Higher tacrolimus trough levels and time in the therapeutic range are associated with the risk of acute rejection in the first month after renal transplantation.

BACKGROUND: Tacrolimus trough levels (C0) are used in most transplant centres for therapeutic drug monitoring (TDM) of tacrolimus (Tac). The target range of Tac C0 has been remarkably changed, with a target as low as 3-7 ng/ml in the 2009 European consensus conference and a target of 4-12 ng/ml (preferably to 7-12 ng/ml) following the second consensus report in 2019. Our aim was to investigate whether reaching early Tac therapeutic targets and maintaining time in the therapeutic range (TTR) according to the new recommendations may be necessary for preventing acute rejection (AR) during the first month after transplantation. METHODS: A retrospective study including 160 adult renal transplant patients (113 men and 47 women) with a median age of 36.3 (20-44) years was conducted between January 2018 and December 2019 at 103 Military Hospital (Vietnam). Tac trough levels were recorded in the first month, and episodes of AR were confirmed by kidney biopsy. Tac TTR was calculated as the percentage of time within the target range of 7-12 ng/ml, according to the 2019 second consensus report. Multivariate Cox analysis was performed to identify the correlation between the Tac target range and TTR with AR. RESULTS: In the first month after RT, 14 (8.8%) patients experienced AR. There was a significant difference in the incidence of AR between the Tac level groups of < 4, 4-7 and > 7 ng/ml (p = 0.0096). In the multivariate Cox analysis, after adjusting for related factors, a mean Tac level > 7 ng/ml was associated with an 86% decreased risk of AR compared with that of 4-7 ng/ml in the first month (HR, 0.14; 95% CI, 0.03-0.66; p = 0.0131). Every 10% increase in TTR was associated with a 28% lower risk of AR (HR, 0.72; 95% CI, 0.55-0.94; p = 0.014). CONCLUSION: Gaining and maintaining Tac C0 according to the 2019 second consensus report might reduce the risk of AR in the first month following transplantation.

Incidence of Respiratory Syncytial Virus Lower Respiratory Tract Infections During the First 2 Years of Life: A Prospective Study Across Diverse Global Settings.

BACKGROUND: The true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life. METHODS: This prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods. RESULTS: Of 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval [CI], 5.88-9.08), 5.50 (95% CI, 4.21-7.07), and 2.87 (95% CI, 2.18-3.70) cases/100 person-years in children aged 0-5, 6-11, and 12-23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0-5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0-2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs. CONCLUSIONS: A substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most. Clinical Trials Registration. NCT01995175.

Evaluation of heavy metal contamination in the coastal aquaculture zone of the Red River Delta (Vietnam).

Coastal aquaculture contributes significantly to the local economy of many countries however water quality issues in the coastal regions are threatening the sustainability of this economic activity. This paper presents the analysis of seven heavy metals (HM) in surface seawater and wastewater from the Red River coastal aquaculture zone during 2019-2020. HM concentrations (µg.L-1) from 72 seawater samples were: Zn: 60.76 (0.5-188.0); Cu: 26.91 (0.10-96.0); Pb: 7.27 (0.8-31.2); Cr: 6.71 (0.6-28.4); As: 1.38 (0.15-5.78); Cd: 0.44 (0.04-2.41); and Hg: 0.34 (0.02-1.39). All mean values of HM in seawater were lower than the Vietnam regulatory limits for aquaculture seawater although high individual HM concentrations were found in some isolated seawater samples. Concerning wastewater quality, only mean As concentration was higher than the Vietnam regulatory limit for surface water quality, despite the fact that high concentrations of other individual HM were observed. The PCA analysis on the entire dataset of seawater and wastewater samples revealed that HM concentrations in seawater originate from various sources including human activities and natural conditions. The total potential ecological risk index (averaging 18.6; from 7.48 to 39.05) for the Red River coastal zone is in the low range. These results provide a scientific basis for better management of the coastal environment which is important for the sustainable development of the aquaculture industry in this area.

