Levo-Tetrahydropalmatine Attenuates Cocaine Self-Administration under a Progressive-Ratio Schedule and Cocaine Discrimination in Rats

Levo-tetrahydropalmatine (l-THP) is an alkaloid found in many traditional Chinese herbal preparations and has a unique pharmacological profile that includes dopamine receptor antagonism. Previously we demonstrated that l-THP attenuates fixed-ratio (FR) cocaine self-administration (SA) and cocaine-induced reinstatement in rats at doses that do not alter food-reinforced responding. This study examined the effects of l-THP on cocaine and food SA under progressive-ratio (PR) schedules of reinforcement and the discriminative stimulus effects of cocaine. In adult male Sprague–Dawley rats self-administering cocaine (0.5 or 1.0 mg/kg/inf), l-THP significantly reduced breaking points at the 1.875, 3.75 and 7.5 mg/kg doses. l-THP also reduced the breaking point and response rate for PR SA of sucrose-sweetened food pellets, although the decrease was significant only at the 7.5 mg/kg l-THP dose. In rats trained to discriminate cocaine (10 mg/kg, ip) from saline, l-THP (1.875, 3.75 and 7.5 mg/kg) produced a rightward shift in the dose–response curve for cocaine generalization. During generalization testing, l-THP reduced response rate, but only at the 7.5 mg/kg dose. l-THP also prevented substitution of the dopamine D2/D3 receptor agonist, (±) 7-OH-DPAT, for cocaine suggesting a potential role for antagonism of D2 and/or D3 receptors in the effects of l-THP. These data further demonstrate that l-THP attenuates the reinforcing and subjective effects of cocaine at doses that do not produce marked motor effects and provide additional evidence that l-THP may have utility for the management of cocaine addiction

Cellular Infiltration and Cytokine Expression Correlate with Fistulizing State in Crohn\u27s Disease

The purpose of this study was to determine the degree of infiltration of different cell subpopulations (tissue dendritic macrophages, T-helper cells, cytotoxic T lymphocytes, monocytes, neutrophils, and B cells) and the expression of the cytokines interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) in inflamed and noninflamed resected tissues from Crohn\u27s disease (CD) and non-CD patients. Twenty-one resected full-thickness intestinal tissue specimens representing 13 subjects (8 CD and 5 non-CD patients) were included in this study. Sections of 20 mu m in thickness were cut and then stained using immunohistochemistry. The sections were analyzed using confocal laser scanning microscopy (CLSM). Patterns of staining for inflamed CD and noninflamed CD tissues versus non-CD tissues demonstrated significant differences in the macrophage and T-helper subpopulations. Surprisingly, the T-helper subset was decreased significantly in the inflamed CD sections compared to the noninflamed CD and non-CD sections. The staining patterns also suggested differences in the expression of both IL-12 and TNF-alpha between the groups, with cytokine overexpression directly relating to the fistulizing state in CD patients. Cytokine expression is upregulated in chronic CD patients; therefore, the degree of inflammation and tissue damage in CD is dependent on the expression of specific cytokines within the tissue. Differentiation of cell subpopulations may be important for establishing a direct relationship with each state of CD (inflammatory, stricturing, and fistulizing states)

A qualitative process evaluation of a randomised controlled trial of a parenting intervention in community (school) settings for children at risk of attention deficit hyperactivity disorder (ADHD)

Background: Interventions for parents of children experiencing emotional and/or behavioural difficulties can help to improve their children’s health, educational and social outcomes. However, the desirability and acceptability of screening and offering such interventions for attention-deficit hyperactivity disorder (ADHD)-type problems are currently unclear. This article is a qualitative process evaluation of a pragmatic cluster randomised controlled trial (Trial registration: ISRCTN87634685; reported elsewhere) to assess the feasibility and acceptability of a school-based parenting intervention programme for parents and teachers of children with high levels of ADHD symptoms. Methods: Parents (n = 22) and teaching staff (n = 29) took part in semi-structured group or individual interviews, either by telephone or face-to-face, following the main trial. Interviews were digitally-recorded, transcribed verbatim and subjected to thematic analysis. Results: The parenting intervention was acceptable to parents and teachers, and they were enthusiastic about the need for parenting groups in the school environment and stressed the importance of parent-school collaboration. Parents generally stated a preference for universal recruitment approaches to such programmes whilst teachers described the need to target specific parents. Most parents who took part in the parenting intervention described it favourably and many saw benefits, at least in the short-term. Parents differed in their preferred group size, with some desiring one-to-one sessions and others favouring a larger group. Non-attending parents reported barriers to attendance such as fear of attending in a group, previous use of the programme, work and other commitments. Suggestions to improve the programme included: clearer communication; offering booster sessions; and greater collaboration with teachers. Conclusions: It is feasible to deliver parenting intervention programmes within or near schools. The intervention was acceptable to the majority of parents, thus retention was high, but recruitment was difficult and reaching the parents with the most need was challenging. The findings of the process evaluation identified greater benefits to families than were apparent in the main trial. Recommendations identified by parents and teaching staff may be used to inform service delivery and future research to enhance recruitment to parenting interventions in the school environmen

