Beyond Patient Reported Pain: Perfusion Magnetic Resonance Imaging Demonstrates Reproducible Cerebral Representation of Ongoing Post-Surgical Pain

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Quantifying the test-retest reliability of cerebral blood flow measurements in a clinical model of on-going post-surgical pain: A study using pseudo-continuous arterial spin labelling

Arterial spin labelling (ASL) is increasingly being applied to study the cerebral response to pain in both experimental human models and patients with persistent pain. Despite its advantages, scanning time and reliability remain important issues in the clinical applicability of ASL. Here we present the test-retest analysis of concurrent pseudo-continuous ASL (pCASL) and visual analogue scale (VAS), in a clinical model of on-going pain following third molar extraction (TME). Using ICC performance measures, we were able to quantify the reliability of the post-surgical pain state and ΔCBF (change in CBF), both at the group and individual case level. Within-subject, the inter- and intra-session reliability of the post-surgical pain state was ranked good-to-excellent (ICC > 0.6) across both pCASL and VAS modalities. The parameter ΔCBF (change in CBF between pre- and post-surgical states) performed reliably (ICC > 0.4), provided that a single baseline condition (or the mean of more than one baseline) was used for subtraction. Between-subjects, the pCASL measurements in the post-surgical pain state and ΔCBF were both characterised as reliable (ICC > 0.4). However, the subjective VAS pain ratings demonstrated a significant contribution of pain state variability, which suggests diminished utility for interindividual comparisons. These analyses indicate that the pCASL imaging technique has considerable potential for the comparison of within- and between-subjects differences associated with pain-induced state changes and baseline differences in regional CBF. They also suggest that differences in baseline perfusion and functional lateralisation characteristics may play an important role in the overall reliability of the estimated changes in CBF. Repeated measures designs have the important advantage that they provide good reliability for comparing condition effects because all sources of variability between subjects are excluded from the experimental error. The ability to elicit reliable neural correlates of on-going pain using quantitative perfusion imaging may help support the conclusions derived from subjective self-report

AT-101 ( R -(−)-gossypol acetic acid) enhances the effectiveness of androgen deprivation therapy in the VCaP prostate cancer model

Prostate cancer remains a leading cause of cancer death in American men. Androgen deprivation therapy (ADT) is the most common treatment for advanced prostate cancer patients; however, ADT fails in nearly all cases resulting in castration resistant or androgen-insensitive (AI) disease. In many cases, this progression results from dysregulation of the pro-survival Bcl-2 family proteins. Inhibition of pro-survival Bcl-2 family proteins, therefore, may be an effective strategy to delay the onset of AI disease. Gossypol, a small molecule inhibitor of pro-survival Bcl-2 family proteins, has been demonstrated to inhibit AI prostate cancer growth. The apoptotic effect of gossypol, however, has been demonstrated to be attenuated by the presence of androgen in a prostate cancer xenograft mouse model (Vertebral Cancer of Prostate [VCaP]) treated with AT-101 ( R -(−)-gossypol acetic acid). This study was undertaken to better understand the in vitro effects of androgen receptor (AR) on AT-101-induced apoptosis. VCaP cells treated with AT-101 demonstrated an increase in apoptosis and downregulation of Bcl-2 pro-survival proteins. Upon AR activation in combination with AT-101 treatment, apoptosis is reduced, cell survival increases, and caspase activation is attenuated. Akt and X inhibitor of apoptosis (XIAP) are downregulated in the presence of AT-101, and AR stimulation rescues protein expression. Combination treatment of bicalutamide and AT-101 increases apoptosis by reducing the expression of these pro-survival proteins. These data suggest that combination therapy of AT-101 and ADT may further delay the onset of AI disease, resulting in prolonged progression-free survival of prostate cancer patients. J. Cell. Biochem. 110: 1187–1194, 2010. Published 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77515/1/22633_ftp.pd