Repeated Morphine Administration Increases TRPV1 mRNA Expression and Autoradiographic Binding at Supraspinal Sites in the Pain Pathway.

Repeated morphine administration induces tolerance to its analgesic effects. A previous study reported that repeated morphine treatment activates transient receptor potential vanilloid type 1 (TRPV1) expression in the sciatic nerve, dorsal root ganglion, and spinal cord, contributing to morphine tolerance. In the present study, we analyzed TRPV1 expression and binding sites in supraspinal pain pathways in morphine-tolerant mice. The TRPV1 mRNA levels and binding sites were remarkably increased in the cortex and thalamus of these animals. Our data provide additional insights into the effects of morphine on TRPV1 in the brain and suggest that changes in the expression of, and binding to TRPV1 in the brain are involved in morphine tolerance.

Separated Micelles Formation of pH-Responsive Random and Block Copolymers Containing Phosphorylcholine Groups.

The self-assembly of pH-responsive random and block copolymers composed of 2-(N,N-diisopropylamino)ethyl methacrylate and 2-methacryloyloxyethyl phosphorylcholine was investigated in aqueous media. Their pH-responsive behaviors were investigated in aqueous media by dynamic light scattering (DLS) and fluorescence measurements using a pyrene hydrophobic fluorescence probe. In an acidic environment, these copolymers existed as single polymer chains that did not interact with each other. In contrast, upon increasing the pH of the solution above the critical value of ~8, separated micelles were formed in the mixture, which was indicated by bimodal distribution in DLS results with radius of 4.5 and 10.4 nm, corresponding to the random and block copolymer micelles, respectively. Fluorescence resonance energy transfer efficiencies were near to zero in the mixture of the donor labeled block and acceptor labeled random copolymers under both acidic and basic pH. These results demonstrated the coexistence of two distinct micelles.

Three Dose Levels of a Maternal Respiratory Syncytial Virus Vaccine Candidate Are Well Tolerated and Immunogenic in a Randomized Trial in Nonpregnant Women.

BACKGROUND: Respiratory syncytial virus (RSV) causes respiratory tract infections, which may require hospitalization especially in early infancy. Transplacental transfer of RSV antibodies could confer protection to infants in their first months of life. METHODS: In this first-in-human, placebo-controlled study, 502 healthy nonpregnant women were randomized 1:1:1:1 to receive a single dose of unadjuvanted vaccine containing 30/60/120 µg of RSV fusion (F) protein stabilized in the prefusion conformation (RSVPreF3) or placebo. RESULTS: Solicited local adverse events (AEs) were more frequently reported in the RSVPreF3 groups (4%-53.2%) versus placebo (0%-15.9%); most were mild/moderate. Unsolicited AEs were comparably reported among groups. Three serious AEs were reported; none was vaccination-related. Compared with prevaccination values, anti-RSV A neutralizing antibody geometric mean titers and anti-RSVPreF3 immunoglobulin G geometric mean concentrations increased 8- to 14-fold and 12- to 21-fold at day 8 and persisted 5- to 6-fold and 6- to 8-fold higher until day 91 in the RSVPreF3 groups versus 1-fold in placebo. Comparisons at day 8 and day 31 showed that the higher dose levels were significantly more immunogenic than the lowest one. CONCLUSIONS: The RSVPreF3 vaccine was well tolerated and immunogenic. The 60 and 120 µg dose levels were selected for further investigation in pregnant women. CLINICAL TRIALS REGISTRATION: NCT03674177.

Respiratory syncytial virus acute respiratory infections in ≥ 65-year-old adults in long-term care facilities in the Czech Republic.

