Publications by authors named "Victoria J Madden"

40 Publications

SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801.

Nature 2021 03 9;591(7850):451-457. Epub 2021 Feb 9.

International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

All coronaviruses known to have recently emerged as human pathogens probably originated in bats. Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801-an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials-markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19.
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http://dx.doi.org/10.1038/s41586-021-03312-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979515PMC
March 2021

Imprecise Visual Feedback About Hand Location Increases a Classically Conditioned Pain Expectancy Effect.

J Pain 2021 Jun 30;22(6):748-761. Epub 2021 Jan 30.

IIMPACT in Health, University of South Australia, Adelaide, Australia.

We tested the hypotheses that rendering sensory input about hand location imprecise increases a classically conditioned pain expectancy effect, increases generalization of the effect to novel locations and reduces extinction of the effect. Forty healthy volunteers performed movements with their right hand along predefined paths. Each path passed through 2 locations that were defined as either i) the conditioned stimulus (CS+; paired with a painful unconditioned stimulus), or ii) unpaired (CS-). During acquisition phase, participants watched their hand as they moved it. Participants were randomly allocated to an Imprecise group, for whom visual feedback of the hand was offset 30 to 50 mm from its true location, or a Precise group, for whom vision was not disrupted. In the test phase, participants moved their hands to 5 locations-the CS+, CS-, and 3 locations that lay between the 2 ("generalization stimuli"). Our primary hypothesis was supported-pain expectancy was greater at the CS+ location in the Imprecise group than in the Precise group (6.9 [SD = 1.9] vs 5.4 [SD = 2.5], P= .02). Pain expectancies generalized to novel locations similarly in both groups and there was no difference in extinction between groups. Our primary hypothesis was supported but our subsequent hypotheses were not. PERSPECTIVE: We conditioned pain expectancy at a certain location of one hand, even though most participants were unaware of the contingency. Conditioned pain expectancy was greater when sensory information about location was less precise. This adds support to the possibility that associative learning may play a role in the progression of an acute pain episode to a more generalized pain disorder.
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http://dx.doi.org/10.1016/j.jpain.2021.01.004DOI Listing
June 2021

Variability in experimental pain studies: nuisance or opportunity?

Br J Anaesth 2021 02 17;126(2):e61-e64. Epub 2020 Dec 17.

IIMPACT in Health, University of South Australia, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1016/j.bja.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014940PMC
February 2021

The prevalence and risk factors for phantom limb pain in people with amputations: A systematic review and meta-analysis.

PLoS One 2020 14;15(10):e0240431. Epub 2020 Oct 14.

Department of Anaesthesia and Perioperative Medicine, Pain Management Unit, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.

Background: Phantom limb pain (PLP)-pain felt in the amputated limb-is often accompanied by significant suffering. Estimates of the burden of PLP have provided conflicting data. To obtain a robust estimate of the burden of PLP, we gathered and critically appraised the literature on the prevalence and risk factors associated with PLP in people with limb amputations.

Methods: Articles published between 1980 and July 2019 were identified through a systematic search of the following electronic databases: MEDLINE/PubMed, PsycINFO, PsycArticles, Cumulative Index to Nursing and Allied Health Literature, Africa-Wide Information, Health Source: Nursing/Academic Edition, SCOPUS, Web of Science and Academic Search Premier. Grey literature was searched on databases for preprints. Two reviewers independently conducted the screening of articles, data extraction and risk of bias assessment. The meta-analyses were conducted using the random effects model. A statistically significant level for the analyses was set at p<0.05.

Results: The pooling of all studies demonstrated a prevalence estimate of 64% [95% CI: 60.01-68.05] with high heterogeneity [I2 = 95.95% (95% CI: 95.10-96.60)]. The prevalence of PLP was significantly lower in developing countries compared to developed countries [53.98% vs 66.55%; p = 0.03]. Persistent pre-operative pain, proximal site of amputation, stump pain, lower limb amputation and phantom sensations were identified as risk factors for PLP.

Conclusion: This systematic review and meta-analysis estimates that six of every 10 people with an amputation report PLP-a high and important prevalence of PLP. Healthcare professionals ought to be aware of the high rates of PLP and implement strategies to reduce PLP by addressing known risk factors, specifically those identified by the current study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240431PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556495PMC
December 2020

Potassium starvation induces autophagy in yeast.

J Biol Chem 2020 10 11;295(41):14189-14202. Epub 2020 Aug 11.

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Autophagy is a conserved process that recycles cellular contents to promote survival. Although nitrogen limitation is the canonical inducer of autophagy, recent studies have revealed several other nutrients important to this process. In this study, we used a quantitative, high-throughput assay to identify potassium starvation as a new and potent inducer of autophagy in the yeast We found that potassium-dependent autophagy requires the core pathway kinases Atg1, Atg5, and Vps34, and other components of the phosphatidylinositol 3-kinase complex. Transmission EM revealed abundant autophagosome formation in response to both stimuli. RNA-Seq indicated distinct transcriptional responses: nitrogen affects transport of ions such as copper, whereas potassium targets the organization of other cellular components. Thus, nitrogen and potassium share the ability to influence molecular supply and demand but do so in different ways. Both inputs promote catabolism through bulk autophagy, but result in distinct mechanisms of cellular remodeling and synthesis.
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http://dx.doi.org/10.1074/jbc.RA120.014687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549029PMC
October 2020

Chronic pain in people with HIV: a common comorbidity and threat to quality of life.

Pain Manag 2020 Jul 2;10(4):253-260. Epub 2020 Jun 2.

Department of Anaesthesia & Perioperative Medicine, Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa.

