Reported Methods, Distributions, and Frequencies of Torture Globally: A Systematic Review and Meta-Analysis.

Importance: Despite its prohibition by the United Nations Convention against Torture and other international treaties, torture has been perpetrated against countless individuals worldwide, and health care practitioners globally are increasingly encountering refugee torture survivors in their clinical practices. The methods, geographic distribution, and frequency of torture globally are not well described, which limits health care practitioners' ability to adequately diagnose and treat the sequelae of torture. Objective: To rank the commonness of torture methods and identify the regions of the world with which they are associated. Data Sources: For this systematic review and meta-analysis, Ovid MEDLINE, Ovid Embase, Web of Science, and The Cochrane Library were searched from inception to July 2021. Study Selection: Included studies were peer-reviewed articles in English, contained an independent sample population of individuals who experienced torture, and outlined the type(s) of torture experienced. Excluded studies were not peer reviewed, lacked an independent sample population, or did not specify torture methods. Articles were chosen for inclusion by 2 independent and blinded reviewers, and a third, independent reviewer resolved discrepancies. Overall, 266 articles-15.3% of the 1739 studies initially identified for full review-met the inclusion criteria. Data Extraction and Synthesis: Data abstraction and quality assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 2 independent and blinded reviewers into predefined templates, and a third, independent reviewer resolved discrepancies. The risk of bias was evaluated using the Downs and Black Checklist. Main Outcomes and Measures: Torture methods were ranked by their average frequencies, numbers of reporting studies, and numbers of countries wherein the methods occurred. Results: A total of 9937 titles and abstracts were screened, and 266 studies encompassing 103 604 individuals (13 350 men, 5610 women, and 84 644 unspecified) were analyzed. Torture was reported for 105 countries; 21 methods accounted for 84% of all reported methods and 10 methods accounted for 78% of all physical tortures. The top 3 methods were beating or blunt-force trauma (reported in 208 studies and 59 countries; average frequency, 62.4%; 95% CI, 57.7%-67.1%), electrical torture (reported in 114 studies and 28 countries; average frequency, 17.2%; 95% CI, 15.0%-19.4%), and starvation or dehydration (reported in 65 studies in 26 countries; average frequency, 12.7%; 95% CI, 10.2%-15.2%). According to the Downs and Black appraisal tool, 50 studies were rated as good or excellent and 216 as fair or poor. Conclusions and Relevance: The findings of this study suggest that torture remains widespread. Although innumerable torture methods exist, a limited number account for the vast majority of reported tortures. So that targeted therapies may be developed, additional investigation is needed to better elucidate the sequelae associated with the most common torture methods, described here.

Stability and Reliability of Enhanced External-Internal Motion Correlation via Dynamic Phase-Shift Corrections Over 30-min Timeframe for Respiratory-Gated Radiotherapy.

To assess the stability of patient-specific phase shifts between external- and internal-respiratory motion waveforms, the reliability of enhanced external-internal correlation with phase-shift correction, and the feasibility of guiding respiratory-gated radiotherapy (RGRT) over 30 min. In this clinical feasibility investigation, external bellows and internal-navigator waveforms were simultaneously and prospectively acquired along with two four-dimensional magnetic resonance imaging (4DMRI) scans (6-15 m each) with 15-20 m intervals in 10 volunteers. A bellows was placed 5 cm inferior to the xiphoid to monitor abdominal motion, and an MR navigator was used to track the diaphragmatic motion. The mean phase-domain (MPD) method was applied, which combines three individual phase-calculating methods: phase-space oval fitting, principal component analysis, and analytic signal analysis, weighted by the reciprocal of their residual errors (RE) excluding outliers (RE >2σ). The time-domain cross-correlation (TCC) analysis was applied for comparison. Dynamic phase-shift correction was performed based on the phase shift detected on the fly within two 10 s moving datasets. Simulating bellows-triggered gating, the median and 95% confidence interval for the navigator's position at beam-on/beam-off and %harm (percentage of beam-on time outside the safety margin) were calculated. Averaged across all subjects, the mean phase shifts are found indistinguishable (p > .05) between scan 1 (55˚ ± 9˚) and scan 2 (59˚ ± 11˚). Using the MPD method the averaged correlation increases from 0.56 ± 0.22 to 0.85 ± 0.11 for scan 1 and from 0.47 ± 0.30 to 0.84 ± 0.08 for scan 2. The TCC correction results in similar results. After phase-shift correction, the number of cases that were suitable for amplitude gating (with <10%harm) increased from 2 to 17 out of 20 cases. A patient-specific, stable phase-shift between the external and internal motions was observed and corrected using the MPD and TCC methods, producing long-lasting enhanced motion correlation over 30m. Phase-shift correction offers a feasible strategy for improving the accuracy of tumor-motion prediction during RGRT.

