliferate and the cushion area elongates to form the AV valves and portions of the AV septae. The signals that initiate region-specific EMT during heart development are unknown. Cilia, known for their role in establishing left-right (LR) asymmetry, function to receive and integrate extracellular signals, including fluid flow, in a range of other organ systems. We hypothesize that cilia could also have a direct role in heart development outside of their role in LR development. Using immunohistochemistry, we demonstrated the presence of cilia on the myocardium, epicardium, and ECCs of wild-type mouse hearts at embryonic day (e) 9.5 and e12.5. To characterize the potential role of these cilia, we compared mice with mutations affecting ciliary biogenesis, motility, and mechanosensation. Using bright field microscopy and in situ hybridization, we analyzed the embryonic heart structure and the expression pattern of Gata4, an EMT transcription factor. We showed that compared to mice with immotile but structurally normal cilia, the mice without cilia had hypocellular ECCs, a thinned compact myocardium (CM), and an up-regulated expression of Gata4. These observations suggest that a subset of cilia called cardiac cilia have a role in cardiogenesis outside of their role in LR development and affect Gata4 expression. One possible function of cardiac cilia is as mechanosensors, integrating fluid flow and influencing cardiac morphogenesis including EMT and development of the CM

Sensitivity and Resistance to Regulation by IL-4 in Th17 Cells: Molecular Mechanisms and Significance in Autoimmune Disease.

Th17 cells promote immune-mediated diseases, including rheumatoid arthritis, and a thorough understanding of Th17 responses may prove therapeutically useful. We therefore chose to characterize the mechanisms of Th17 suppression by the Th2 cytokine IL-4. After one week of in vitro differentiation or a two week immunization in vivo, IL-4 inhibits expression of several Th17-family genes, including IL-17A, IL-17F and RORγt, and this suppression overcomes stimulation by TGFβ, IL-6 and IL-23. However, suppression by IL-4 is unstable and does not induce Th2 conversion. The mechanism of suppression downstream of the IL-4R is dependent on STAT6 but independent of STAT5, IRS-2 and GATA-3. At the chromatin level, IL-4 up-regulates markers of active transcription at the Il17a locus, including histone acetylation and PolII binding, despite clear down-regulation of IL-17A message. However, IL-4 also displaces the transcriptional inducer STAT3 from the Il17a promoter, suggesting that a transcriptional repressor may take its place. We found that Th17 cells undergo a process of maturation, whereby in vitro-generated Th17 cells stimulated for three weeks or in vivo-generated Th17 cells re-stimulated for three days become resistant to suppression by IL-4. This transition depends on a combination of TCR and cytokine stimuli and results in desensitization of the IL-4R. Specifically, mature Th17 cells lose the ability to phosphorylate STAT6 in response to IL-4, despite normal expression of the IL-4R. The suppression of IL-4R signaling did not depend on SOCS5, but may be mediated by SOCS1. To explore the regulation of IL-17 by IL-4 and IFNγ in collagen-induced arthritis (CIA), we treated mice with cytokine-neutralizing antibodies in vivo during disease. The results showed that IFNγ plays a protective role via down-regulation of IL-17. IL-4, once released from suppression by IFNγ, also plays a protective role, particularly in bone and cartilage erosion. However, the protective role of IL-4 is not mediated by suppression of IL-17. Interestingly, when both IFNγ and IL-4 are neutralized, mice develop severe arthritis independent of IL-17. These results indicate that regulation of Th17-driven tissue inflammation is possible. However, effective use of such approaches depends on detailed understanding of Th17 differentiation and maturation in a specific autoimmune disease.PhDImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/77923/1/ltesmer_1.pd

Disconnected Young People in New York City: Crisis and Opportunity

Commissioned by JobsFirstNYC, this report examines what is known about New York City's disconnected youth -- 16 to 24 year-olds who are not working and not in school. The report explores the roots of disconnection and identifies five priority populations of young people who are at high risk of becoming disconnected. It presents information about specific areas of the city with high concentrations of disconnected young people and summarizes a number of promising strategies for reclaiming this important human resource

Accessibility of Pregnancy Termination: A Pilot Study of Genetic Counselors and Abortion Providers Throughout the United States

Recent literature suggests that availability and accessibility of pregnancy termination services affects patient care and decision-making. Because of this, there is a need to evaluate the impact of new legislation on accessibility. This study evaluated the accessibility of pregnancy termination throughout the United States by surveying prenatal genetic counselors and abortion providers. 116 responses from currently practicing prenatal genetic counselors and 30 responses from abortion providers within the United States were used in data analysis. Accessibility of pregnancy termination was assessed using the variables of cost, time, and distance. The degree of legislative impact was estimated using Guttmacher Institute’s Policy Trends in the States 2017, which categorizes states into four regions: supportive, middle-ground, hostile, and extremely hostile, based on the number of abortion restrictions enacted. Overall, the findings show some evidence indicating that access to abortion is more limited in states with increased legislation. Genetic counselors in hostile states were more likely to refer patients to outside providers at every evaluated gestational age range than counselors in supportive states, with 89.9% of counselors referring to providers greater than 4 hours away for referrals over 24 weeks gestation compared to 56.5% in supportive states. Counselors in hostile states were also more likely to report factors such as insurance coverage, out of pocket costs, wait times, travel, and the availability of appointments as having an impact on patients’ decisions to terminate a pregnancy than counselors in supportive states

