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The aim of this study was to calculate the cost of a range of needle and syringe program (NSP) models to contribute to planning for effective NSP delivery. Existing health service data was used to estimate the cost per needle distributed across four modes of service delivery (Primary NSP, including one model of Primary NSP providing primary health care; Secondary NSP; Vending Machine and Outreach) over three years. Costs were primarily affected by the ratio of the volume of equipment distributed to staff costs. The average cost per unit for Primary, Secondary and Outreach modes was approximately $1.00. The cost for Vending Machine provision (accounting for income from service users) was the cheapest option at $0.30–0.40 per unit. When income from services users are not included in calculations, other considerations may be more important than cost when making decisions about providing access to NSP services to a marginalized client group with diverse needs.

In view of the limitations of the current domestic power monitoring system, in this paper an intelligent single-phase electrical appliances analysis and monitoring system have been designed.The system takes STM32 as the control core, and the electric energy metering circuit is used to collect signals. The learning and recognition functions of electrical appliances are designed.The whole single-phase electrical appliances analysis and monitoring system can be used to monitor the operation of one or more electrical appliances in the circuit and display specific electrical parameters.The system uses a special measurement chip RN8208G, and the current precision can reach 1 mA. It is reliable, suitable for long-term operation and not easy to make mistakes.In this paper, the design of a specific electrical monitoring system is novel and has broad prospects for development.

In this paper, a smart trash can based on the voice control is proposed. The garbage bin takes the Microcontroller as the control core and has a voice interaction function, that is, according to the speech recognition function instruction, the obstacle avoidance can be automatically realized during the movement process, and when the capacity reaches the preset value, it can prompt people to clean up. Meanwhile, the status of all trash cans can be displayed on the LCD screen. After debugging, the design has diversified functions and fully demonstrates practicality.

The two crucial issues for hot topics discovery based on online reviews are that the sparsity of short text features and the “long tail” phenomenon of hot topics. This paper focuses on these two key issues, and proposes an improved similarity calculation method to calculate the similarity of short texts, and a novel clustering algorithm based on the time factor and dynamic adjustment of comparison times to automatically discard a large number of outliers. Moreover, the validity and advancement of the new method are presented by comparative experiments using real data sets.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is a major ionotropic glutamate receptor subtype in the mammalian brain. Like other glutamate receptors, the AMPA receptor is regulated by phosphorylation. By phosphorylating specific serine resides in AMPA receptor subunits (GluA1 and GluA2), various protein kinases regulate subcellular/subsynaptic expression and function of the receptor. In this study, we conducted a time course study to evaluate the temporal property of responses of phosphorylation at those sites to dopamine stimulation with the psychostimulant amphetamine in the adult rat striatum and medial prefrontal cortex (mPFC) in vivo. We focused on biochemically-enriched AMPA receptors from synaptic and extrasynaptic compartments. We found that acute injection of amphetamine induced a rapid and relatively sustained increase in GluA1 S845 phosphorylation at both synaptic and extrasynaptic sites in the striatum. Similar results were observed in the mPFC. In contrast to S845, amphetamine did not induce a significant change in GluA1 S831 phosphorylation in synaptic and extrasynaptic pools in the striatum and mPFC. GluA2 S880 phosphorylation in synaptic and extrasynaptic fractions in the two brain regions also remained stable in response to amphetamine. These results support S845 to be a principal site on AMPA receptors sensitive to acute stimulant exposure. Its phosphorylation levels are rapidly upregulated by amphetamine in the two defined subsynaptic microdomains (synaptic versus extrasynaptic locations) in striatal and cortical neurons.

Objectives To analyse changes in testing for sexually transmissible infections (STI) among gay and bisexual men in Melbourne, Sydney and Queensland, Australia, particularly comprehensive STI testing (at least four tests from different anatomical sites in the previous year), and the characteristics of men who had such testing. Method Data were analysed from repeated, cross-sectional, community-based surveys conducted during 2003–2012. Trends in specific STI tests and comprehensive testing were assessed and the characteristics of participants who reported comprehensive STI testing were identified using multivariate logistic regression, stratified by HIV status. Results Among HIV-negative and unknown status men (n=51 009), comprehensive STI and HIV testing increased substantially from 13% in 2003 to 34% in 2012. During the same period, comprehensive STI testing (excluding HIV testing) increased from 24% to 57% among HIV-positive men (n=5532). In both HIV status groups, comprehensive testing was more commonly reported by men who had unprotected anal intercourse with casual partners, and men with higher numbers of partners. Among HIV-negative/unknown status participants, comprehensive STI and HIV testing was also associated with education level, regional location and finding partners online. Among HIV-positive men, comprehensive STI testing was also associated with free time spent with gay men and illicit drug use. Comprehensive testing was related to a high annual rate of diagnosis with STIs (20% of HIV-negative/unknown status men and 38% of HIV-positive men). Conclusions There has been a substantial improvement in the proportion of gay and bisexual men in Melbourne, Sydney and Queensland who report comprehensive testing. Comprehensive testing is most likely among men whose practices put them at increased risk of infection, and is associated with a high rate of STI diagnosis. However, opportunities for comprehensive testing are still being missed, suggesting a need for its ongoing promotion.

Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction. Accumulating data have demonstrated roles of ionotropic glutamate receptors and group I and II metabotropic glutamate receptors (mGluRs) in this event. Emerging evidence also identifies Gαi/o-coupled group III mGluRs (mGluR4/7/8 subtypes enriched in the limbic system) as direct substrates of drugs of abuse and active regulators of drug action. Auto- and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways, respectively. These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis. In response to operant administration of common addictive drugs, such as psychostimulants (cocaine and amphetamine), alcohol and opiates, limbic group III mGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior. As a result, a loss-of-function mutation (knockout) of individual group III receptor subtypes often promotes drug seeking. This review summarizes the data from recent studies on three group III receptor subtypes (mGluR4/7/8) expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs (psychostimulants, alcohol, and opiates).

The AMPA receptor is regulated by phosphorylation. Two major phosphorylation sites (S831 and S845) are located in the intracellular C-terminal tail of GluA1 subunits. The phosphorylation on these sites controls receptor expression and function and is subject to the regulation by psychostimulants. In this study, we further characterized the regulation of S831 and S845 phosphorylation by amphetamine (AMPH) in the adult rat striatum and medial prefrontal cortex (mPFC) in vivo. We focused on the specific fraction of GluA1/AMPA receptors enriched from synaptic and extrasynaptic membranes, using a pre-validated biochemical fractionation procedure. We found that acute AMPH administration elevated GluA1 S845 phosphorylation in the defined synaptic membrane from the striatum in a dose-dependent manner. AMPH also induced a comparable increase in S845 phosphorylation in the extrasynaptic fraction of striatal GluA1. Similar increases in S845 phosphorylation in both synaptic and extrasynaptic pools were observed in the mPFC. In contrast, S831 phosphorylation was not altered in synaptic and extrasynaptic GluA1 in striatal neurons and synaptic GluA1 in mPFC neurons in response to AMPH, although a moderate increase in S831 phosphorylation was seen in extrasynaptic GluA1 in the mPFC after an AMPH injection at a high dose. Total synaptic and extrasynaptic GluA1 expression remained stable in the two regions after AMPH administration. Our data demonstrate the differential sensitivity of S845 and S831 phosphorylation to dopamine stimulation. S845 is a primary site where phosphorylation of GluA1 is upregulated by AMPH in striatal and mPFC neurons at both synaptic and extrasynaptic compartments.