OBJECTIVES: Due to immunosenescence and presence of comorbidities, respiratory syncytial virus (RSV) disease burden is a major health concern in older adults, which is expected to increase with the life expectancy rise. Data on RSV burden are scarce in older adults residing in long-term care facilities, a vulnerable population living in crowded settings. Therefore, two independent prospective studies were conducted during the 2003-2004 and 2004-2005 RSV seasons to assess RSV acute respiratory illnesses (ARIs) and lower respiratory tract infections (LRTIs) in ≥ 65-year-old adults residing in long-term care facilities in the Czech Republic. METHODS: RSV ARI episodes were confirmed by polymerase chain reaction in nasal swabs collected within 3 days of symptoms onset. The mortality and morbidity of RSV-confirmed ARIs, as well as the risk factors associated with RSV-confirmed ARIs were evaluated. RESULTS: Among 1,251 participants in the 2003-2004 season (ARI surveillance between October and March), there were no RSV-positive cases in 255 ARI and 105 LRTI episodes. Among 1,280 participants in the 2004-2005 season (ARI surveillance between October and April), there were 39 and 26 RSV-positive cases in 335 ARI and 217 LRTI episodes, respectively, and RSV-positive ARI and LRTI episode incidence rates were 45.82 and 30.40 per 1,000 person-years. Among 290 RSV-negative and 39 RSV-positive ARI cases in the 2004-2005 season, 15 and 4 hospitalizations, 188 and 26 LRTIs, and 11 and 3 deaths were reported. Risk factors associated with RSV-positive ARI were female gender (odds ratio: 4.98), chronic heart failure class II (odds ratio: 2.31) and diabetes requiring insulin treatment (odds ratio: 9.82). CONCLUSIONS: These studies showed that RSV was an important cause of ARI in older adults living in long-term care facilities in the 2004-2005 season, with fluctuating yearly incidences.

Sphagneticola Trilobata (L.) Pruski (Asteraceae) Methanol Extract Induces Apoptosis in Leukemia Cells through Suppression of BCR/ABL.

We will study the effects of the methanol extract of Sphagneticola trilobata (L.) Pruski (Asteraceae) (MeST) on the growth of leukemia cells that may contain the BCR/ABL gene. This study also clarifies the mechanism of this effect on these cells. For this purpose, the cells harboring wild-type BCR/ABL, imatinib-resistant BCR/ABL (K562 and TCCYT315I), or Ba/F3 cells transfected with wild-type or mutant BCR/ABL genes were used. The results showed that MeST effectively inhibited the viability of leukemia cells in both a dose- and time-dependent manner. The effect of MeST seems to be more sensitive in the cells that carry imatinib-resistant BCR/ABL (especially the T315I BCR/ABL mutation) than those with wild-type BCR/ABL. Furthermore, we have demonstrated that the death caused by MeST is apoptosis and the treatment with MeST could suppress the expression of BCR/ABL, subsequently altering the downstream cascade of BCR/ABL such as AKT and MAPK signaling. In conclusion, MeST has been able to suppress the growth of leukemia cells harboring BCR/ABL. The mechanism of the anti-leukemic effect of MeST on cells harboring imatinib-resistant BCR/ABL mutations could be due to the disruption of the BCR/ABL oncoprotein signaling cascade.

Trace Metal Element Analysis in Some Seafood in the Coastal Zone of the Red River (Ba Lat Estuary, Vietnam) by Green Sample Preparation and Inductively Coupled Plasma-Mass Spectrometry (ICP-MS).

Fisheries and aquaculture production in the coastal zone of Vietnam contribute significantly to the national economy. However, seafood quality and safety, especially in terms of metal contents, are of increasing concern, for both domestic and international markets. This paper presents the results of an investigation in some trace metal elements (iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), arsenic (As), cadmium (Cd), and mercury (Hg)) concentrations in some fishes, crustaceans, and molluscs in the coastal zone of the Red River (in the Ba Lat estuary in Thai Binh and Nam Dinh provinces) during four sampling campaigns in 2020. All samples were treated by a green sample preparation using microwave digestion and then analyzed by inductively coupled plasma-mass spectrometry (ICP-MS). The results showed that the trace metal element concentrations in fish, crustacean, and mollusc samples decreased in the following order: Fe > Zn > Mn > Cu > As > Cd ∼ Hg. In more details, the ranges of trace metal elements in seafood samples were 13.13-202.73; 7.63-82.71; 0.48-22.73; 0.72-15.58; 0.18-5.12; 0.001-1.114; and 0.001-0.923 mg·kg-1 for Fe, Zn, Mn, Cu, As, Cd, and Hg, respectively. The research results contribute to the dataset of the seafood (both fishery and aquacultural seafood) quality in the Red River coastal zone. Although the mean values of different trace metal elements observed in this study were lower than the allowed values of Vietnam's or European's threshold for food safety, some high concentrations were detected. The survey results suggest the need to expand the monitoring scope (frequency of monitoring, number of samples, and observed variables) for obtaining a fully comprehensive assessment of seafood quality in this region. Our results also indicate that it is necessary to manage water quality in coastal areas, especially where aquaculture activities are carried out.

