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1.  Prognostic value of coping strategies in a community-based sample of persons with chronic symptomatic knee osteoarthritis 
Pain  2013;154(12):2775-2781.
Radiographic knee osteoarthritis (OA) is a highly prevalent condition that has been the focus of a number of studies identifying factors that are prognostic of continued or worsening pain and function. Although prior prognostic studies have identified a number of demographic, physical, and psychological factors that are predictive of outcome, minimal focus has been placed on pain coping skills as prognostic factors, despite cross-sectional evidence suggesting that pain coping skills are associated with pain and function in knee OA. The present study reports on the use of pain coping skills as prognostic factors for changes in pain and/or function over a 1-year period. Participants were drawn from the Osteoarthritis Initiative, a prospective longitudinal cohort study of persons recruited from the community who either had knee OA or were at high risk for developing knee OA. Data from the Coping Strategies Questionnaire were compared against 1-year change in pain, function, or both, using established criteria for defining whether the patient got better, worse, or stayed the same over the 1-year period. Results revealed a significant effect for praying/hoping, increased behavioral activities, and pain catastrophizing as prognostic of pain outcomes; ignoring pain and praying/hoping were prognostic of function outcomes; and increased behavioral activities and pain catastrophizing were prognostic of a combined pain and function outcome. The findings provide important new evidence regarding the potential clinical relevance of a number of pain coping responses hypothesized to influence future pain and function in persons with arthritis.
PMCID: PMC4298486  PMID: 23969326
Coping; Disability; Function; Pain
2.  Effects of non-pharmacological pain treatments on brain states 
To (1) evaluate the effects of a single session of four non-pharmacological pain interventions, relative to a sham tDCS procedure, on pain and electroencephalogram- (EEG-) assessed brain oscillations, and (2) determine the extent to which procedure-related changes in pain intensity are associated with changes in brain oscillations.
30 individuals with spinal cord injury and chronic pain were given an EEG and administered measures of pain before and after five procedures (hypnosis, meditation, transcranial direct current stimulation [tDCS], and neurofeedback) and a control sham tDCS procedure.
Each procedure was associated with a different pattern of changes in brain activity, and all active procedures were significantly different from the control procedure in at least three bandwidths. Very weak and mostly non-significant associations were found between changes in EEG-assessed brain activity and pain.
Different non-pharmacological pain treatments have distinctive effects on brain oscillation patterns. However, changes in EEG-assessed brain oscillations are not significantly associated with changes in pain, and therefore such changes do not appear useful for explaining the benefits of these treatments.
The results provide new findings regarding the unique effects of four non-pharmacological treatments on pain and brain activity.
PMCID: PMC3759647  PMID: 23706958
spinal cord injury; chronic pain; electroencephalography; brain states; non-pharmacological treatments
Pain  2013;154(12):10.1016/j.pain.2013.08.024.
Pain behaviors that are maintained beyond the acute stage post-injury can contribute to subsequent psychosocial and physical disability. Critical to the study of pain behaviors is the availability of psychometrically sound pain behavior measures. In this study we developed a self-report measure of pain behaviors, the Pain Behaviors Self Report (PaB-SR). PaB-SR scores were developed using item response theory and evaluated using a rigorous, multiple-witness approach to validity testing. Participants included: a) 661 survey participants with chronic pain and with multiple sclerosis (MS), back pain, or arthritis; b) 618 survey participants who were significant others of a chronic pain participant; and c) 86 participants in a videotaped pain behavior observation protocol. Scores on the PaB-SR were found to be measurement invariant with respect to clinical condition. PaB-SR scores, observer-reports, and the video-taped protocol yielded distinct, but convergent views of pain behavior, supporting the validity of the new measure. The PaB-SR is expected to be of substantial utility to researchers wishing to explore the relationship between pain behaviors and constructs such as pain intensity, pain interference, and disability.
PMCID: PMC3875313  PMID: 23994451
Chronic pain; assessment; psychometrics
4.  Co-Occurring Depression and Pain in Multiple Sclerosis 
Depression and pain are highly prevalent among individuals with multiple sclerosis, and they often co-occur. The purpose of this article is to summarize the literature and theory related to the comorbidity of pain and depression, and describe how their presence can impact individuals with MS. Additionally, the article discusses how existing treatments for pain and depression could be adapted to address shared mechanisms and overcome barriers to treatment utilization.
