In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain

<p>Abstract</p> <p>Background</p> <p><it>In vivo </it>proton magnetic resonance spectroscopy (¹H-MRS) studies of HIV-infected humans have demonstrated significant metabolic abnormalities that vary by brain region, but the causes are poorly understood. Metabolic changes in the frontal cortex, basal ganglia and white matter in 18 SIV-infected macaques were investigated using MRS during the first month of infection.</p> <p>Results</p> <p>Changes in the N-acetylaspartate (NAA), choline (Cho), <it>myo</it>-inositol (MI), creatine (Cr) and glutamine/glutamate (Glx) resonances were quantified both in absolute terms and relative to the creatine resonance. Most abnormalities were observed at the time of peak viremia, 2 weeks post infection (wpi). At that time point, significant decreases in NAA and NAA/Cr, reflecting neuronal injury, were observed only in the frontal cortex. Cr was significantly elevated only in the white matter. Changes in Cho and Cho/Cr were similar across the brain regions, increasing at 2 wpi, and falling below baseline levels at 4 wpi. MI and MI/Cr levels were increased across all brain regions.</p> <p>Conclusion</p> <p>These data best support the hypothesis that different brain regions have variable intrinsic vulnerabilities to neuronal injury caused by the AIDS virus.</p

A systematic review and meta-synthesis of the impact of low back pain on people's lives

Copyright @ 2014 Froud et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background - Low back pain (LBP) is a common and costly problem that many interpret within a biopsychosocial model. There is renewed concern that core-sets of outcome measures do not capture what is important. To inform debate about the coverage of back pain outcome measure core-sets, and to suggest areas worthy of exploration within healthcare consultations, we have synthesised the qualitative literature on the impact of low back pain on people’s lives. Methods - Two reviewers searched CINAHL, Embase, PsycINFO, PEDro, and Medline, identifying qualitative studies of people’s experiences of non-specific LBP. Abstracted data were thematic coded and synthesised using a meta-ethnographic, and a meta-narrative approach. Results - We included 49 papers describing 42 studies. Patients are concerned with engagement in meaningful activities; but they also want to be believed and have their experiences and identity, as someone ‘doing battle’ with pain, validated. Patients seek diagnosis, treatment, and cure, but also reassurance of the absence of pathology. Some struggle to meet social expectations and obligations. When these are achieved, the credibility of their pain/disability claims can be jeopardised. Others withdraw, fearful of disapproval, or unable or unwilling to accommodate social demands. Patients generally seek to regain their pre-pain levels of health, and physical and emotional stability. After time, this can be perceived to become unrealistic and some adjust their expectations accordingly. Conclusions - The social component of the biopsychosocial model is not well represented in current core-sets of outcome measures. Clinicians should appreciate that the broader impact of low back pain includes social factors; this may be crucial to improving patients’ experiences of health care. Researchers should consider social factors to help develop a portfolio of more relevant outcome measures.Arthritis Research U

INvestigational Vertebroplasty Efficacy and Safety Trial (INVEST): a randomized controlled trial of percutaneous vertebroplasty