Pipercyclobutanamide D, a new member of the cyclobutanamide-type alkaloid, from the roots of Piper nigrum.

From the EtOH-soluble extract of the roots of Piper nigrum, one new dimeric alkamide, pipercyclobutanamide D (1) was isolated. Its structure was elucidated on the basis of NMR spectroscopic interpretation. The relative configuration of 1 was determined based on the NOESY analysis. Compound 1 showed α-glucosidase inhibitory activity with an IC50 value of 158.5 µM. In addition, compound 1 exhibited cytotoxicity against the MCF-7 and HepG2 cell lines with the IC50 values of 45.6 and 63.9 µM, respectively. Plausible biosynthetic pathway for the formation of 1 was proposed based on regioselective [2 + 2] cycloaddition reaction.

Adsorption Characteristics of Synthesized Polyelectrolytes onto Alumina Nanoparticles and their Application in Antibiotic Removal.

The present study aims to investigate the adsorption of synthesized poly(2-acrylamide-2-methylpropane sulfonic acid) (PAMPs) onto alumina nanoparticles and their application in the removal of ciprofloxacin (CFX) antibiotic from a water environment. The PAMPs were successfully synthesized and characterized by nuclear magnetic resonance and gel-permeation chromatography methods. The number- and weight-average molecular weights of PAMPs were 6.76 × 105 and 7.28 × 106 g/mol, respectively. The charge reversal of nanoalumina after PAMPs modification from positive to -37.5 mV was determined by ζ-potential measurement, while the appearance of C ═ O and N-H functional groups in PAMPs observed by Fourier-transform infrared spectroscopy confirmed them as the main indicators for adsorption of PAMPs onto a nanoalumina surface. The maximum adsorption capacity of PAMPs onto nanoalumina in 100 mg/L KCl was about 10 mg/g. The adsorption isotherms were fitted well by a two-step adsorption model. Application of PAMPs-modified nanoalumina (PAMNA) in CFX removal was also thoroughly studied. The optimum conditions for CFX removal using PAMNA were found to be pH 6, 10 mM NaCl, contact time 90 min, and adsorption dosage 5 mg/mL. The CFX adsorption isotherms and kinetics were in accordance with the two-step and pseudo-second-order models, respectively. The application for CFX removal in actual hospital wastewater was greater than 80%. The results of this study demonstrate that PAMNA is a new and promising material for antibiotic removal from wastewater.

Evidence for Asthma in the Lungs of Mice Inoculated with Different Doses of Toxocara canis.

Toxocara canis, a common roundworm that mainly causes toxocariasis, is a zoonotic parasite found worldwide. Humans, an accidental host, can acquire T. canis infection through accidental ingestion of T. canis-embryonated egg-contaminated food, water, and soil, and by encapsulated larvae in a paratenic host's viscera or meat. Long-term residence of T. canis larvae in a paratenic host's lungs may induce pulmonary inflammation that contributes to lung injury, airway inflammatory hyperresponsiveness, and collagen deposition in mice and clinical patients. This study intended to investigate the relationship between T. canis infection and allergic asthma in BALB/c mice inoculated with high, moderate, and low doses of T. canis eggs for a 13-week investigation. The airway hyperresponsiveness (AHR) to methacholine, collagen deposition, cytokine levels, and pathological changes in lung tissues was assessed in infected mice at weeks 1, 5, and 13 postinfection. The cell composition in bronchoalveolar lavage fluid of infected mice was assessed at weeks 5 and 13 postinfection. Compared with uninfected control mice, all groups of T. canis-infected mice exhibited significant AHR, a dose-dependent increase in eosinophilic infiltration leading to multifocal interstitial and alveolar inflammation with abundant mucus secretion, and collagen deposition in which the lesion size increased with the infective dose. Infected mice groups also showed significant expressions of eotaxin and type 2 T-helper-dominant cytokines such as interleukin (IL)-4, IL-5, and IL-13. Overall, these results suggest that T. canis larval invasion of the lungs may potentially cause pulmonary inflammatory injury and could subsequently contribute to the development of allergic manifestations such as asthma.

