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

Temporal Streaming of Shared Memory

Coherent read misses in shared-memory multiprocessors account for a substantial fraction of execution time in many important scientific and commercial workloads. We propose Temporal Streaming, to eliminate coherent read misses by streaming data to a processor in advance of the corresponding memory accesses. Temporal streaming dynamically identifies address sequences to be streamed by exploiting two common phenomena in shared-memory access patterns: (1) temporal address correlation — groups of shared addresses tend to be accessed together and in the same order, and (2) temporal stream locality — recently- accessed address streams are likely to recur. We present a practical design for temporal streaming. We evaluate our design using a combination of trace-driven and cycle- accurate full-system simulation of a cache-coherent distributed shared-memory system. We show that temporal streaming can eliminate 98% of coherent read misses in scientific applications, and between 43% and 60% in database and web server workloads. Our design yields speedups of 1.07 to 3.29 in scientific applications, and 1.06 to 1.21 in commercial workloads

Memory coherence activity prediction in commercial workloads

Recent research indicates that prediction-based coherence optimizations offer substantial performance improvements for scientific applications in distributed shared memory multiprocessors. Important commercial applications also show sensitivity to coherence latency, which will become more acute in the future as technology scales. Therefore it is important to investigate prediction of memory coherence activity in the context of commercial workloads.This paper studies a trace-based Downgrade Predictor (DGP) for predicting last stores to shared cache blocks, and a pattern-based Consumer Set Predictor (CSP) for predicting subsequent readers. We evaluate this class of predictors for the first time on commercial applications and demonstrate that our DGP correctly predicts 47%-76% of last stores. Memory sharing patterns in commercial workloads are inherently non-repetitive; hence CSP cannot attain high coverage. We perform an opportunity study of a DGP enhanced through competitive underlying predictors, and in commercial and scientific applications, demonstrate potential to increase coverage up to 14%

Store-Ordered Streaming of Shared Memory

Coherence misses in shared-memory multiprocessors account for a substantial fraction of execution time in many important scientific and commercial workloads. Memory streaming provides a promising solution to the coherence miss bottleneck because it improves memory level parallelism and lookahead while using on-chip resources efficiently. We observe that the order in which shared data are consumed by one processor is correlated to the order in which they were produced by another. We investigate this phenomenon and demonstrate that it can be exploited to send Store- ORDered Streams (SORDS) of shared data from producers to consumers, thereby eliminating coherent read misses. Using a trace-driven analysis of all user and OS memory references in a cache-coherent distributed shared- memory multiprocessor, we show that SORDS based memory streaming can eliminate between 36% and 100% of all coherent read misses in scientific workloads and between 23% and 48%in online transaction processing workloads

SimFlex: a fast, accurate, flexible full-system simulation framework for performance evaluation of server architecture

The new focus on commercial workloads in simulation studies of server systems has caused a drastic increase in the complexity and decrease in the speed of simulation tools. The complexity of a large-scale full-system model makes development of a monolithic simulation tool a prohibitively difficult task. Furthermore, detailed full-system models simulate so slowly that experimental results must be based on simulations of only fractions of a second of execution of the modelled system. This paper presents SimFlex, a simulation framework which uses component-based design and rigorous statistical sampling to enable development of complex models and ensure representative measurement results with fast simulation turnaround. The novelty of SimFlex lies in its combination of a unique, compile-time approach to component interconnection and a methodology for obtaining accurate results from sampled simulations on a platform capable of evaluating unmodified commercial workload

Specificity of Synaptic Connectivity between Layer 1 Inhibitory Interneurons and Layer 2/3 Pyramidal Neurons in the Rat Neocortex

Understanding the structure and function of the neocortical microcircuit requires a description of the synaptic connectivity between identified neuronal populations. Here, we investigate the electrophysiological properties of layer 1 (L1) neurons of the rat somatosensory neocortex (postnatal day 24–36) and their synaptic connectivity with supragranular pyramidal neurons. The active and passive properties of visually identified L1 neurons (n = 266) suggested division into 4 groups according to the Petilla classification scheme with characteristics of neurogliaform cells (NGFCs) (n = 72), classical-accommodating (n = 137), fast-spiking (n = 23), and burst-spiking neurons (n = 34). Anatomical reconstructions of L1 neurons supported the existence of 4 major neuronal groups. Multiparameter unsupervised cluster analysis confirmed the existence of 4 groups, revealing a high degree of similarity with the Petilla scheme. Simultaneous recordings between synaptically connected L1 neurons and L2/3 pyramidal neurons (n = 384) demonstrated neuronal class specificity in both excitatory and inhibitory connectivity and the properties of synaptic potentials. Notably, all groups of L1 neurons received monosynaptic excitatory input from L2/3 pyramidal neurons (n = 33), with the exception of NGFCs (n = 68 pairs tested). In contrast, NGFCs strongly inhibited L2/3 pyramidal neurons (n = 12 out 27 pairs tested). These data reveal a high specificity of excitatory and inhibitory connections in the superficial layers of the neocortex

Distinct functions for Rho1 in maintaining adherens junctions and apical tension in remodeling epithelia

Maintenance and remodeling of adherens junctions (AJs) and cell shape in epithelia are necessary for the development of functional epithelia and are commonly altered during cancer progression/metastasis. Although formation of nascent AJs has received much attention, whether shared mechanisms are responsible for the maintenance and remodeling of AJs in dynamic epithelia, particularly in vivo, is not clear. Using clonal analysis in the postmitotic Drosophila melanogaster pupal eye epithelium, we demonstrate that Rho1 is required to maintain AJ integrity independent of its role in sustaining apical cell tension. Rho1 depletion in a remodeling postmitotic epithelium disrupts AJs but only when depleted in adjacent cells. Surprisingly, neither of the Rho effectors, Rok or Dia, is necessary downstream of Rho1 to maintain AJs; instead, Rho1 maintains AJs by inhibiting Drosophila epithelial cadherin endocytosis in a Cdc42/Par6-dependent manner. In contrast, depletion of Rho1 in single cells decreases apical tension, and Rok and myosin are necessary, while Dia function also contributes, downstream of Rho1 to sustain apical cell tension

Gain-of-function screen for genes that affect Drosophila muscle pattern formation.

This article reports the production of an EP-element insertion library with more than 3,700 unique target sites within the Drosophila melanogaster genome and its use to systematically identify genes that affect embryonic muscle pattern formation. We designed a UAS/GAL4 system to drive GAL4-responsive expression of the EP-targeted genes in developing apodeme cells to which migrating myotubes finally attach and in an intrasegmental pattern of cells that serve myotubes as a migration substrate on their way towards the apodemes. The results suggest that misexpression of more than 1.5% of the Drosophila genes can interfere with proper myotube guidance and/or muscle attachment. In addition to factors already known to participate in these processes, we identified a number of enzymes that participate in the synthesis or modification of protein carbohydrate side chains and in Ubiquitin modifications and/or the Ubiquitin-dependent degradation of proteins, suggesting that these processes are relevant for muscle pattern formation

Spike firing and IPSPs in layer V pyramidal neurons during beta oscillations in rat primary motor cortex (M1) in vitro

Beta frequency oscillations (10-35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson's Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27-30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 µM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at -80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABAA antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub-beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation