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1.  Sympathetic Nerve Fibers in Human Cervical and Thoracic Vagus Nerves 
Background
Vagus nerve stimulation therapy (VNS) has been used for chronic heart failure (CHF), and is believed to improve imbalance of autonomic control by increasing parasympathetic activity. Although it is known that there is neural communication between the VN and the cervical sympathetic trunk, there are few data regarding the quantity and/or distribution of the sympathetic components within the VN.
Objective
To examine the sympathetic component within human VN and correlate these with the presence of cardiac and neurologic diseases.
Methods
We performed immunohistochemistry on 31 human cervical and thoracic VNs (total 104 VNs) from autopsies and we reviewed the patients’ records. We correlated the quantity of sympathetic nerve fibers within the VNs with cardiovascular and neurologic disease states.
Results
All 104 VNs contain TH positive (sympathetic) nerve fibers; the mean TH positive areas were 5.47% in right cervical, 3.97% in left cervical, 5.11% in right thoracic, and 4.20% in left thoracic VN. The distribution of TH positive nerve fibers varied from case to case: central, peripheral, or scattered throughout nerve bundles. No statistically significant differences in nerve morphology were seen between diseases in which VNS is considered effective (depression and CHF), and other cardiovascular diseases, or neurodegenerative disease.
Conclusion
Human VNs contain sympathetic nerve fibers. The sympathetic component within the VN could play a role in physiologic effects reported with VNS. The recognition of sympathetic nerve fibers in the VNs may lead to better understanding of the therapeutic mechanisms of VNS.
doi:10.1016/j.hrthm.2014.04.032
PMCID: PMC4108556  PMID: 24768897
Cervical vagus nerves; Sympathetic nerves; Ganglion cells; Heart failure; Vagal nerve stimulation
2.  Cost-effectiveness of electroconvulsive therapy compared to repetitive transcranial magnetic stimulation for treatment-resistant severe depression: a decision model 
Psychological Medicine  2014;45(7):1459-1470.
Background
Electroconvulsive therapy (ECT) is widely applied to treat severe depression resistant to standard treatment. Results from previous studies comparing the cost-effectiveness of this technique with treatment alternatives such as repetitive transcranial magnetic stimulation (rTMS) are conflicting.
Method
We conducted a cost-effectiveness analysis comparing ECT alone, rTMS alone and rTMS followed by ECT when rTMS fails under the perspective of the Spanish National Health Service. The analysis is based on a Markov model which simulates the costs and health outcomes of individuals treated under these alternatives over a 12-month period. Data to populate this model were extracted and synthesized from a series of randomized controlled trials and other studies that have compared these techniques on the patient group of interest. We measure effectiveness using quality-adjusted life years (QALYs) and characterize the uncertainty using probabilistic sensitivity analyses.
Results
ECT alone was found to be less costly and more effective than rTMS alone, while the strategy of providing rTMS followed by ECT when rTMS fails is the most expensive and effective option. The incremental cost per QALY gained of this latter strategy was found to be above the reference willingness-to-pay threshold used in these types of studies in Spain and other countries. The probability that ECT alone is the most cost-effective alternative was estimated to be around 70%.
Conclusions
ECT is likely to be the most cost-effective option in the treatment of resistant severe depression for a willingness to pay of €30 000 per QALY.
doi:10.1017/S0033291714002554
PMCID: PMC4413854  PMID: 25354790
Cost-effectiveness; decision model; depression; electroconvulsive therapy; repetitive transcranial magnetic stimulation
3.  Prediction of High-Risk Plaque Development and Plaque Progression with the Carotid Atherosclerosis Score: A Prospective MRI Study 
JACC. Cardiovascular imaging  2014;7(4):366-373.
Objectives
The aim of this prospective study was to evaluate the Carotid Atherosclerosis Score (CAS) for predicting the development of high-risk plaque features and plaque burden progression.
Background
Prior studies have shown that carotid intraplaque hemorrhage (IPH) and a disrupted luminal surface (DLS), as identified by magnetic resonance imaging (MRI), are associated with greater risk for cerebrovascular events. Based on data from a large cross-sectional study, a scoring system was developed to determine which plaque features are associated with the presence of IPH and DLS. However, the predictive value of CAS has not been previously tested in a prospective, longitudinal study.