Synthesis of Amphiphilic Statistical Copolymers Bearing Methoxyethyl and Phosphorylcholine Groups and Their Self-Association Behavior in Water.

Biocompatible amphiphilic statistical copolymers P(MEA/MPCm) composed of 2-methoxyethyl acrylate (MEA) and 2-methacryloyloxyethyl phosphorylcholine (MPC) were prepared with three different mol% of the hydrophilic unit MPC (m = 6, 12 and 46 mol%). The monomer reactivity ratios of MEA (rMEA) and MPC (rMPC) were 0.53 and 2.21, respectively. The rMEA × rMPC value of 1.17 demonstrated that statistical copolymerization was successful. P(MEA/MPC12) and P(MEA/MPC46) copolymers did not undergo aggregation in water, whereas the P(MEA/MPC6) copolymer formed micelles in water with a hydrodynamic radius (Rh) of 96.9 nm and a critical aggregation concentration, which was determined using pyrene fluorescence, at 0.0082 g/L. The restricted motion of the protons in the hydrophobic MEA units in the micelles' cores provided additional evidence of self-association in P(MEA/MPC6).

Presumed Risk Factors and Biomarkers for Severe Respiratory Syncytial Virus Disease and Related Sequelae: Protocol for an Observational Multicenter, Case-Control Study From the Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity. CLINICAL TRIALS REGISTRATION: NCT03756766.

Vietnam Climate Change and Health Vulnerability and Adaptation Assessment, 2018.

BACKGROUND: The Global Climate Risk Index 2020 ranked Vietnam as the sixth country in the world most affected by climate variability and extreme weather events over the period 1999-2018. Sea level rise and extreme weather events are projected to be more severe in coming decades, which, without additional action, will increase the number of people at risk of climate-sensitive diseases, challenging the health system. This article summaries the results of a health vulnerability and adaptation (V&A) assessment conducted in Vietnam as evidences for development of the National Climate Change Health Adaptation Plan to 2030. METHODS: The assessment followed the first 4 steps outlined in the World Health Organization's Guidelines in conducting "Vulnerability and Adaptation Assessments." A framework and list of indicators were developed for semi-quantitative assessment for the period 2013 to 2017. Three sets of indicators were selected to assess the level of (1) exposure to climate change and extreme weather events, (2) health sensitivity, and (3) adaptation capacity. The indicators were rated and analyzed using a scoring system from 1 to 5. RESULTS: The results showed that climate-sensitive diseases were common, including dengue fever, diarrheal, influenza, etc, with large burdens of disease that are projected to increase. From 2013 to 2017, the level of "exposure" to climate change-related hazards of the health sector was "high" to "very high," with an average score from 3.5 to 4.4 (out of 5.0). For "health sensitivity," the scores decreased from 3.8 in 2013 to 3.5 in 2017, making the overall rating as "high." For "adaptive capacity," the scores were from 4.0 to 4.1, which meant adaptive capacity was "very low." The overall V&A rating in 2013 was "very high risk" (score 4.1) and "high risk" with scores of 3.8 in 2014 and 3.7 in 2015 to 2017. CONCLUSIONS: Adaptation actions of the health sector are urgently needed to reduce the vulnerability to climate change in coming decades. Eight adaptation solutions, among recommendations of V&A assessment, were adopted in the National Health Climate Change Adaptation Plan.