Investigations of Aerobic Methane Oxidation in Two Marine Seep Environments: Part 1—Chemical Kinetics

Microbial aerobic oxidation is known to be a significant sink of marine methane (CH4), contributing to the relatively minor atmospheric release of this greenhouse gas over vast stretches of the ocean. However, the chemical kinetics of aerobic CH4 oxidation are not well established, making it difficult to predict and assess the extent that CH4 is oxidized in seawater following seafloor release. Here we investigate the kinetics of aerobic CH4 oxidation using mesocosm incubations of fresh seawater samples collected from seep fields in Hudson Canyon, U.S. Atlantic Margin and MC118, Gulf of Mexico to gain a fundamental chemical understanding of this CH4 sink. The goals of this investigation were to determine the response or lag time following CH4 release until more rapid oxidation begins, the reaction order, and the stoichiometry of reactants utilized (i.e., CH4, oxygen, nitrate, phosphate, trace metals) during CH4 oxidation. The results for both Hudson Canyon and MC118 environments show that CH4 oxidation rates sharply increased within less than one month following the CH4 inoculation of seawater. However, the exact temporal characteristics of this more rapid CH4 oxidation varied based on location, possibly dependent on the local circulation and biogeochemical conditions at the point of seawater collection. The data further suggest that methane oxidation behaves as a first‐order kinetic process and that the reaction rate constant remains constant once rapid CH4 oxidation begins

Investigations of Aerobic Methane Oxidation in Two Marine Seep Environments: Part 2—Isotopic Kinetics

During aerobic oxidation of methane (CH4) in seawater, a process which mitigates atmospheric emissions, the 12C‐isotopologue reacts with a slightly greater rate constant than the 13C‐isotopologue, leaving the residual CH4 isotopically fractionated. Prior studies have attempted to exploit this systematic isotopic fractionation from methane oxidation to quantify the extent that a CH4 pool has been oxidized in seawater. However, cultivation‐based studies have suggested that isotopic fractionation fundamentally changes as a microbial population blooms in response to an influx of reactive substrates. Using a systematic mesocosm incubation study with recently collected seawater, here we investigate the fundamental isotopic kinetics of aerobic CH4 oxidation during a microbial bloom. As detailed in a companion paper, seawater samples were collected from seep fields in Hudson Canyon, U.S. Atlantic Margin, and atop Woolsey Mound (also known as Sleeping Dragon) which is part of lease block MC118 in the northern Gulf of Mexico, and used in these investigations. The results from both Hudson Canyon and MC118 show that in these natural environments isotopic fraction for CH4 oxidation follows a first‐order kinetic process. The results also show that the isotopic fractionation factor remains constant during this methanotrophic bloom once rapid CH4 oxidation begins and that the magnitude of the fractionation factor appears correlated with the first‐order reaction rate constant. These findings greatly simplify the use of natural stable isotope changes in CH4 to assess the extent that CH4 is oxidized in seawater following seafloor release

Median Nerve Mobility Measurement using a Motion Tracking Analysis Program: A Reliability Study

Objective: To evaluate relative and absolute reliability and repeatability in assessing median nerve mobility at the level of the wrist and distal upper arm of the right upper extremity during wrist extension. Methods: Six healthy participants participated in the study. Median nerve mobility was captured three times at both sites using Sonocyte Turbo by two sonologists for a total of 72 video clips (36 for each site and 18 by each sonologist). Longitudinal movement was measured using Motion Tracking Analysis Program (MTAP) by the two assessors who were rehabilitation medicine residents. After one month, the assessors remeasured the longitudinal excursion of the median nerve of the previous video clips. Results: There was moderate agreement between the two sonologists of the median nerve mobility at the level of the distal upper arm and the wrist respectively. There was a moderate to almost perfect agreement between the two assessors’ readings in the mobility of the nerve at level of the distal upper arm and wrist for the first and second readings. Repeatability testing showed that there was variable agreement at the level of the distal upper arm and at the wrist. Conclusion: MTAP using fast template tracking with an adaptive template is a reliable tool that can be employed in the accurate assessment of median nerve mobility at the distal upper arm and wrist

Evaluation and application of static headspace-multicapillary column-gas chromatography-ion mobility spectrometry for complex sample analysis.