PMCID: PMC3857561  PMID: 24314687
Depression; pain; multiple sclerosis
5.  Cross-cultural adaptation, evaluation and validation of the Spouse Response Inventory: a study protocol 
BMJ Open  2014;4(10):e005119.
Since the response of spouses has been proven to be an important reinforcement of pain behaviour and disability it has been addressed in research and therapy. Fordyce suggested pain behaviour and well behaviour be considered in explaining suffering in chronic pain patients. Among existing instruments concerning spouse's responses the aspect of well behaviour has not been examined so far. The SRI (Spouse Response Inventory) tries to consider pain behaviour and well behaviour and appears to be acceptable because of its brevity and close proximity to daily language. The aim of the study is the translation into German, followed by evaluation and validation, of the SRI on a German sample of patients with chronic pain.
Methods and analyses
The study is comprehensively designed: initially, the focus will lie on the translation of the instrument following the guidelines for cross-cultural translation and adaptation and evaluation of the German version according to the source study. Subsequently, a validation referring to predictive, incremental and construct validation will be conducted using instruments based on similar or close but different constructs. Evaluation of the resulting SRI-G (SRI-German) will be conducted on a sample of at least 30 patients with chronic pain attending a comprehensive pain centre. For validation at least 120 patients with chronic headache, back pain, cancer related pain and somatoform pain disorder shall be included, for a total of 480 patients. Separate analyses according to specific pain diagnoses will be performed to ensure psychometric property, interpretability and control of diagnosis of specific limitations. Analyses will include comprehensive investigation of psychometric property of the scale by hierarchical regression analyses, correlation analyses, multivariate analysis of variance and exploratory factor analyses (SPSS).
The study protocol was approved by the Ethics Committee of the University of Dresden (EK 335 122008) based on the Helsinki declaration.
PMCID: PMC4202021
chronic pain; multimodal pain therapy; spouse response inventory; validation; crosscultural adaptation; study protocol
6.  Transcranial Direct Current Stimulation in Neuropathic Pain 
Journal of pain & relief  2013;Suppl 3:001.
Neuropathic pain (NP) is one of the most common problems contributing to suffering and disability worldwide. Unfortunately, NP is also largely refractory to treatments, with a large number of patients continuing to report significant pain even when they are receiving recommended medications and physical therapy. Thus, there remains an urgent need for additional effective treatments. In recent years, nonpharmacologic brain stimulation techniques have emerged as potential therapeutic options. Many of these techniques and procedures – such as transcranial magnetic stimulation, spinal cord stimulation, deep brain stimulation, and motor cortical stimulation – have very limited availability, particularly in developing countries. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation procedure that has shown promise for effectively treating NP, and also has the potential to be widely available. This review describes tDCS and the tDCS procedures and principles that may be helpful for treating NP. The findings indicate that the analgesic benefits of tDCS can occur both during stimulation and beyond the time of stimulation. The mechanisms of cortical modulation by tDCS may involve various activities in neuronal networks such as increasing glutamine and glutamate under the stimulating electrode, effects on the μ-opioid receptor, and restoration of the defective intracortical inhibition. Additional research is needed to determine (1) the factors that may moderate the efficacy of tDCS, (2) the dose (e.g. number and frequency of treatment sessions) that results in the largest benefits and (3) the long-term effects of tDCS treatment.
PMCID: PMC4193292  PMID: 25309825
Transcranial direct current stimulation; Neuropathic pain; Noninvasive brain stimulation
7.  Combining Cognitive Behavioral Therapy and Milnacipran for Fibromyalgia: A Feasibility Randomized-controlled Trial 
The Clinical journal of pain  2013;29(9):747-754.
To evaluate the feasibility of a randomized-controlled trial (RCT) and to obtain estimates of the effects of combined cognitive behavioral therapy (CBT) and milnacipran for the treatment of fibromyalgia (FM).
Fifty eight patients with FM were randomized to one of the 3 treatment arms: (1) combination therapy (n=20), (2) milnacipran + education (n=19), and (3) placebo + CBT (n=19). Subjects received either milnacipran (100 mg/day) or placebo. Subjects also received 8 sessions of phone-delivered CBT or educational instructions, but only from baseline to week 9. Assessments were conducted at baseline, week 9 and 21. The primary endpoints were baseline to week 21 changes in weekly average pain intensity and physical function (SF-36 physical function scale).
