Medicinal cannabis for the treatment of chronic refractory pain: An investigation of the adverse event profile and health-related quality of life impact of an oral formulation

Introduction: Medicinal cannabis is prescribed in Australia for patients with chronic refractory pain conditions. However, measures of safety and effectiveness of different cannabinoids are lacking. We designed an observational study to capture effectiveness, adverse events (AEs), and health-related quality of life (HRQoL) measures in patients prescribed an oral medicinal cannabis formulation at Cannabis Access Clinics through the Cannabis Access Clinics Observational study (CACOS). Objectives: We aimed to evaluate effectiveness, reported AEs, and change in patient-reported outcomes in individuals prescribed a cannabinoid oil formulation for management of chronic pain. Methods: A cross-sectional analysis was conducted on patients prescribed an oil formulation of Δ9-tetrahydrocannabinol and cannabidiol for pain symptoms of at least 3-month duration. Clinician-reported AEs were organized by system, organ, class, and frequency. Analysis of patient-reported responses to a questionnaire was conducted using published minimal clinically important differences to determine meaningful change in HRQoL over time. Results: More than half (n = 91/151, 60.3%) of the participants experienced at least one AE during the observation period (mean 133 ± 116 days). No serious AEs were reported. Patient-reported pain impact scores were significantly reduced across the cohort (p = 0.034), and pain intensity scores verged on significance (p = 0.053). The majority of patients saw meaningful improvements in sleep (49.3%) and fatigue (35.6%). Conclusion: This analysis presents real-world data collected as part of standard of care. More than one-third of patients benefited from oral medicinal cannabis, which is impactful given the refractory nature of their pain. Amelioration of the impact of pain confirms continued prescribing of this formulation and validates our observational methodology as a tool to determine the therapeutic potency of medicinal cannabinoids

Revised stratigraphy of the Blanchetown Clay, Murray Basin: age constraints on the evolution of paleo Lake Bungunnia

Paleo Lake Bungunnia covered more than 40 000 km2 of southern Australia during the Plio-Pleistocene, although the age and origin of the lake remain controversial. The Blanchetown Clay is the main depositional unit and outcrop at Nampoo Station in far-western New South Wales provides the most continuous lacustrine section preserved in the basin. Here the Blanchetown Clay represents the maximum lake fill and comprises: (i) a basal well-sorted sand with interbedded clay (Chowilla Sand), representing initial flooding at the time of lake formation; (ii) a thick sequence of green-grey clay comprised dominantly of kaolinite and illite, with the apparently cyclic occurrence of illite interpreted to represent cool and dry glacial climatic intervals; and (iii) a 2.6 m-thick sequence of finely laminated silt and silty clay, here defined as the Nampoo Member of the Blanchetown Clay. New magnetostratigraphic data constrain the age of the oldest lake sediments to be younger than 2.581 Ma (Matuyama-Gauss boundary) and probably as young as 2.4 Ma. This age is significantly younger than the age of 3.2 Ma previously suggested for lake formation. The youngest Blanchetown Clay is older than 0.781 Ma (Brunhes-Matuyama boundary) and probably as old as 1.2 Ma. The Nampoo Station section provides a framework for the construction of a regional Plio-Pleistocene stratigraphy in the Murray Basin.<br /

Electronic sculpting of ligand-GPCR subtype selectivity:the case of angiotensin II

GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (<i>K</i>_i = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range

Molecular Basis of ß-­arrestin Coupling to Formoterol-­Bound ß1-­adrenoceptor

The β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the β1AR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G-protein-mimetic nanobody6 Nb80. βarr1 couples to β1AR in a manner distinct to that7 of Gs coupling to β2AR-the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. β1AR coupled to βarr1 shows considerable differences in structure compared with β1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of β1AR, and find that formoterol has a lower affinity for the β1AR-βarr1 complex than for the β1AR-Gs complex. The structural differences between these complexes of β1AR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors

The Atacama Cosmology Telescope: A Measurement of the 600< ell <8000 Cosmic Microwave Background Power Spectrum at 148 GHz

We present a measurement of the angular power spectrum of the cosmic microwave background (CMB) radiation observed at 148 GHz. The measurement uses maps with 1.4' angular resolution made with data from the Atacama Cosmology Telescope (ACT). The observations cover 228 square degrees of the southern sky, in a 4.2-degree-wide strip centered on declination 53 degrees South. The CMB at arcminute angular scales is particularly sensitive to the Silk damping scale, to the Sunyaev-Zel'dovich (SZ) effect from galaxy clusters, and to emission by radio sources and dusty galaxies. After masking the 108 brightest point sources in our maps, we estimate the power spectrum between 600 < \ell < 8000 using the adaptive multi-taper method to minimize spectral leakage and maximize use of the full data set. Our absolute calibration is based on observations of Uranus. To verify the calibration and test the fidelity of our map at large angular scales, we cross-correlate the ACT map to the WMAP map and recover the WMAP power spectrum from 250 < ell < 1150. The power beyond the Silk damping tail of the CMB is consistent with models of the emission from point sources. We quantify the contribution of SZ clusters to the power spectrum by fitting to a model normalized at sigma8 = 0.8. We constrain the model's amplitude ASZ < 1.63 (95% CL). If interpreted as a measurement of sigma8, this implies sigma8^SZ < 0.86 (95% CL) given our SZ model. A fit of ACT and WMAP five-year data jointly to a 6-parameter LCDM model plus terms for point sources and the SZ effect is consistent with these results.Comment: 15 pages, 8 figures. Accepted for publication in Ap

Crucial Role of Mechanisms and Modes of Toxic Action for Understanding Tissue Residue Toxicity and Internal Effect Concentrations of Organic Chemicals

