Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors?

© 2015, BMJ Publishing Group. All rights reserved. Objectives: Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness. Setting: 17 hospice/palliative care services (tertiary services) in 11 European countries. Participants: 2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment. Primary outcome measures: The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588). Secondary outcome measures: The same measures for people on oxycodone (n=402) or fentanyl (n=429). Results: SNPs not in Hardy-Weinberg equilibrium or with allele frequencies ( < 5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone. Conclusions: This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy

Outline analysis of the grapevine (Vitis vinifera L.) berry shape by elliptic Fourier descriptors

Grapevine berry morphology is one of the most important features in table grape production. In this study, berry samples of 46 grapevine accessions were investigated for 3 consecutive years with elliptic Fourier descriptors (EFD) to evaluate shape diversity. Ten reference shapes obtained from the OIV descriptor list were involved and principal component (PC) scores summarizing the EFD's were statistically evaluated with Two way ANOVA and discriminant analysis. The cummulative contribution of the five principal components was 96.83 %. Two way ANOVA revealed that berry shape had high variability within the accessions and years. Based on the linear discriminant analysis, reference shapes were compared to those of the accessions and graphic reconstruction was carried out. OIV references were considered as unknown samples and grouped into the accession classes. Overall correct classification of the accessions into their group was 13.88 %. Our results showed that EFD together with reference shapes are a powerful method to discribe berry shape and possibly give the future basis of uvometric evaluation of grapevine cultivars

The effects of a single mild dose of morphine on chemoreflexes and breathing in obstructive sleep apnea

The effect of morphine on breathing and ventilatory chemoreflexes in obstructive sleep apnea (OSA) is unknown. It has been assumed that acute morphine use may induce deeper respiratory depression in OSA but this has not been investigated. We evaluated awake ventilatory chemoreflexes and overnight polysomnography on 10 mild-moderate OSA patients before and after giving 30 mg oral controlled-release morphine. Morphine plasma concentrations were analysed. We found a 30-fold range of morphine plasma concentrations with the fixed dose of morphine, and a higher plasma morphine concentration was associated with a higher CO(2) recruitment threshold (VRT) (r=0.86, p=0.006) and an improvement in sleep time with Sp(O(2)) (T90) (r=-0.87, p=0.005) compared to the baseline. The improvement in T90 also significantly correlated with the increase of VRT (r=-0.79, r=0.02). In conclusion, in mild-to-moderate OSA patients, a single common dose of oral morphine may paradoxically improve OSA through modulating chemoreflexes. There is a large inter-individual variability in the responses, which may relate to individual morphine metabolism.David Wang, Andrew A. Somogyi, Brendon J. Yee, Keith K. Wong, Jasminder Kaur, Paul J. Wrigley, Ronald R. Grunstei

Leaf number and plant height of three Canna x generalis cultivars

The aim of this three-year study was to evaluate the effect of three treatments (tiophanate methyl, charcosal dust, and control) on leaf number and plant height on three Canna x generalis cultivars (City of Portland, Richard Wallace and Robert Kemp). Results showed that the 3-year means of leaf number ranged from 13.7 to 22.4 for the three cultivars. The largest leaf numbers were for cultivar Robert Camp (22.4 in 2010) and the lowest for cultivar City of Portland (13.7 in 2011). Tiophanate methyl treatment produced the highest number of leaves and the values were significantly different at P&lt; 0.05 from the control for all years and for all cultivars. Numbers of leaves in charcosal dust treatments were larger than the control treatments but it was not significantly different. Results on plant height ranged from 65.8 to 160.1 cm for the three cultivars. The largest plant height was for cultivar Robert Camp (160.1 cm in 2010) and the lowest for cultivar City of Portland (65.8 cm in 2011). Tiophanate methyl treatment produced the highest plant height and the values were significantly different at P&lt; 0.05 from the control for all years and for all cultivars. Plant heights in charcosal dust treatments were larger than the control treatments but it was not significantly different

