Fasting and exercise increase plasma cannabinoid levels in THC pre-treated rats: an examination of behavioural consequences

Rationale

Δ⁹-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in fat tissue where it can remain for prolonged periods. Under conditions of increased fat utilisation, blood cannabinoid concentrations can increase. However, it is unclear whether this has behavioural consequences.

Objectives

Here, we examined whether rats pre-treated with multiple or single doses of THC followed by a washout would show elevated plasma cannabinoids and altered behaviour following fasting or exercise manipulations designed to increase fat utilisation.

Methods

Behavioural impairment was measured as an inhibition of spontaneous locomotor activity or a failure to successfully complete a treadmill exercise session. Fat utilisation was indexed by plasma free fatty acid (FFA) levels with plasma concentrations of THC and its terminal metabolite (-)-11-nor-9-carboxy-?⁹-tetrahydrocannabinol (THC-COOH) also measured.

Results

Rats given daily THC (10 mg/kg) for 5 days followed by a 4-day washout showed elevated plasma THC-COOH when fasted for 24 h relative to non-fasted controls. Fasted rats showed lower locomotor activity than controls suggesting a behavioural effect of fat-released THC. However, rats fasted for 20 h after a single 5-mg/kg THC injection did not show locomotor suppression, despite modestly elevated plasma THC-COOH. Rats pre-treated with THC (5 mg/kg) and exercised 20 h later also showed elevated plasma THC-COOH but did not differ from controls in their likelihood of completing 30 min of treadmill exercise.

Conclusions

These results confirm that fasting and exercise can increase plasma cannabinoid levels. Behavioural consequences are more clearly observed with pre-treatment regimes involving repeated rather than single THC dosing.     

Understanding Prolonged Cessation from Heroin Use: Findings from a Community-Based Sample

Background: There is abundant literature describing heroin initiation, co-morbidities, and treatment. Few studies focus on cessation, examining the factors that motivate and facilitate it.

Methods: The CHANGE study utilized mixed methods to investigate heroin cessation among low-income New York City participants. This paper describes findings from qualitative interviews with 20 former and 11 current heroin users. Interviews focused on background and current activities, supports, drug history, cessation attempts, and motivators and facilitators to cessation. Results: Participants found motivation for cessation in improved quality of life, relationships, and fear of illness, incarceration and/or death. Sustained cessation required some combination of treatment, strategic avoidance of triggers, and engagement in alternative activities, including support groups, exercise, and faith-based practice. Several reported that progress toward goals served as motivators that increased confidence and facilitated cessation. Ultimatums were key motivators for some participants. Beyond that, they could not articulate factors that distinguished successful from unsuccessful cessation attempts, although data suggest that those who were successful could describe more individualized and concrete—rather than general—motivators and strategies. Conclusions: Our findings indicate that cessation may be facilitated by multifaceted and individualized strategies, suggesting a need for personal and comprehensive approaches to treatment.     

Imaging features of immune-mediated genitourinary disease

Purpose

Imaging features of immune-mediated genitourinary diseases often overlap, and the same disease may manifest in different ways, so understanding imaging findings in the context of the patient’s entire clinical picture is important in providing the correct diagnosis.

Methods

In this article, diseases mediated by the immune system which affect the genitourinary system are reviewed. Examples of immune-mediated genitourinary disease including IgG4-related disease, post-transplant lymphoproliferative disorder, immunodeficiency-associated lymphoproliferative disorder due to immunosuppressive and immunomodulatory medications, lymphoma, leukemia, myeloma, amyloidosis, and histiocytosis.

Results

Clinical and imaging features will be presented which may help narrow the differential diagnosis for each disease.

Conclusion

Recognition of immune-related genitourinary disease is important for appropriate medical management as they may mimic other diseases both by imaging and clinical presentation.

     

Unwrapping of transient responses from high rate overlapping pattern electroretinograms by deconvolution

Objective

Due to overlapping, temporal information is mostly lost in high rate steady-state pattern electroretinograms (PERG_SS). This study develops a deconvolution method and a display/recording system to “unwrap” PERG_SS and obtain a transient, “per stimulus” response (PERG_tr) regardless of reversal rate.

Methods

Processing and instrumentation, including high temporal resolution display and acquisition were developed for deconvolving PERGs acquired at high rates by slight jittering of reversal onsets at a given mean rate.

Results

The system was successfully tested at eight rates from 2.2 to 78.1 rps. At medium rates (17.4–41.2 rps) recordings with conventional morphology (N35–P50–N95) but earlier peaks and higher amplitudes were extracted up to 40 rps. At higher rates, smaller triphasic responses were obtained, exhibiting similar peak latencies, but reversed polarity. Oscillating potentials (OPs) were also recorded at all rates after deconvolution.

Conclusions

Transient PERGs and OPs can be extracted from quasi steady-state PERG recordings obtained at high rates with a deconvolution algorithm using high temporal resolution display and acquisition systems.

Significance

The methodology to extract transient and oscillatory responses from steady-state PERGs could be useful in understanding high rate responses and diagnosis of various retinal diseases by revealing temporal information on waveform components which cannot be normally observed.     