Compared to milnacipran, combination therapy demonstrated a moderate effect on improving SF-36 physical function (mean difference (SE) = 9.42 (5.48), p=0.09, effect size (ES) =0.60) and in reducing weekly average pain intensity (mean difference (SE) = −1.18 (0.62), p=0.07, ES=0.67). Compared to milnacipran, CBT had a moderate to large effect in improving SF-36 physical function (mean difference (SE) = 11.0 (5.66), p=0.06, ES=0.70). Despite the presence of concomitant centrally-acting therapies, dropout rate was lower than anticipated (15% at week 21). Importantly, at least 6 out of the 8 phone-based therapy sessions were successfully completed by 89% of the subjects; and adherence to the treatment protocols was >95%.
In this pilot study, a therapeutic approach that combines phone-based CBT and milnacipran was feasible and acceptable. Moreover, the preliminary data supports conducting a fully powered RCT.
PMCID: PMC4185390  PMID: 23446065
Fibromyalgia; Cognitive Behavioral Therapy; Milnacipran; Pain; Physical Function
8.  The association of age, pain, and fatigue with physical functioning and depressive symptoms in persons with spinal cord injury 
To describe the relationship of pain and fatigue with physical and psychological functioning in adults with spinal cord injury (SCI).
Cross-sectional survey.
Community-based survey.
Convenience sample of individuals with SCI.
Not applicable.
Outcome measures
Physical functioning (Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Functioning item bank items), depression (Patient Health Questionnaire-9 (PHQ-9)), pain severity (0–10 Numerical Rating Scale (NRS)), and fatigue (0–10 NRS).
Pain and fatigue were independently associated with depression, but only pain was associated with physical functioning. Additionally, depression was more severe among middle-aged participants relative to younger or older participants. Physical functioning declined with increasing age, as well as with higher level of injury.
The findings support the need for continued development of effective treatments for both pain and fatigue in order to prevent and mitigate the negative effects these symptoms can have on functioning.
PMCID: PMC3739898  PMID: 23941796
Pain; Fatigue; Spinal cord injuries; Depression; Mood; Function; Physical; Outcomes; Rehabilitation; Model system
9.  Moderate-vigorous physical activity improves long-term clinical outcomes without worsening pain in fibromyalgia 
Arthritis care & research  2013;65(8):1211-1218.
To evaluate the relationship between long-term maintenance of moderate-vigorous physical activity (MVPA) and clinical outcomes in fibromyalgia (FM).
Patients with FM (n=170) received individualized exercise prescriptions and completed baseline and follow-up physical activity assessments using the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire at weeks 12, 24, and 36. The primary outcome was the change in the Fibromyalgia Impact Questionnaire-Physical Impairment (FIQ-PI) score. Secondary outcomes included improvements in overall well-being (FIQ-Total), pain severity ratings, and depression.
Using a threshold increase in MVPA of ≥10 metabolic equivalent hours per week (MET h/wk) above usual activities, 27 subjects (15.9%) increased and sustained (SUS-PA), 68 (40%) increased, but then declined (UNSUS-PA), and 75 (44.1%) did not achieve this benchmark (LO-PA). Compared to LO-PA subjects, both SUS-PA and UNSUS-PA subjects reported greater improvement in FIQ-PI (p<0.01) and FIQ-Total (p<0.05). Additionally, the SUS-PA group reported greater improvement in pain severity compared to the LO-PA group (p<0.05). However, there were no significant group differences between SUS-PA and UNSUS-PA for any primary or secondary outcome measure.
Increased participation in MVPA for at least 12 weeks improves physical function and overall well-being in patients with FM. Although sustained physical activity was not associated with greater clinical benefit compared to unsustained physical activity, these findings also suggest that performing greater volumes of physical activity is not associated with worsening pain in FM. Future research is needed to determine the relationship between sustained MVPA participation and subsequent improvement in patient outcomes.
PMCID: PMC3672379  PMID: 23401486
10.  Research to Encourage Exercise for Fibromyalgia (REEF): Use of Motivational Interviewing, Outcomes from a Randomized Controlled Trial 
The Clinical journal of pain  2013;29(4):296-304.
Regular exercise is associated with important benefits in patients with fibromyalgia (FM). Unfortunately, long-term maintenance of exercise after a structured program is rare. The present study tested the efficacy of Motivational Interviewing (MI) to promote exercise and improve symptoms in patients with FM.