Methods
120 asymptomatic subjects with 50-79% carotid stenosis underwent carotid MRI scans at baseline and three-years thereafter. Presence of IPH and DLS, wall volume, maximum wall thickness, and maximum percent lipid-rich necrotic core area were measured at both time points. Baseline CAS values were calculated based on previously published criteria.
Results
Of the 73 subjects without IPH or DLS at baseline, nine (12%) developed one or both of these features during follow-up. There was a significant increasing trend between CAS and the development of new DLS (p<0.001) and with plaque burden progression (p=0.03), but not with the development of new IPH (p=0.3). Percent carotid stenosis was not significantly associated with new DLS (p=0.2), new IPH (p=0.1) or plaque progression (p=0.6)..
Conclusion
CAS was found to have a significant increasing relationship with incident DLS and plaque progression in this prospective study. CAS can potentially provide improved risk stratification beyond luminal stenosis.
doi:10.1016/j.jcmg.2013.09.022
PMCID: PMC4046843  PMID: 24631510
Carotid Atherosclerosis Score; Stenosis; Plaque progression; Disrupted Luminal Surface
4.  Evaluation of Inapparent Dengue Infections During an Outbreak in Southern China 
PLoS Neglected Tropical Diseases  2015;9(3):e0003677.
Few studies evaluating inapparent dengue virus (DENV) infections have been conducted in China. In 2013, a large outbreak of DENV occurred in the city of Zhongshan, located in Southern China, which provided an opportunity to assess the clinical spectrum of disease. During the outbreak, an investigation of 887 index case contacts was conducted to evaluate inapparent and symptomatic DENV infections. Post-outbreak, an additional 815 subjects from 4 towns with, and 350 subjects from 2 towns without reported autochthonous DENV transmission, as determined by clinical diagnosis, were evaluated for serological evidence of dengue IgG antibodies. Between July and November 2013, there were 19 imported and 809 autochthonous dengue cases reported in Zhongshan. Of 887 case contacts enrolled during the outbreak, 13 (1.5%) exhibited symptomatic DENV infection, while 28 (3.2%) were inapparent. The overall I:S ratio was 2.2:1 (95% CI: 1.1-4.2:1). Post-outbreak serological data showed that the proportion of DENV IgG antibody detection from the 4 towns with and the 2 towns without reported DENV transmission was 2.7% (95% CI: 1.6%-3.8%) and 0.6% (95% CI: 0-1.4%), respectively. The I:S ratio in the 3 towns where clinical dengue cases were predominately typed as DENV-1 was 11.0:1 (95% CI: 3.7-∞:1). The ratio in the town where DENV-3 was predominately typed was 1.0:1 (95% CI: 0.5-∞:1). In this cross-sectional study, data suggests a high I:S ratio during a documented outbreak in Zhongshan, Southern China. These results have important implications for dengue control, implying that inapparent cases might influence DENV transmission more than previously thought.
Author Summary
In this report, we evaluated individuals with symptomatic and asymptomatic dengue virus (DENV) infections during a 2013 DENV outbreak in Southern China, as well as performed post-outbreak serological testing for DENV IgG antibodies, to better understand DENV transmission. These findings suggest a high rate of asymptomatic cases, which has important implications for future dengue control.
doi:10.1371/journal.pntd.0003677
PMCID: PMC4380470  PMID: 25826297
5.  Protein kinase C and P2Y12 take center stage in thrombin-mediated activation of mammalian target of rapamycin complex 1 in human platelets 
Background
Rapamycin, an inhibitor of mammalian target of rapamycin complex-1 (mTORC1), reduces platelet spreading, thrombus stability, and clot retraction. Despite an important role of mTORC1 in platelet function, little is known about how it is regulated. The objective of this study was to determine the signaling pathways that regulate mTORC1 in human platelets.
Methods
Mammalian target of rapamycin complex-1 activation was assessed by measuring the phosphorylation of its downstream substrate ribosomal S6 kinase 1 (p70S6K).