Evidence indicates that over half of all people with HIV (PWH) will experience nonmalignant chronic pain throughout their lifetimes, with increasing prevalence as they age. Peripheral neuropathy resulting from the neurotoxic effects of HIV itself and the medications used to treat HIV were widely considered the primary cause of acute and chronic pain early on in the antiretroviral treatment era. However, recent studies suggest a predominance of non-neuropathic (e.g., musculoskeletal) pain in PWH with uncertain etiology. Chronic pain is often widespread in PWH, affecting multiple body locations. Additional research is needed to better understand contributors to chronic pain in PWH, which is likely to include biological (e.g., immune dysregulation), psychological (e.g., substance abuse) and social (e.g., stigma) factors.
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http://dx.doi.org/10.2217/pmt-2020-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7421257PMC
July 2020

State of the art: What have the pain sciences brought to physiotherapy?

S Afr J Physiother 2020 24;76(1):1390. Epub 2020 Feb 24.

Pain Management Unit, Department of Anaesthesia and Perioperative Medicine, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.

Background: Pain is the most common reason for patients to seek help from a health care professional. In the past few decades, research has yielded gains in the Pain Sciences - multiple fields of scientific research that, when integrated, help to clarify what causes and influences human pain.

Objectives: In this article, we discuss the key areas in which the Pain Sciences have shifted the physiotherapy profession.

Method: A narrative review of the Pain Sciences literature was conducted. The review analyses how the Pain Sciences have influenced physiotherapy in several categories: assessment; clinical reasoning; treatment; research rigor and building the profile of the profession.

Results: Scientific research on pain has largely converged in support of three 'game-changing' concepts that have shifted the physiotherapy profession's understanding and treatment of pain: (1) pain is not a signal originating from bodily tissues, (2) pain is not an accurate measure of tissue damage and (3) the plasticity of the nervous system means the nervous system itself is a viable target of treatment. These three concepts have influenced physiotherapy assessment and treatment approaches, and research design to consider pain mechanisms using patient-centred models.

Conclusion: The Pain Sciences have shifted physiotherapists' assessment and treatment approaches and shifted the status of the physiotherapy profession. Ultimately the Pain Sciences have embedded interdisciplinary teams and expanded physiotherapy practice.

Clinical Implications: We believe that the pain sciences should be embedded in undergraduate and postgraduate education and training of physiotherapists (including the three key concepts regarding pain) to benefit physiotherapists and their patients.
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http://dx.doi.org/10.4102/sajp.v76i1.1390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059532PMC
February 2020

The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial.

Physiotherapy 2020 12 28;109:65-74. Epub 2019 Jun 28.

Pain Management Unit, Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Division of Physiotherapy, Department of Health and Rehabilitation Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. Electronic address:

Objective: To investigate whether graded motor imagery (GMI) is effective for reducing phantom limb pain (PLP) in people who have undergone limb amputations.

Design: A single-blinded randomised, controlled trial.

Setting: Physiotherapy out-patient departments in three secondary level hospitals in Cape Town, South Africa.

Participants: Twenty-one adults (≥18 years) who had undergone unilateral upper or lower limb amputations and had self-reported PLP persisting beyond three months.

Interventions: A 6-week GMI programme was compared to routine physiotherapy. The study outcomes were evaluated at baseline, 6 weeks, 3 months and 6 months.

Outcome Measures: The pain severity scale of the Brief Pain Inventory (BPI) was used to assess the primary outcome - PLP. The pain interference scale of the BPI and the EuroQol EQ-5D-5L were used to assess the secondary outcomes - pain interference with function and health-related quality of life (HRQoL) respectively.

Results: The participants in the experimental group had significantly greater improvements in pain than the control group at 6 weeks and 6 months. Further, the participants in the experimental group had significantly greater improvements than the control group in pain interference at all follow-up points. There was no between-group difference in HRQoL.

Conclusion: The results of the current study suggest that GMI is better than routine physiotherapy for reducing PLP. Based on the significant reduction in PLP and pain interference within the participants who received GMI, and the ease of application, GMI may be a viable treatment for treating PLP in people who have undergone limb amputations.

Clinical Trial Registration Number: (PACTR201701001979279).
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http://dx.doi.org/10.1016/j.physio.2019.06.009DOI Listing
December 2020

Barriers to implementing clinical trials on nonpharmacological treatments in developing countries: lessons learnt from addressing pain in HIV.

Pain Rep 2019 Nov-Dec;4(6):e783. Epub 2019 Dec 6.

Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Pain affects over half of the people living with HIV/AIDS (LWHA), and pharmacological treatment has limited efficacy. Preliminary evidence supports nonpharmacological interventions. We previously piloted a multimodal intervention in amaXhosa women LWHA and chronic pain in South Africa with improvements seen in all outcomes, in both intervention and control groups. A multicentre, single-blind randomised controlled trial with 160 participants recruited was conducted to determine whether the multimodal peer-led intervention reduced pain in different populations of both male and female South Africans LWHA. Participants were followed up at weeks 4, 8, 12, 24, and 48 to evaluate effects on the primary outcome of pain, and on depression, self-efficacy, and health-related quality of life. We were unable to assess the efficacy of the intervention due to a 58% loss to follow-up (LTFU). Secondary analysis of the LTFU found that sociocultural factors were not predictive of LTFU. Depression, however, did associate with LTFU, with greater severity of depressive symptoms predicting LTFU at week 8 ( = 0.01). We were unable to evaluate the effectiveness of the intervention due to the high LTFU and the risk of retention bias. The different sociocultural context in South Africa may warrant a different approach to interventions for pain in HIV compared with resource-rich countries, including a concurrent strategy to address barriers to health care service delivery. We suggest that assessment of pain and depression need to occur simultaneously in those with pain in HIV. We suggest investigation of the effect of social inclusion on pain and depression.
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http://dx.doi.org/10.1097/PR9.0000000000000783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903358PMC
December 2019

Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander disease severity.

