Effects of Heavy Metals and Psychostimulants on Dopamine Transporter Function

Heavy metals may alter the abuse liability of drugs due to actions on the dopamine transporter (DAT). This study examined the effects of extended, low-level heavy metal and psychostimulant co-exposure on DAT function. SK-N-SH cells, incubated in the presence of multiple concentrations of lead (Pb), mercury (Hg), cocaine (COC) and methamphetamine (MA), were used to measure LDH activity to determine optimum time/concentration for sublethal exposure assays. Parallel studies were conducted on non-neuronal vs. neuronal cell lines, COS-7(hDAT) and N2A(hDAT) respectively. [3H]GBR12935 binding assays were performed to determine DAT expression at the plasma membrane. [3H]Dopamine uptake assays were conducted to establish effects on DAT functioning. LDH activity significantly increased in both a concentration- and time-dependent manner. Sublethal concentrations of drugs/metals were chosen for further studies (10 ?M for HgCl2 and PbCl2; 100 nM for COC and MA), using a 72 h exposure. COS-7(hDAT) cells revealed expression of DAT, but no DA uptake. N2A(hDAT) cells showed higher expression of functioning DAT. Statistical analysis of the treatment effect on DAT density or DA uptake through the DAT revealed no significance in either cell line. Overall, a trend was observed where DAT density was increased, but caused functional decreases in DA clearance were observed. Individuals exposed to low-levels of Hg, may be at risk for increased DA neurotransmission/ turnover following psychostimulant use, resulting in an elevated addictive, or toxic, potential of these already addictive drugs.Department of Biochemistry and Molecular Biolog

From the Community to the Clinic: Building Community Health Worker-Inclusive Healthcare Teams

Multidisciplinary clinical teams with strong community linkages can engage with patient needs and address the social determinants of health. Community Health Workers (CHWs) have emerged as one such embodiment of this cultural shift in improving delivery and coordination of care to reach patient communities. However, misunderstandings of CHWs’ contributions have limited their uptake into clinical teams. In partnership with the Southwestern Area Health Education Center, this project investigated the context and perspectives of CHW engagement in Connecticut, focusing barriers and facilitators of CHW integration into clinical teams. Through experimentation, innovation, and mutual learning, integrated, CHW-inclusive healthcare teams can begin taking the necessary steps to bridge the divide between the community and the clinic. Commitment to service should be meaningfully considered in the CHW hiring process. Being altruistic, compassionate, nonjudgmental, and service-oriented are important attributes facilitating camaraderie and trust within healthcare teams, while also enhancing CHWs’ long-term commitments to organizations. Purposively seeking out these traits during the onboarding process can foster a team dynamic anchored by CHWs mutual commitment to serving and connecting with patients. Organizations should foster mutual understanding and respect for the varied roles CHWs play. Clearly defining roles and responsibilities and demonstrating the value that CHWs bring outside of the context of clinical care can improve collaboration, encourage skills-sharing, and promote an organizational climate of respect. Organizational decision-makers should increase the visibility of CHWs and include CHWs in conversations and meetings with other clinical team members where added value can be consistently demonstrated and where mutual learning and collaboration can meaningfully occur. Healthcare organizations should critically consider how to holistically support the CHW workforce. Organizational levers that promote retention, mutual learning, networking, and management of job stress amongst CHWs can improve their ability to function effectively and contribute to a diverse team culture. The fact that CHWs not only navigate the disparate worlds of the community and the clinic but also endure the stress of managing complex intra- and extra-organizational relationships should be recognized, valued, and appreciated by organizational leadership.https://elischolar.library.yale.edu/ysph_pbchrr/1049/thumbnail.jp

Addressing People and Place Microenvironments in Weight Loss Disparities (APP-Me): Design of a randomized controlled trial testing timely messages for weight loss behavior in low income black and white women

Background Behavioral interventions for weight loss have been less effective in lower income and black women. These poorer outcomes may in part be related to these women having more frequent exposures to social and physical situations that are obesogenic, i.e., eating and sedentary cues or situations. Objectives Working with obese, lower income black and white women, Addressing People and Place Microenvironments (APP-Me) was designed to create awareness of self-behavior at times and places of frequent eating and sedentary behavior. Design APP-Me is being evaluated in a randomized controlled trial with 240 participants recruited from federally qualified health centers located in a single Midwestern city. All participants complete four weeks of ecological momentary assessments (EMA) of situations and behavior. At the end of the four weeks, participants are randomized to enhanced usual care (UC) or UC plus APPMe. Methods APP-Me is an automated short messaging system (SMS). Messages are text, image, audio, or a combination, and are delivered to participants’ mobile devices with the intent of creating awareness at the times and places of frequent eating or sedentary behavior. The EMA data inform the timing of message deliveries. Summary This project aims to create and test timely awareness messages in a subpopulation that has not responded well to traditional behavioral interventions for weight loss. Novel aspects of the study include the involvement of a low income population, the use of data on time and place of obesogenic behavior, and message delivery time tailored to an individual’s behavioral patterns

Adapting Dietary Guidelines to Client-Centered Preferences at the Downtown Evening Soup Kitchen (DESK)

