Automated radiosynthesis of [11C]UCB-J for imaging synaptic density by positron emission tomography

An automated radiosynthesis of carbon-11 positron emission tomography radiotracer [¹¹C]UCB-J for imaging the synaptic density biomarker synaptic vesicle glycoprotein SV2A was established using Synthra RNPlus synthesizer. Commercially available trifluoroborate UCB-J analogue was used as a radiolabelling precursor, and the desired radiolabelled product was isolated in 11 ± 2% (n = 7) nondecay corrected radiochemical yield and formulated as a 10% EtOH solution in saline with molar activities of 20 to 100 GBq/μmol. The method was based upon the palladium(0)-mediated Suzuki cross-coupling reaction and [¹¹C]CH₃I as a radiolabelling synthon. The isolated product was cGMP compliant as demonstrated by the results of quality control analysis.     

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long–Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol- and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucrose-seeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanol-seeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.     

Evaluation of a Community Health Worker Intervention to Reduce HIV/AIDS Stigma and Increase HIV Testing Among Underserved Latinos in the Southwestern U.S.

Objectives

Latinos are at an elevated risk for HIV infection. Continued HIV/AIDS stigma presents barriers to HIV testing and affects the quality of life of HIV-positive individuals, yet few interventions addressing HIV/AIDS stigma have been developed for Latinos.

Methods

An intervention led by community health workers (promotores de salud, or promotores) targeting underserved Latinos in three southwestern U.S. communities was developed to decrease HIV/AIDS stigma and increase HIV knowledge and perception of risk. The intervention was led by HIV-positive and HIV-affected (i.e., those who have, or have had, a close family member or friend with HIV/AIDS) promotores, who delivered interactive group-based educational sessions to groups of Latinos in Spanish and English. To decrease stigma and motivate behavioral and attitudinal change, the educational sessions emphasized positive Latino cultural values and community assets. The participant pool comprised 579 Latino adults recruited in El Paso, Texas (n=204); San Ysidro, California (n=175); and Los Angeles, California (n=200).

Results

From pretest to posttest, HIV/AIDS stigma scores decreased significantly (p<0.001). Significant increases were observed in HIV/AIDS knowledge (p<0.001), willingness to discuss HIV/AIDS with one''s sexual partner (p<0.001), and HIV risk perception (p=0.006). Willingness to test for HIV in the three months following the intervention did not increase. Women demonstrated a greater reduction in HIV/AIDS stigma scores when compared with their male counterparts, which may have been related to a greater increase in HIV/AIDS knowledge scores (p=0.016 and p=0.007, respectively).

Conclusion

Promotores interventions to reduce HIV/AIDS stigma and increase HIV-related knowledge, perception of risk, and willingness to discuss sexual risk with partners show promise in reaching underserved Latino communities.Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has disproportionately affected U.S. Latinos during the last 25 years. Although Latinos constitute 16% of the U.S. population, they account for 19% of those living with HIV and 21% of new HIV infections.¹ Since 2006, the Centers for Disease Control and Prevention (CDC) has recommended HIV testing for all people aged 13–64 years.² However, nearly half (46%) of Latino adults aged 18–64 years have never been tested, compared with 23% of black and 50% of white adults.³ Additionally, HIV testing often occurs at a late stage among HIV-positive Latinos. More than one-third (36%) of HIV-positive Latinos were diagnosed with AIDS within one year of learning their HIV status, compared with 32% of white people and 31% of black people.³ Late HIV testing hinders treatment options and may contribute to unknowing HIV transmission.Factors contributing to low HIV testing rates among Latinos include poverty, lack of health-care access, and limited availability of culturally and linguistically responsive services.^1,4–6 HIV/AIDS stigma is another factor.^7,8 UNAIDS (Joint United Nations Programme on AIDS) defines HIV stigma as the “devaluation of people either living with or associated with HIV/AIDS.”⁹ Stigma often results from fears about HIV as well as the associations of HIV with stigmatized groups such as homosexuals, sex workers, and injection drug users.^9,10HIV/AIDS stigma has negative consequences both at a population level and for individuals who are its targets, including people living with HIV/AIDS. Stigmatizing attitudes toward people living with HIV/AIDS are associated with decreased HIV testing, limited utilization of HIV prevention services, and high-risk sexual behaviors.^7,10,11 Additionally, for people living with HIV/AIDS, the stigma associated with HIV/AIDS contributes to unwillingness to disclose HIV status, unsafe sexual behaviors, delays in care seeking, reduced treatment adherence, mental health issues, and difficulties obtaining social support.^9,11–14Despite significant implications, few interventions have been developed to reduce HIV/AIDS stigma.^10,11,15 Existing interventions have often focused on specific populations (e.g., university students and health-care providers), with few interventions focused on Latinos,^11,15,16 who have high levels of stigmatizing attitudes toward people living with HIV/AIDS^1,17,18 that contribute to negative outcomes.^7,19Among Latinos, research indicates that community health workers (promotores de salud, hereinafter “promotores”) are an effective and culturally acceptable means of reaching the population with health information and motivating health behaviors.^20,21 Promotores are well positioned to promote changes in their communities because they share language and cultural values, are held in high esteem, and are perceived as role models.²¹ Promotores have been used to address health conditions ranging from chronic diseases to preventive screenings.^20–22 Several interventions have incorporated promotores into HIV prevention, finding significant changes in HIV risk behaviors, HIV counseling and testing, and other psychosocial constructs important to prevention.^16,23–29 To date, few studies have used promotores in interventions to reduce HIV stigma among Latinos.¹⁶We describe and report findings of an intervention using promotores to reduce HIV/AIDS stigma and increase willingness to seek HIV testing among Latinos in three communities in the southwestern United States: Los Angeles, California; San Ysidro, California; and El Paso, Texas.     