BACKGROUND We aimed to describe the current use of antiretrovirals(ARVs) before unprotected anal intercourse (UAI) among Australian gay men, which may represent informal HIV preexposure prophylaxis (PrEP). METHODS Using data from Australian Gay Community Periodic Surveys conducted in 2011, we assessed the preventive use of ARVs before UAI and its association with sociodemographic characteristics, sexual practices, and drug use in the preceding 6 months. Associations were assessed using multivariate logistic regression analysis. RESULTS Of 3677 sexually active non-HIV-positive men, 2.5%reported taking ARVs before UAI. The likelihood of ARV use before UAI was significantly higher if any of the following behaviors were also reported: .1 sex partner; UAI with casual partners, irrespective of reporting UAI with regular partners [adjusted odds ratio (AOR) = 2.36; 95% confidence interval (CI): 1.24 to 4.48] or not (AOR = 2.71; 95% CI: 1.44 to 5.07); injecting drugs at least monthly (AOR = 2.56; 95% CI: 1.03 to 6.36); using “party” drugs,occasionally (AOR = 2.23; 95% CI: 1.33 to 3.73) or regularly(AOR = 5.34; 95% CI: 2.99 to 9.56); and group sex while using party drugs, occasionally (AOR = 2.42; 95% CI: 1.29 to 4.53) or regularly (AOR = 5.31; 95% CI: 2.62 to 10.76). Among non-HIV positive men in regular relationships with HIV-positive partners or partners of unknown HIV status, 1.7% and 4.7%, respectively, reported preventive ARV use before UAI. CONCLUSIONS Our findings illustrate sporadic use of ARVs before UAI among gay men in Australia, which was associated with high-risk casual sex and party drug use. These initial data contribute to a much needed understanding of the informal use of ARVs for HIV prevention.

The metabotropic glutamate receptor 1 (mGluR1) is a Gαq-protein-coupled receptor and is distributed in broad regions of the mammalian brain. As a key element in excitatory synaptic transmission, the receptor regulates a wide range of cellular and synaptic activities. In addition to regulating its targets, the receptor itself is believed to be actively regulated by intracellular signals, although underlying mechanisms are essentially unknown. Here we found that a synapse-enriched protein kinase, Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα), directly binds to the intracellular C terminus (CT) of mGluR1a. This binding is augmented by Ca2+in vitro. The direct interaction promotes CaMKIIα to phosphorylate mGluR1a at a specific threonine site (T871). In rat striatal neurons, the mGluR1 agonist triggers the receptor-associated phosphoinositide signaling pathway to induce Ca2+-dependent recruitment of CaMKIIα to mGluR1a–CT. This enables the kinase to inhibit the response of the receptor to subsequent agonist exposure. Our data identify an agonist-induced and Ca2+-dependent protein–protein interaction between a synaptic kinase and mGluR1, which constitutes a feedback loop facilitating desensitization of mGluR1a.

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Injecting drug use is commonly reported among gay and bisexual men in Australia. We examined the prevalence and covariates of injecting drug use among men participating in the Sydney Gay Community Periodic Survey between 2004-06 and 2011. In 2004-06, data was collected about which drugs were injected, while in 2011, data was collected about hepatitis C (HCV) and esoteric sexual practices. In 2004-06, 5.6 % of men reported injecting drugs in the previous 6 months; 3.4 % reported methamphetamine injection and 0.4 % heroin injection. In 2011, men who injected drugs were less likely to be employed full-time, and more likely to be HCV-positive, HIV-positive, to have used party drugs for sex, and to have engaged in esoteric sexual practices. The strong associations between injecting drug use, sexual risk practices and blood-borne virus infection suggests the need for combined sexual health and harm reduction services for gay and bisexual men who inject drugs.

An online survey was conducted among people living with HIV (PLHIV) in Australia to discern key factors associated with distinctive ART use patterns. The sample (N = 358), was further divided into three groups: those on ART continuously since initiation (n = 208, 58.1%); those on ART intermittently (n = 117, 32.7%); and those not on ART at the time of survey (n = 33, 9.2%). ART non-users were the most likely to hold serious concerns about ART that outweighed perceived necessities (benefits) from ART (AOR = 0.13; 95% CI 0.06–0.29; p

Smoking is an important factor that causes periodontitis, which manifests as alveolar bone injury and absorption, and has a high incidence and unfavorable treatment efficacy. Nicotine causes ischemia and inflammation of the periodontium and inhibits the mineralization of alveolar bones. Previous studies have revealed the anti‑tumor biological activities of catalpol, in addition to neuroprotection and anti‑inflammation. The present study therefore investigated the underlying protective mechanism of catalpol in alveolar bone injury. A total of 24 Wistar rats were infused with nicotine (0.7 mg/kg for 30 days), followed by subcutaneous injection of catalpol (2 µg/kg for 14 days). The loss of alveolar bone was examined, and bone alkaline phosphatase (AP) and osteocalcin levels were examined by ELISA. The expression of tumor necrosis factor (TNF)‑α and cyclooxygenase‑2 (COX‑2) was quantified by reverse transcription‑quantitative polymerase chain reaction analysis and western blotting. Treatment with nicotine decreased AP and osteocalcin levels, increased TNF‑α and COX‑2 expression levels, and led to alveolar bone loss compared with the control group. Catalpol decreased bone loss, increased AP and osteocalcin, and decreased TNF‑α and COX‑2 expression compared with the nicotine treatment group. Catalpol may alleviate nicotine‑induced injury and alveolar bone loss via inhibition of inflammatory factors, and facilitate the mineralization of alveolar bones.

A synaptic pool of extracellular signal-regulated kinases (ERK) controls synaptic transmission, although little is known about its underlying signaling mechanisms. Here, we found that synaptic ERK2 directly binds to postsynaptic metabotropic glutamate receptor 1a (mGluR1a). This binding is direct and the ERK-binding site is located in the intracellular C-terminus (CT) of mGluR1a. Parallel with this binding, ERK2 phosphorylates mGluR1a at a cluster of serine residues in the distal part of mGluR1a-CT. In rat cerebellar neurons, ERK2 interacts with mGluR1a at synaptic sites, and active ERK constitutively phosphorylates mGluR1a under normal conditions. This basal phosphorylation is critical for maintaining adequate surface expression of mGluR1a. ERK is also essential for controlling mGluR1a signaling in triggering distinct postreceptor signaling transduction pathways. In summary, we have demonstrated that mGluR1a is a sufficient substrate of ERK2. ERK that interacts with and phosphorylates mGluR1a is involved in the regulation of the trafficking and signaling of mGluR1.