The Downtown Evening Soup Kitchen (DESK) in New Haven, Connecticut exists to serve individuals who are food insecure, through the provision of meals. A majority of DESK’s food is sourced through donations and federal programs. A significant portion of these donations are from Yale University Dining, where trays of food from the dining hall are delivered multiple times a week. Connecticut faces a 6.4 percent prevalence of households with low food security, exceeding the 5.2 percent national average (Coleman-Jensen, 2017). Meals served at soup kitchens tend to contain high levels of fat and low levels of fiber, vitamins, and minerals (Lyles et al., 2013; Sisson, 2011), contributing to malnutrition, obesity, high blood pressure, and many other chronic conditions (Sisson, 2011). Currently, there are no national guidelines to regulate the nutrition of meals served specifically at these institutions, allowing for the continued distribution of meals with insufficient nutritional value (Koh et al., 2015; Kourgialis et al., 2001). The objectives of this study were as follows: Conduct a nutritional assessment of the dinners served by DESK, establish effective principles for the DESK menu based on the 2015-2020 Dietary Guidelines for Americans, and incorporate client food preferences in menu adaptations.https://elischolar.library.yale.edu/ysph_pbchrr/1018/thumbnail.jp

Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al

Metabolic analysis of the interaction between plants and herbivores

Insect herbivores by necessity have to deal with a large arsenal of plant defence metabolites. The levels of defence compounds may be increased by insect damage. These induced plant responses may also affect the metabolism and performance of successive insect herbivores. As the chemical nature of induced responses is largely unknown, global metabolomic analyses are a valuable tool to gain more insight into the metabolites possibly involved in such interactions. This study analyzed the interaction between feral cabbage (Brassica oleracea) and small cabbage white caterpillars (Pieris rapae) and how previous attacks to the plant affect the caterpillar metabolism. Because plants may be induced by shoot and root herbivory, we compared shoot and root induction by treating the plants on either plant part with jasmonic acid. Extracts of the plants and the caterpillars were chemically analysed using Ultra Performance Liquid Chromatography/Time of Flight Mass Spectrometry (UPLCT/MS). The study revealed that the levels of three structurally related coumaroylquinic acids were elevated in plants treated on the shoot. The levels of these compounds in plants and caterpillars were highly correlated: these compounds were defined as the ‘metabolic interface’. The role of these metabolites could only be discovered using simultaneous analysis of the plant and caterpillar metabolomes. We conclude that a metabolomics approach is useful in discovering unexpected bioactive compounds involved in ecological interactions between plants and their herbivores and higher trophic levels.

Hybrid closed‐loop glucose control with faster insulin aspart compared with standard insulin aspart in adults with type 1 diabetes: A double‐blind, multicentre, multinational, randomized, crossover study

Abstract: Aim: To evaluate the use of hybrid closed‐loop glucose control with faster‐acting insulin aspart (Fiasp) in adults with type 1 diabetes (T1D). Research Design and Methods: In a double‐blind, multinational, randomized, crossover study, 25 adults with T1D using insulin pump therapy (mean ± SD, age 38 ± 9 years, HbA1c 7.4% ± 0.8% [57 ± 8 mmol/mol]) underwent two 8‐week periods of unrestricted living comparing hybrid closed‐loop with Fiasp and hybrid closed‐loop with standard insulin aspart in random order. During both interventions the CamAPS FX closed‐loop system incorporating the Cambridge model predictive control algorithm was used. Results: In an intention‐to‐treat analysis, the proportion of time sensor glucose was in the target range (3.9–10.0 mmol/L; primary endpoint) was not different between interventions (75% ± 8% vs. 75% ± 8% for hybrid closed‐loop with Fiasp vs. hybrid closed‐loop with standard insulin aspart; mean‐adjusted difference −0.6% [95% CI −1.8% to 0.7%]; p < .001 for non‐inferiority [non‐inferiority margin 5%]). The proportion of time with sensor glucose less than 3.9 mmol/L (median [IQR] 2.4% [1.2%–3.2%] vs. 2.9% [1.7%–4.0%]; p = .01) and less than 3.0 mmol/L (median [IQR] 0.4% [0.2%–0.7%] vs. 0.7% [0.2%–0.9%]; p = .03) was reduced with Fiasp versus standard insulin aspart. There was no difference in mean glucose (8.1 ± 0.8 vs. 8.0 ± 0.8 mmol/L; p = .13) or glucose variability (SD of sensor glucose 2.9 ± 0.5 vs. 2.9 ± 0.5 mmol/L; p = .90). Total daily insulin requirements did not differ (49 ± 15 vs. 49 ± 15 units/day; p = .45). No severe hypoglycaemia or ketoacidosis occurred. Conclusions: The use of Fiasp in the CamAPS FX closed‐loop system may reduce hypoglycaemia without compromising glucose control compared with standard insulin aspart in adults with T1D

Quality standards for the management of alcohol-related liver disease: consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology ARLD special interest group

Objective Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care.Design A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology ALD Special Interest Group developed the quality standards, with input from the British Liver Trust and patient representatives.Results The standards cover three broad themes: the recognition and diagnosis of people with ALD in primary care and the liver outpatient clinic; the management of acutely decompensated ALD including acute alcohol-related hepatitis and the posthospital care of people with advanced liver disease due to ALD. Draft quality standards were initially developed by smaller working groups and then an anonymous modified Delphi voting process was conducted by the entire group to assess the level of agreement with each statement. Statements were included when agreement was 85% or greater. Twenty-four quality standards were produced from this process which support best practice. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice and an audit tool provided.Conclusion It is hoped that services will review their practice against these recommendations and key performance indicators and institute service development where needed to improve the care of patients with ALD