Results
Thrombin or the protein kinase C (PKC) activator phorbal 12-myristate 13-acetate stimulated activation of mTORC1 in a PKC-dependent, Akt-independent manner that correlated with phosphorylation of tuberin/tuberous sclerosis 2 (TSC2) (Ser939 and Thr1462). In contrast, insulin-like growth factor 1 (IGF-1)–stimulated TSC2 phosphorylation was completely dependent on phosphoinositide 3 kinase (PI3 kinase)/Akt but did not result in any detectable mTORC1 activation. Early (Ser939 and Thr1462) and late (Thr1462) TSC2 phosphorylation in response to thrombin were directly PKC dependent, whereas later TSC2 (Ser939) and p70S6K phosphorylation were largely dependent on paracrine signaling through P2Y12. PKC-mediated adenosine diphosphate (ADP) secretion was essential for thrombin-stimulated mTORC1 activation, as (i) ADP rescued p70S6K phosphorylation in the presence of a PKC inhibitor and (ii) P2Y12 antagonism prevented thrombin-mediated mTORC1 activation. Rescue of mTORC1 activation with exogenous ADP was completely dependent on the Src family kinases but independent of PI3 kinase/Akt. Interestingly, although inhibition of Src blocked the ADP rescue, it had little effect on thrombin-stimulated p70S6K phosphorylation under conditions where PKC was not inhibited.
Conclusion
These results demonstrate that thrombin activates the mTORC1 pathway in human platelets through PKC-mediated ADP secretion and subsequent activation of P2Y12, in a manner largely independent of the canonical PI3 kinase/Akt pathway.
doi:10.1111/jth.12552
PMCID: PMC4238809  PMID: 24612393
P2Y12 purinoceptor; platelets; protease-activated receptors; protein kinase C; target of rapamycin complex 1
6.  Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies 
Brain  2013;136(2):508-521.
The β-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and β-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of β-tropomyosin-related myopathies through the identification of a novel β-tropomyosin mutation in two clinical contexts not previously associated with β-tropomyosin. The first clinical phenotype is core-rod myopathy, with a β-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of β-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric β-tropomyosin, a change predicted to alter protein–protein binding between β-tropomyosin and other molecules and to disturb head-to-tail polymerization of β-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del β-tropomyosin in the developing zebrafish. p.K7del β-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail β-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel β-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with β-tropomyosin and pathogenic data from the first animal model of β-tropomyosin-related myopathies.
doi:10.1093/brain/aws344
PMCID: PMC3572924  PMID: 23413262
nemaline; myopathies; muscle and nerve pathology; mutation; neuromuscular disorders
7.  Sustained acceleration in carotid atherosclerotic plaque progression with intraplaque hemorrhage: A long-term time course study 
JACC. Cardiovascular imaging  2012;5(8):798-804.
Objectives
The purpose of this study was to determine the immediate and long-term effects of intraplaque hemorrhage (IPH) on plaque progression in the carotid artery.
Background
Previous studies have associated IPH in the carotid artery with more rapid plaque progression. However, the time course and long-term effect remain unknown. Carotid magnetic resonance imaging (MRI) is a non-invasive imaging technique that has been validated with histology for the accurate in vivo detection of IPH and measurement of plaque burden.
Methods
Asymptomatic subjects with 50–79% carotid stenosis underwent carotid MRI at baseline and then serially every 18 months for a total of 54 months. Subjects with IPH present in at least one carotid artery at 54 months were selected. Subsequently, presence/absence of IPH and wall volume were determined independently in all time points for both sides. A piecewise progression curve was fit using linear mixed model to compare progression rates defined as annualized changes in wall volume between periods defined by their relationship to IPH development.
Results
From 14 patients that showed IPH at 54 months, 12 arteries were found to have developed IPH during the study period. The progression rates were −20.5±13.1, 20.5±13.6 and 16.5±10.8 mm3/year before, during and after IPH development, respectively. The progression rate during IPH development tended to be higher than the period before (p=0.080), but comparable to the period after (p=0.845). The progression rate in the combined period during/after IPH development was 18.3±6.5 mm3/year, which indicated significant progression (p=0.008 compared to a slope of 0) and was higher than the period before IPH development (p=0.018). No coincident ischemic events were noted for new IPH.