This article reviews the mechanistic basis of the tissue residue approach for toxicity assessment (TRA). The tissue residue approach implies that whole-body or organ concentrations (residues) are a better dose metric for describing toxicity to aquatic organisms than is the aqueous concentration typically used in the external medium. Although the benefit of internal concentrations as dose metrics in ecotoxicology has long been recognized, the application of the tissue residue approach remains limited. The main factor responsible for this is the difficulty of measuring internal concentrations. We propose that environmental toxicology can advance if mechanistic considerations are implemented and toxicokinetics and toxicodynamics are explicitly addressed. The variability in ecotoxicological outcomes and species sensitivity is due in part to differences in toxicokinetics, which consist of several processes, including absorption, distribution, metabolism, and excretion (ADME), that influence internal concentrations. Using internal concentrations or tissue residues as the dose metric substantially reduces the variability in toxicity metrics among species and individuals exposed under varying conditions. Total internal concentrations are useful as dose metrics only if they represent a surrogate of the biologically effective dose, the concentration or dose at the target site. If there is no direct proportionality, we advise the implementation of comprehensive toxicokinetic models that include deriving the target dose. Depending on the mechanism of toxicity, the concentration at the target site may or may not be a sufficient descriptor of toxicity. The steady-state concentration of a baseline toxicant associated with the biological membrane is a good descriptor of the toxicodynamics of baseline toxicity. When assessing specific-acting and reactive mechanisms, additional parameters (e.g., reaction rate with the target site and regeneration of the target site) are needed for characterization. For specifically acting compounds, intrinsic potency depends on 1) affinity for, and 2) type of interaction with, a receptor or a target enzyme. These 2 parameters determine the selectivity for the toxic mechanism and the sensitivity, respectively. Implementation of mechanistic information in toxicokinetic–toxicodynamic (TK–TD) models may help explain timedelayed effects, toxicity after pulsed or fluctuating exposure, carryover toxicity after sequential pulses, and mixture toxicity.We believe that this mechanistic understanding of tissue residue toxicity will lead to improved environmental risk assessment

Spectrum of neuroimaging findings post-proton beam therapy in a large pediatric cohort

PURPOSE: Proton beam therapy (PBT) is now well established for the treatment of certain pediatric brain tumors. The intrinsic properties of PBT are known to reduce long-term negative effects of photon radiotherapy (PRT). To better understand the intracranial effects of PBT, we analyzed the longitudinal imaging changes in a cohort of children with brain tumors treated by PBT with clinical and radiotherapy dose correlations. MATERIALS AND METHODS: Retrospective imaging review of 46 patients from our hospital with brain tumors treated by PBT. The imaging findings were correlated with clinical and dose parameters. RESULTS: Imaging changes were assessed by reviewing serial magnetic resonance imaging (MRI) scans following PBT over a follow-up period ranging from 1 month to 7 years. Imaging changes were observed in 23 patients undergoing PBT and categorized as pseudoprogression (10 patients, 43%), white matter changes (6 patients, 23%), parenchymal atrophy (6 patients, 23%), and cerebral large vessel arteriopathy (5 patients, 25%). Three patients had more than one type of imaging change. Clinical symptoms attributable to PBT were observed in 13 (28%) patients. CONCLUSION: In accordance with published literature, we found evidence of varied intracranial imaging changes in pediatric brain tumor patients treated with PBT. There was a higher incidence (10%) of large vessel cerebral arteriopathy in our cohort than previously described in the literature. Twenty-eight percent of patients had clinical sequelae as a result of these changes, particularly in the large vessel arteriopathy subgroup, arguing the need for angiographic and perfusion surveillance to pre-empt any morbidities and offer potential neuro-protection

Mapping the Complete Reaction Path of a Complex Photochemical Reaction

We probe the dynamics of dissociating CS2 molecules across the entire reaction pathway upon excitation. Photoelectron spectroscopy measurements using laboratory-generated femtosecond extreme ultraviolet pulses monitor the competing dissociation, internal conversion, and intersystem crossing dynamics. Dissociation occurs either in the initially excited singlet manifold or, via intersystem crossing, in the triplet manifold. Both product channels are monitored and show that despite being more rapid, the singlet dissociation is the minor product and that triplet state products dominate the final yield. We explain this by consideration of accurate potential energy curves for both the singlet and triplet states. We propose that rapid internal conversion stabilises the singlet population dynamically, allowing for singlet-triplet relaxation via intersystem crossing and efficient formation of spin-forbidden dissociation products on longer timescales. The study demonstrates the importance of measuring the full reaction pathway for defining accurate reaction mechanisms

The Atacama Cosmology Telescope (ACT): Beam Profiles and First SZ Cluster Maps

The Atacama Cosmology Telescope (ACT) is currently observing the cosmic microwave background with arcminute resolution at 148 GHz, 218 GHz, and 277 GHz. In this paper, we present ACT's first results. Data have been analyzed using a maximum-likelihood map-making method which uses B-splines to model and remove the atmospheric signal. It has been used to make high-precision beam maps from which we determine the experiment's window functions. This beam information directly impacts all subsequent analyses of the data. We also used the method to map a sample of galaxy clusters via the Sunyaev-Zel'dovich (SZ) effect, and show five clusters previously detected with X-ray or SZ observations. We provide integrated Compton-y measurements for each cluster. Of particular interest is our detection of the z = 0.44 component of A3128 and our current non-detection of the low-redshift part, providing strong evidence that the further cluster is more massive as suggested by X-ray measurements. This is a compelling example of the redshift-independent mass selection of the SZ effect.Comment: 16 pages, 10 figures. Accepted for publication in ApJS. See Marriage et al. (arXiv:1010.1065) and Menanteau et al. (arXiv:1006.5126) for additional cluster result