Integrative settings approach to workplace health promotion to address contemporary challenges for worker health in the Asia-Pacific.

Workplaces in the rapidly industrializing Asia-Pacific region face growing pressures from high-speed development driven by global competition, migration and the aging of the workforce. Apart from addressing work-related injuries, workplaces in the region also have to deal with increasing occupational stress, chronic diseases and their associated socio-economic burden. Meanwhile, interventions in workplace health are still dominated by a narrow behavioral change model. To this end, the integrative workplace health promotion model, initiated by the World Health Organization from successful post-1990 pilot projects, emerges as a timely, comprehensive and appropriate means to manage contemporary workplace health and safety issues in the region. In this paper, we highlight the key workplace health challenges in the Asia-Pacific region and the utility of the integrative workplace health promotion model in addressing them. We provide a brief overview of the pressing challenges confronting workplaces in the region, then explain the why, what and how of integrative workplace health promotion. We illustrate this model by reviewing successful examples of good practice and evidence of their achievements from workplace health promotion programs in Asia-Pacific from 2002 to date, with specific attention to government-led workplace health promotion programs in Shanghai, Singapore and Taiwan. Drawing from these successful examples, we recommend government policies and facilitating strategies needed to guide, support and sustain industries in implementing integrative workplace health promotion. We conclude that consistent supportive government policies, coupled with facilitation by international bodies towards capacity and professional network building, are crucial to developing and sustaining healthy workplaces in the region.

Construction of DNA ladder based on 16S rRNA gene of Bacillus subtilis using touchdown PCR technique

Aim@#DNA molecular size markers or DNA ladders play a vital role in molecular biology laboratories where DNA electrophoresis experiments are usually conducted. This study aimed to produce a 100 bp DNA ladder at laboratory scale, which could be applied to determine the size of DNA fragments in molecular biology experiments.@*Methodology and results@#In this study, 14 primers including 4 forwards and 10 reverses were designed based on the 16S rRNA gene sequence of Bacillus subtilis. These primers were able to amplify 10 DNA fragments with accurate sizes from 100 to 1000 bp. Furthermore, touchdown PCR was involved to maximize the specificity and yield of PCR products. Ten DNA fragments with the sizes including 100, 200, 300, 400, 500, 600, 700, 800, 900 and 1000 bp were synthesized, and such bands were equivalent with commercial DNA ladders. Moreover, the quantity and quality of PCR products were measured using a nanodrop spectrophotometer. The optimal concentration ratios between such fragments (100- 1000 bp) were 800, 300, 150, 150, 500, 50, 50, 50, 50 and 50 (ng/µL), respectively. These ratios showed the clear and high resolution on 1.5% agarose gel. @*Conclusion, significance and impact of the study@#The results indicated that 16S rRNA gene of B. subtilis was a potential material for DNA ladder preparation due to the multiple copies number of this gene. Furthermore, in combination with touchdown PCR, the nonspecific bands were reduced, and the products could be used directly without the need of purification step.

Transient receptor potential vanilloid 1 mediates cocaine reinstatement via the D1 dopamine receptor in the nucleus accumbens.

PURPOSE: The transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that mediates synaptic modification in the nucleus accumbens (NAc). However, no study has yet examined the mechanism of TRPV1 in the NAc on cocaine reinstatement. We investigated the mechanism of TRPV1 in NAc on cocaine reinstatement using the conditioned place preference (CPP) test in mice. METHODS: We examined the effect of capsazepine (5 mg/kg, a TRPV1 antagonist, administered intraperitoneally (i.p.)), capsaicin (0.3 mg/kg, a TRPV1 agonist, administered i.p.), and genetic deletion of TRPV1 on the reinstatement of cocaine-induced CPP (15 mg/kg, administered i.p.). The expression of TRPV1 and Ca2+/calmodulin-mediated kinase II (CaMKII) in the NAc were determined after cocaine reinstatement. Microinjection of SB366791 (0.2 ng, a selective TRPV1 antagonist) in the NAc was assessed on SKF-81297 (1 µg, D1-like dopamine (DA) receptor agonist) primed cocaine reinstatement. RESULTS: Capsazepine suppressed and capsaicin potentiated cocaine CPP in the reinstatement phase. In addition, genetic deletion of TRPV1 inhibited cocaine-priming reinstatement. Cocaine reinstatement was mediated by increased TRPV1 expression in the NAc, which involves CaMKII. Microinjection of SB366791 in the NAc prevented the cocaine reinstatement evoked by microinjection of SKF-81297 in the NAc. CONCLUSIONS: These findings suggest that activation of TRPV1 mediates the stimulation of D1-like DA receptors and CaMKII in the NAc, resulting in the facilitation of cocaine reinstatement behaviors. Thus, our findings reveal a previously unknown TRPV1 mechanism in the reinstatement to drugs of abuse.