Elife 2019 11 4;8. Epub 2019 Nov 4.

Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, United States.

Alexander disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense mutations cause AxD, but the mechanism linking different mutations to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes to investigate the hypothesis that AxD-causing mutations perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation of GFAP-Ser13 in patients who died young, independently of the mutation they carried. AxD iPSC-astrocytes accumulated pSer13-GFAP in cytoplasmic aggregates within deep nuclear invaginations, resembling the hallmark Rosenthal fibers observed in vivo. Ser13 phosphorylation facilitated GFAP aggregation and was associated with increased GFAP proteolysis by caspase-6. Furthermore, caspase-6 was selectively expressed in young AxD patients, and correlated with the presence of cleaved GFAP. We reveal a novel PTM signature linking different GFAP mutations in infantile AxD.
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http://dx.doi.org/10.7554/eLife.47789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927689PMC
November 2019

A systematic review of experimental methods to manipulate secondary hyperalgesia in humans: protocol.

Syst Rev 2019 08 19;8(1):208. Epub 2019 Aug 19.

School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Background: Neuropathic pain affects 7-10% of people, but responds poorly to pharmacotherapy, indicating a need for better treatments. Mechanistic research on neuropathic pain frequently uses human surrogate models of the secondary hyperalgesia that is a common feature of neuropathic pain. Experimentally induced secondary hyperalgesia has been manipulated with pharmacological and non-pharmacological methods to clarify the relative contributions of different mechanisms to secondary hyperalgesia. However, this literature has not been systematically synthesised. The aim of this systematic review is to identify, describe, and compare methods that have been used to manipulate experimentally induced secondary hyperalgesia in healthy humans.

Methods: A systematic search strategy will be supplemented by reference list checks and direct contact with identified laboratories to maximise the identification of data reporting the experimental manipulation of experimentally induced secondary hyperalgesia in healthy humans. Duplicated screening, risk of bias assessment, and data extraction procedures will be used. Authors will be asked to provide data as necessary. Data will be pooled and meta-analyses conducted where possible, with subgrouping according to manipulation method. Manipulation methods will be ranked for potency and risk.

Discussion: The results of this review will provide a useful reference for researchers interested in using experimental methods to manipulate secondary hyperalgesia in humans and will help to clarify the relative contributions of different mechanisms to secondary hyperalgesia.

Systematic Review Registration: This protocol will be registered on PROSPERO before the review begins. Review records will be updated on PROSPERO once the review is complete. This review is intended for publication in a peer-reviewed journal. Analyses and scripts will be made publicly available.
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http://dx.doi.org/10.1186/s13643-019-1120-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700765PMC
August 2019

Shifting beliefs across society would lay the foundation for truly biopsychosocial care.

J Physiother 2019 07 13;65(3):121-122. Epub 2019 Jun 13.

Department of Anaesthesia and Perioperative Medicine, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.

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http://dx.doi.org/10.1016/j.jphys.2019.04.001DOI Listing
July 2019

Distorted distance perception to reachable points in people with chronic shoulder pain.

Musculoskelet Sci Pract 2019 07 7;42:120-124. Epub 2019 May 7.

Nucleus of Neuroscience and Behavior and Nucleus of Applied Neuroscience, Universidade de São Paulo, São Paulo, Brazil; Department of Experimental Psychology, Universidade de São Paulo, São Paulo, Brazil.

Perception is not simply a carbon copy of the real world, but is subject to distortions that may reflect protective drive. This study aimed to investigate whether people with chronic shoulder pain show perceptual distortions of space and body that may promote protective behavior. Eighty-four people with shoulder pain and 51 healthy controls participated. Participants estimated (1) distances to points on a cork-board within and outside reaching distance, and (2) the perceived length of their own arms. A novel measure of movement-related pain was also used to determine whether movement-related pain relates to perceptual distortion. Overall, distance and arm length estimates did not differ between groups, nor did participants perceive their arms to be of different length. However, a moderate correlation between movement-related pain and the index of distance perception was found within the pain group, specifically for distance estimates to points within reach. Our results suggest that distorted perception is not a typical consequence of chronic shoulder pain; however, that it may occur in cases where pain is strongly linked to movement. Our findings have implications for understanding avoidance of movement in people with persistent pain.
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http://dx.doi.org/10.1016/j.msksp.2019.04.015DOI Listing
July 2019

Modulating pain thresholds through classical conditioning.

PeerJ 2019 8;7:e6486. Epub 2019 Mar 8.

Research Centre for Health Psychology, KU Leuven, Leuven, Belgium.

Background: Classical conditioning has frequently been shown to be capable of evoking fear of pain and avoidance behavior in the context of chronic pain. However, whether pain itself can be conditioned has rarely been investigated and remains a matter of debate. Therefore, the present study investigated whether pain threshold ratings can be modified by the presence of conditioned non-nociceptive sensory stimuli in healthy participant.