Psychostimulants have an impact on protein synthesis, although underlying molecular mechanisms are unclear. Eukaryotic initiation factor 2α-subunit (eIF2α) is a key player in initiation of protein translation and is regulated by phosphorylation. While this factor is sensitive to changing synaptic input and is critical for synaptic plasticity, its sensitivity to stimulants is poorly understood. Here we systematically characterized responses of eIF2α to a systemic administration of the stimulant amphetamine (AMPH) in dopamine responsive regions of adult rat brains. Intraperitoneal injection of AMPH at 5 mg/kg increased eIF2α phosphorylation at serine 51 in the striatum. This increase was transient. In the medial prefrontal cortex (mPFC), AMPH induced a relatively delayed phosphorylation of the factor. Pretreatment with a dopamine D1 receptor antagonist SCH23390 blocked the AMPH-stimulated eIF2α phosphorylation in both the striatum and mPFC. Similarly, a dopamine D2 receptor antagonist eticlopride reduced the effect of AMPH in the two regions. Two antagonists alone did not alter basal eIF2α phosphorylation. AMPH and two antagonists did not change the amount of total eIF2α proteins in both regions. These results demonstrate the sensitivity of eIF2α to stimulant exposure. AMPH possesses the ability to stimulate eIF2α phosphorylation in striatal and mPFC neurons in vivo in a D1 and D2 receptor-dependent manner.

Background In Australia, the preventative use of antiretroviral drugs [pre-exposure prophylaxis (PrEP) and treatment as prevention] is being embraced to protect individuals at high risk of HIV and reduce onward transmission. Methods: The adaptation of a behavioural surveillance system, the Gay Community Periodic Surveys, was reviewed to monitor the uptake and effect of new prevention strategies in Australia’s primary HIV-affected population (gay and bisexual men, GBM). The national trends in key indicators during 2000–15 were reviewed and a new measure to take account of antiretroviral-based prevention was developed. Results: Between 2000 and 2015, there were significant increases (P

This study assesses association between CD4 level at initiation of antiretroviral treatment (ART) on subsequent treatment outcomes and mortality among people infected with HIV via various routes in Hunan province, China. Over a period of 10 years, a total of 7333 HIV-positive patients, including 553 (7.5%) MSM, 5484 (74.8%) heterosexuals, 1164 (15.9%) injection drug users (IDU) and 132 (1.8%) former plasma donors (FPD), were recruited. MSM substantially demonstrated higher initial CD4 cell level (242, IQR 167-298) than other populations (Heterosexuals: 144 IQR 40-242, IDU: 134 IQR 38-224, FPD: 86 IQR 36-181). During subsequent long-term follow up, the median CD4 level in all participants increased significantly from 151 cells/mm³ (IQR 43-246) to 265 cells/mm³ (IQR 162-380), whereas CD4 level in MSM remained at a high level between 242 and 361 cells/mm³. Consistently, both cumulative immunological and virological failure rates (10.4% and 26.4% in 48 months, respectively) were the lowest in MSM compared with other population groups. Survival analysis indicated that initial CD4 counts ≤ 200 cells/mm³ (AHR = 3.14; CI, 2.43-4.06) significantly contributed to HIV-related mortality during treatment. Timely diagnosis and treatment of HIV patients are vital for improving CD4 level and health outcomes.

Several key members of the non-receptor tyrosine kinase (nRTK) family are abundantly present within excitatory synapses in the mammalian brain. These neuron-enriched nRTKs interact with glutamate receptors and phosphorylate the receptors at tyrosine sites. The N-methyl-D-aspartate receptor is a direct substrate of nRTKs and has been extensively investigated in its phosphorylation responses to nRTKs. The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor is the other glutamate receptor subtype that is subject to nRTK-mediated tyrosine phosphorylation. Recently, group I metabotropic glutamate receptors (mGluR1/5) were found to be sensitive to nRTKs. Robust tyrosine phosphorylation may occur in C-terminal tails of mGluR5. Tyrosine phosphorylation of glutamate receptors is either constitutive or induced activity-dependently by changing cellular and/or synaptic input. Through inducing tyrosine phosphorylation, nRTKs regulate trafficking, subcellular distribution, and function of modified receptors. Available data show that nRTK-glutamate receptor interactions and tyrosine phosphorylation of the receptors undergo drastic adaptations in mood disorders such as major depressive disorder. The remodeling of the nRTK-glutamate receptor interplay contributes to the long-lasting pathophysiology and symptomology of depression. This review summarizes the recent progress in tyrosine phosphorylation of glutamate receptors and analyzes the role of nRTKs in regulating glutamate receptors and depression-like behavior.

We aimed to compare rates of illicit drug-related hospitalisations in HIV-negative (HIV−ve) (n = 1325) and HIV-positive (HIV+ve) (n = 557) gay and bisexual men (GBM) with rates seen in the general male population and to examine the association between self-reported illicit drug use and drug-related hospitalisation. Participants were asked how often they used a range of illicit drugs in the previous 6 months at annual interviews. Drug-related hospital admissions were defined as hospital admissions for mental or behavioural disorders due to illicit drug use (ICD 10: F11–16, F18, F19), drug poisoning (T40–T45, T50) or toxic effect of gases (T53, T59, T65). Drug-related hospitalisations were 4.8 times higher in the HIV−ve cohort [SIR 4.75 (95 % CI 3.30–6.91)] and 3.5 times higher in the HIV+ve cohort [SIR 3.51 (1.92–5.88)] compared with the general population. Periods of weekly drug use [IRR 1.86 (1.01–3.46)], poly-drug use [IRR 2.17 (1.07–4.38)] and cannabis use [low use-IRR 1.95 (1.01–3.77), high use-IRR 2.58 (1.29–5.16)] were associated with drug-related hospitalisation in both cohorts, as was being a consistently high meth/amphetamine user throughout follow-up [IRR 3.24 (1.07–9.83)] and being an inconsistent or consistent injecting drug user throughout follow-up [IRR 3.94 (1.61–9.66), IRR 4.43(1.04–18.76), respectively]. Other risk factors for drug-related hospitalisation indicated the likelihood of comorbid drug and mental health issues in GBM hospitalised for drug use.