Orexin/hypocretin role in reward: implications for opioid and other addictions

Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for anti-craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug-induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid-mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co-express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the ‘anti-reward’ effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction-related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Preferred Functions of Personal Health Records in Rural Primary Health Clinics in Canada: Health Care Team Perspectives

Background  Personal health records (PHR) provide opportunities for improved patient engagement, collection of patient-generated data, and overcome health-system inefficiencies. While PHR use is increasing, uptake in rural populations is lower than in urban areas. Objectives  The study aimed to identify priorities for PHR functionality and gain insights into meaning, value, and use of patient-generated data for rural primary care providers. Methods  We performed PHR preimplementation focus groups with rural providers and their health care teams from five primary care clinics in a sparsely populated mountainous region of British Columbia, Canada to obtain their understanding of PHR functionality, needs, and perceived challenges. Results  Eight general practitioners (GP), five medical office assistants, two nurse practitioners (NP), and two registered nurses (14 females and 3 males) participated in focus groups held at their respective clinics. Providers (GPs, NPs, and RNs) had been practicing for a median of 9.5 (range = 1–38) years and had used an electronic medical record for 7.0 (1–20) years. Participants expressed interest in incorporating functionality around two-way communication and appointment scheduling, previsit data gathering, patient and provider data sharing, virtual care including visits using videoconferencing tools, and postvisit sharing of educational materials. Three further themes emerged from the focus groups: (1) the context in which the providers'' practice matters, (2) the need for providing patients and providers with choice (e.g., which data to share, who gets to initiate/respond in communications, and processes around virtual care visits), and (3) perceived risks of system use (e.g., increased complexity for older patients and workload barriers for the health care team). Conclusion  Rural primary care teams perceived PHR opportunities for increased patient engagement and access to patient-generated data, while worries about changes in workflow were the biggest perceived risk. Recommendations for PHR adoption in a rural primary health network include setting provider-patient expectations about response times, ability to share notes selectively, and automatically augmented note-taking from virtual-care visits.     

Brassinosteroids inhibit pathogen-associated molecular pattern-triggered immune signaling independent of the receptor kinase BAK1

Plants and animals use innate immunity as a first defense against pathogens, a costly yet necessary tradeoff between growth and immunity. In Arabidopsis, the regulatory leucine-rich repeat receptor-like kinase (LRR-RLK) BAK1 combines with the LRR-RLKs FLS2 and EFR in pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and the LRR-RLK BRI1 in brassinosteroid (BR)-mediated growth. Therefore, a potential tradeoff between these pathways mediated by BAK1 is often postulated. Here, we show a unidirectional inhibition of FLS2-mediated immune signaling by BR perception. Unexpectedly, this effect occurred downstream or independently of complex formation with BAK1 and associated downstream phosphorylation. Thus, BAK1 is not rate-limiting in these pathways. BRs also inhibited signaling triggered by the BAK1-independent recognition of the fungal PAMP chitin. Our results suggest a general mechanism operative in plants in which BR-mediated growth directly antagonizes innate immune signaling.