Linkage analysis of longitudinal data and design consideration

BACKGROUND: Statistical methods have been proposed recently to analyze longitudinal data in genetic studies. So far, little attention has been paid to examine the relationship among key factors in genetic longitudinal studies including power, the number of families or sibships, and the number of repeated measures per individual subjects. RESULTS: We proposed a variance component model that extends classic variance component models for a single quantitative trait to mapping longitudinal traits. Our model includes covariate effects and allows genetic effects to vary over time. Using our proposed model, we examined the power, pedigree structures, and sample size through simulation experiments. CONCLUSION: Our simulation results provide useful insights into the study design for genetic, longitudinal studies. For example, collecting a small number of large sibships is much more powerful than collecting a large number of small sibships or increasing the number of repeated measures, when the total number of measurements is comparable

Pharmacologic modulation of hand pain in osteoarthritis: A double-blind placebo-controlled functional magnetic resonance imaging study using naproxen

Objective.In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging(fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC)joint. Methods.A placebo-controlled, double-blind,2-period crossover study was performed in 19 individuals with painful OA of the CMC joint of the right hand.Following placebo or naproxen treatment periods, a functionally relevant task was performed, and behavioral measures of the pain experience were collected in identical fMRI examinations. Voxelwise and a priori region of interest analyses were performed to detect between period differences in brain activity. Results.Significant reductions in brain activity following treatment with naproxen, compared to placebo, were observed in brain regions commonly associated with pain perception, including the bilateral primary somatosensory cortex, thalamus, and amygdala.Significant relationships between changes in perceived pain intensity and changes in brain activity were also observed in brain regions previously associated with pain intensity. Conclusion.This study demonstrates the sensitivity of fMRI to detect the mechanisms underlying treatments of known efficacy. The data illustrate the enticing potential of fMRI as an adjunct to self-report for detecting early signals of efficacy of novel therapies,both pharmacologic and nonpharmacologic, in small numbers of individuals with persistent pain

Correction to: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease.

Following publication of the original article [1], the author identified an error in Fig. 4E. The data and statistics were correct, but the synaptophysin blot was incorrect. The incorrect (Fig. 1) and correct figure (Fig. 2) are shown in this correction article. (Figure presented.)

The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease

Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD

Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice.

Hepatocellular carcinoma (HCC) represents the fifth-most common form of cancer worldwide and carries a high mortality rate attributed to lack of effective treatment. Males are 8 times more likely to develop HCC than females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28 (tripartite protein 28), a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver. Trim28(hep-/-) mice display sex-specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and aging precipitate alterations of TRIM28-dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male-restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances, and altered responses to gut microbiota in the pathogenesis of Trim28(hep-/-) -associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high-fat diet challenge. This work underpins how discrete polyphenic traits in epigenetically metastable conditions can contribute to a cancer-prone state and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota, and cancer. (Hepatology 2017;66:235-251)

Rituximab therapy for juvenile-onset systemic lupus erythematosus

Rituximab (RTX), an anti-CD20 monoclonal antibody, has been proposed for use in the therapy of systemic lupus erythematosus (SLE). We present the initial long-term experience of the safety and efficacy of rituximab for treatment of SLE in children. Eighteen patients (mean age 14 ± 3 years) with severe SLE were treated with rituximab after demonstrating resistance or toxicity to conventional regimens. There was a predominance of female (16/18) and ethnic African (13/18) patients. All had lupus nephritis [World Health Organization (WHO) classes 3–5] and systemic manifestations of vasculitis. Clinical disease activity of the SLE was scored with the SLE-disease activity index 2K (SLEDAI-2K). Patients were followed-up for an average of 3.0 ± 1.3 years (range 0.5 to 4.8 years). B-cell depletion occurred within 2 weeks in all patients and persisted for up to 1 year in some. Clinical activity scores, double-stranded DNA (dsDNA) antibodies, renal function and proteinuria [urine protein to creatinine ratio (Upr/cr)] improved in 93% of the patients. Five patients required multiple courses of RTX for relapse, with B-cell repopulation. One died of infectious endocarditis related to severe immunosuppression. In conclusion, our data support the efficacy of rituximab as adjunctive treatment for SLE in children. Although rituximab was well tolerated by the majority of patients, randomized controlled trials are required to establish its long-term safety and efficacy