Opioids depress cortical centers responsible for the volitional control of respiration

Respiratory depression limits provision of safe opioid analgesia and is the main cause of death in drug addicts. Although opioids are known to inhibit brainstem respiratory activity, their effects on cortical areas that mediate respiration are less well understood. Here, functional magnetic resonance imaging was used to examine how brainstem and cortical activity related to a short breath hold is modulated by the opioid remifentanil. We hypothesized that remifentanil would differentially depress brain areas that mediate sensory-affective components of respiration over those that mediate volitional motor control. Quantitative measures of cerebral blood flow were used to control for hypercapnia-induced changes in blood oxygen level-dependent (BOLD) signal. Awareness of respiration, reflected by an urge-to-breathe score, was profoundly reduced with remifentanil. Urge to breathe was associated with activity in the bilateral insula, frontal operculum, and secondary somatosensory cortex. Localized remifentanil-induced decreases in breath hold-related activity were observed in the left anterior insula and operculum. We also observed remifentanil-induced decreases in the BOLD response to breath holding in the left dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, and periaqueductal gray, brain areas that mediate task performance. Activity in areas mediating motor control (putamen, motor cortex) and sensory-motor integration (supramarginal gyrus) were unaffected by remifentanil. Breath hold-related activity was observed in the medulla. These findings highlight the importance of higher cortical centers in providing contextual awareness of respiration that leads to appropriate modulation of respiratory control. Opioids have profound effects on the cortical centers that control breathing, which potentiates their actions in the brainstem

Study of direct versus orbital entry for Mars missions. Volume 6 - Appendix D - Subsystem studies and parametric data Final report

Subsystems analyses and parametric data on configurations for direct versus orbital entry for Mars mission

Deriving a preference-based measure for cancer using the EORTC QLQ-C30 : a confirmatory versus exploratory approach

Background: To derive preference-based measures from various condition-specific descriptive health-related quality of life (HRQOL) measures. A general 2-stage method is evolved: 1) an item from each domain of the HRQOL measure is selected to form a health state classification system (HSCS); 2) a sample of health states is valued and an algorithm derived for estimating the utility of all possible health states. The aim of this analysis was to determine whether confirmatory or exploratory factor analysis (CFA, EFA) should be used to derive a cancer-specific utility measure from the EORTC QLQ-C30. Methods: Data were collected with the QLQ-C30v3 from 356 patients receiving palliative radiotherapy for recurrent or metastatic cancer (various primary sites). The dimensional structure of the QLQ-C30 was tested with EFA and CFA, the latter based on a conceptual model (the established domain structure of the QLQ-C30: physical, role, emotional, social and cognitive functioning, plus several symptoms) and clinical considerations (views of both patients and clinicians about issues relevant to HRQOL in cancer). The dimensions determined by each method were then subjected to item response theory, including Rasch analysis. Results: CFA results generally supported the proposed conceptual model, with residual correlations requiring only minor adjustments (namely, introduction of two cross-loadings) to improve model fit (increment χ2(2) = 77.78, p 75% observation at lowest score), 6 exhibited misfit to the Rasch model (fit residual > 2.5), none exhibited disordered item response thresholds, 4 exhibited DIF by gender or cancer site. Upon inspection of the remaining items, three were considered relatively less clinically important than the remaining nine. Conclusions: CFA appears more appropriate than EFA, given the well-established structure of the QLQ-C30 and its clinical relevance. Further, the confirmatory approach produced more interpretable results than the exploratory approach. Other aspects of the general method remain largely the same. The revised method will be applied to a large number of data sets as part of the international and interdisciplinary project to develop a multi-attribute utility instrument for cancer (MAUCa)

CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency

Tumor necrosis factor (TNF) mediates a wide variety of disease states including septic shock, acute and chronic inflammation, and cachexia. Recently, a multivalent guanylhydrazone (CNI-1493) developed as an inhibitor of macrophage activation was shown to suppress TNF production and protect against tissue inflammation and endotoxin lethality [Bianchi, M., Ulrich, P., Bloom, O., Meistrell, M., Zimmerman, G. A., Schmidtmayerova, H., Bukrinsky, M., Donnelley, T., Bucala, R., Sherry, B., Manogue, K. R., Tortolani, A. J., Cerami, A. & Tracey, K. J. (1995) Mol. Med. 1, 254-266, and Bianchi, M., Bloom, O., Raabe, T., Cohen, P. S., Chesney, J., Sherry, B., Schmidtmayerova, H., Zhang, X., Bukrinsky, M., Ulrich, P., Cerami, A. & Tracey, J. (1996) J. Exp. Med., in press]. We have now elucidated the mechanism by which CNI-1493 inhibits macrophage TNF synthesis and show here that it acts through suppression of TNF translation efficiency. CNI-1493 blocked neither the lipopolysaccharide (LPS)-induced increases in the expression of TNF mRNA nor the translocation of nuclear factor NF-kappa B to the nucleus in macrophages activated by 15 min of LPS stimulation, indicating that CNI-1493 does not interfere with early NF-kappa B-mediated transcriptional regulation of TNF. However, synthesis of the 26-kDa membrane form of TNF was effectively blocked by CNI-1493. Further evidence for the translational suppression of TNF is given by experiments using chloram-phenicol acetyltransferase (CAT) constructs containing elements of the TNF gene that are involved in TNF translational regulation. Both the 5' and 3' untranslated regions of the TNF gene were required to elicit maximal translational suppression by CNI-1493. Identification of the molecular target through which CNI-1493 inhibits TNF translation should provide insight into the regulation of macrophage activation and mechanisms of inflammation

Far-field Unlabelled Super-Resolution Imaging with Superoscillatory Illumination

Unlabelled super-resolution is the next grand challenge in imaging. Stimulated emission depletion and single-molecule microscopies have revolutionised the life sciences but are still limited by the need for reporters (labels) embedded within the sample. While the Veselago-Pendry “super-lens” using a negative-index metamaterial is a promising idea for imaging beyond the diffraction limit, there are substantial technological challenges to its realisation. Another route to far-field subwavelength focusing is using optical superoscillations: engineered interference of multiple coherent waves creating an, in principle, arbitrarily small hotspot. Here we demonstrate microscopy with superoscillatory illumination of the object and describe its underlying principles. We show that far-field images taken with superoscillatory illumination are themselves superoscillatory and hence can reveal fine structural details of the object that are lost in conventional far-field imaging. We show that the resolution of a superoscillatory microscope is determined by the size of the hotspot, rather than the bandwidth of the optical instrument. We demonstrate high-frame-rate polarisation-contrast imaging of unmodified living cells with resolution significantly exceeding that achievable with conventional instruments. This non-algorithmic, low-phototoxicity imaging technology is a powerful tool both for biological research and for super-resolution imaging of samples that do not allow labelling, such as the interior of silicon chips

Author Correction: Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation (Nature Communications, (2019), 10, 1, (952), 10.1038/s41467-019-08750-9)

© 2020, The Author(s). This article contained an error in the ordinate axis in Fig. 2d, where the units were reported as nmol/L. The unit should have been reported as pg/ml. This has now been corrected in both the PDF and HTML versions of the Article

Differences in client and therapist views of the working alliance in drug treatment

Background - There is growing evidence that the therapeutic alliance is one of the most consistent predictors of retention and outcomes in drug treatment. Recent psychotherapy research has indicated that there is a lack of agreement between client, therapist and observer ratings of the therapeutic alliance; however, the clinical implications of this lack of consensus have not been explored. Aims - The aims of the study are to (1) explore the extent to which, in drug treatment, clients and counsellors agree in their perceptions of their alliance, and (2) investigate whether the degree of disagreement between clients and counsellors is related to retention in treatment. Methods - The study recruited 187 clients starting residential rehabilitation treatment for drug misuse in three UK services. Client and counsellor ratings of the therapeutic alliance (using the WAI-S) were obtained during weeks 1-12. Retention was in this study defined as remaining in treatment for at least 12 weeks. Results - Client and counsellor ratings of the alliance were only weakly related (correlations ranging from r = 0.07 to 0.42) and tended to become more dissimilar over the first 12 weeks in treatment. However, whether or not clients and counsellors agreed on the quality of their relationship did not influence whether clients were retained in treatment. Conclusions - The low consensus between client and counsellor views of the alliance found in this and other studies highlights the need for drug counsellors to attend closely to their clients' perceptions of the alliance and to seek regular feedback from clients regarding their feelings about their therapeutic relationship