High-Dose Ionizing Radiation Impairs Healthy Dendrite Growth in C. elegans.

Purpose: The nervous system is vulnerable to radiation damage, and further optimization is required to increase the efficacy of radiation therapy while reducing harm to neurons. Given recent developments in heavy ion therapy, experimental models would be valuable to improve these therapies. We used the nematode Caenorhabditis elegans (C. elegans) to evaluate the effects of high-dose radiation on neuron development. Methods and Materials: In this study, we used confocal microscopy to assess dendritic growth of the PVD nociceptor after high-dose gamma-irradiation from a Cs-137 source. Results: Irradiation during an early larval stage (L2) delayed overall development but also independently impaired dendrite outgrowth in the PVD nociceptive neuron. Irradiation at L4 larval stage did not result in significant alterations in dendrite morphology. Conclusions: The nematode C. elegans can serve as a high-throughput model to study the effects of high-dose radiation on dendrite growth. We propose that C. elegans can be useful for studies of experimental radiation therapy modalities and dose rates for translational research.

Perspectives of internal medicine physicians regarding medication abortion provision in the primary care setting.

OBJECTIVE: To better understand medication abortion attitudes and interest in future provision among Internal Medicine primary care providers (IM PCPs), and to characterize barriers to provision. STUDY DESIGN: We conducted a survey with IM attendings and trainees at a large academic medical center in Western Pennsylvania. We used descriptive statistics to characterize attitudes towards medication abortion provision, including the belief that it is within their scope of practice and interest in future provision, and to explore perceived barriers to provision. We used logistic regression models to assess factors associated with each of these attitudes. RESULTS: Of 397 eligible attendings and trainees, 121 (30%) completed the survey. Among those surveyed, 44% believed medication abortion is within the scope of practice of IM PCPs with trainees and female-identifying providers being significantly more likely to believe medication abortion is within their scope of practice compared to attending physicians and male physicians (60% vs 30%, p < 0.01 and 53% vs 31%, p = 0.01, respectively). Similarly, 43% endorsed interest in future provision, with trainees (67% vs 23%, p < 0.001) and female providers (54% vs 27%, p = 0.002) being more likely to express interest. The most cited barriers to provision included limited training in residency (70%) and low familiarity with abortion medications (57%). CONCLUSIONS: Many IM providers- particularly trainees- believe medication abortion is within their scope of practice and would like to provide this care. Interventions are needed to provide education and assistance complying with state and federal regulations to enable safe and efficient medication abortion provision by IM providers. IMPLICATIONS: IM departments and residency programs should seek to ensure training is offered to clinicians interested in providing medication abortion as a part of their primary care practice.

Mechanisms that regulate morphogenesis of a highly branched neuron in C. elegans.

The shape of an individual neuron is linked to its function with axons sending signals to other cells and dendrites receiving them. Although much is known of the mechanisms for axonal outgrowth, the striking complexity of dendritic architecture has hindered efforts to uncover pathways that direct dendritic branching. Here we review the results of an experimental strategy that exploits the power of genetic analysis and live cell imaging of the PVD sensory neuron in C. elegans to reveal key molecular drivers of dendrite morphogenesis.

A pulmonary embolism response team's initial 20 month experience treating 87 patients with submassive and massive pulmonary embolism.

Pulmonary Embolism Response Teams (PERTs) have emerged to provide rapid multidisciplinary assessment and treatment of PE patients. However, descriptive institutional experience and preliminary outcomes data from such teams are sparse. PERT activations were identified through a retrospective review. Only confirmed submassive or massive PEs were included in the data analysis. In addition to baseline variables, the therapeutic intervention, length of stay (LOS), in-hospital mortality, and bleeding rate/severity were recorded. A total of 124 PERT activations occurred over 20 months: 43 in the first 10 months and 81 in the next 10. A total of 87 submassive (90.8%) and massive (9.2%) PE patients were included. The median age was 65 (51-75 IQR) years. Catheter-directed thrombolysis (CDT) was administered to 25 patients, systemic thrombolysis (ST) to six, and anticoagulation alone (AC) to 54. The median ICU stay and overall LOS were 6 (3-10 IQR) and 7 (4-14 IQR) days, respectively, with no association with any variables except a brain natriuretic peptide (BNP) >100 pg/mL ( p=0.008 ICU LOS; p=0.047 overall LOS). Twelve patients (13.7%) died in the hospital, nine of whom had metastatic or brain cancer, with a median overall LOS of 13 (11-17 IQR) days. There were five major bleeds: one in the CDT group, one in the ST group, and three in the AC group. Overall, (1) PERT activations increased after the first 10 months; (2) BNP >100 pg/mL was associated with a longer LOS; (3) rates of mortality and bleeding did not correlate with treatment; and (4) the majority of in-hospital deaths occurred in patients with advanced cancer.