216 patients with FM were randomized to 6 MI sessions (n=107) or an equal number of FM self-management lessons (education control/EC, n=109). Co-primary endpoints were an increase of 30 minutes in moderate-vigorous physical activity and improvement in the Fibromyalgia Impact Questionnaire-Physical Impairment (FIQ-PI) score, assessed at pre-treatment, post-treatment, and 3- and 6-month follow-up. Secondary outcomes included clinically meaningful improvements in FIQ score, pain severity ratings, and a 6-minute walk test.
There were no significant treatment group differences in either co-primary endpoint at 6-month follow-up. However, more MI participants than controls exhibited meaningful improvements in FIQ score at 6-month follow-up (62.9% vs. 49.5%, p=0.06). Compared to EC subjects, MI subjects also displayed a larger increment in their 6-minute walk test (43.9 vs. 24.8 meters, p=0.03). Additionally, MI was superior to EC in increasing the number of hours of physical activity immediately post-intervention and in reducing pain severity both immediately after the intervention and at 3-month follow-up.
Despite a lack of benefits on long term outcome, MI appears to have short-term benefits with respect to self-report physical activity and clinical outcomes. This is the first study in FM that explicitly addresses exercise maintenance as a primary aim.
PMCID: PMC3541460  PMID: 23042474
Fibromyalgia; Exercise; Physical activity; Motivational interviewing; Physical function; Pain
11.  Alexithymia Is Associated with Greater Risk of Chronic Pain and Negative Affect and with Lower Life Satisfaction in a General Population: The Hisayama Study 
PLoS ONE  2014;9(3):e90984.
Chronic pain is a significant health problem worldwide, with a prevalence in the general population of approximately 40%. Alexithymia — the personality trait of having difficulties with emotional awareness and self-regulation — has been reported to contribute to an increased risk of several chronic diseases and health conditions, and limited research indicates a potential role for alexithymia in the development and maintenance of chronic pain. However, no study has yet examined the associations between alexithymia and chronic pain in the general population.
We administered measures assessing alexithymia, pain, disability, anxiety, depression, and life satisfaction to 927 adults in Hisayama, Japan. We classified the participants into four groups (low-normal alexithymia, middle-normal alexithymia, high-normal alexithymia, and alexithymic) based on their responses to the alexithymia measure. We calculated the risk estimates for the criterion measures by a logistic regression analysis.
Controlling for demographic variables, the odds ratio (OR) for having chronic pain was significantly higher in the high-normal (OR: 1.49, 95% CI: 1.07–2.09) and alexithymic groups (OR: 2.56, 95% CI: 1.47–4.45) compared to the low-normal group. Approximately 40% of the participants belonged to these two high-risk groups. In the subanalyses of the 439 participants with chronic pain, the levels of pain intensity, disability, depression, and anxiety were significantly increased and the degree of life satisfaction was decreased with elevating alexithymia categories.
The findings demonstrate that, in the general population, higher levels of alexithymia are associated with a higher risk of having chronic pain. The early identification and treatment of alexithymia and negative affect may be beneficial in preventing chronic pain and reducing the clinical and economic burdens of chronic pain. Further research is needed to determine if this association is due to a causal effect of alexithymia on the prevalence and severity of chronic pain.
PMCID: PMC3951296  PMID: 24621785
12.  Pain Catastrophizing in Youths With Physical Disabilities and Chronic Pain 
Journal of Pediatric Psychology  2012;38(2):192-201.
Objective The current study examined the associations between catastrophizing and pain intensity, psychological adjustment, functional ability, and community participation in youths with physical disability and chronic pain. Methods Participants consisted of 80 youths, aged 8–20 years, with cerebral palsy (n = 34), neuromuscular disease (n = 22), or spina bifida (n = 24). Measures from a cross-sectional survey included demographic, pain, and disability information, the Pain Catastrophizing Scale, the Child Health Questionnaire, and the Functional Disability Inventory. Results Results suggested that catastrophizing was significantly associated with pain intensity and psychological adjustment; however, catastrophizing did not demonstrate significant associations with functional ability or community participation. Conclusions The study extends previous findings of significant associations between catastrophizing and both pain intensity and psychological adjustment to samples of youths with chronic pain and disabilities not previously examined. Further research that examines the causal association between catastrophizing and outcomes in youths with chronic pain and physical disability is warranted.