Introduction and Aims The findings of Australian drug surveys are typically not stratified by sexual orientation, despite the higher prevalence of drug use generally reported among gay and bisexual men. This paper aims to examine trends in drug use among gay and bisexual men in eastern Australia between 2004 and 2011. Design and Methods Data from the cross-sectional, ongoing Gay Community Periodic Surveys (GCPS) were used to analyse drug trends among gay and bisexual men in Sydney, Melbourne and Queensland. Between 2004 and 2011, 45 273 eligible questionnaires were completed. Results There was a downward trend in recent drug use (previous 6 months) between 2004 and 2011 from 62.2% to 57.5%. However, this trend was not found among men in Queensland, bisexual men, men aged over 40 years or HIV-positive men. Club drug use peaked in 2006 (45.1%), before steadily declining to 32.4% in 2011. There were significant reductions in use of ecstasy, methamphetamine, ketamine and cannabis, increased use of cocaine, gamma hydroxybutyrate, erectile dysfunction medications, amyl nitrite and lysergic acid diethylamide, and no change in heroin use. Recent injecting drug use fluctuated over time but experienced an overall downward trend from 5.5% in 2004 to 4.0% in 2011. Discussion and Conclusions Drug use trends among gay and bisexual men in Australia are broadly consistent with downward and upward drug trends reported in other Australian drug surveys. The risks associated with drug use in this population and high rates of use supports the ongoing role of the GCPS in monitoring drug trends among homosexually active men.

To assess the changing health promotion needs of human immunodeficiency virus (HIV)-positive gay men in Australia, we analysed the social and behavioural characteristics of HIV-positive men in the Australian Gay Community Periodic Surveys. We looked at change over time in the characteristics of HIV-positive men (from 2000-2001 to 2008-2009) and compared HIV-positive men with their HIV-negative peers within each time period. Multivariate logistic regression analysis was used to assess independent changes over time within each HIV status group. A total of 21,620 responses were included in the analyses; 10,537 in 2000-2001 and 11,083 in 2008-2009. Between the two time periods, HIV-positive and HIV-negative men became more similar in the following areas: paid employment, sexual identity, number of male sex partners, the likelihood of having a regular male partner and having a seroconcordant regular male partner. The two groups diverged in these areas: age, ethnicity, educational level, social engagement with gay men, types of relationship with regular male partners, likelihood of unprotected anal intercourse with casual male partners and likelihood of HIV disclosure to casual male partners. Workforce participation and educational attainment have improved among HIV-positive gay men since 2000, but they still lag behind their HIV-negative peers in these areas. Because HIV-positive men are an ageing cohort, support services will need to increasingly address issues of HIV, sexuality and ageing with HIV-positive men. The increase in unprotected anal intercourse and HIV disclosure with casual partners means that education and support services will increasingly need to address effective HIV disclosure and non-condom-based risk reduction strategies with both HIV-positive and HIV-negative gay men.

Methyl CpG-binding protein-2 (MeCP2) is a transcriptional regulator that binds to methylated DNA at CpG sites and functions to silence DNA transcription. MeCP2 is subject to the phosphorylation modification at serine 421 (S421), which releases MeCP2 from DNA and thus facilitates gene expression. As a transcriptional repressor densely expressed in limbic reward circuits of adult mammalian brains, MeCP2 is recently emerging as a critical epigenetic factor in experience-dependent neural plasticity and psychostimulant addiction. In this study, we investigated the regulation of MeCP2 phosphorylation in the rat striatum by the psychostimulant cocaine in vivo. We found that acute systemic injection of cocaine increased MeCP2 phosphorylation at S421 in the rat striatum, including both the caudate putamen and the nucleus accumbens, while cocaine did not affect MeCP2 phosphorylation in the medial prefrontal cortex. The cocaine-stimulated MeCP2 phosphorylation in the nucleus accumbens was a rapid and transient event, as it was evident at 20 min and returned to normal levels 3 h after drug injection. The cocaine effect in the caudate putamen was however relatively delayed. Reliable induction of MeCP2 phosphorylation in this region was detected at 60 min. Pretreatment with an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist significantly reduced the cocaine-stimulated MeCP2 phosphorylation in the caudate putamen, although not in the nucleus accumbens. Our data support that MeCP2 is a sensitive target of psychostimulants. Its phosphorylation status is regulated by psychostimulant exposure. NMDA receptors play a region-specific role in linking cocaine to MeCP2 phosphorylation in striatal neurons in vivo.

Objective Three decades into the HIV epidemic and with the advancement of HIV treatments, condom and non-condom-based anal intercourse among gay men in resource-rich countries needs to be re-assessed. Methods The proportions of men engaging in a range of anal intercourse practices were estimated from the ongoing cross-sectional Gay Community Periodic Surveys in six states in Australia from 2007 to 2009. Comparisons were made between HIV-negative men, HIV-positive men with an undetectable viral load and those with a detectable viral load. Results Condoms play a key role in gay men’s anal intercourse practices: 33.8% of HIV-negative men, 25.1% of HIV-positive men with an undetectable viral load and 22.5% of those with a detectable viral load reported consistent condom use with all male partners in the 6 months before the survey. Among HIV-negative men, the second largest group were men who had unprotected anal intercourse (UAI) only in the context of HIV-negative seroconcordant regular relationships. Among HIV-positive men, the second largest group was men who had UAI in casual encounters preceded by HIV status disclosure to some, but not all, casual partners. Conclusions A minority, yet sizeable proportion, of men consistently engaged in a number of UAI practices in specific contexts, suggesting they have adopted deliberate HIV risk-reduction strategies. While it is important that HIV behavioural prevention continues to reinforce condom use, it needs to address both the challenges and opportunities of the substantial uptake of non-condom-based risk-reduction strategies.

Background Palmitoylation is emerging as one of the most important posttranslational modifications of excitatory synaptic proteins in mammalian brain cells. As a reversible and regulatable modification sensitive to changing synaptic inputs, palmitoylation of ionotropic glutamate receptors contributes not only to the modulation of normal receptor and synaptic activities but also to the pathogenesis of various neuropsychiatric disorders. Here we report that palmitoylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is regulated by the psychostimulant, cocaine, and such regulation is involved in cocaine action. Methods We tested palmitoylation and surface expression of AMPA receptors in striatal neurons and psychomotor behavior in response to cocaine in rats. Results All four AMPA receptor subunits (GluA1-4 or GluR1-4) are palmitoylated in the nucleus accumbens (NAc) of adult rats. Among them, GluA1 and GluA3 are preferentially upregulated in their palmitoylation levels by a systemic injection of cocaine. The upregulated GluA1 and 3 palmitoylation is a transient and reversible event. Consequently, it increases the susceptibility of surface-expressed GluA1 and 3 to internalization trafficking, leading to a temporal loss of surface receptor expression. Blockade of the regulated GluA1/3 palmitoylation with a palmitoylation inhibitor in the local NAc reverses the loss of surface GluA1/3. The inhibition of palmitoylation concurrently sustains behavioral responsivity to cocaine as well. Conclusions Our data identify a novel drug–palmitoylation coupling in the center of limbic reward circuits. Through palmitoylating selective AMPA receptor subunits, cocaine activity dependently regulates trafficking and subcellular localization of the receptor in NAc neurons and dynamically controls psychomotor sensitivity to the psychoactive drug in vivo.

