Pharmacokinetics and Pharmacodynamics in Space

The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic regimens

Intranasal scopolamine preparation and method

A new method and preparation for intranasal delivery of scopolamine provides a safe and effective treatment for motion sickness and other conditions requiring anticholinergic therapy. The preparation can be in the form of aqueous nasal drops, mist spray, gel or oinment. Intranasal delivery of scopolamine has similar bioavailability and effect of intravenous delivery and is far superior to oral dosage. Scopolamine is prepared in a buffered saline solution at the desired dosage rate for effective anticholinergic response

Civic pride or civic duty? : an examination of willingness to support a professional sport stadium referendum.

Professional sport stadium subsidization is abundant across the United States, where the voting public is sometimes provided the opportunity to approve the measures through referendum. Many of these referendums are approved by the voters (Kellison & Mondello, 2014; Mondello & Anderson, 2004), despite research stating professional sport stadiums bring little to no economic benefit to a municipality (Baade, 1994, 1996; Baade & Dye, 1988a, 1990; Baade et al., 2008; Coates & Humphreys, 1999, 2002; Euchner, 1993; Zipp, 1996). Therefore, the purpose of this study was to understand what factors may influence a constituent’s willingness to support a professional sport stadium referendum. Research has suggested economic benefits such as local economic growth (Santo, 2007), noneconomic benefits such as increased quality of life and civic pride (Castellanos et al., 2011; Fenn & Crooker, 2009; Johnson & Whitehead, 2000; Johnson et al., 2001; Santo, 2007), stakeholder influence (Friedman & Mason, 2004, 2005), and team identification (Depken, 2000) may influence a constituent’s support when faced with a stadium construction projects. The current study examined how voter perceptions of these areas may influence their willingness to support a stadium project. The city of San Diego, California and the 2016 NFL Chargers stadium proposal served as the case study. Ultimately, 182 participants completed the survey. Structural equation modeling was utilized to examine the relationship between the factors. Good model fit was obtained through a number of theoretically acceptable respecifications for both the measurement model and structural model. Results from the structural model supported hypothesis 1 (b = 0.22, p \u3c .001) and hypothesis 4 (b = 0.60, p \u3c .001). A separate mediation analysis utilizing the phantom model approach (macho & Ledermann, 2011) and bootstrapping found no mediating relationship, failing to support hypotheses 6-9. It was ultimately found that voters value the perceived economic benefits associated with the potential professional sport stadium project. Voters’ perceptions of community leaders associated with the project also influenced their willingness to support the stadium project. Team identification and perceptions surrounding noneconomic benefits had no effect on their willingness to support the stadium project

Legal Implications of Conducting Background Checks on Intercollegiate Student Athletes

Non

Structural Insights into Rational Design of Single-Domain Antibody-Based Antitoxins against Botulinum Neurotoxins.

Botulinum neurotoxin (BoNT) is one of the most acutely lethal toxins known to humans, and effective treatment for BoNT intoxication is urgently needed. Single-domain antibodies (VHH) have been examined as a countermeasure for BoNT because of their high stability and ease of production. Here, we investigate the structures and the neutralization mechanisms for six unique VHHs targeting BoNT/A1 or BoNT/B1. These studies reveal diverse neutralizing mechanisms by which VHHs prevent host receptor binding or block transmembrane delivery of the BoNT protease domain. Guided by this knowledge, we design heterodimeric VHHs by connecting two neutralizing VHHs via a flexible spacer so they can bind simultaneously to the toxin. These bifunctional VHHs display much greater potency in a mouse co-intoxication model than similar heterodimers unable to bind simultaneously. Taken together, our studies offer insight into antibody neutralization of BoNTs and advance our ability to design multivalent anti-pathogen VHHs with improved therapeutic properties

Effect of antiorthostatic BedRest (BR) on GastroIntestinal Motility (GIM) of normal subjects

The combined effects of postural changes, fluid shifts and diuresis associated with the absence of the gravity vector may decrease gastrointestinal motility (GIM) during space flight. GIM can be estimated from the mouth to cecum transit time (MCTT) of orally administered lactulose (LAC); this test is used to assess changes in GIM in normal subjects and in patients with GI pathology and related disease conditions. Since bedrest (BR) mimics some of the physiological changes that occur during space flight, the effect of ten days of BR on GIM was evaluated from the MCTT of LAC. Methods: Subjects were 12 nonsmoking males between the ages of 35 and 50. After an 8-10 hour fast, subjects ingested Cephulac (registered) (20 g solution) with a low-fiber breakfast on four different days (45, 30, 25, and 20) before BR and on three separate days (4, 7, and 10) during BR. Breath-H2 concentrations were measured before and at 10 minute intervals for 4 hours after breakfast using a Quintron breathalyzer and MCTT was determined from these data. Results: MCTT ranged between 10 and 122 minutes during ambulation and 80 to 120 minutes during BR with means of 79 minutes and 122 minutes respectively. Conclusion: Mean MCTT during BR was 54 percent longer than during ambulation, suggesting that absorption and availability of orally administered medications and nutrients may be delayed or impaired as a result of decreased GIM during bedrest

