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1.  Proton MR Spectroscopy Correlates Diffuse Axonal Abnormalities with Post-Concussive Symptoms in Mild Traumatic Brain Injury 
Journal of Neurotrauma  2013;30(13):1200-1204.
There are no established biomarkers for mild traumatic brain injury (mTBI), in part because post-concussive symptoms (PCS) are subjective and conventional imaging is typically unremarkable. To test whether diffuse axonal abnormalities quantified with three-dimensional (3D) proton magnetic resonance spectroscopic imaging (1H-MRSI) correlated with patients' PCS, we retrospectively studied 26 mTBI patients (mean Glasgow Coma Scale [GCS] score of 14.7), 18- to 56-year-olds and 13 controls three to 55 days post-injury. All were scanned at 3 Tesla with T1- and T2-weighted MRI and 3D 1H-MRSI (480 voxels over 360 cm3, ∼30% of the brain). On scan day, patients completed a symptom questionnaire, and those who indicated at least one of the most common subacute mTBI symptoms (headache, dizziness, sleep disturbance, memory deficits, blurred vision) were grouped as PCS-positive. Global gray matter and white matter (GM/WM) absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) in PCS-positive and PCS-negative patients were compared to age- and gender-matched controls using two-way analysis of variance. The results showed that the PCS-negative group (n=11) and controls (n=8) did not differ in any GM or WM metabolite level. The PCS-positive patients (n=15) had lower WM NAA than the controls (n=12; 7.0±0.6 versus 7.9±0.5mM; p=0.0007). Global WM NAA, therefore, showed sensitivity to the TBI sequelae associated with common PCS in patients with mostly normal neuroimaging, as well as GCS scores. This suggests a potential biomarker role in a patient population in which objective measures of injury and symptomatology are currently lacking.
PMCID: PMC3700460  PMID: 23339670
diffuse axonal injury; magnetic resonance spectroscopy; mild traumatic brain injury; N-acetyl-aspartate; post-concussive symptoms
2.  TWIST1 associates with NF-κB subunit RELA via carboxyl-terminal WR domain to promote cell autonomous invasion through IL8 production 
BMC Biology  2012;10:73.
Metastasis is the primary cause of death for cancer patients. TWIST1, an evolutionarily conserved basic helix-loop-helix (bHLH) transcription factor, is a strong promoter of metastatic spread and its expression is elevated in many advanced human carcinomas. However, the molecular events triggered by TWIST1 to motivate dissemination of cancer cells are largely unknown.
Here we show that TWIST1 induces the production of interleukin 8 (IL8), which activates matrix metalloproteinases and promotes invasion of breast epithelial and cancer cells. In this novel mechanism, TWIST1-mediated IL8 transcription is induced through the TWIST1 carboxy-terminal WR (Trp-Arg) domain instead of the classic DNA binding bHLH domain. Co-immunoprecipitation analyses revealed that the WR domain mediates the formation of a protein complex comprised of TWIST1 and the nuclear factor-kappaB (NF-κB) subunit RELA (p65/NF-κB3), which synergistically activates the transcriptional activity of NF-κB. This activation leads to increased DNA binding affinity of RELA to the IL8 promoter and thus induces the expression of the cytokine. Blockage of IL8 signaling by IL8 neutralizing antibodies or receptor inhibition reduced the invasiveness of both breast epithelial and cancer cells, indicating that TWIST1 induces autonomous cell invasion by establishing an IL8 antocrine loop.
Our data demonstrate that the TWIST1 WR domain plays a critical role in TWIST1-induced IL8 expression through interactions with and activation of NF-κB. The produced IL8 signals through an autocrine loop and promotes extracellular matrix degradation to enable cell invasion across the basement membrane.
PMCID: PMC3482588  PMID: 22891766
TWIST1; WR domain; RELA; NF-κB; IL8
3.  A Novel Interdisciplinary Analgesic Program Reduces Pain and Improves Function in Older Adults Following Orthopedic Surgery 
To examine the effect of a multi-component intervention on pain and function following orthopedic surgery.
Controlled prospective propensity score matched clinical trial.
New York City acute rehabilitation hospital.
249 patients admitted to rehabilitation following hip fracture repair (N=51) hip (N=64) or knee (N=134) arthroplasty.
Pain assessment at rest and with physical therapy (PT) by staff using numeric rating scales (1 to 5). Physician protocols for standing analgesia and pre-emptive analgesia prior to PT were implemented on the intervention unit. Control unit patients received usual care.
Pain, analgesic prescribing, gait speed, transfer time, and percent of PT sessions completed during admission. Pain and difficulty walking at 6, 12, 18, and 24 weeks following discharge.