Exploiting Term Hiding to Reduce Run-time Checking Overhead

One of the most attractive features of untyped languages is the flexibility in term creation and manipulation. However, with such power comes the responsibility of ensuring the correctness of these operations. A solution is adding run-time checks to the program via assertions, but this can introduce overheads that are in many cases impractical. While static analysis can greatly reduce such overheads, the gains depend strongly on the quality of the information inferred. Reusable libraries, i.e., library modules that are pre-compiled independently of the client, pose special challenges in this context. We propose a technique which takes advantage of module systems which can hide a selected set of functor symbols to significantly enrich the shape information that can be inferred for reusable libraries, as well as an improved run-time checking approach that leverages the proposed mechanisms to achieve large reductions in overhead, closer to those of static languages, even in the reusable-library context. While the approach is general and system-independent, we present it for concreteness in the context of the Ciao assertion language and combined static/dynamic checking framework. Our method maintains the full expressiveness of the assertion language in this context. In contrast to other approaches it does not introduce the need to switch the language to a (static) type system, which is known to change the semantics in languages like Prolog. We also study the approach experimentally and evaluate the overhead reduction achieved in the run-time checks.Comment: 26 pages, 10 figures, 2 tables; an extension of the paper version accepted to PADL'18 (includes proofs, extra figures and examples omitted due to space reasons

Ileal transposition:A non-restrictive bariatric surgical procedure that reduces body fat and increases ingestion-related energy expenditure

Background: Ileal Transposition (IT) was developed as a model to study body weight reduction without the restrictive or malabsorptive aspects of other bariatric surgeries, but the exact mechanisms of the alterations in body weight after IT are not completely understood. Objective: To provide a detailed description of the surgical procedure of IT, and describe its effect on energy balance parameters. Methods: Adult male Lewis rats underwent either IT (IT+) or sham (IT-) surgery. Following surgery body weight and energy intake were monitored. After attaining weight stability (> 30 days), energy expenditure and its components were assessed using indirect calorimetry at a day of fasting, limited intake, and ad libitum intake. At the end of the study body composition analysis was performed. Results: IT+ resulted in transiently reduced energy intake, increased ingestion-related energy expenditure (IEE) and decreased body and adipose tissue weight when compared to IT-. At weight stability, neither energy budget (i.e., energy intake - energy expenditure), nor energy efficiency was different in IT+ rats compared to IT-. Conclusion: Our data show that the primary cause of weight reduction following IT+ is a transient reduction in energy intake. If the increased IEE is related to a higher level of satiety, compensatory feeding to bridge body weight difference between IT+ and IT- rats is less likely to occur

Morphine activates neuroinflammation in a manner parallel to endotoxin

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yi

Buprenorphine maintenance subjects are hyperalgesic and have no antinociceptive response to a very high morphine dose

Objective. Acute pain management in opioiddependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Design. Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Setting. Ambulatory. Subjects. Twelve buprenorphine-maintained subjects: once daily sublingual dose (range 5 2–22 mg); no dose change for 1.5–12 months. Ten healthy controls. Methods. Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Results. Cold pressor responses (seconds): baseline: control 34 6 6 vs buprenorphine 17 6 2 (P 5 0.009); morphine infusion-end: control 52 6 11(P 5 0.04), buprenorphine 17 6 2 (P> 0.5); electrical stimulation responses (volts): baseline: control 65 6 6 vs buprenorphine 53 6 5 (P 5 0.13); infusion-end: control 74 6 5 (P 5 0.007), buprenorphine 53 6 5 (P> 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P 5 0.03); infusion-end: control 15 (P 5 0.09), buprenorphine 12 (P< 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 6 1, buprenorphine 136 6 10. Conclusions. Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.Peter Athanasos, Walter Ling, Felix Bochner, Jason M. White, and Andrew A. Somogy

Hall Effect of Spin Waves in Frustrated Magnets

We examine a possible spin Hall effect for localized spin systems with no charge degrees of freedom. In this scenario, a longitudinal magnetic field gradient induces a transverse spin current carried by spin wave excitations with an anomalous velocity which is associated with the Berry curvature raised by spin chirality, in analogy with anomalous Hall effects in itinerant electron systems. Our argument is based on a semiclassical equations of motion applicable to general spin systems. Also, a microscopic model of frustrated magnets which exhibits the anamalous spin Hall effect is presented.Comment: 5 pages, title and presentation style are changed, accepted for publication in Phys. Rev. Let