Single-molecule imaging of Tau dynamics on the microtubule surface.

The microtubule-associated protein Tau is primarily expressed in neurons and plays an integral role in the regulation of multiple functions within the axon. In the adult brain, the six Tau isoforms are expressed allowing for a complex system of control. Despite Tau's central role, the mechanisms by which Tau acts are not fully understood. We have used single-molecule total internal reflection fluorescence (TIRF) microscopy and the methods described in this chapter to further our knowledge of Tau's behavior and function. We have demonstrated that Tau's dynamic binding behavior allows for regulation of motor protein motility and microtubule dynamics in an isoform-specific manner. The continued use and refinement of the single-molecule techniques detailed here can only further our knowledge of Tau and other proteins integral to the maintenance of axonal transport.

Phosphoregulation of Tau modulates inhibition of kinesin-1 motility.

Microtubule-based axonal transport is tightly regulated by numerous pathways, ensuring appropriate delivery of specific organelle cargoes to selected subcellular domains. Highlighting the importance of this process, pathological evidence has linked alterations in these pathways to the pathogenesis of several neurodegenerative diseases. An important regulator of this system, the microtubule-associated protein Tau, has been shown to participate in signaling cascades, modulate microtubule dynamics, and preferentially inhibit kinesin-1 motility. However, the cellular means of regulating Tau's inhibition of kinesin-1 motility remains unknown. Tau is subject to various posttranslational modifications, including phosphorylation, but whether phosphorylation regulates Tau on the microtubule surface has not been addressed. It has been shown that tyrosine 18 phosphorylated Tau regulates inhibition of axonal transport in the disease state. Tyrosine 18 is both a disease- and nondisease-state modification and is therefore an attractive starting point for understanding control of Tau's inhibition of kinesin-1 motility. We show that pseudophosphorylation of tyrosine 18 reduces 3RS-Tau's inhibition of kinesin-1 motility. In addition, we show that introduction of negative charge at tyrosine 18 shifts Tau's previously described static-dynamic state binding equilibrium toward the dynamic state. We also present the first evidence of Tau's static-dynamic state equilibrium under physiological conditions.

Giving Back: A mixed methods study of the contributions of US-Based Nigerian physicians to home country health systems.

BACKGROUND: There is increased interest in the capacity of US immigrants to contribute to their homelands via entrepreneurship and philanthropy. However, there has been little research examining how immigrant physicians may support health systems and what factors facilitate or raise barriers to increased support. METHODS: This study used an observational design with paper questionnaire and interview components. Our sample was drawn from attendees of a 2011 conference for US Based Nigerian physicians; respondents who were not US residents, physicians, and of Nigerian birth or parentage were excluded from further analysis. Respondents were randomly selected to complete a follow-up interview with separate scripts for those having made past financial contributions or medical service trips to support Nigerian healthcare (Group A) and those who had done neither (Group B). Survey results were analyzed using Fischer exact tests and interviews were coded in pairs using thematic content analysis. RESULTS: Seventy-five of 156 (48 %) individuals who attended the conference met inclusion criteria and completed the survey, and 13 follow-up interviews were completed. In surveys, 65 % percent of respondents indicated a donation to an agency providing healthcare in Nigeria the previous year, 57 % indicated having gone on medical service trips in the prior 10 years and 45 % indicated it was "very likely" or "likely" that they would return to Nigeria to practice medicine. In interviews, respondents tended to favor gifts in kind and financial gifts as modes of contribution, with medical education facilities as the most popular target. Personal connections, often forged in medical school, tended to facilitate contributions. Individuals desiring to return permanently focused on their potential impact and worried about health system under-preparedness; those not desiring permanent return centered on how safety, financial security and health systems issues presented barriers. CONCLUSIONS: This study demonstrates several mechanisms by which health systems may benefit from expatriate engagement. Greater identification of reliable local partners for diaspora, deeper collaboration with those partners and a focus on sustainable interventions might improve the quantity and impact of contributions. Ethnic medical associations have a unique role in organizing and facilitating diaspora response. Public-private partnerships may help diaspora negotiate the challenges of repatriation.