Methods: In 51 healthy volunteers, pain threshold to electrocutaneous stimuli was determined prior to participation in a simultaneous conditioning paradigm. Participants underwent an acquisition phase in which one non-painful vibrotactile stimulus (CS) was repeatedly paired with a painful electrocutaneous stimulus, whereas a second vibrotactile stimulus of the same quality and intensity (CS) was paired with a non-painful electrocutaneous stimulus. Stimulation was provided on the lower back with close proximity between the conditioned stimulus and the unconditioned stimulus. In the test phase, electrocutaneous stimuli at the individually-set threshold intensity were simultaneously delivered together with either a CS or CS. Pain intensity ratings were obtained after each trial; expectancy ratings were obtained after each block. The primary outcome was the percentage of test stimuli that were rated as painful.

Results: Test stimuli were more likely to be rated as painful when they were paired with the CS than when they were paired with the CS. This effect was not influenced by contingency awareness, nor by expectancies or mood states.

Discussion: The findings support the notion that the judgement of an event being painful or non-painful can be influenced by classical conditioning and corroborate the possible role of associative learning in the development and maintenance of chronic pain.
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http://dx.doi.org/10.7717/peerj.6486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410694PMC
March 2019

The prevalence of phantom limb pain and associated risk factors in people with amputations: a systematic review protocol.

Syst Rev 2019 01 10;8(1):17. Epub 2019 Jan 10.

Department of Anaesthesia and Perioperative Medicine, University of Cape Town, Cape Town, South Africa.

Background: The prevalence of phantom limb pain (PLP) in people with amputations is unclear because of the conflicting reports across the literature. It is proposed that the conflicting reports on the prevalence of PLP are a consequence of variations in the time period during which the studies were undertaken, countries in which the studies were conducted and recruitment processes implemented during collection of epidemiological data. In consideration of these factors, we aim to gather and critically appraise relevant literature to determine the prevalence estimate of and risk factors for PLP in people with amputations.

Methods: We will use a customised search strategy containing relevant words and terms to search the following databases: MEDLINE/PubMed (via EBSCOhost), PsycINFO (via EBSCOhost), PsycArticles, Cumulative Index to Nursing and Allied Health Literature (CINAHL) (via EBSCOhost), Africa-Wide Information (via EBSCOhost), Health Source: Nursing/Academic Edition (via EBSCOhost) SCOPUS, Web of Science and Academic Search Premier (via EBSCOhost). The risk of bias assessment will be conducted using a risk of bias assessment tool for prevalence studies, and data will be extracted using a piloted customised data extraction sheet. Data extracted from individual studies will be entered into Review Manager 5 and assessed for clinical and statistical heterogeneity. Studies will be pooled for meta-analysis using the random-effects model to determine a summary estimate of the prevalence of PLP across included studies. A statistically significant level will be set at p < 0.05.

Discussion: As far as we know, a systematic review and meta-analysis on the prevalence of, and risk factors for PLP in people with amputations has not been conducted. Given the varying reports in the literature, it is necessary to determine an estimate of the prevalence of PLP to generate an informed conclusion on this subject. The results of this review will be published in an internationally accredited journal and used to inform researchers, clinicians, policy-makers and the public about the burden of, and risk factors for PLP. This will be done with a further aim to improve the quality of pain management in society.

Systematic Review Registration: PROSPERO CRD42018094821.
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http://dx.doi.org/10.1186/s13643-018-0938-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329075PMC
January 2019

Was That Painful or Nonpainful? The Sensation and Pain Rating Scale Performs Well in the Experimental Context.

J Pain 2019 04 2;20(4):472.e1-472.e12. Epub 2018 Nov 2.

School of Health Sciences, University of South Australia, Adelaide, Australia.

In experiments on pain, participants are frequently exposed to nonpainful and painful stimuli; however, the conventional pain-rating scales lack a nonpainful range and a clear point of transition from nonpainful to painful events. The Sensation and Pain Rating Scale (SPARS) assesses the full stimulus intensity range, extending from no sensation (rating: -50) to worst pain imaginable (rating: +50), and it explicitly identifies pain threshold (rating: 0). Here, we tested the SPARS in 2 experiments by using laser heat stimuli to establish its stimulus-response characteristics (Experiment 1, N = 19, 13 stimulus intensities applied 26 times each across a 1-4 J range), and compared it to 0 to 100 scales that assess nonpainful (0: no sensation, 100: pain) and painful (0: no pain, 100: worst pain imaginable) events (Experiment 2, N = 7, 9 stimulus intensities applied 36 times each across a 1.5-4.5 J range). Despite high inter- and intraindividual variations, we found a reasonably consistent curvilinear stimulus-response relationship (the curve flattens around pain threshold), with stable response characteristics across the range of the scale. The SPARS ratings transformed to a 0 to 100 range tended to be lower than the 0 to 100 pain rating scale in the noxious stimulus intensity range and greater than the 0 to 100 nonpainful sensation scale in the non-noxious stimulus range, likely reflecting differences in scale dimensionality. The SPARS overcomes limitations in scale range inherent to conventional pain rating scales. As such, it is well suited to experimental studies that must quantify a wider range of perceptual intensity or distinguish between painful and nonpainful events. PERSPECTIVE: This article presents the stimulus-response characteristics of a new scale designed to allow participants to rate a range of nonpainful and painful stimuli. The scale could be useful for research that involves exposing participants to a range of stimulation intensities or requires a clear distinction between nonpainful and painful events.
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http://dx.doi.org/10.1016/j.jpain.2018.10.006DOI Listing
April 2019

An image-based small-molecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells.

FASEB J 2018 05 18;32(5):2841-2854. Epub 2018 Jan 18.

Department of Cell Biology and Physiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.