Impact of preoperative opioid use disorder on outcomes following lumbar-spine surgery.

OBJECTIVES: Opioid use disorder (OUD) has previously been shown to negatively impact postoperative outcomes. As the number of spine surgeries continues to rise annually, more patients with preexisting OUD will be seen in operating rooms. Our retrospective cohort study aims to expand on the independent association between preoperative OUD and outcomes following lumbar-spine surgery. PATIENTS AND METHODS: Using 2007-2014 data from the State Inpatient Databases (SID) for the states of California (2007-2011), Florida, New York, Maryland, and Kentucky, we identified patients ≥18 years of age undergoing lumbar-spine surgery. Our primary variable of interest was present-on-admission OUD. Outcomes of interest included a range of postoperative complications divided into those specific to spinal surgery and general surgical complications, length of stay (LOS), 30- and 90-day readmission rates, and total hospital charges. RESULTS: Of the 267,976 patients undergoing lumbar-spine surgery, 1902 patients were identified as having OUD. After adjusting for patient- and hospital-level confounders, we found that patients with OUD were more likely to experience complications related specifically to spine surgery (aOR = 1.51, 95%CI = 1.33-1.71) as well as general postoperative complications (aOR = 1.63, 95%CI = 1.36-1.96) compared to those without OUD. OUD was additionally associated with longer LOS (aIRR = 1.29, CI = 1.24-1.34) and higher total charges (aIRR = 1.14, CI = 1.11-1.18). Whereas no statistically significant difference was detected for 30-day-readmission rates, patients with OUD experienced higher rates of readmission within 90 days of discharge (aOR = 1.20, CI = 1.08-1.35). CONCLUSIONS: Our study strengthens the evidence that patients with OUD fare poorly after lumbar-spine surgery. More research is needed to determine whether reducing opioid use before surgery can mitigate the postoperative risks associated with OUD.

Challenges for Students in the Creation, Growth, and Management of an Academic, Student-run Asylum Clinic.

Medical school asylum clinics are complex organizations that blend medical and legal expertise with service to assist individuals seeking refuge from human rights violations. The balance of power shared by the students and faculty who lead these clinics varies widely across institutions, usually in an inverse reciprocal relationship. The Weill Cornell Center for Human Rights will observe its 10th anniversary in 2020 and is notable for espousing maximal student autonomy in the organization's governance with minimal faculty control or administration participation. This level of autonomy requires that, in addition to successfully running the organization, student leaders must adeptly manage logistical, administrative, and ethical challenges without compromising the trust and confidence of the medical college and larger university. This article describes a series of difficult decisions involving policy, conflict resolution, and resource management made expeditiously by the student leadership. Ethical dilemmas, operational challenges, and the difficulties imposed by an unexpected global catastrophe-the COVID-19 pandemic-are presented alongside detailed descriptions of how these issues were deliberated and resolved by the student leadership.

Challenges in Founding and Developing Medical School Student-Run Asylum Clinics.

In response to the rapidly rising number of asylum applications, student-run asylum clinics (SRACs) designed to provide pro bono forensic medical evaluations have emerged at medical schools across the United States. Distinct from traditional student-run clinics in the services they provide and in their operational models, SRACs face a unique set of challenges. This study aims to identify the common challenges in building SRACs and to collect insights to inform a structured approach to collaborative problem-solving. This study gathered data from online surveys and semi-structured phone interviews with representative medical student SRAC leaders. 14 clinics participated in the 2017 online survey, 15 clinics in the 2018 online survey, and eight clinics in the 2018-2019 phone interviews. We identified common challenges in five areas: volunteer recruitment, clinic operations, case demand, institutional support, and leadership. SRACs stand to benefit from ongoing extramural collaborations to overcome shared challenges.

A coding tool and abuse data for female asylum seekers.