Microdamage repair and remodeling requires mechanical loading

Bone remodeling is necessary to avoid microdamage accumulation, which could lead to whole-bone failure. Previous studies have shown that this bone-repair mechanism is triggered by osteocyte apoptosis. Through the use of a rodent hindlimb suspension model and tibial four-point bending model, the effects of disuse on microdamage remodeling was examined. At day 0, male rats were assigned to one of three groups: weight bearing (WB), hindlimb suspension (HS), or hindlimb suspension with daily intermittent weight bearing following damage-inducing loading (HW). Within each group, the rats were further divided into subgroups corresponding to three sacrifice time points [day 14 (WB and HS only), day 18, or day 35]. At day 14, animals were anesthetized, and their left tibiae underwent cyclic four-point bending to produce fatigue-induced microdamage. At sacrifice, the tibiae were examined using 3D micro-computed tomography (µCT), flow cytometry, and histologic and immunohistochemical stains. The results indicate that only the WB and HW groups had a significant increase in intracortical TRAP-positive resorption pits following damage induction, which was paralleled by a significant decrease in microdamage over time in combination with a shift in the osteoclast lineage owing to a decrease in monocytes. These results demonstrate that osteocyte apoptosis may be insufficient for repair of microdamage without the stimulation provided through physiologic loading. In addition, this potentially could have clinical implications for the current therapeutic paradigm for treating stress fractures, where extended non-weight bearing is employed. © 2010 American Society for Bone and Mineral ResearchPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71374/1/91016_ftp.pd

Deaths in Custody; Is Ireland’s Investigative Process Compliant with Article 2 of the European Convention on Human Rights?

This research report examines the investigative process regarding deaths in custody in Ireland and other jurisdictions. The students completed this research as part of the LLB Bachelor of Law programme. This project was designed and completed in collaboration with the Irish Penal Reform Trust

A polymorphism in the interleukin-4 receptor affects the ability of interleukin-4 to regulate Th17 cells: a possible immunoregulatory mechanism for genetic control of the severity of rheumatoid arthritis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94408/1/Wallis_2011_Polymorphism_interleukin-4_receptor.pdf165

Evaluation of Social Media Use by Emergency Medicine Residents and Faculty

Introduction Clinicians and residency programs are increasing their use of social media (SM) websites for educational and promotional uses, yet little is known about the use of these sites by residents and faculty. The objective of the study is to assess patterns of SM use for personal and professional purposes among emergency medicine (EM) residents and faculty. Methods In this multi-site study, an 18-question survey was sent by e-mail to the residents and faculty in 14 EM programs and to the Council of Emergency Medicine Residency Directors (CORD) listserv via the online tool SurveyMonkey™. We compiled descriptive statistics, including assessment with the chi-square test or Fisher’s exact test. StatsDirect software (v 2.8.0, StatsDirect, Cheshire, UK) was used for all analyses. Results We received 1,314 responses: 63% of respondents were male, 40% were <30 years of age, 39% were between the ages 31 and 40, and 21% were older than 40. The study group consisted of 772 residents and 542 faculty members (15% were program directors, 21% were assistant or associate PDs, 45% were core faculty, and 19% held other faculty positions. Forty-four percent of respondents completed residency more than 10 years ago. Residents used SM markedly more than faculty for social interactions with family and friends (83% vs 65% [p<0.0001]), entertainment (61% vs 47% [p<0.0001]), and videos (42% vs 23% [p=0.0006]). Residents used Facebook™ and YouTube™ more often than faculty (86% vs 67% [p<0.001]; 53% vs 46% [p=0.01]), whereas residents used Twitter™ (19% vs 26% [p=0.005]) and LinkedIn™ (15% vs 32% [p<0.0001]) less than faculty. Overall, residents used SM sites more than faculty, notably in daily use (30% vs 24% [p<0.001]). For professional use, residents were most interested in its use for open positions/hiring (30% vs 18% [p<0.0001]) and videos (33% vs 26% [p=0.005]) and less interested than faculty with award postings (22% vs 33% [p<0.0001]) or publications (30% vs 38% [p=0.0007]). Conclusion EM residents and faculty have different patterns and interests in the personal and professional uses of social media. Awareness of these utilization patterns could benefit future educational endeavors