A Cell-Based Pharmacokinetics Assay for Evaluating Tubulin-Binding Drugs

Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate pharmacological effects of drugs in target organs or cells in vivo. This underscores the increasing need to improve the types and qualities of cellular pharmacokinetic information for drug preclinical screening and clinical efficacy assessments. Here we report a whole cell-based method to assess drugs that disturb microtubule dynamics to better understand different formulation-mediated intracellular drug release profiles. As proof of concept for this approach, we compared the well-known taxane class of anti-microtubule drugs based on paclitaxel (PTX), including clinically familiar albumin nanoparticle-based Abraxane™, and a polymer nanoparticle-based degradable paclitaxel carrier, poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX, also known as CT-2103) versus control PTX. This in vitro cell-based evaluation of PTX efficacy includes determining the cellular kinetics of tubulin polymerization, relative populations of cells under G2 mitotic arrest, cell proliferation and total cell viability. For these taxane tubulin-binding compounds, the kinetics of cell microtubule stabilization directly correlate with G2 arrest and cell proliferation, reflecting the kinetics and amounts of intracellular PTX release. Each individual cell-based dose-response experiment correlates with published, key therapeutic parameters and taken together, provide a comprehensive understanding of drug intracellular pharmacokinetics at both cellular and molecular levels. This whole cell-based evaluating method is convenient, quantitative and cost-effective for evaluating new formulations designed to optimize cellular pharmacokinetics for drugs perturbing tubulin polymerization as well as assisting in explaining drug mechanisms of action at cellular levels.     

Incremental prognostic value of coronary computed tomographic angiography over coronary artery calcium score for risk prediction of major adverse cardiac events in asymptomatic diabetic individuals

Background

Coronary artery disease (CAD) diagnosis by coronary computed tomographic angiography (CCTA) is useful for identification of symptomatic diabetic individuals at heightened risk for death. Whether CCTA-detected CAD enables improved risk assessment of asymptomatic diabetic individuals beyond clinical risk factors and coronary artery calcium scoring (CACS) remains unexplored.

Methods

From a prospective 12-center international registry of 27,125 individuals undergoing CCTA, we identified 400 asymptomatic diabetic individuals without known CAD. Coronary stenosis by CCTA was graded as 0%, 1–49%, 50–69%, and ≥70%. CAD was judged on a per-patient, per-vessel and per-segment basis as maximal stenosis severity, number of vessels with ≥50% stenosis, and coronary segments weighted for stenosis severity (segment stenosis score), respectively. We assessed major adverse cardiovascular events (MACE) – inclusive of mortality, nonfatal myocardial infarction (MI), and late target vessel revascularization ≥90 days (REV) – and evaluated the incremental utility of CCTA for risk prediction, discrimination and reclassification.

Results

Mean age was 60.4 ± 9.9 years; 65.0% were male. At a mean follow-up 2.4 ± 1.1 years, 33 MACE occurred (13 deaths, 8 MI, 12 REV) [8.25%; annualized rate 3.4%]. By univariate analysis, per-patient maximal stenosis [hazards ratio (HR) 2.24 per stenosis grade, 95% confidence interval (CI) 1.61–3.10, p < 0.001], increasing numbers of obstructive vessels (HR 2.30 per vessel, 95% CI 1.75–3.03, p < 0.001) and segment stenosis score (HR 1.14 per segment, 95% CI 1.09–1.19, p < 0.001) were associated with increased MACE. After adjustment for CAD risk factors and CACS, maximal stenosis (HR 1.80 per grade, 95% CI 1.18–2.75, p = 0.006), number of obstructive vessels (HR 1.85 per vessel, 95% CI 1.29–2.65, p < 0.001) and segment stenosis score (HR 1.11 per segment, 95% CI 1.05–1.18, p < 0.001) were associated with increased risk of MACE. Beyond age, gender and CACS (C-index 0.64), CCTA improved discrimination by maximal stenosis, number of obstructive vessels and segment stenosis score (C-index 0.77, 0.77 and 0.78, respectively). Similarly, CCTA findings improved risk reclassification by per-patient maximal stenosis [integrated discrimination improvement (IDI) index 0.03, p = 0.03] and number of obstructive vessels (IDI index 0.06, p = 0.002), and by trend for segment stenosis score (IDI 0.03, p = 0.06).

Conclusion

For asymptomatic diabetic individuals, CCTA measures of CAD severity confer incremental risk prediction, discrimination and reclassification on a per-patient, per-vessel and per-segment basis.     

Pulmonary disorders and exercise

The respiratory system rarely limits exercise in the normal subject. In patients with chronic pulmonary processes or in the elite athlete, however, the respiratory system may indeed be the limiting factor. Common respiratory disorders include chest pain syndromes, cough, exercise-induced asthma, and vocal cord dysfunction. Chronic lung diseases such as asthma, COPD, and interstitial lung disease impact exercise capacity and endurance. Exercise testing can be useful to distinguish acute and chronic pulmonary causes of dyspnea during exercise, as well as to differentiate between cardiac and pulmonary causes.