Vimentin is a cytoskeletal intermediate filament protein that is expressed in mesenchymal cells and cancer cells during the epithelial-mesenchymal transition. The goal of this study was to identify vimentin-targeting small molecules by using the Tocriscreen library of 1120 biochemically active compounds. We monitored vimentin filament reorganization and bundling in adrenal carcinoma SW13 vimentin-positive (SW13-vim) cells via indirect immunofluorescence. The screen identified 18 pharmacologically diverse hits that included 2 statins-simvastatin and mevastatin. Simvastatin induced vimentin reorganization within 15-30 min and significant perinuclear bundling within 60 min (IC = 6.7 nM). Early filament reorganization coincided with increased vimentin solubility. Mevastatin produced similar effects at >1 µM, whereas the structurally related pravastatin and lovastatin did not affect vimentin. In vitro vimentin filament assembly assays revealed a direct targeting mechanism, as determined biochemically and by electron microscopy. In SW13-vim cells, simvastatin, but not pravastatin, reduced total cell numbers (IC = 48.1 nM) and promoted apoptosis after 24 h. In contrast, SW13-vim cell viability was unaffected by simvastatin, unless vimentin was ectopically expressed. Simvastatin similarly targeted vimentin filaments and induced cell death in MDA-MB-231 (vim), but lacked effect in MCF7 (vim) breast cancer cells. In conclusion, this study identified vimentin as a direct molecular target that mediates simvastatin-induced cell death in 2 different cancer cell lines.-Trogden, K. P., Battaglia, R. A., Kabiraj, P., Madden, V. J., Herrmann, H., Snider, N. T. An image-based small-molecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells.
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http://dx.doi.org/10.1096/fj.201700663RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901388PMC
May 2018

Biased Intensity Judgements of Visceral Sensations After Learning to Fear Visceral Stimuli: A Drift Diffusion Approach.

J Pain 2017 10 19;18(10):1197-1208. Epub 2017 May 19.

Health Psychology, Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium.

A growing body of research has identified fear of visceral sensations as a potential mechanism in the development and maintenance of visceral pain disorders. However, the extent to which such learned fear affects visceroception remains unclear. To address this question, we used a differential fear conditioning paradigm with nonpainful esophageal balloon distensions of 2 different intensities as conditioning stimuli (CSs). The experiment comprised of preacquisition, acquisition, and postacquisition phases during which participants categorized the CSs with respect to their intensity. The CS+ was always followed by a painful electrical stimulus (unconditioned stimulus) during the acquisition phase and in 60% of the trials during postacquisition. The second stimulus (CS-) was never associated with pain. Analyses of galvanic skin and startle eyeblink responses as physiological markers of successful conditioning showed increased fear responses to the CS+ compared with the CS-, but only in the group with the low-intensity stimulus as CS+. Computational modeling of response times and response accuracies revealed that differential fear learning affected perceptual decision-making about the intensities of visceral sensations such that sensations were more likely to be categorized as more intense. These results suggest that associative learning might indeed contribute to visceral hypersensitivity in functional gastrointestinal disorders.

Perspective: This study shows that associative fear learning biases intensity judgements of visceral sensations toward perceiving such sensations as more intense. Learning-induced alterations in visceroception might therefore contribute to the development or maintenance of visceral pain.
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http://dx.doi.org/10.1016/j.jpain.2017.04.011DOI Listing
October 2017

Classical Conditioning Fails to Elicit Allodynia in an Experimental Study with Healthy Humans.

Pain Med 2017 Jul;18(7):1314-1325

Sansom Institute for Health Research.

Objective: Associative learning has been proposed as a mechanism behind the persistence of pain after tissue healing. The simultaneous occurrence of nociceptive and non-nociceptive input during acute injury mimics the pairings thought to drive classical conditioning effects. However, empirical evidence for classically conditioned allodynia is lacking. We aimed to manipulate pain thresholds with a classical conditioning procedure that used non-nociceptive somatosensory stimuli as conditioned stimuli (CS) and nociceptive stimuli as unconditioned stimuli. We also explored the influence of gender, depression, anxiety, negative affect, and pain catastrophizing on the main manipulation.

Design: Thirty-four healthy humans participated in a differential classical conditioning procedure that used vibrotactile stimulations at two different locations as CS. In an acquisition phase, CS+ was paired with painful thermal stimulation, and CS- with nonpainful thermal stimulation. Heat pain threshold was assessed during paired heat-CS trials before and after acquisition. A 2 (time: 1 and 2) x 2 (condition: CS+ and CS-) repeated-measures analysis of variance compared pain thresholds before and after acquisition. Exploratory analyses explored the influence of gender, depression, anxiety, negative affect, and pain catastrophizing. Postexperiment questions investigated participants' awareness of the contingencies employed.

Results: The classical conditioning procedure did not alter pain thresholds. Exploratory analyses did not reveal any influence of individual differences. Thirty of the 34 participants were unaware of the contingencies between stimuli.

Conclusions: The results of this study provide no evidence that allodynia can be induced in healthy humans using a classical conditioning procedure with simultaneous timing.
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http://dx.doi.org/10.1093/pm/pnw221DOI Listing
July 2017

Pain by Association? Experimental Modulation of Human Pain Thresholds Using Classical Conditioning.

J Pain 2016 10 22;17(10):1105-1115. Epub 2016 Jul 22.