Our aim was to clarify the role of alcohol and other drug (AOD) use in major depression among gay men attending general medical practices. A secondary analysis was conducted on survey data collected from 531 gay men attending high-HIV-caseload general practices in Adelaide and Sydney, Australia. The survey contained demographic, social, behavioural and AOD variables. Participants were classified into those with (n = 130) and without major depression (n = 401) using the PHQ-9 screening tool. Although rates of drug use were very high in the sample, multivariate logistic regression analysis showed that the majority of variables independently associated with major depression were social and behavioural factors. Only one AOD variable was associated with major depression: the use of three or more drug types in the past 6 months. Attending to specific patterns of AOD use may assist in the identification of gay men most at risk of major depression.

The data for this article are from a primary health care project on HIV and depression, in which the prevalence, nature, clinical management, and self-management of depression among homosexually active men attending high-HIV-caseload general practice clinics were investigated. One of the qualitative arms consisted of in-depth interviews with general practitioners (GPs) with high caseloads of gay men. The approach to discourse analysis was informed by Halliday’s systemic functional linguistics. GPs constructed three discourses of depression: engaging with psychiatric discourse, engaging with the patient’s world, and engaging with social structures. When GPs drew on the discourse of psychiatry, this discourse was positioned as only one possible construction of depression. This discourse was also contextualized in the social lives of gay men, and it was explicitly challenged and rejected. Engaging with their patients’ social world was considered vital for recognizing depression in gay men. Finally, the GPs’ construction of depression was inextricably linked to social disadvantage and marginalization. Depression is highly heterogeneous and constructed in terms of social relationships rather than as an independent entity that resides in the individual. There is a synergy between GPs’ constructions of depression and men’s experiences of depression, which differs from conventional medical views, and which enables GPs to be highly effective in dealing with the mental health issues of their gay patients.

Protein-protein interactions represent an important mechanism for posttranslational modifications of protein expression and function. In brain cells, surface-expressed and membrane-bound neurotransmitter receptors are common proteins that undergo dynamic protein-protein interactions between their intracellular domains and submembranous regulatory proteins. Recently, the Gα(i/o)-coupled muscarinic M4 receptor (M4R) has been revealed to be one of these receptors. Through direct interaction with the intracellular loops or C-terminal tails of M4Rs, M4R interacting proteins (M4RIPs) vigorously regulate the efficacy of M4R signaling. A synapse-enriched protein kinase, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), exemplifies a prototype model of M4RIPs, and is capable of binding to the second intracellular loop of M4Rs. Through an activity- and phosphorylation-dependent mechanism, CaMKII potentiates the M4R/Gα(i/o)-mediated inhibition of M4R efficacy in inhibiting adenylyl cyclase and cAMP production. In striatal neurons where M4Rs are most abundantly expressed, M4RIPs dynamically control M4R activity to maintain a proper cholinergic tone in these neurons. This is critical for maintaining the acetylcholine-dopamine balance in the basal ganglia, which determines the behavioral responsiveness to dopamine stimulation by psychostimulants.

Analysis of cancer risk in primary immune deficiency (PID) offers insight into the relationship between immune function and cancer. Data on Australian patients (n = 1132) notified voluntarily to the Australasian Society of Clinical Immunology and Allergy PID Registry (1990-2008) were linked with national death and cancer registries. Person-years of follow-up commenced from up to 15 years before registration on the PID Registry or January 1982, the inception of national cancer registration. Site-specific, 5-year age-, sex-, calendar year–, and state-standardized incidence ratios (SIRs) with 95% confidence intervals (95% CIs) were calculated for all cancers except nonmelanocytic skin cancer. During an average of 16 person-years follow-up, a 1.6-fold excess relative risk of cancer was observed (n = 58; SIR 1.60, 95% CI 1.22-2.07) for all PID combined. Relative risk was increased for non-Hodgkin lymphoma (n = 16; SIR 8.82, 95% CI 5.04-14.30), leukemia (n = 4; SIR 5.36, 95% CI 1.46-13.73), and stomach cancer (n = 3; SIR 6.10, 95% CI 1.26-17.84). Excess cancer risk was observed for predominantly antibody deficiencies and other well-defined immunodeficiency syndromes. Results suggest that predominantly antibody deficiencies may be associated with a narrower range of solid cancers than immunodeficiency characterized by predominantly T-cell deficiency, such as iatrogenic and HIV-related immunodeficiency, although this requires confirmation in larger cohorts.

We introduced polyethyleneimine (PEI)-cholesterol (PC) as a nanocarrier incorporating berberine (BER) and miR-122 for the treatment of oral squamous cell carcinoma (OSCC). BER was stabilized by incorporating PC to form ber-PC. Ber-PC was further electrostatically complexed with miR-122 to yield mr-ber-PC for the co-delivery of BER and miR-122. mr-ber-PC treatment dramatically decreased the level of invasion and migration of OSCC cells compared with single drug treatments. The present study suggested that PC could be a multifunctional nanocarrier for the co-delivery of anticancer drug BER and miR-122 to significantly increase the anticancer therapeutic effects.

OBJECTIVE: To assess circumcision status as a risk factor for HIV seroconversion in homosexual men. DESIGN, SETTING AND PARTICIPANTS: The Health in Men (HIM) study was a prospective cohort of homosexual men in Sydney, Australia. HIV-negative men (n = 1426) were recruited primarily from community-based sources between 2001 and 2004 and followed to mid-2007. Participants underwent annual HIV testing, and detailed information on sexual risk behaviour was collected every 6 months. MAIN OUTCOME MEASURE: HIV incidence in circumcised compared with uncircumcised participants, stratified by whether or not men predominantly practised the insertive role in anal intercourse. RESULTS: There were 53 HIV seroconversions during follow-up; an incidence of 0.78 per 100 person-years. On multivariate analysis controlling for behavioural risk factors, being circumcised was associated with a nonsignificant reduction in risk of HIV seroconversion [hazard ratio 0.78, 95% confidence interval (CI) 0.42-1.45, P = 0.424]. Among one-third of study participants who reported a preference for the insertive role in anal intercourse, being circumcised was associated with a significant reduction in HIV incidence after controlling for age and unprotected anal intercourse (UAI) (hazard ratio 0.11, 95% CI 0.03-0.80, P = 0.041). Those who reported a preference for the insertive role overwhelmingly practised insertive rather than receptive UAI. CONCLUSIONS: Overall, circumcision did not significantly reduce the risk of HIV infection in the HIM cohort. However, it was associated with a significant reduction in HIV incidence among those participants who reported a preference for the insertive role in anal intercourse. Circumcision may have a role as an HIV prevention intervention in this subset of homosexual men.