Background: The treatment of painful osteoporotic vertebral compression fractures has historically been limited to several weeks of bed rest, anti-inflammatory and analgesic medications, calcitonin injections, or external bracing. Percutaneous vertebroplasty (the injection of bone cement into the fractured vertebral body) is a relatively new procedure used to treat these fractures. There is increasing interest to examine the efficacy and safety of percutaneous vertebroplasty and to study the possibility of a placebo effect or whether the pain relief is from local anesthetics placed directly on the bone during the vertebroplasty procedure. Methods/Designs: Our goal is to test the hypothesis that patients with painful osteoporotic vertebral compression fractures who undergo vertebroplasty have less disability and pain at 1 month than patients who undergo a control intervention. The control intervention is placement of local anesthesia near the fracture, without placement of cement. One hundred sixty-six patients with painful osteoporotic vertebral compression fractures will be recruited over 5 years from US and foreign sites performing the vertebroplasty procedure. We will exclude patients with malignant tumor deposit (multiple myeloma), tumor mass or tumor extension into the epidural space at the level of the fracture. We will randomly assign participants to receive either vertebroplasty or the control intervention. Subjects will complete a battery of validated, standardized measures of pain, functional disability, and health related quality of life at baseline and at post-randomization time points (days 1, 2, 3, and 14, and months 1, 3, 6, and 12). Both subjects and research interviewers performing the follow-up assessments will be blinded to the randomization assignment. Subjects will have a clinic visit at months 1 and 12. Spine X-rays will be obtained at the end of the study (month 12) to determine subsequent fracture rates. Our co-primary outcomes are the modified Roland score and pain numerical rating scale at 1 month. Discussion: Although extensively utilized throughout North America for palliation of pain, vertebroplasty still has not undergone rigorous study. The study outlined above represents the first randomized, controlled study that can account for a placebo effect in the setting of vertebroplasty. Trial Registration: Current Controlled Trials ISRCTN81871888.The source of funding for the study and all authors for this publication was National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Minocycline Inhibition of Monocyte Activation Correlates with Neuronal Protection in SIV NeuroAIDS

Background: Minocycline is a tetracycline antibiotic that has been proposed as a potential conjunctive therapy for HIV-1 associated cognitive disorders. Precise mechanism(s) of minocycline’s functions are not well defined. Methods: Fourteen rhesus macaques were SIV infected and neuronal metabolites measured by proton magnetic resonance spectroscopy (1H MRS). Seven received minocycline (4 mg/kg) daily starting at day 28 post-infection (pi). Monocyte expansion and activation were assessed by flow cytometry, cell traffic to lymph nodes, CD16 regulation, viral replication, and cytokine production were studied. Results: Minocycline treatment decreased plasma virus and pro-inflammatory CD14+CD16+ and CD14loCD16+ monocytes, and reduced their expression of CD11b, CD163, CD64, CCR2 and HLA-DR. There was reduced recruitment of monocyte/ macrophages and productively infected cells in axillary lymph nodes. There was an inverse correlation between brain NAA/ Cr (neuronal injury) and circulating CD14+CD16+ and CD14loCD16+ monocytes. Minocycline treatment in vitro reduced SIV replication CD16 expression on activated CD14+CD16+ monocytes, and IL-6 production by monocytes following LPS stimulation. Conclusion: Neuroprotective effects of minocycline are due in part to reduction of activated monocytes, monocyte traffic. Mechanisms for these effects include CD16 regulation, reduced viral replication, and inhibited immune activation. Citation: Campbell JH, Burdo TH, Autissier P, Bombardier JP, Westmoreland SV, et al. (2011) Minocycline Inhibition of Monocyte Activation Correlate

Proton Magnetic Resonance Spectroscopy Reveals Neuroprotection by Oral Minocycline in a Nonhuman Primate Model of Accelerated NeuroAIDS

Background: Despite the advent of highly active anti-retroviral therapy (HAART), HIV-associated neurocognitive disorders continue to be a significant problem. In efforts to understand and alleviate neurocognitive deficits associated with HIV, we used an accelerated simian immunodeficiency virus (SIV) macaque model of NeuroAIDS to test whether minocycline is neuroprotective against lentiviral-induced neuronal injury. Methodology/Principal Findings: Eleven rhesus macaques were infected with SIV, depleted of CD8+ lymphocytes, and studied until eight weeks post inoculation (wpi). Seven animals received daily minocycline orally beginning at 4 wpi. Neuronal integrity was monitored in vivo by proton magnetic resonance spectroscopy and post-mortem by immunohistochemistry for synaptophysin (SYN), microtubule-associated protein 2 (MAP2), and neuronal counts. Astrogliosis and microglial activation were quantified by measuring glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1), respectively. SIV infection followed by CD8+ cell depletion induced a progressive decline in neuronal integrity evidenced by declining N-acetylaspartate/creatine (NAA/Cr), which was arrested with minocycline treatment. The recovery of this ratio was due to increases in NAA, indicating neuronal recovery, and decreases in Cr, likely reflecting downregulation of glial cell activation. SYN, MAP2, and neuronal counts were found to be higher in minocycline-treated animals compared to untreated animals while GFAP and IBA-1 expression were decreased compared to controls. CSF and plasma viral loads were lower in MN-treated animals. Conclusions/Significance: In conclusion, oral minocycline alleviates neuronal damage induced by the AIDS virus

Linear regression analyses reveal significant relationships between circulating pro-inflammatory monocytes and NAA/Cr.