Sansom Institute for Health Research, University of South Australia, Adelaide, Australia; Neuroscience Research Australia, Sydney, Australia. Electronic address:

Unlabelled: A classical conditioning framework is often used for clinical reasoning about pain that persists after tissue healing. However, experimental studies demonstrating classically conditioned pain in humans are lacking. The current study tested whether non-nociceptive somatosensory stimuli can come to modulate pain thresholds after being paired with painful nociceptive stimuli in healthy humans. We used a differential simultaneous conditioning paradigm in which one nonpainful vibrotactile conditioned stimulus (CS(+)) was simultaneously paired with an unconditioned painful laser stimulus, and another vibrotactile stimulus (CS(-)) was paired with a nonpainful laser stimulus. After acquisition, at-pain-threshold laser stimuli were delivered simultaneously with a CS(+) or CS(-) vibrotactile stimulus. The primary outcome was the percentage of at-threshold laser stimuli that were reported as painful. The results were as expected: after conditioning, at-threshold laser trials paired with the CS(+) were reported as painful more often, as more intense, and as more unpleasant than those paired with the CS(-). This study provides new evidence that pain thresholds can be modulated via classical conditioning, even when the stimulus used to test the threshold cannot be anticipated. As such, it lays a critical foundation for further investigations of classical conditioning as a possible driver of persistent pain.

Perspective: This study provides new evidence that human pain thresholds can be influenced by non-nociceptive somatosensory stimuli, via a classical conditioning effect. As such, it lays a critical foundation for further investigations of classical conditioning as a possible driver of persistent pain.
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http://dx.doi.org/10.1016/j.jpain.2016.06.012DOI Listing
October 2016

Local and Systemic Inflammation in Localized, Provoked Vestibulodynia: A Systematic Review.

Obstet Gynecol 2016 08;128(2):337-47

Sansom Institute for Health Research, University of South Australia, and the Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, South Australia, Australia.

Objective: To synthesize and critically evaluate all available evidence investigating whether localized, provoked vestibulodynia is associated with a specific inflammatory profile at both a local and a systemic level.

Data Sources: Comprehensive electronic searches were performed in MEDLINE, EMBASE, Scopus, PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Collaboration databases, and ClinicalTrials.gov. The search strategy was developed using MeSH terms related to localized, provoked vestibulodynia, and inflammatory markers.

Methods Of Study Selection: Two independent investigators screened titles and abstracts and performed data extraction and risk of bias assessments. Studies were included if they reported at least one baseline inflammatory marker in women with localized, provoked vestibulodynia and compared them with healthy women. Reference lists from published reviews on localized, provoked vestibulodynia were screened for additional studies.

Tabulation, Integration, And Results: There were 1,619 studies identified. Eighteen studies met the inclusion criteria, including 400 women with localized, provoked vestibulodynia and 212 healthy women in a control group. Risk of bias assessment revealed that the methodologic quality was generally low. Fifteen studies investigated local inflammation and three studies investigated systemic inflammation. On a local level, the number of mast cells expressed in vestibular tissues was greater in women with localized, provoked vestibulodynia expressed than in women in the control group. Several studies reported undefined inflammatory infiltrate in vestibular tissues to a greater level in women with localized, provoked vestibulodynia than in women in the control group. Systemically, levels of natural killer cells were lower in women with localized, provoked vestibulodynia than in women in the control group. There were no systemic differences in systemic interferon-α and interferon-υ levels between groups.

Conclusion: There is limited and contradictory evidence regarding the characteristics of local and systemic inflammation in women with localized, provoked vestibulodynia.
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http://dx.doi.org/10.1097/AOG.0000000000001510DOI Listing
August 2016

When touch predicts pain: predictive tactile cues modulate perceived intensity of painful stimulation independent of expectancy.

Scand J Pain 2016 04 1;11:11-18. Epub 2015 Dec 1.

The Sansom Institute for Health Research, University of South Australia, Australia; PainAdelaide, and Neuroscience Research Australia, Australia. Electronic address:

Aims: Non-nociceptive somatosensory input, such as tactile or proprioceptive information, always precedes nociceptive input during a painful event. This relationship provides clear opportunities for predictive associative learning, which may shape future painful experiences. In this differential classical conditioning study we tested whether pain-associated tactile cues (conditioned stimuli; CS) could alter the perceived intensity of painful stimulation, and whether this depends on duration of the CS-seeing that CS duration might allow or prevent conscious expectation.

Methods: Subjects underwent a classical differential conditioning task in which a tactile cue at location A (CS+) preceded painful electrical stimulation at location B (UShigh), whereas a tactile cue at location C (CS-) preceded non-painful electrical stimulation at location B (USlow). At test, we compared the pain evoked by a moderately painful stimulus (USmed) when preceded by either the CS+ or CS-. CS duration was manipulated between subjects. Participants were assigned to one of three groups: Long CS (4s, allowing conscious expectation), Short CS (110ms) and CS-US indistinguishable (20ms), preventing conscious expectation). We hypothesised that more pain would be evoked by the US when preceded by the CS+ relative to the CS-, and that the effect would be independent of CS duration.

Results: Fifty-four healthy participants (31 females, age=26, SD=9) were included in the analysis. The hypotheses were supported in that more intense pain was evoked by the USmed when paired with the tactile CS+, than when paired with the tactile CS-; mean difference 3mm on a 150mm VAS (CI 0.4-4.8mm). CS duration did not moderate the effect. The effect was greater in those participants where calibration was optimal, as indicated by a relatively more painful UShigh.

Conclusion: We conclude that pain-associated tactile cues can influence pain, and that this effect is not dependent on stimulus duration. This suggests that explicit expectation is not a requirement for predictive cues to modulate pain. That the presence of the CS+ resulted in only a 5.3% higher intensity rating compared with the CS- may reflect a limitation of laboratory studies, where a limited number of trials, an artificial context and the use of experimental pain are likely to reveal only glimpses of what is clinically possible.