Ras-guanine nucleotide-releasing factors (Ras-GRFs) are densely expressed in neurons of the mammalian brain. As a Ras-specific activator predominantly concentrated at synaptic sites, Ras-GRFs activate the Ras-mitogen-activated protein kinase (Ras-MAPK) cascade in response to changing synaptic inputs, thereby modifying a variety of cellular and synaptic activities. While the Ras-MAPK cascade in the limbic reward circuit is well-known to be sensitive to dopamine inputs, the sensitivity of its upstream activator (Ras-GRFs) to dopamine remains to be investigated. In this study, the response of Ras-GRFs in their protein expression to dopamine stimulation was evaluated in the rat striatum in vivo. A single systemic injection of the psychostimulant amphetamine produced an increase in Ras-GRF1 protein levels in both the dorsal (caudoputamen) and ventral (nucleus accumbens) striatum. The increase in Ras-GRF1 proteins was dose-dependent. The reliable increase was seen 2.5 h after drug injection and returned to normal levels by 6 h. In contrast to Ras-GRF1, protein levels of Ras-GRF2 in the striatum were not altered by amphetamine. In addition to the striatum, the medial prefrontal cortex is another forebrain site where amphetamine induced a parallel increase in Ras-GRF1 but not Ras-GRF2. No significant change in Ras-GRF1/2 proteins was observed in the hippocampus. These data demonstrate that Ras-GRF1 is a susceptible and selective target of amphetamine in striatal and cortical neurons. Its protein expression is subject to the modulation by acute exposure of amphetamine.

Acid-sensing ion channels (ASICs) are ligand-gated cation channels activated by a drop in extracellular pH. They are enriched in the mammalian brain with a high synaptic density. Accumulating evidence suggests that ASIC1 contributes to synaptic activity related to learning/memory and fear conditioning, and also plays critical roles in neurodegenerative diseases. In this study, we explored the effect of the psychostimulant, cocaine, on protein expression of ASICs in the mouse forebrain in vivo. We found that chronic systemic injection of cocaine (20 mg/kg, once daily for 5 consecutive days; 14 days of withdrawal) increased ASIC1, but not ASIC2, protein levels in the striatum, including the dorsal (caudate putamen) and the ventral (nucleus accumbens) striatum. No significant changes in ASIC1 or 2 protein levels in the median prefrontal cortex and the hippocampus were observed following the chronic cocaine administration. These data demonstrate that chronic cocaine exposure can upregulate ASIC expression in the striatum in a subunit-selective manner.

Objective To investigate the relationship between nonoccupational postexposure prophylaxis (NPEP) use and future HIV risk behaviours and HIV infection in a cohort of HIV-negative homosexual men in Sydney, Australia. Design Prospective analysis of NPEP use in a community cohort from 2001 to 2007. Methods In the Health in Men study cohort, men were annually questioned about NPEP use and tested for HIV. Every 6 months, detailed quantitative data on unprotected anal intercourse were collected. Cox regression models examined risk factors for incident NPEP use, HIV seroconversion and time trends in NPEP use. The change in the number of unprotected anal intercourse acts with nonseroconcordant partners before and after NPEP was examined using the Wilcoxon signed-rank test. Results One thousand four hundred and twenty-seven participants were enrolled. At baseline, 78.5% of participants had heard of NPEP, which increased to 97.4% by the fifth annual interview. NPEP use increased significantly from 2.9 per 100 person-years in 2002 to 7.1 per 100 person-years in 2007 (P = 0.007). Unprotected anal intercourse was a strong predictor of incident NPEP use. Use of NPEP was not associated with changes in HIV risk behaviour. Men who received NPEP had a significantly higher rate of subsequent HIV seroconversion (hazard ratio 2.67, 95% confidence interval 1.40-5.08, P = 0.003). Conclusion Awareness of the availability of NPEP in this cohort was nearly universal. Use was common and increased rapidly over the study period. NPEP was targeted mostly towards high-risk behaviours. Use of NPEP was not associated with reductions in risk behaviour, and men who received NPEP continued to be at high risk of subsequent HIV infection.

Introduction Sexual expression affects physical, mental and social well-being. There is a lack of understanding of male sexual dysfunction in homosexually active men. Aim We investigated gay men's self-report of a number of sexual problems. Methods The survey data were from a sample of 542 self-identified gay men, 40% of whom were HIV positive, recruited from six high HIV-caseload general practices in Australia. Main Outcome Measures The reporting of experiencing three or more sexual problems over a period of at least 1 month in the 12 months prior to a survey was defined here as having “multiple” sexual problems. We explored a number of factors, including HIV status, depression, alcohol and other drug use, and sexual risk-taking with casual male partners, in association with multiple sexual problems. Results Rates of a range of self-reported sexual problems were high, with erectile dysfunction and lack of sexual desire being the most commonly reported. These high rates were consistent with the limited data from previous Australian studies. Men who had multiple sexual problems were likely to suffer from major depression ( P P = 0.002). Factors independently associated with multiple sexual problems among the HIV-negative gay men were poorer general health and interpersonal isolation, whereas for the HIV-positive gay men, they were adoption of avoidant strategies to cope with daily life stress, sexual risk-taking in casual encounters, and the use of antidepressants. Conclusions Our findings underscore the complex interactions between depression, sexual dysfunction, sexual risk taking, HIV infection, and general well-being among homosexually active men. Mao L, Newman CE, Kidd MR, Saltman DC, Rogers GD, and Kippax SC. Self-reported sexual difficulties and their association with depression and other factors among gay men attending high HIV-caseload general practices in Australia. J Sex Med 2009;6:1378–1385.

Background Anaesthetics may target ionotropic glutamate receptors in brain cells to produce their biological actions. Membrane-bound ionotropic glutamate receptors undergo dynamic trafficking between the surface membrane and intracellular organelles. Their subcellular distribution is subject to modulation by changing synaptic inputs and determines the efficacy and strength of excitatory synapses. It has not been explored whether anaesthesia has any impact on surface glutamate receptor expression. In this study, the effect of general anaesthesia on expression of N -methyl- d -aspartate (NMDA) receptors in the surface and intracellular pools of cortical neurones was investigated in vivo . Methods General anaesthesia was induced by intraperitoneal injection of chloral hydrate in adult male mice. Surface protein cross-linking assays were performed to detect changes in distribution of NMDA receptor subunits (NR1, NR2A, and NR2B) in the surface and intracellular compartments of cerebral cortical neurones. Results Chloral hydrate did not alter the total amounts of NR1, NR2A, and NR2B proteins in cortical neurones. However, the drug reduced NR1 proteins in the surface pool of these neurones, and induced a proportional increase in NR1 in the intracellular pool. Similar redistribution of NR2B subunits was observed between the two distinct pools. The changes in NR1 and NR2B were rapid and remained throughout the duration of anaesthesia. NR2A proteins were not altered in the surface or intracellular pool in response to chloral hydrate. Conclusions These data demonstrate that subcellular expression of NR1 and NR2B in cortical neurones is sensitive to anaesthesia. Chloral hydrate reduces surface-expressed NMDA receptors (specifically NR2B-containing NMDA receptors) in these neurones in vivo .