With 1 in 3 women affected, accounting for one billion women worldwide, Violence Against Women (VAW) constitutes one of the widest reaching human rights violations globally. Although the forms they take may vary, these abuses are not confined to a single social class, geographic region, or culture. Existing studies have yet to describe the full burden of abuse that asylum-seeking women endure throughout their lifetimes. We describe a novel coding tool that classifies types of abuse, identifies abuse perpetrators, and estimates how long and how often each abuse was experienced. The authors used this tool to describe and categorize the abuses endured by 85 cisgender, adult women seeking asylum in the United States who presented to the Weill Cornell Center for Human Rights for forensic medical evaluations from 2013 to 2017. We reviewed a total of 180 legal and forensic medical affidavits that were written in support of the applicants' asylum claims. Using the coding tool, we identified each abuse, classified every perpetrator, and, whenever possible, estimated how long and how frequently each abuse was endured. Interpretations of the raw data contained in this article and a discussion of their significance can be found in our associated publication: "Gender-Based Violence experienced by Women Seeking Asylum in the United State: A Lifetime of Multiple Traumas Inflicted by Multiple Perpetrators" [1]. The coding instrument described herein characterizes VAW by classifying the narrative data that are included in interviews, focus groups, medical records, and the like. Our coding instrument is the first of its kind to describe all types and severities of violence endured by women, classify the perpetrators of that violence, and delineate the timeline of violence over each individual's life. We hope that this holistic approach to classifying and describing VAW will enable other research groups to examine untested or unrealized associations between victims, perpetrators, and abuses. Ultimately, obtaining more complete data will empower us to advocate more effectively and to design more comprehensive care for victims of VAW.

Chronic pain diagnosis in refugee torture survivors: A prospective, blinded diagnostic accuracy study.

BACKGROUND: An estimated 87% of torture survivors experience chronic pain such as brachial plexopathy from upper extremity suspension or lumbosacral plexus injury from leg hyperextension. However, a vast majority of pain is undetected by evaluators due to a lack of diagnostic tools and confounding psychiatric illness. This diagnostic gap results in exclusive psychological treatment rather than multimodal therapies, substantially limiting rehabilitation. We hypothesized that the United Nations Istanbul Protocol (UNIP) would have a sensitivity of approximately 15% for pain detection, and that the use of a validated pain screen would improve its sensitivity by at least 29%, as compared to the reference standard (pain specialist evaluation). METHODS AND FINDINGS: This prospective blind-comparison-to-gold-standard study of survivors of torture, as defined by the World Medical Association, took place at Weill Cornell Medicine between February 1, 2017, and June 21, 2019. 11 women and 9 men, for a total of 20 participants, were included in the analysis. Five participants received 2 UNIP evaluations, for a total of 25 unique evaluations included in the analysis. Participants were representative of a global population, with home countries in Africa, Central America, South Asia, the Caribbean, and the Middle East. Methods of torture experienced were homogeneous, following the predictable pattern of systematic torture. Participants first received the standard evaluation protocol for torture survivors (UNIP) by a trained evaluator, and subsequently received a validated pain screen (Brief Pain Inventory-Short Form [BPISF]) followed by a noninvasive examination by a pain specialist physician (reference standard). The primary outcome was the diagnostic and treatment capability of the standard protocol (index test) versus the validated pain screen (BPISF), as compared to the reference standard. Trained evaluators performing the initial assessment with the UNIP (index test) were blinded to the study, and the pain specialist physician (reference standard) was blinded to the outcome of the initial UNIP evaluation and the BPISF; data from the initial UNIP assessment were not gathered by the principal investigator until all other study procedures were completed. Providers using only the UNIP captured pain in a maximum of 16% of evaluations, as compared to 85% of participants being diagnosed with pain by the reference standard. When employed, the validated pain screen had a sensitivity of 100% (95% CI 72%-100%) and a negative predictive value of 100%, as compared to a sensitivity of 24% (95% CI 8%-50%) and a negative predictive value of 19% (95% CI 5%-46%) for the index test. The difference in the sensitivity of the UNIP as compared to the BPISF was significant, with p < 0.001. No adverse events owing to participation in the study were reported by participants. Limitations of the study include small sample size, its single-site nature, and the exclusion of individuals who did not speak 1 of the 5 study languages. CONCLUSIONS: These data indicate that a validated pain screen can supplement the current global standard assessment of torture survivors, the UNIP, to increase the accuracy of pain diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03018782.

Gender-based violence experienced by women seeking asylum in the United State: A lifetime of multiple traumas inflicted by multiple perpetrators.