SparkMaster 2: a new software for automatic analysis of calcium spark data

Background: Calcium (Ca) sparks are elementary units of subcellular Ca release in cardiomyocytes and other cells. Accordingly, Ca spark imaging is an essential tool for understanding the physiology and pathophysiology of Ca handling and is used to identify new drugs targeting Ca-related cellular dysfunction (eg, cardiac arrhythmias). The large volumes of imaging data produced during such experiments require accurate and high-throughput analysis. Methods: We developed a new software tool SparkMaster 2 (SM2) for the analysis of Ca sparks imaged by confocal line-scan microscopy, combining high accuracy, flexibility, and user-friendliness. SM2 is distributed as a stand-alone application requiring no installation. It can be controlled using a simple-to-use graphical user interface, or using Python scripting. Results: SM2 is shown to have the following strengths: (1) high accuracy at identifying Ca release events, clearly outperforming previous highly successful software SparkMaster; (2) multiple types of Ca release events can be identified using SM2: Ca sparks, waves, miniwaves, and long sparks; (3) SM2 can accurately split and analyze individual sparks within spark clusters, a capability not handled adequately by prior tools. We demonstrate the practical utility of SM2 in two case studies, investigating how Ca levels affect spontaneous Ca release, and how large-scale release events may promote release refractoriness. SM2 is also useful in atrial and smooth muscle myocytes, across different imaging conditions. Conclusions: SparkMaster 2 is a new, much-improved user-friendly software for accurate high-throughput analysis of line-scan Ca spark imaging data. It is free, easy to use, and provides valuable built-in features to facilitate visualization, analysis, and interpretation of Ca spark data. It should enhance the quality and throughput of Ca spark and wave analysis across cell types, particularly in the study of arrhythmogenic Ca release events in cardiomyocytes

Supporting Family Members of Youth in Mental Health Crisis

The Sibling Support Program: A Family-Centered Mental Health Initiative, developed at the E.K. Shriver Center of UMass Medical School, addresses the impact of a youth’s mental health challenges on typically-developing siblings and caregivers. The project is an IRB-approved research study at Cambridge Health Alliance, and the principles of the project have been implemented at three sites in Worcester that provide gradated levels of care, ranging from residential to community-based. Findings show that regardless of the severity of a child’s mental health challenges, as evidenced by the level of care the child receives, family members display a similar need for support. The three sites in Worcester are: Continuing Care Units (CCU) at Worcester Recovery Center & Hospital; the Center for Autism and Neurodevelopmental Disorders (CANDO) at UMass Medical School; and a community collaboration between the Massachusetts Child Psychiatry Access Program (McPAP), the Parent/Professional Advocacy League (PPAL), and the department of psychiatry at UMass Medical School. The project aims to increase resiliency and mitigate the trauma commonly experienced by siblings of youth with mental health needs; build skills, competency and confidence among parents; strengthen the family unit; and build capacity among psychiatry trainees. Interventions include psycho-educational groups for caregivers and sibling support groups for children growing up alongside the affected youth. Participants completed surveys following the intervention to report on knowledge learned, satisfaction level, and behavioral change anticipated by the participant. This innovative program utilizes parent mentors and trainees to deliver interventions, with high satisfaction scores among participants. Results suggest that a child’s mental health challenges can be traumatic for family members, and that sharing stories and being introduced to coping skills can help alleviate the stress and anxiety related to living with a child with mental health issues. The program serves as a training elective for psychiatry residents at UMMS

Analysis of mangrove forest succession, using sediment cores: A case study in the cananéia -iguape coastal system, São Paulo-Brazil

Sediment cores are an essential tool for the analysis of the dynamics of mangrove succession. Coring was used to correlate changes in depositional environments and lateral sedimentary facies with discrete stages of forest succession at the Cananeia-Iguape Coastal System in southeastern Brazil. A local level successional pattern was examined based on four core series T1) a sediment bank; T2) a smooth cordgrass Spartina alterniflora bank; T3) an active mangrove progradation fringe dominated by Laguncularia racemosa, and; T4) a mature mangrove forest dominated by Avicennia schaueriana. Cores were macroscopically described in terms of color, texture, sedimentary structure and organic components. The base of all cores exhibited a similar pattern suggesting common vertical progressive changes in depositional conditions and subsequent successional colonization pattern throughout the forest. The progradation zone is an exposed bank, colonized by S. alterniflora. L. racemosa, replaces S. alterniflora as progradation takes place. As the substrate consolidates A. schaueriana replaces L. racemosa and attains the greatest structural development in the mature forest. Cores collected within the A. schaueriana dominated stand contained S. alterniflora fragments near the base, confirming that a smooth cordgrass habitat characterized the establishment and early seral stages. Cores provide a reliable approach to describe local-level successional sequences in dynamic settings subject to drivers operating on multiple temporal and spatial scales where spatial heterogeneity can lead to multiple equilibria and where similar successional end-points may be reached through convergent paths