Recent studies demonstrate that activation of Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors upregulates phosphorylation of mitogen-activated protein kinases (MAPKs) in heterologous cells and neurons. In cultured rat striatal neurons, the present work systematically evaluated the role of a number of protein kinases in forming a signaling cascade transducing NMDA receptor signals to MAPKs. It was found that a brief NMDA application consistently induced rapid and transient phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2), a best characterized subclass of MAPKs. This ERK1/2 phosphorylation was resistant to the inhibition of protein kinase C, p38 MAPK, cyclin-dependent kinase 5, receptor tyrosine kinase (epidermal growth factor receptors), or non-receptor tyrosine kinases (including Src) by their selective inhibitors. However, the increase in ERK1/2 phosphorylation was partially blocked by a protein kinase A (PKA) inhibitor. The inhibitors for Ca(2+)/calmodulin-dependent protein kinase (CaMK) or phosphatidylinositol 3-kinase (PI3-kinase) completely blocked the NMDA-stimulated ERK1/2 phosphorylation. In an attempt to characterize the sequential role of CaMK and PI3-kinase, we found that NMDA increased PI3-kinase phosphorylation on Tyr(508), which kinetically corresponded to the ERK1/2 phosphorylation and was blocked by the CaMK inhibitor. These results indicate that the protein kinases are differentially involved in linking NMDA receptors to ERK1/2 in striatal neurons.

Using two cohort studies (Health in men-HIM and positive health-PH) and repeated large cross-sectional surveys (Gay Community Periodic Survey-GCPS) of gay men in Sydney, Australia, we examined the association between viral load and unprotected anal intercourse (UAI) between HIV sero-discordant regular partners. Between 2001 and 2007, we conducted 243 interviews with 102 HIV-negative gay men in HIM and 148 interviews with 99 HIV-positive gay men in PH who were in regular relationships with HIV sero-discordant partners. During the same time period, 437 HIV positive men with HIV sero-discordant regular partners completed questionnaires for the GCPS. All completed interviews or questionnaires during that time period were used for these analyses. Amongst the HIV-negative respondents, sero-discordant UAI was more likely to be reported when the men believed their HIV-positive regular partner had an undetectable rather than a detectable viral load (P = 0.002). Amongst the HIV-positive respondents, sero-discordant UAI was as likely to be reported when they themselves reported having an undetectable or a detectable viral load. Use of viral load in negotiating condom use between sero-discordant gay couples may be understood very differently by the HIV-negative and HIV-positive men within those partnerships.

OBJECTIVES: Social factors associated with Major Depressive Disorder (MDD) were identified among gay men attending high HIV caseload general practices in Sydney and Adelaide. METHODS: Men who visited four participating practices were invited to self-complete a survey. A self-screening tool (PHQ-9), based on the Diagnostic and Statistical Manual of Mental Disorders, version four (DSM-IV), was used to measure depressive disorders. RESULTS: The rate of MDD (PHQ-9 score 10 or above) among the 195 HIV-positive gay men was significantly higher than that among the 314 non-HIV-positive gay men (31.8% vs 20.1%, p=0.002). Current MDD was independently associated with younger age, lower income, recent major adverse life events, adopting denial and isolation as coping strategies, less social support, less gay community involvement and recent sexual problems. HIV-status, however, was not independently associated with MDD. CONCLUSION: Socio-economic hardship, interpersonal isolation and personal withdrawal were significantly and independently associated with major depression in this population of gay men. Implications: The study provides further evidence of health inequity affecting gay men in Australia. Structural health promotion approaches focused on homophobia and discrimination, as well as community-engaged primary health care responses are called for to mitigate this inequity.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is central to synaptic transmission. Here we show that synaptic CaMKIIalpha binds to the N-terminal region of the third intracellular loop of the limbic dopamine D3 receptor (D3R). This binding is Ca(2+) sensitive and is sustained by autophosphorylation of CaMKII, providing an unrecognized route for the Ca(2+)-mediated regulation of D3Rs. The interaction of CaMKIIalpha with D3Rs transforms D3Rs into a biochemical substrate of the kinase and promotes the kinase to phosphorylate D3Rs at a selective serine site (S229). In accumbal neurons in vivo, CaMKIIalpha is recruited to D3Rs by rising Ca(2+) to increase the CaMKIIalpha-mediated phosphorylation of D3Rs, thereby transiently inhibiting D3R efficacy. Notably, the D3R inhibition is critical for integrating dopamine signaling to control behavioral sensitivity to the psychostimulant cocaine. Our data identify CaMKIIalpha as a recruitable regulator of dopamine receptor function. By binding and phosphorylating limbic D3Rs, CaMKIIalpha modulates dopamine signaling and psychomotor function in an activity-dependent manner.

Metabotropic glutamate receptors (mGluRs) are densely expressed in the limbic system of the mammalian brain. Increasing evidence suggests a critical role of mGluRs in the pathogenesis of various mental illnesses, including drug abuse and addiction. In this study, we investigated the effect of psychostimulant, cocaine, on protein expression of a specific mGluR subtype, mGluR8, in the rat forebrain in vivo. A rabbit antibody against the extracellular N-terminus of mGluR8 was developed to detect changes in mGluR8 proteins in immunoblot assays. With this antibody, we found that acute systemic injection of cocaine reduced mGluR8 protein levels in the striatum. The reduction of mGluR8 proteins was rapid and transient as it was induced 25 min after cocaine injection and returned to the normal level by 6 h. No significant change in mGluR8 protein levels in the prefrontal cortex and the hippocampus was observed following cocaine administration. These data demonstrate that protein expression of mGluR8 is subject to the modulation by dopamine stimulation. Acute exposure to cocaine results in a dynamic and region-specific downregulation of mGluR8 expression in the striatum. © 2008 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND: In contrast to the broad literature on depression in the general population, little is known about the management of depression affecting gay men and HIV-positive men attending general practice clinics. OBJECTIVE: This paper explores qualitative descriptions of how depression in gay men and HIV-positive men is managed by GPs. METHODS: As part of the qualitative component of a mixed method study on HIV and depression, semi-structured interviews were conducted with 16 GPs in three geographical settings in Australia: Sydney, Adelaide and a rural coastal town. RESULTS: GPs identified a range of features in their experience of managing depression in gay men and in HIV-positive men. Some were common to the care of other groups with depression, but this paper reports on features unique to this patient group. These include capitalizing on the high frequency of contact with this patient group, taking advantage of the specialist multidisciplinary teams who provide support, building upon the unusual willingness of this patient group to take medication, appreciating the central importance to many gay men of sexual functioning, and recreational drug use, responding to social isolation in this patient group and coping with increasing challenges for the HIV general practice workforce. CONCLUSIONS: Despite the identification of several key strengths in working with this patient group, the ability of GPs to develop their capacity to manage depression in gay men and men with HIV is uncertain in the context of a growing range of challenges for GPs in both mental health and HIV care.