<p>Regression analyses were performed between the absolute numbers of each monocyte subset and the percent change in neuronal metabolite values (NAA/Cr) in the frontal cortex relative to pre-infection levels for all animals from 28 days pi until necropsy. Minocycline treated and non-treated animals were examined at 4 time-points except for the two animals that were time-sacrificed at 6 weeks pi, have three time-points. We found a significant inverse relationship between both CD14+CD16+ (<b>B</b>; r² = 0.59, <i>p</i> = 0.0004) and CD14^loCD16+ (<b>C</b>; r² = 0.45, <i>p</i> = 0.04) monocytes and decreased NAA/Cr, while no relationship between CD14+CD16− monocytes and NAA/Cr levels were observed (<b>A</b>; r² = 0.30, <i>p</i> = 0.3776).</p

Reduced CD68+, MAC387+, and SIV p28+ productively infected cells in lymph nodes with minocycline treatment.

<p>Immunohistochemistry was performed to compare CD68+ resident macrophages, newly infiltrating MAC387+ monocytes/macrophages, and SIV-infected cells in the axillary lymph node from untreated and minocycline treated animals. A reduced number of resident CD68+ macrophages (<b>A</b>–<b>B</b>) and newly infiltrating MAC387+ monocytes/macrophages (<b>C</b>–<b>D</b>) in an axillary lymph node of minocycline treated animals (<b>B</b>, <b>D</b>) and an untreated controls (<b>A</b>, <b>C</b>). In addition, there was a significantly higher number of productively infected SIV p28+ cells in the lymph node of untreated animals (<b>E</b>) compared to minocycline treated animals (<b>F</b>). All scale bars are 50 µm.</p

SIV-infected, CD8+ T Lymphocyte depleted animals used in this study.

<p>Note.-dpi = days post infection.</p><p>*Untreated animals time-sacrificed at 6 weeks pi; all other animals sacrificed at 8 weeks pi.</p>a<p>Transiently CD8+ lymphocyte depleted (≤21 dpi), persistently CD8+ lymphocyte depleted (>28 dpi).</p>b<p>Viral RNA quantitiated using RT PCR and are results of duplicate measurements.</p

Reduction of CD16 expression and viral replication in CD14+ monocytes during <i>in vitro</i> minocycline treatment.

<p>CD14+ monocytes were infected with SIVmac316STOP virus and cultured with M-CSF in the presence or absence of minocycline for 24 and 72 hours. With M-CSF treatment, all monocytes expressed CD14 and CD16 prior to minocycline treatment. By flow cytometry, monocytes were first gated based on size (FSC) and granularity (SSC). From this gate HLA-DR+ CD14+ monocytes were selected (<b>A</b>) and CD16 expression on these cells between treatment groups was compared. Histograms represent the median fluorescence intensity (MFI) of CD16 from one representative experiment out of three (<b>B</b>). Averages of MFI ± standard error of the mean in a given treatment group are indicated in the upper left hand corner of the graphs. CD16 expression was significantly higher on untreated than 20 µM minocycline treated monocytes at 48 hours pi (<i>p</i> = 0.021). Untreated monocytes had significantly higher CD16 expression than both 10 µM and 20 µM treated cells at 96 hours pi (<i>p</i> = 0.001). After 96 hours of infection, SIV-p27 was reduced with minocycline treatment (<b>C</b>), with significant differences between control and 20 µM minocycline (<i>p</i> = 0.039). Studies presented here are the results of n = 3 three independent experiments with n = 3 animals per experiment performed in triplicate wells. P values were determined using a Mann-Whitney U test.</p