PMCID: PMC3579163  PMID: 23033363
catastrophizing; chronic pain; functional ability; pain interference; physical disabilities; psychological adjustment
13.  Construct and Criterion-Based Validity of Brief Pain Coping Scales in Persons with Chronic Knee Osteoarthritis Pain 
Pain medicine (Malden, Mass.)  2012;14(2):265-275.
A recent trend in clinical practice is to adopt short screening and diagnostic self-report instruments for patients with chronic pain. Brief 2-item pain coping and beliefs measures have recently been developed and have potential to improve decision making in clinical practice. Our study examined the construct and criterion-based validity of the 2-item per scale version of the Coping Strategies Questionnaire (CSQ).
We used data obtained on a community-based sample of 873 persons with chronic knee osteoarthritis pain from the Osteoarthritis Initiative, a large longitudinal cohort study. Persons were administered the two-item per scale version of the CSQ. The International Classification of Functioning framework was used to select a variety of criterion-based measures for comparison to the CSQ. Spearman correlations and hierarchical regression models were used to characterize construct validity and Receiver Operating Characteristic Curves, sensitivity and specificity were used to describe criterion-based validity.
Construct validity of the CSQ scales were generally supported, with the Catastrophizing and Praying or Hoping scales demonstrating the strongest construct validity across criterion measures. Criterion-based validity for the CSQ scales varied depending on the criterion measure. The Catastrophizing and Praying or Hoping scales also had the strongest criterion-based validity with ROC curve areas as high as 0.71 (95%CI= 0.67, 0.75), p<0.001 for identifying persons with substantial physical function deficits.
The findings suggest that several of the 2-item CSQ scales demonstrate a modest level of construct validity along with fair criterion-based validity. The Catastrophizing and Praying or Hoping scales appear to hold the most promise for clinical applications and future longitudinal research.
PMCID: PMC3594566  PMID: 23240934
Pain; Coping; Disability; Function
14.  Acceptance of Pain in Neurological Disorders: Associations With Functioning and Psychosocial Well-Being 
Rehabilitation psychology  2013;58(1):1-9.
Chronic pain acceptance has been shown to be related to positive adjustment to chronic pain in patients presenting with pain as a primary problem. However, the role of pain acceptance in adjustment to chronic pain secondary to a neurological disorder that is often associated with physical disability has not been determined. The purpose of this study was to examine whether two domains of chronic pain acceptance—activity engagement and pain willingness—predict adjustment to pain, controlling for pain intensity and key demographic and clinical variables in individuals with muscular dystrophy (MD), multiple sclerosis (MS), post-polio syndrome (PPS), or spinal cord injury (SCI).
Participants were 508 community-dwelling adults with a diagnosis of MD, MS, PPS, or SCI who also endorsed a chronic pain problem. Participants completed self-report measures of pain acceptance, quality of life, pain interference, pain intensity, depression, and social role satisfaction.
Hierarchical linear regressions indicated that activity engagement predicted lower pain interference and depression, and greater quality of life and social role satisfaction. Pain willingness predicted less pain interference and depression. Together, the two pain acceptance subscales accounted for more variance in outcomes than did self-reported pain intensity.
Findings correspond with the broader pain acceptance literature, although activity engagement appears to be a more robust predictor of adjustment than does pain willingness. This research supports the need for future studies to determine the extent to which treatments that increase acceptance result in positive outcomes in persons with chronic pain secondary to neurological disorders.
PMCID: PMC3670089  PMID: 23437995
chronic pain acceptance; multiple sclerosis; muscular dystrophy; post-polio syndrome; spinal cord injury
15.  The association of depression with pain-related treatment utilization in patients with multiple sclerosis 
Pain medicine (Malden, Mass.)  2012;13(12):1648-1657.
To better understand the association of depression with pain treatment utilization in an MS population.
Cross-sectional survey.
Community-based survey.
Convenience sample of 117 individuals with MS.
Main Outcome Measures
Participants provided demographic information, descriptive information on utilization of pain treatments, pain intensity ratings on a 0–10 Numeric Rating Scale, and depressive symptoms on the Patient Health Questionnaire-9 (PHQ-9).