In multivariable analyses compared to controls, intervention patients were significantly more likely to report no or mild pain at rest (66% versus 49%, P=.004) and with PT (52% versus 38%, P=.02) on average for the first 7 days of rehabilitation; had faster 8 foot walk times on days four (9.3 seconds versus 13.2 seconds, P=.02) and seven (6.9 versus 9.2 seconds, P=.02); received more analgesia (8.0 milligrams of morphine sulfate equivalents/day, P<0.001); were more likely to receive standing analgesia (98% versus 48%, P<.001); and had significantly shorter lengths of stay (10.1 versus 11.3 days, P=.005). At 6 months compared to controls, intervention patients were less likely to report moderate/severe pain with walking (15% versus 4%, P=.02), that pain did not interfere with walking (7% versus 18%, P=.004), and were less likely to be taking analgesics (35% versus 51%, P=.03).
The intervention improved post-operative pain, reduced chronic pain, and improved function.
PMCID: PMC2729399  PMID: 19054187
pain; function; orthopaedic surgery
4.  Traumatic brain injury: future assessment tools and treatment prospects 
Traumatic brain injury (TBI) is widespread and leads to death and disability in millions of individuals around the world each year. Overall incidence and prevalence of TBI are likely to increase in absolute terms in the future. Tackling the problem of treating TBI successfully will require improvements in the understanding of normal cerebral anatomy, physiology, and function throughout the lifespan, as well as the pathological and recuperative responses that result from trauma. New treatment approaches and combinations will need to be targeted to the heterogeneous needs of TBI populations. This article explores and evaluates the research evidence in areas that will likely lead to a reduction in TBI-related morbidity and improved outcomes. These include emerging assessment instruments and techniques in areas of structural/chemical and functional neuroimaging and neuropsychology, advances in the realms of cell-based therapies and genetics, promising cognitive rehabilitation techniques including cognitive remediation and the use of electronic technologies including assistive devices and virtual reality, and the emerging field of complementary and alternative medicine.
PMCID: PMC2626927  PMID: 19183780
traumatic brain injury; assessments; treatments
5.  MRI findings in Painful Post-stroke Shoulder 
Background and Purpose
Describe the structural abnormalities in the painful shoulder of stroke survivors and their relationships to clinical characteristics.
Eight-nine chronic stroke survivors with post-stroke shoulder pain underwent T1 and T2 weighed multiplanar, multisequence magnetic resonance imaging of the painful paretic shoulder. All scans were reviewed by one radiologist for the following abnormalities: rotator cuff, biceps and deltoid tears, tendonopathies and atrophy, subacromial bursa fluid, labral ligamentous complex abnormalities, and acromio-clavicular capsular hypertrophy. Clinical variables included subject demographics, stroke characteristics and the Brief Pain Inventory Questions 12 (BPI 12). The relationship between MRI findings and clinical characteristics were assessed via logistic regression.
Thirty-five percent of subjects exhibited a tear of at least 1 rotator cuff, biceps or deltoid muscle. Fifty-three percent of subjects exhibited tendonopathy of at least 1 rotator cuff, bicep or deltoid muscle. The prevalence of rotator cuff tears increased with age. However, rotator cuff tears and rotator cuff and deltoid tendonopathies were not related to severity of post-stroke shoulder pain. In approximately 20% of cases, rotator cuff and deltoid muscles exhibited evidence of atrophy. Atrophy was associated with reduced motor strength and reduced severity of shoulder pain.
Rotator cuff tears and rotator cuff and deltoid tendonopathies are highly prevalent in post-stroke shoulder pain. However, their relationship to shoulder pain is uncertain. Atrophy is less common, but is associated with less severe shoulder pain.
PMCID: PMC2398766  PMID: 18388345
Shoulder pain; Magnetic Resonance Imaging
6.  PCR candidate region mismatch scanning: adaptation to quantitative, high-throughput genotyping 
Nucleic Acids Research  2001;29(5):1114-1124.
Linkage and association analyses were performed to identify loci affecting disease susceptibility by scoring previously characterized sequence variations such as microsatellites and single nucleotide polymorphisms. Lack of markers in regions of interest, as well as difficulty in adapting various methods to high-throughput settings, often limits the effectiveness of the analyses. We have adapted the Escherichia coli mismatch detection system, employing the factors MutS, MutL and MutH, for use in PCR-based, automated, high-throughput genotyping and mutation detection of genomic DNA. Optimal sensitivity and signal-to-noise ratios were obtained in a straightforward fashion because the detection reaction proved to be principally dependent upon monovalent cation concentration and MutL concentration. Quantitative relationships of the optimal values of these parameters with length of the DNA test fragment were demonstrated, in support of the translocation model for the mechanism of action of these enzymes, rather than the molecular switch model. Thus, rapid, sequence-independent optimization was possible for each new genomic target region. Other factors potentially limiting the flexibility of mismatch scanning, such as positioning of dam recognition sites within the target fragment, have also been investigated. We developed several strategies, which can be easily adapted to automation, for limiting the analysis to intersample heteroduplexes. Thus, the principal barriers to the use of this methodology, which we have designated PCR candidate region mismatch scanning, in cost-effective, high-throughput settings have been removed.
PMCID: PMC29718  PMID: 11222761

Results 1-6 (6)