Immunogenicity and Safety of 3 Formulations of a Respiratory Syncytial Virus Candidate Vaccine in Nonpregnant Women: A Phase 2, Randomized Trial.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of respiratory tract illness and hospitalization in neonates and infants. RSV vaccination during pregnancy may protect offspring in their first months of life. METHODS: This randomized, observer-blind, multicenter, phase 2 study evaluated the immunogenicity and safety of an RSV candidate vaccine in healthy nonpregnant women aged 18-45 years. Four hundred participants were randomized (1:1:1:1) to receive a single intramuscular dose of vaccine containing 30 µg, 60 µg, or 120 µg of RSV fusion protein engineered to preferentially maintain a prefusion conformation (RSV-PreF vaccine) or placebo. RESULTS: Thirty days postvaccination, RSV-A neutralizing antibody geometric mean titers (GMTs) increased 3.75-, 4.42- and 4.36-fold; RSV-B neutralizing antibody GMTs 2.36-, 2.54- and 2.76-fold; and palivizumab competing antibody (PCA) concentrations 11.69-, 14.38- and 14.24-fold compared with baseline levels in the 30 µg, 60 µg, and 120 µg RSV-PreF groups, respectively. Antibody titers and PCA concentrations at day 30 were significantly higher with the 120 µg compared to the 30 µg RSV-PreF vaccine. All RSV-PreF vaccine formulations and the placebo had similar reactogenicity profiles. No serious adverse events were considered to be related to the RSV-PreF vaccine. CONCLUSIONS: The 3 formulations of the investigational RSV-PreF vaccine were well-tolerated and induced RSV-A and RSV-B neutralizing antibodies and PCAs in healthy, nonpregnant women. CLINICAL TRIALS REGISTRATION: NCT02956837.

Colloidal Stabilizer-Assisted Polymerization-Induced Precipitation Method for Colloidally Stable Polyacid Particles.

Near-monodispersed, colloidally stable, submicrometer-sized poly(acid phosphoxy ethyl methacrylate) (PAPEMA) latex particles were synthesized by free-radical dispersion polymerization using poly( N-vinylpyrrolidone) (PNVP) as both a steric colloidal stabilizer and a precipitating agent. Polymerization in the absence of PNVP led to a homogeneous transparent solution of PAPEMA, which indicates that the PNVP is essential for latex formation and the complex of PNVP and PAPEMA was formed during the dispersion polymerization. Dispersion copolymerizations with a divinyl cross-linking comonomer (∼20 wt % based on acid phosphoxy ethyl methacrylate) were also successful in synthesizing near-monodispersed, colloidally stable cross-linked PAPEMA latex particles, and the softness and p Ka values of the resulting PAPEMA latex particles can be controlled by varying the divinyl comonomer concentration. These sterically stabilized latex particles were characterized by electron microscopy, dynamic light scattering, X-ray photoelectron spectroscopy, elemental microanalysis, and Fourier transform infrared spectroscopy. Characterization results indicated that the PNVP colloidal stabilizer was likely to be located homogeneously on the particle surfaces and within the interior of particles. Finally, it was demonstrated that the PAPEMA latex particles worked as an effective surface modifier for metal surfaces.