Estimates by the World Health Organization indicate that 1 in 3 women-more than one billion people worldwide-have experienced some form of Gender-Based Violence (GBV). Violence Against Women (VAW) is a prominent subset of GBV, defined by the United Nations as any act "that results in, or is likely to result in, physical, sexual, or mental harm or suffering to women, including threats of such acts, coercion or arbitrary deprivation of liberty, whether occurring in public or in private life." VAW can include verbal harassment, physical abuse, sexual abuse, honor killing, and femicide and can occur at the hands of individuals, institutions, or states. Whereas numerous studies have documented the multiple forms of physical, sexual, and psychological violence experienced by women, a thorough characterization of the abuses experienced by asylum-seeking women in the United States has not yet been undertaken. Our analysis of the affidavits for 85 cisgender, female asylum seekers who applied for forensic medical evaluations through a student-run asylum clinic, reveals a life-long pattern of multiple types of VAW inflicted by multiple perpetrators. These findings have implications for the focus of the medico-legal documentation submitted in support of female asylum seekers as well as for the design of comprehensive healthcare services for women and girls who are granted relief.

Evaluating the Impact of Student-run Asylum Clinics in the US from 2016-2018.

Individuals applying for asylum must demonstrate a well-founded fear of persecution. By documenting signs of torture and other forms of abuse, medical evaluations can provide forensic evidence to support asylum claims. The backlog of pending immigration cases in the United States recently exceeded one million. Student-run asylum medicine clinics conduct forensic evaluations to assist in the asylum adjudication process. The Physicians for Human Rights National Student Advisory Board administered surveys to student-run clinics in the US in 2017 and 2018. Retrospective analysis evaluated the completion rates of forensic evaluations, caseload capacities, and training frequencies. Student-run asylum clinics completed 38.8% more forensic evaluations in 2017 than in 2016. In 2016, 33% of clinics received forensic evaluation requests that exceeded their capacity, a figure that rose to 50% in 2017. The number of clinicians trained by asylum clinics increased nearly fourfold between 2016 and 2017, and the number of students trained grew by 81%. A recent surge in armed conflict has contributed to record numbers of asylum applications in the US. The results of this survey reveal the burgeoning capability of student-run asylum clinics to provide evaluations, a trend that underscores medical students' ability to significantly impact human rights issues. Student-run asylum clinics are poised to fill an increasingly important role in supporting victims of torture and persecution.

Effects of dopaminergic and serotonergic compounds in rats trained to discriminate a high and a low training dose of the synthetic cathinone mephedrone.

RATIONALE: The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused. OBJECTIVE: Direct-acting 5-HT2A/2C receptor agonists and antagonists and D1-3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT2A/2C and D1-3 receptor antagonists were examined in both groups. METHODS: Male Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N = 24) or a high dose of 3.2 mg/kg mephedrone (N = 11) from saline. RESULTS: In the low training-dose group, mephedrone, MDMA, methamphetamine, d-amphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates. CONCLUSIONS: A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine, whereas a higher training dose of mephedrone requires a discriminative stimulus that was only mimicked by MDMA. Dopaminergic or serotoninergic antagonists failed to produce significant blockade of mephedrone at either training dose.

Enhancement of Long-Term External-Internal Correlation by Phase-Shift Detection and Correction Based on Concurrent External Bellows and Internal Navigator Signals.

PURPOSE: The purpose of this study was to enhance the correlation between external and internal respiratory motions by dynamically determining and correcting the patient-specific phase shift between external and internal respiratory waveforms acquired concurrently during respiratory-correlated 4-dimensional magnetic resonance imaging scans. METHODS AND MATERIALS: Internal-navigator and external-bellows waveforms were acquired simultaneously during 6- to 15-minute respiratory-correlated 4-dimensional magnetic resonance imaging scans in 10 healthy participants under an institutional review board-approved protocol. The navigator was placed at the right lung-diaphragm interface, and the bellows were placed ∼5 cm inferior to the sternum. Three segments of each respiratory waveform, at the beginning, middle, and end of a scan, were analyzed. Three phase-domain methods were employed to estimate the phase shift, including analytical signal analysis, phase-space oval fitting, and principal component analysis. A robust strategy for estimating the phase shift was realized by combining these methods in a weighted average and by eliminating outliers (>2 σ) caused by breathing irregularities. Whether phase-shift correction affects the external-internal correlation was evaluated. The cross-correlation between the 2 waveforms in the time domain provided an independent check of the correlation enhancement. RESULTS: Phase-shift correction significantly enhanced the external-internal correlation in all participants across the entire 6- to 15-minute scans. On average, the correlation increased from 0.45 ± 0.28 to 0.85 ± 0.15 for the combined method. The combined method exhibited a 99.5% success rate and revealed that the phase of the external waveform leads that of the internal waveform in all 10 participants by 57 o ± 17o (1.6 ± 0.5 bins) on average. Seven participants exhibited highly reproducible phase shifts over time, evidenced by standard deviations (σ) < 4o, whereas 8o < σ < 12o in the remaining 3 participants. Regardless, phase-shift correction significantly improved the correlation in all participants. CONCLUSIONS: Correcting the phase shift estimated by the phase-domain methods provides a new approach for enhancing the correlation between external and internal respiratory motions. This strategy holds promise for improving the accuracy of respiratory-gated radiation therapy.