Conclusions
The development of IPH posed an immediate and long-term promoting effect on plaque progression. IPH appears to alter the biology and natural history of carotid atherosclerosis. Early identification of patients with IPH may prove invaluable in optimizing management to minimize future sequelae.
doi:10.1016/j.jcmg.2012.03.014
PMCID: PMC3422506  PMID: 22897993
carotid arteries; intraplaque hemorrhage; atherosclerosis; magnetic resonance imaging
8.  Automated analysis of atrial late gadolinium enhancement imaging that correlates with endocardial voltage and clinical outcomes: A 2-center study 
Heart Rhythm  2013;10(8):1184-1191.
Background
For late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) assessment of atrial scar to guide management and targeting of ablation in atrial fibrillation (AF), an objective, reproducible method of identifying atrial scar is required.
Objective
To describe an automated method for operator-independent quantification of LGE that correlates with colocated endocardial voltage and clinical outcomes.
Methods
LGE CMR imaging was performed at 2 centers, before and 3 months after pulmonary vein isolation for paroxysmal AF (n = 50). A left atrial (LA) surface scar map was constructed by using automated software, expressing intensity as multiples of standard deviation (SD) above blood pool mean. Twenty-one patients underwent endocardial voltage mapping at the time of pulmonary vein isolation (11 were redo procedures). Scar maps and voltage maps were spatially registered to the same magnetic resonance angiography (MRA) segmentation.
Results
The LGE levels of 3, 4, and 5SDs above blood pool mean were associated with progressively lower bipolar voltages compared to the preceding enhancement level (0.85 ± 0.33, 0.50 ± 0.22, and 0.38 ± 0.28 mV; P = .002, P < .001, and P = .048, respectively). The proportion of atrial surface area classified as scar (ie, >3 SD above blood pool mean) on preablation scans was greater in patients with postablation AF recurrence than those without recurrence (6.6% ± 6.7% vs 3.5% ± 3.0%, P = .032). The LA volume >102 mL was associated with a significantly greater proportion of LA scar (6.4% ± 5.9% vs 3.4% ± 2.2%; P = .007).
Conclusions
LA scar quantified automatically by a simple objective method correlates with colocated endocardial voltage. Greater preablation scar is associated with LA dilatation and AF recurrence.
doi:10.1016/j.hrthm.2013.04.030
PMCID: PMC3734347  PMID: 23685170
2D, 2-dimensional; AF, atrial fibrillation; CMR, cardiovascular magnetic resonance; ECG, electrocardiogram; LA, left atrial/atrium; LGE, late gadolinium enhancement; MRA, Magnetic resonance angiography; PAF, paroxysmal atrial fibrillation; RF, radiofrequency; SD, standard deviation; Atrial fibrillation; Delayed-enhancement magnetic resonance imaging; Radiofrequency ablation
9.  Regulating in vivo calcification of alginate microbeads 
Biomaterials  2010;31(18):4926-4934.
Alginate calcification has been previously reported clinically and during animal implantation; however no study has investigated the mechanism, extensively characterized the mineral, or evaluated multiple methods to regulate or eliminate mineralization. In the present study, alginate calcification was first studied in vitro: calcium-crosslinked alginate beads sequestered surrounding phosphate while forming traces of hydroxyapatite. Calcification in vivo was then examined in nude mice using alginate microbeads with and without adipose stem cells (ASCs). Variables included the delivery method, site of delivery, sex of the animal, time in vivo, crosslinking solution, and method of storage prior to delivery. Calcium-crosslinked alginate microbeads mineralized when injected subcutaneously or implanted intramuscularly after 1–6 months. More extensive analysis with histology, microCT, FTIR, XRD, and EDS showed calcium phosphate deposits throughout the microbeads with surface mineralization that closely matched hydroxyapatite found in bone. Incorporating 25 mM bisphosphonate reduced alginate calcification whereas using barium chloride eliminated mineralization. Buffering the crosslinking solution with HEPES at pH 7.3 while washing and storing samples in basal media prior to implantation also eliminated calcification in vivo. This study shows that alginate processing prior to implantation can significantly influence bulk hydroxyapatite formation and presents a method to regulate alginate calcification.
doi:10.1016/j.biomaterials.2010.03.001
PMCID: PMC3358131  PMID: 20363022
Calcification; Alginate; Microencapsulation; Adipose stem cell microbeads; Bone tissue engineering
10.  Fast Bound Pool Fraction Imaging of the In Vivo Rat Brain: Association with Myelin Content and Validation in the C6 Glioma Model 
NeuroImage  2010;54(3):2052-2065.