Group I metabotropic glutamate receptors (mGluR1 and mGluR5 subtypes) are densely expressed in mammalian brain. They are actively involved in the regulation of normal cellular activity and synaptic plasticity, and are frequently linked to the pathogenesis of various mental illnesses. Like ionotropic glutamate receptors, group I mGluRs are subject to the regulation by protein phosphorylation. Accumulative data demonstrate sufficient phosphorylation of the intracellular mGluR1/5 domains at specific serine/threonine sites by protein kinase C in heterologous cells or neurons, which serves as an important mechanism for regulating the receptor signaling and desensitization. Emerging evidence also shows the significant involvements of G protein-coupled receptor kinases, Ca2+/calmodulin-dependent protein kinase II, tyrosine kinases, and protein phosphatases in controlling the phosphorylation status of group I mGluRs. This review analyzes the recent data concerning group I mGluR phosphorylation and the phosphorylation-dependent regulation of group I mGluR function. Future research directions in this area with newly available high throughput and proteomic approaches are also discussed in the end.

The parvicellular part of the ventroposteromedial nucleus of the thalamus (VPMpc) is positioned at the key site between the gustatory parabrachial nuclei (PbN) and the gustatory cortex for relaying and processing gustatory information via the thalamocortical pathway. Although neuroanatomical and electrophysiological studies have provided information regarding the gustatory projection from PbN to VPMpc, the exact relationship between PbN and VPMpc, especially the efferent projection involving VPMpc to PbN, is obscure. Here we investigated the reciprocal connection between these two gustatory relays in urethane-anesthetized hamsters. We recorded from 114 taste-responsive neurons in the PbN and examined their responsiveness to electrical stimulation of the VPMpc bilaterally. Stimulation of either or both of the ipsilateral or contralateral VPMpc antidromically activated 109 gustatory PbN neurons. Seventy-two PbN neurons were antidromically activated after stimulation of both sides of the VPMpc, indicating that taste neurons in the PbN project heavily to the bilateral VPMpc. Stimulation of VPMpc also orthodromically activated 110 of PbN neurons, including 106 VPMpc projection neurons. Seventy-eight neurons were orthodromically activated bilaterally. Among orthodromic activations of the PbN cells, the inhibitory response was the dominant response; 106 cells were inhibited, including 10 neurons that were also excited contralaterally, indicating that taste neurons in the PbN are subject to strong inhibitory control from VPMpc. Moreover, stimulation of VPMpc altered taste responses of the neurons in the PbN, indicating that VPMpc modulates taste responses of PbN neurons. These results may provide functional insight of neural circuitry for taste processing and modulation involving these two nuclei.

Group I mGluRs (mGluR1/5) are G-protein-coupled receptors and are abundantly expressed in most of medium spiny projection neurons in the striatum. Recent evidence demonstrates that group I mGluRs are among essential regulators for constitutive and inducible gene expression in host neurons. Upon activation, mGluR1/5 signals activate extracellular signal-regulated kinases (ERKs) which in turn phosphorylate transcription factors such as cAMP response element-binding protein (CREB) and Elk-1, and thereby facilitate immediate early gene and opioid peptide gene expression. The conventional mGluR1/5 signaling cascade (phosphoinositide hydrolysis and intracellular Ca(2+) release) participates in linking mGluR1/5 to ERK. Additionally, the prominent mGluR1/5 adaptor protein Homer contributes to assemble an efficient signaling apparatus connecting mGluR1/5 to gene expression. The mGluR1/5 linkage to transcription also functions in dopamine-stimulated gene expression. Together, the mGluR1/5-mediated gene expression constitutes a transcription-dependent mechanism underlying molecular adaptations and plasticity related to the pathogenesis of various mental illnesses.

Taste receptors on the left and right sides of the anterior tongue are innervated by chorda tympani (CT) fibers, which carry taste information to the ipsilateral nucleus of the solitary tract (NST). Although the anterior tongue is essential for taste, patients with unilateral CT nerve damage often report no subjective change in their taste experience. The standing theory that explains the taste constancy is the “release of inhibition”, which hypothesizes that within the NST there are inhibitory interactions between inputs from the CT and glossopharyngeal nerves and that the loss of taste information from the CT is compensated by a release of inhibition on the glossopharyngeal nerve input. However, the possibility of compensation by taste input from the other side of the tongue has never been investigated in rodents. We recorded from 95 taste-responsive neurons in the NST and examined their responsiveness to stimulation of the contralateral CT. Forty-six cells were activated, mostly with excitatory responses (42 cells). Activation of NST cells induced by contralateral CT stimulation was blocked by microinjection of lidocaine into the contralateral NST but was not affected by anesthetization of the contralateral parabrachial nuclei (PbN). In addition, the NST cells that were activated by contralateral CT stimulation showed reduced responsiveness to taste stimulation after microinjection of lidocaine into the contralateral NST. These results demonstrate that nearly half of the taste neurons in the NST receive gustatory information from both sides of the tongue. This “cross talk” between bilateral NST may also contribute to the “taste constancy”.

Background.Criteria for antiretroviral treatment (ART) were adjusted to enable early HIV treatment for people living HIV/AIDS (PLHIV) in China in recent years. This study aims to determine how pretreatment waiting time after HIV confirmation affects subsequent adherence and outcomes over the course of treatment.Methods.A retrospective observational cohort study was conducted using treatment data from PLHIV in Yuxi, China, between January 2004 and December 2015.Results.Of 1,663 participants, 348 were delayed testers and mostly initiated treatment within 28 days. In comparison, 1,315 were nondelayed testers and the median pretreatment waiting time was 599 days, but it significantly declined over the study period. Pretreatment CD4 T-cell count drop (every 100 cells/mm3) contributed slowly in CD4 recovery after treatment initiation (8% less,P<0.01) and increased the risk of poor treatment adherence by 15% (ARR = 1.15, 1.08–1.25). Every 100 days of extensive pretreatment waiting time increased rates of loss to follow-up by 20% (ARR = 1.20, 1.07–1.29) and mortality rate by 11% (ARR = 1.11, 1.06–1.21), based on multivariable Cox regression.Conclusion.Long pretreatment waiting time in PLHIV can lead to higher risk of poor treatment adherence and HIV-related mortality. Current treatment guidelines should be updated to provide ART promptly.