Implications: Pain-associated visual and auditory cues have been shown to enhance pain in laboratory and clinical scenarios, supposedly by influencing expectation of impending harm. We show that pain-associated somatosensory cues can also modulate pain and that this can occur independently of expectation. This points to a larger potential role for associative learning in the development and treatment of pain than has previously been considered. We suggest that research into associative mechanisms underpinning pain, as distinct from those that link pain to pain-related fear and avoidance, is worthwhile.
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http://dx.doi.org/10.1016/j.sjpain.2015.09.007DOI Listing
April 2016

High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy.

Proc Natl Acad Sci U S A 2016 Feb 8;113(8):2218-22. Epub 2016 Feb 8.

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599

Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2(Akita) gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.
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http://dx.doi.org/10.1073/pnas.1600511113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776516PMC
February 2016

Can Pain or Hyperalgesia Be a Classically Conditioned Response in Humans? A Systematic Review and Meta-Analysis.

Pain Med 2016 06 14;17(6):1094-111. Epub 2015 Dec 14.

*Sansom Institute for Health Research, University of South Australia, Adelaide, Australia; Neuroscience Research Australia, Sydney, Australia.

Background: Clinical scenarios of repeated pain usually involve both nociceptive and non-nociceptive input. It is likely that associations between these stimuli are learned over time. Such learning may underlie subsequent amplification of pain, or evocation of pain in the absence of nociception.

Methods: We undertook a systematic review and meta-analysis to evaluate the evidence that allodynia or hyperalgesia can be a classically conditioned response. A sensitive search of the literature covered Medline, Embase, CINAHL, AMED, PubMed, Scopus, PsycArticles, PsycINFO, Cochrane Library, and Web of Science. Additional studies were identified by contacting experts and searching published reviews. Two reviewers independently assessed studies for inclusion, evaluated risk of bias, and extracted data. Studies were included if they aimed to elicit or amplify pain using a classical conditioning procedure in healthy, adult humans. Studies were excluded if they did not distinguish between classical conditioning and explicit verbal suggestion as learning sources, or did not use experiential learning.

Results: Thirteen studies, with varying risk of bias, were included. Ten studies evaluated classically conditioned hyperalgesia: nine found hyperalgesia; one did not. Pooled effects (n = 8 with full data) showed a significant pain increase after conditioning (mean difference of 7.40 [95%CI: 4.00-10.80] on a 0-100 pain scale). Three studies evaluated conditioned allodynia and found conflicting results.

Conclusion: The existing literature suggests that classical conditioning can amplify pain. No conclusions can be drawn about whether or not classical conditioning can elicit pain. Rigorous experimental conditioning studies with nociceptive unconditioned stimuli are needed to fill this gap in knowledge.
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http://dx.doi.org/10.1093/pm/pnv044DOI Listing
June 2016

Do clinicians think that pain can be a classically conditioned response to a non-noxious stimulus?

Man Ther 2016 Apr 22;22:165-73. Epub 2015 Dec 22.

Sansom Institute for Health Research, University of South Australia, Adelaide, Australia; Neuroscience Research Australia, Sydney, Australia.

Background: Anecdotally, clinical presentations in which pain seems to be elicited by non-noxious stimuli are often explained using a classical conditioning framework. We were primarily interested in whether (a) clinicians think that pain can be a classically conditioned response to a non-noxious stimulus, and (b) clinicians think that there is evidence to support that idea.

Method: Practising healthcare clinicians participated anonymously in an online survey. The information collected included descriptive demographics, clinical experience, personal experience of chronic pain, beliefs about pain, and beliefs about classical conditioning and pain. Responses to the pre-requisite question - whether pain can occur without nociception - were compared to a historical data set from 2004.

Results: 1090 people from 57 countries and eight distinct types of health profession completed the survey. 86% stated that pain can occur without nociception; 96% of those believed that pain can be a classically conditioned response to a non-noxious stimulus; 98% of those believed that there is evidence to support that statement. The 2004 data showed that 44% of participants distinguished between pain and nociception.

Conclusions: This broad sample overwhelmingly endorsed the ideas that clinicians think that pain can be a classically conditioned response to a non-noxious stimulus and think that there is evidence to support that idea, revealing a discrepancy between beliefs in the clinical community and the scientific evidence. The distinction between nociception and pain has become more accepted by the clinical community over the last 10 years.
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http://dx.doi.org/10.1016/j.math.2015.12.003DOI Listing
April 2016

The effect of repeated laser stimuli to ink-marked skin on skin temperature-recommendations for a safe experimental protocol in humans.

PeerJ 2016 14;4:e1577. Epub 2016 Jan 14.

Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia; Neuroscience Research Australia, Sydney, Australia.

Background. Nd:YAP laser is widely used to investigate the nociceptive and pain systems, generating perpetual and laser-evoked neurophysiological responses. A major procedural concern for the use of Nd:YAP laser stimuli in experimental research is the risk of skin damage. The absorption of Nd:YAP laser stimuli is greater in darker skin, or in pale skin that has been darkened with ink, prompting some ethics boards to refuse approval to experimenters wishing to track stimulus location by marking the skin with ink. Some research questions, however, require laser stimuli to be delivered at particular locations or within particular zones, a requirement that is very difficult to achieve if marking the skin is not possible. We thoroughly searched the literature for experimental evidence and protocol recommendations for safe delivery of Nd:YAP laser stimuli over marked skin, but found nothing. Methods. We designed an experimental protocol to define safe parameters for the use of Nd:YAP laser stimuli over skin that has been marked with black dots, and used thermal imaging to assess the safety of the procedure at the forearm and the back. Results. Using thermal imaging and repeated laser stimulation to ink-marked skin, we demonstrated that skin temperature did not increase progressively across the course of the experiment, and that the small change in temperature seen at the forearm was reversed during the rest periods between blocks. Furthermore, no participant experienced skin damage due to the procedure. Conclusion. This protocol offers parameters for safe, confident and effective experimentation using repeated Nd:YAP laser on skin marked with ink, thus paving the way for investigations that depend on it.
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http://dx.doi.org/10.7717/peerj.1577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715456PMC
January 2016

Neck Pain and Proprioception Revisited Using the Proprioception Incongruence Detection Test.