Participants reporting clinical levels of depressive symptoms (PHQ-9 ≥ 10) reported that they tried more pain treatments previously relative to participants with PHQ-9 < 10; however, the two groups did not differ in the number of treatments they were currently using. Additionally, participants with PHQ-9 ≥ 10 had more visits to providers for pain treatment relative to the group with PHQ-9 < 10. In subsequent analyses, results showed that these differences were no longer significant after controlling for level of pain intensity.
The results demonstrate that depression is not associated with higher pain treatment utilization. These findings support the assertion in previous studies that the mechanism by which depression impacts medical utilization is through increased appointments for nonspecific complaints, not for specific medical problems. While this suggests that treating depression may not be helpful in reducing pain treatment utilization specifically, it remains important to treat depression to reduce pain-related suffering and medical utilization more broadly.
PMCID: PMC3527650  PMID: 23137071
Pain; Depression; Medical Utilization; Multiple Sclerosis
16.  Chronic Pain in Neuromuscular Disease 
PMCID: PMC3670094  PMID: 23137744
Neuromuscular disease; Chronic pain; Pain intensity; Muscular dystrophy; Regional pain
17.  Physical activity and depression in middle and older-aged adults with multiple sclerosis 
Disability and health journal  2012;5(4):269-276.
Depression is common among people with multiple sclerosis (MS), and research shows that individuals, including individuals with MS, who are more physically active report lower rates of depression. However, little is known about the relative importance of level of physical activity (e.g., moderate versus vigorous) in relationship to depression, or the role that age might play in this relationship among people with MS. The current study sought to (1) clarify the associations between moderate and vigorous physical activity and depression in a sample of individuals with MS, (2) determine the associations between age and physical activity, and (3) test for the potential moderating influence of age on the associations between physical activity and depression.
Cross-sectional survey.
112 individuals with MS completed a survey assessing demographic variables, amount of moderate and vigorous physical activity, and depression.
There was a gradual decrease in the amount of moderate and vigorous physical activity as age increased, but this decrease was not statistically significant. Moderate physical activity was significantly (negatively) associated with depression across all age cohorts. Time spent in vigorous physical activity was significantly (negatively) associated with depression among the middle-aged but not younger or older participants who are physically active.
The findings support a link between moderate physical activity and depression and, for middle-aged individuals, vigorous physical activity and depression in persons with MS. The findings indicate that research examining the impact of activity enhancing treatments on depression in individuals with MS is warranted.
PMCID: PMC3462318  PMID: 23021738
Multiple sclerosis; physical activity; depression
18.  Defining mild, moderate, and severe pain in persons with multiple sclerosis 
Pain medicine (Malden, Mass.)  2012;13(10):1358-1365.
To identify empirically-derived cutoffs for mild, moderate, and severe pain
Community-based survey.
Convenience sample of 236 individuals with MS and pain.
Not applicable.
Main Outcome Measures
0-10 Numeric Rating Scale for pain severity (both average and worst pain) and Brief Pain Inventory for pain interference.
The optimal classification scheme for average pain was 0-2 = mild, 3-5 = moderate, and 6-10 = severe. Alternatively, the optimal classification scheme for worst pain was 0-4 = mild, 5-7 = moderate, 8-10 = severe.
The present study furthers our ability to use empirically-based cutoffs to inform the use of clinical guidelines for pain treatment as well as our understanding of the factors that might impact the cutoffs that are most appropriate for specific pain populations. The results of the present study also add to the existing literature by drawing similarities to studies of other populations but also by highlighting that clear, between-condition differences may exist that warrant using different cutoffs for patients with different medical conditions. Specifically, the present study highlights that cutoffs may be lower for persons with MS than other populations of persons with pain.
PMCID: PMC3473137  PMID: 22925457
Pain; pain severity; pain interference; multiple sclerosis
19.  Sub-micron Hard X-ray Fluorescence Imaging of Synthetic Elements 
Analytica chimica acta  2012;722:21-28.
Synchrotron-based X-ray fluorescence microscopy (SXFM) using hard X-rays focused into sub-micron spots is a powerful technique for elemental quantification and mapping, as well as microspectroscopic measurement such as μ-XANES (X-ray absorption near edge structure). We have used SXFM to image and simultaneously quantify the transuranic element plutonium at the L3 or L2 edge as well as lighter biologically essential elements in individual rat pheochromocytoma (PC12) cells after exposure to the long-lived plutonium isotope 242Pu. Elemental maps reveal that plutonium localizes principally in the cytoplasm of the cells and avoids the cell nucleus, which is marked by the highest concentrations of phosphorus and zinc, under the conditions of our experiments. The minimum detection limit under typical acquisition conditions for an average 202 μm2 cell is 1.4 fg Pu/cell or 2.9 × 10−20 moles Pu/μm2, which is similar to the detection limit of K-edge SXFM of transition metals at 10 keV. Copper electron microscopy grids were used to avoid interference from gold X-ray emissions, but traces of strontium present in naturally occurring calcium can still interfere with plutonium detection using its Lα X-ray emission.