An evaluation of static headspace-multicapillary column-gas chromatography-ion mobility spectrometry (SHS-MCC-GC-IMS) has been undertaken to assess its applicability for the determination of 32 volatile compounds (VCs). The key experimental variables of sample incubation time and temperature have been evaluated alongside the MCC-GC variables of column polarity, syringe temperature, injection temperature, injection volume, column temperature and carrier gas flow rate coupled with the IMS variables of temperature and drift gas flow rate. This evaluation resulted in six sets of experimental variables being required to separate the 32 VCs. The optimum experimental variables for SHS-MCC-GC-IMS, the retention time and drift time operating parameters were determined; to normalise the operating parameters, the relative drift time and normalised reduced ion mobility for each VC were determined. In addition, a full theoretical explanation is provided on the formation of the monomer, dimer and trimer of a VC. The optimum operating condition for each VC calibration data was obtained alongside limit of detection (LOD) and limit of quantitation (LOQ) values. Typical detection limits ranged from 0.1ng bis(methylthio)methane, ethylbutanoate and (E)-2-nonenal to 472ng isovaleric acid with correlation coefficient (R(2)) data ranging from 0.9793 (for the dimer of octanal) through to 0.9990 (for isobutyric acid). Finally, the developed protocols were applied to the analysis of malodour in sock samples. Initial work involved spiking an inert matrix and sock samples with appropriate concentrations of eight VCs. The average recovery from the inert matrix was 101±18% (n=8), while recoveries from the sock samples were lower, that is, 54±30% (n=8) for sock type 1 and 78±24% (n=6) for sock type 2. Finally, SHS-MCC-GC-IMS was applied to sock malodour in a field trial based on 11 volunteers (mixed gender) over a 3-week period. By applying the SHS-MCC-GC-IMS database, four VCs were identified and quantified: ammonia, dimethyl disulphide, dimethyl trisulphide and butyric acid. A link was identified between the presence of high ammonia and dimethyl disulphide concentrations and a high malodour odour grading, that is, ≥ 6. Statistical analysis did not find any correlation between the occurrence of dimethyl disulphide and participant gender

Protocol evaluating the effectiveness of a school-based group programme for parents of children at risk of ADHD: The 'PArents, Teachers and CHildren WORKing together (PATCHWORK)' cluster RCT protocol

Introduction Early intervention for childhood behavioural problems may help improve health and educational outcomes in affected children and reduce the likelihood of developing additional difficulties. The National Institute for Health and Clinical Excellence guidelines for attention deficit/hyperactivity disorder (ADHD), a common childhood behavioural disorder, recommend a stepped care approach for the identification and management of these problems. Parents of children with high levels of hyperactivity and inattention may benefit from intervention programmes involving behavioural management and educational approaches. Such interventions may be further enhanced by providing training and feedback to teachers about the strategies discussed with parents. In relation to children with high levels of hyperactivity, impulsiveness and inattention, we aim to test the feasibility and effectiveness of a parenting programme (with and without an accompanying teacher session) in primary schools. Methods and analysis This clustered (at the level of school) randomised controlled trial (RCT) focuses on children in their first four school years (ages 4–8 years) in the East Midlands area of England. Parents will complete a screening measure, the Strengths and Difficulties Questionnaire, to identify children with high levels of hyperactivity/inattention. Three approaches to reducing hyperactivity and attention problems will be compared: a group programme for parents (parent-only intervention); group programme for parents combined with feedback to teachers (combined intervention); and waiting list control (no intervention). Differences between arms on the short version of Conners’ Parent and Teacher Rating Scales Revised will be compared and also used to inform the sample size required for a future definitive cluster RCT. A preliminary cost-effectiveness analysis will also be conducted. Ethics and dissemination The outcomes of this study will inform policy makers about the feasibility, acceptability and effectiveness of delivering targeted behavioural interventions within a school setting. The study has received ethical approval from the University of Nottingham Medical School Ethics Committee