Phys Ther 2016 05 24;96(5):671-8. Epub 2015 Sep 24.

G.L. Moseley, PhD, Sansom Institute for Health Research, University of South Australia, and Neuroscience Research Australia, Randwick, Australia.

Background: Proprioceptive imprecision is believed to contribute to persistent pain. Detecting imprecision in order to study or treat it remains challenging given the limitations of current tests.

Objectives: The aim of this study was to determine whether proprioceptive imprecision could be detected in people with neck pain by testing their ability to identify incongruence between true head motion and a false visual reference using the Proprioception Incongruence Detection (PID) Test.

Design: A cross-sectional study was conducted.

Methods: Twenty-four people with neck pain and 24 matched controls repeatedly rotated to specific markers within a virtual world and indicated if their true head rotation was more or less than the rotation suggested by the visual feedback. Visual feedback was manipulated at 6 corrections, ranging from 60% of true movement to 140% of true movement. A standard repositioning error (RPE) test as undertaken for comparison.

Results: Healthy controls were better able to detect incongruence between vision and true head rotation (X̅=75.6%, SD=8.5%) than people with neck pain were (X̅=69.6%, SD=12.7%). The RPE test scores were not different between groups. The PID Test score related to self-reported pain intensity but did not relate to RPE test score.

Limitations: Causality cannot be established from this cross-sectional study, and further work refining the PID Test is needed for it to offer clinical utility.

Conclusions: Proprioceptive precision for neck movement appears worse in people with neck pain than in those without neck pain, and the extent of the deficit appears to be related to usual pain severity. The PID Test appears to be a more sensitive test than the RPE test and is likely to be useful for assessment of proprioceptive function in research and clinical settings.
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http://dx.doi.org/10.2522/ptj.20150210DOI Listing
May 2016

Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice.

Proc Natl Acad Sci U S A 2015 May 20;112(18):5815-20. Epub 2015 Apr 20.

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599

Nephropathy develops in many but not all patients with long-standing type 1 diabetes. Substantial efforts to identify genotypic differences explaining this differential susceptibility have been made, with limited success. Here, we show that the expression of the transforming growth factor β1 gene (Tgfb1) affects the development of diabetic nephropathy in mice. To do this we genetically varied Tgfb1 expression in five steps, 10%, 60%, 100%, 150%, and 300% of normal, in mice with type 1 diabetes caused by the Akita mutation in the insulin gene (Ins2(Akita)). Although plasma glucose levels were not affected by Tgfb1 genotype, many features of diabetic nephropathy (mesangial expansion, elevated plasma creatinine and urea, decreased creatinine clearance and albuminuria) were progressively ameliorated as Tgfb1 expression decreased and were progressively exacerbated when expression was increased. The diabetic 10% hypomorphs had comparable creatinine clearance and albumin excretion to wild-type mice and no harmful changes in renal morphology. The diabetic 300% hypermorphs had ∼1/3 the creatinine clearance of wild-type mice, >20× their albumin excretion, ∼3× thicker glomerular basement membranes and severe podocyte effacement, matching human diabetic nephropathy. Switching Tgfb1 expression from low to high in the tubules of the hypomorphs increased their albumin excretion more than 10-fold but creatinine clearance remained high. Switching Tgfb1 expression from low to high in the podocytes markedly decreased creatinine clearance, but minimally increased albumin excretion. Decreasing expression of Tgfb1 could be a promising option for preventing loss of renal function in diabetes.
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http://dx.doi.org/10.1073/pnas.1504777112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426439PMC
May 2015

Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade.

Proc Natl Acad Sci U S A 2015 Apr 6;112(16):5141-6. Epub 2015 Apr 6.

Department of Pathology and Laboratory Medicine and

We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction.
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http://dx.doi.org/10.1073/pnas.1504557112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413291PMC
April 2015

Bogus visual feedback alters onset of movement-evoked pain in people with neck pain.

Psychol Sci 2015 Apr 17;26(4):385-92. Epub 2015 Feb 17.

Sansom Institute for Health Research, University of South Australia

Pain is a protective perceptual response shaped by contextual, psychological, and sensory inputs that suggest danger to the body. Sensory cues suggesting that a body part is moving toward a painful position may credibly signal the threat and thereby modulate pain. In this experiment, we used virtual reality to investigate whether manipulating visual proprioceptive cues could alter movement-evoked pain in 24 people with neck pain. We hypothesized that pain would occur at a lesser degree of head rotation when visual feedback overstated true rotation and at a greater degree of rotation when visual feedback understated true rotation. Our hypothesis was clearly supported: When vision overstated the amount of rotation, pain occurred at 7% less rotation than under conditions of accurate visual feedback, and when vision understated rotation, pain occurred at 6% greater rotation than under conditions of accurate visual feedback. We concluded that visual-proprioceptive information modulated the threshold for movement-evoked pain, which suggests that stimuli that become associated with pain can themselves trigger pain.
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http://dx.doi.org/10.1177/0956797614563339DOI Listing
April 2015