PMCID: PMC3688452  PMID: 22444530
20.  Direct Determination of the Intracellular Oxidation State of Plutonium 
Inorganic chemistry  2011;50(16):7591-7597.
Microprobe X-ray absorption near edge structure (μ-XANES) measurements were used to determine directly, for the first time, the oxidation state of intracellular plutonium in individual 0.1 μm2 areas within single rat pheochromocytoma cells (PC12). The living cells were incubated in vitro for 3 hours in the presence of Pu added to the media in different oxidation states (Pu(III), Pu(IV), and Pu(VI)) and in different chemical forms. Regardless of the initial oxidation state or chemical form of Pu presented to the cells, the XANES spectra of the intracellular Pu deposits was always consistent with tetravalent Pu even though the intracellular milieu is generally reducing.
PMCID: PMC3688463  PMID: 21755934
21.  A Proteomic Approach to Identification of Plutonium Binding Proteins in Mammalian Cells 
Journal of proteomics  2011;75(5):1505-1514.
Plutonium can enter the body through different routes and remains there for decades; however its specific biochemical interactions are poorly defined. We, for the first time, have studied plutonium-binding proteins using a metalloproteomic approach with rat PC12 cells. A combination of immobilized metal ion chromatography, 2D gel electrophoresis, and mass spectrometry were employed to analyze potential plutonium-binding proteins. Our results show that several proteins from PC12 cells show affinity towards Pu4+-NTA (plutonium bound to nitrilotriacetic acid). Proteins from seven different spots in the 2D gel were identified. In contrast to the previously known plutonium-binding proteins transferrin and ferritin, which bind ferric ions, most identified proteins in our experiment are known to bind calcium, magnesium, or divalent transition metal ions. The identified plutonium interacting proteins also have functional roles in downregulation of apoptosis and other pro-proliferative processes. MetaCore analysis based on this group of proteins produced a pathway with a statistically significant association with development of neoplastic diseases.
PMCID: PMC3688465  PMID: 22146473
PC12 cells; 2-D gel electrophoresis; proteomics; plutonium-binding proteins; IMAC; anti-apoptotic; GO process
22.  Plutonium Uptake and Distribution in Mammalian Cells: Molecular vs Polymeric Plutonium 
To study the cellular responses to molecular and polymeric forms of plutonium using PC12 cells derived from rat adrenal glands.
Materials and methods
Serum starved PC12 cells were exposed to polymeric and molecular forms of plutonium for three hours. Cells were washed with 10 mM EGTA, 100 mM NaCl at pH 7.4 to remove surface sorbed plutonium. Localization of plutonium in individual cell was quantitatively analyzed by synchrotron X-ray fluorescence (XRF) microscopy.
Molecular plutonium complexes introduced to cell growth media in the form of NTA, citrate, or transferrin complexes were taken up by PC12 cells, and mostly co-localized with iron within the cells. Polymeric plutonium prepared separately was not internalized by PC12 cells but it was always found on the cell surface as big agglomerates; however polymeric plutonium formed in situ was mostly found within the cells as agglomerates.
PC12 cells can differentiate molecular and polymeric forms of plutonium. Molecular plutonium is taken up by PC12 cells and mostly co-localized with iron but aged polymeric plutonium is not internalized by the cells.
PMCID: PMC3679905  PMID: 21770702
PC12 Cells; plutonium polymer; molecular plutonium; X-ray fluorescence microscopy
23.  Psychosocial Factors and Adjustment to Chronic Pain in Persons With Physical Disabilities: A Systematic Review 
To systematically review the research findings regarding the associations between psychosocial factors and adjustment to chronic pain in persons with physical disabilities.
Data Sources
A key word literature search was conducted using articles listed in PubMed, PsychInfo, and CINAHL up to March 2010, and manual searches were made of all retrieved articles to identify published articles that met the review inclusion criteria.