Lower Urinary Tract Symptoms in Women With Female Genital Mutilation.

OBJECTIVE: This study aimed to describe symptom prevalence and quality of life impact from lower urinary tract symptoms (LUTS) in women living with female genital mutilation (FGM) in the United States. METHODS: A convenience sample of English-speaking women with FGM were invited to complete an anonymous survey including the Female Lower Urinary Tract Symptoms questionnaire to assess symptom prevalence and bother and the Pelvic Floor Impact Questionnaire-7 to assess quality of life impact from pelvic floor disorders. Data are reported as median (interquartile range). Correlations were calculated using Spearman ρ. RESULTS: Thirty women with an age of 29 (24-40) years were included. Sixty-seven percent self-identified as black/African and 77% were Muslim. Women reported being circumcised between ages 1 week and 16 years (median, 6 years). Forty percent reported type I circumcision, 23% reported type II, 23% reported type III, and 13% were unsure. Fifty percent were vaginally parous. Seventy-three percent of women reported the presence of LUTS. Twenty-seven percent voided at least 9 times per day, and 60% had nocturia at least 2 times. Bothersome voiding symptoms were commonly reported: urinary hesitancy (40%), strained urine flow (30%), and intermittent urine stream (47%). Fifty-three percent reported urgency urinary incontinence and 43% reported stress urinary incontinence. Symptom prevalence and bother were correlated for all 12 items (ρ = 0.51-0.90, P < 0.001). Median Pelvic Floor Impact Questionnaire-7 score was 102 (8-144), with 63% reporting urinary symptoms having "moderate" or "quite a bit of" impact on their activities, relationships, or feelings. CONCLUSION: Lower urinary tract symptoms are common and bothersome in women with FGM. Providers caring for patients with FGM should inquire about LUTS.

Homeostatic enhancement of sensory transduction.

Our sense of hearing boasts exquisite sensitivity, precise frequency discrimination, and a broad dynamic range. Experiments and modeling imply, however, that the auditory system achieves this performance for only a narrow range of parameter values. Small changes in these values could compromise hair cells' ability to detect stimuli. We propose that, rather than exerting tight control over parameters, the auditory system uses a homeostatic mechanism that increases the robustness of its operation to variation in parameter values. To slowly adjust the response to sinusoidal stimulation, the homeostatic mechanism feeds back a rectified version of the hair bundle's displacement to its adaptation process. When homeostasis is enforced, the range of parameter values for which the sensitivity, tuning sharpness, and dynamic range exceed specified thresholds can increase by more than an order of magnitude. Signatures in the hair cell's behavior provide a means to determine through experiment whether such a mechanism operates in the auditory system. Robustness of function through homeostasis may be ensured in any system through mechanisms similar to those that we describe here.

Medical Students' Attitudes toward Torture, Revisited.

This paper reports the findings of a survey of medical students' attitudes toward torture and discusses variables that may correlate with those attitudes. In late 2016, 483 enrolled medical and MD-PhD students at the Weill Cornell Medical College received an anonymous, institutional review board-approved survey that included questions about torture and its effectiveness, demographic questions, inquiries about personal experiences of harassment or discrimination, and questions regarding engagement in human rights activities. Some questions were drawn from a 2008 University of Illinois survey of medical students' attitudes toward torture, the only prior such survey at a US medical university. Of the 483 students who were contacted, 121 (25%) returned completed questionnaires, with responses indicating strong opposition to torture and skepticism about its usefulness. Respondents expressed greater opposition to torture in this survey than those who participated in the 2008 survey. Respondents' involvement in Weill Cornell's human rights program was associated with significantly stronger opposition to torture, while personal experiences of harassment were associated with a trend toward weaker opposition to torture. Respondents' answers closely approximate the clearly stated ethics of the profession, suggesting that human rights education during medical school may contribute to the development of proper values in young physicians even before they proceed into practice.

Myeloperoxidase Nuclear Imaging for Epileptogenesis.

PURPOSE: To determine if myeloperoxidase (MPO) is involved in epileptogenesis and if molecular nuclear imaging can be used to noninvasively map inflammatory changes in epileptogenesis. MATERIALS AND METHODS: The animal and human studies were approved by the institutional review boards. Pilocarpine-induced epileptic mice were treated with 4-aminobenzoic acid hydrazide (n = 46), a specific irreversible MPO inhibitor, or saline (n = 42). Indium-111-bis-5-hydroxytryptamide-diethylenetriaminepentaacetate was used to image brain MPO activity (n = 6 in the 4-aminobenzoic acid hydrazide and saline groups; n = 5 in the sham group) by using single photon emission computed tomography/computed tomography. The role of MPO in the development of spontaneous recurrent seizures was assessed by means of clinical symptoms and biochemical and histopathologic data. Human brain specimens from a patient with epilepsy and a patient without epilepsy were stained for MPO. The Student t test, one-way analysis of variance, and Mann-Whitney and Kruskal-Wallis tests were used. Differences were regarded as significant if P was less than .05. RESULTS: MPO and leukocytes increased in the brain during epileptogenesis (P < .05). Blocking MPO delayed spontaneous recurrent seizures (99.6 vs 142 hours, P = .016), ameliorated the severity of spontaneous recurrent seizures (P < .05), and inhibited mossy fiber sprouting (Timm index, 0.31 vs 0.03; P = .003). Matrix metalloproteinase activity was upregulated during epileptogenesis in an MPO-dependent manner (1.44 vs 0.94 U/mg, P = .049), suggesting that MPO acts upstream of matrix metalloproteinases. MPO activity was mapped during epileptogenesis in vivo in the hippocampal regions. Resected temporal lobe tissue from a human patient with refractory epilepsy but not the temporal lobe tissue from a patient without seizures demonstrated positive MPO immunostaining, suggesting high translational potential for this imaging technology. CONCLUSION: The findings of this study highlight an important role for MPO in epileptogenesis and show MPO to be a potential therapeutic target and imaging biomarker for epilepsy.

Demyelinating diseases: myeloperoxidase as an imaging biomarker and therapeutic target.

PURPOSE: To evaluate myeloperoxidase (MPO) as a newer therapeutic target and bis-5-hydroxytryptamide-diethylenetriaminepentaacetate-gadolinium (Gd) (MPO-Gd) as an imaging biomarker for demyelinating diseases such as multiple sclerosis (MS) by using experimental autoimmune encephalomyelitis (EAE), a murine model of MS. MATERIALS AND METHODS: Animal experiments were approved by the institutional animal care committee. EAE was induced in SJL mice by using proteolipid protein (PLP), and mice were treated with either 4-aminobenzoic acid hydrazide (ABAH), 40 mg/kg injected intraperitoneally, an irreversible inhibitor of MPO, or saline as control, and followed up to day 40 after induction. In another group of SJL mice, induction was performed without PLP as shams. The mice were imaged by using MPO-Gd to track changes in MPO activity noninvasively. Imaging results were corroborated by enzymatic assays, flow cytometry, and histopathologic analyses. Significance was computed by using the t test or Mann-Whitney U test. RESULTS: There was a 2.5-fold increase in myeloid cell infiltration in the brain (P = .026), with a concomitant increase in brain MPO level (P = .0087). Inhibiting MPO activity with ABAH resulted in decrease in MPO-Gd-positive lesion volume (P = .012), number (P = .009), and enhancement intensity (P = .03) at MR imaging, reflecting lower local MPO activity (P = .03), compared with controls. MPO inhibition was accompanied by decreased demyelination (P = .01) and lower inflammatory cell recruitment in the brain (P < .0001), suggesting a central MPO role in inflammatory demyelination. Clinically, MPO inhibition significantly reduced the severity of clinical symptoms (P = .0001) and improved survival (P = .0051) in mice with EAE. CONCLUSION: MPO may be a key mediator of myeloid inflammation and tissue damage in EAE. Therefore, MPO could represent a promising therapeutic target, as well as an imaging biomarker, for demyelinating diseases and potentially for other diseases in which MPO is implicated.