Study Selection
To be included in the review, articles needed to (1) be written in English, (2) include adults with a physical disability who report having pain, (3) include at least 1 measure of a psychosocial predictor domain, (4) include at least 1 criterion measure of pain or patient functioning, and (5) report the results of associations between the psychosocial factors and criterion measures used in the study. Twenty-nine studies met the inclusion criteria.
Data Extraction
Three reviewers tabulated study details and findings.
Data Synthesis
The disability groups studied included spinal cord injury (SCI), acquired amputation, cerebral palsy (CP), multiple sclerosis (MS), and muscular dystrophy (MD). Psychosocial factors were shown to be significantly associated with pain and dysfunction in all disability groups. The psychosocial factors most closely associated with pain and dysfunction across the samples included (1) catastrophizing cognitions; (2) task persistence, guarding, and resting coping responses; and (3) perceived social support and solicitous responding social factors. Pain-related beliefs were more strongly associated with pain and dysfunction in the SCI, CP, MS, and MD groups than in the acquired amputation group.
The findings support the importance of psychosocial factors as significant predictors of pain and functioning in persons with physical disabilities. Clinical trials to test the efficacy of psychosocial treatments for pain and dysfunction are warranted, as are studies to determine whether psychosocial factors have a causal influence on pain and adjustment in these populations.
PMCID: PMC3028590  PMID: 21187217
Amputation; Pain; Psychological adaptation
24.  Nanocarriers Enhance Doxorubicin Uptake in Drug-Resistant Ovarian Cancer Cells 
Cancer research  2011;72(3):769-778.
Resistance to anthracyclines and other chemotherapeutics due to P-glycoprotein (PGP)-mediated export is a frequent problem in cancer treatment. Here we report that iron oxide-titanium dioxide core-shell nanocomposites can serve as efficient carriers for doxorubicin to overcome this common mechanism of drug resistance in cancer cells. Doxorubicin nanocarriers (DNCs) increased effective drug uptake in drug-resistant ovarian cells. Mechanistically, doxorubicin bound to the TiO2 surface by a labile bond that was severed upon acidification within cell endosomes. Upon its release doxorubicin traversed the intracellular milieu and entered the cell nucleus by a route that evaded PGP-mediated drug export. Confocal and x-ray fluorescence microscopy with flow cytometry were used to demonstrate the ability of DNC to modulate transferrin uptake and distribution in cells. Increased transferrin uptake occurred through clathrin-mediated endocytosis, indicating that nanocomposites and DNCs may both interfere with removal of transferrin from cells. Together, our findings show that DNCs not only provide an alternative route of delivery of doxorubicin to PGP-over-expressing cancer cells, but may also boost the uptake of transferrin-tagged therapeutic agents.
PMCID: PMC3657469  PMID: 22158944
doxorubicin; nanocarrier; titanium dioxide; endocytosis; transferrin
25.  Changes in pain-related beliefs, coping, and catastrophizing predict changes in pain intensity, pain interference, and psychological functioning in individuals with Myotonic Muscular Dystrophy and Facioscapulohumeral Dystrophy 
The Clinical journal of pain  2012;28(1):47-54.
The primary aim of this study was to test hypothesized associations between changes in psychological variables (i.e., pain beliefs, catastrophizing and coping strategies) and changes in pain intensity and related adjustment (i.e., pain interference and psychological functioning) in individuals with Myotonic Muscular Dystrophy (MMD) and Facioscapulohumeral Muscular Dystrophy (FSHD).
A sample of 107 adults with a diagnosis of MMD or FSHD, reporting pain in the past three months, completed assessments at two time-points, separated by about 24 months.
Results showed that changes in pain-related psychological variables were significantly associated with changes in psychological functioning, pain intensity and pain interference. Specifically, increases in the belief that emotion influences pain, and catastrophizing were associated with decreases in psychological functioning. Increases in the coping strategies of asking for assistance and resting, and the increases of catastrophizing were associated with increases in pain intensity. Finally, increases in pain intensity and asking for assistance were associated with increases in pain interference.
The results support the utility of the biopsychosocial model of pain for understanding pain and its impact in individuals with MMD or FSHD. These findings may inform the design and implementation of psychosocial pain treatments for people with muscular dystrophy and chronic pain.
PMCID: PMC3170694  PMID: 21642844
Myotonic dystrophy; Facioscapulohumeral muscular dystrophy; pain; psychological factors

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