Cross-relaxation imaging (CRI) is a quantitative magnetic resonance technique that measures the kinetic parameters of magnetization transfer between protons bound to water and protons bound to macromolecules. In this study, in vivo, four-parameter CRI of normal rat brains (N=5) at 3.0 T was first directly compared to histology. The bound pool fraction, f, was strongly associated with myelin density (Pearson’s r = 0.99, p <0.001). The correlation persisted in separate analyses of gray matter (GM; r = 0.89, p =0.046) and white matter (WM; r = 0.97, p =0.029). Subsequently, a new time-efficient approach for solely capturing the whole-brain parametric map of f was proposed, validated with histology, and used to estimate myelin density. Since the described approach for the rapid acquisition of f applied constraints to other CRI parameters, a theoretical analysis of error was performed. Estimates of f in normal and pathologic tissue were expected to have <10% error. A comparison of values for f obtained from the traditional four-parameter fit of CRI data versus the proposed rapid acquisition of f was within this expected margin for in vivo rat brain gliomas (N=4; mean ± SE; 3.9 ± 0.2% vs. 4.0 ± 0.2%, respectively). In both whole-brain f maps and myelin density maps, replacement of normal GM and WM by proliferating and invading tumor cells could be readily identified. The rapid, whole-brain acquisition of the bound pool fraction may provide a reliable method for detection of glioma invasion in both GM and WM during animal and human imaging.
doi:10.1016/j.neuroimage.2010.10.065
PMCID: PMC3008309  PMID: 21029782
bound pool fraction; cross-relaxation imaging; glioma; magnetization transfer ratio; myelin; quantitative magnetization transfer; rat brain
11.  Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution 
Biochemical Pharmacology  2007;74(1):74-85.
Non-steroidal anti-inflammatory drugs (NSAIDs) contribute to gastrointestinal ulcer formation by inhibiting epithelial cell migration and mucosal restitution; however, the drug-affected signaling pathways are poorly defined. We investigated whether NSAID inhibition of intestinal epithelial migration is associated with depletion of intracellular polyamines, depolarization of membrane potential (Em) and altered surface expression of K+ channels. Epithelial cell migration in response to the wounding of confluent IEC-6 and IEC-Cdx2 monolayers was reduced by indomethacin (100 μM), phenylbutazone (100 μM) and NS-398 (100 μM) but not by SC-560 (1 μM). NSAID-inhibition of intestinal cell migration was not associated with depletion of intracellular polyamines. Treatment of IEC-6 and IEC-Cdx2 cells with indomethacin, phenylbutazone and NS-398 induced significant depolarization of Em, whereas treatment with SC-560 had no effect on Em. The Em of IEC-Cdx2 cells was: −38.5±1.8 mV under control conditions; −35.9±1.6 mV after treatment with SC-560; −18.8±1.2 mV after treatment with indomethacin; and −23.7±1.4 mV after treatment with NS-398. Whereas SC-560 had no significant effects on the total cellular expression of Kv1.4 channel protein, indomethacin and NS-398 decreased not only the total cellular expression of Kv1.4, but also the cell surface expression of both Kv1.4 and Kv1.6 channel subunits in IEC-Cdx2. Both Kv1.4 and Kv1.6 channel proteins were immunoprecipitated by Kv1.4 antibody from IEC-Cdx2 lysates, indicating that these subunits co-assemble to form heteromeric Kv channels. These results suggest that NSAID inhibition of epithelial cell migration is independent of polyamine-depletion, and is associated with depolarization of Em and decreased surface expression of heteromeric Kv1 channels.
doi:10.1016/j.bcp.2007.03.030
PMCID: PMC3269908  PMID: 17499219
12.  Efficient Flow Suppressed MRI Improves Inter-Scan Reproducibility of Carotid Atherosclerosis Plaque Burden Measurements 
Background
To determine if better flow-suppression can meaningfully improve the reproducibility of measurements associated with carotid atherosclerotic disease, particularly for lumen and wall areas.
Methods
Eighteen subjects with carotid artery stenosis identified by duplex ultrasound (11 with 16–49% stenosis; 7 with 50–79% stenosis) underwent two carotid MRI examinations on a 3T scanner with a 4-channel phased array coil. High-resolution intermediate-weighted TSE (TR/TE=4000/8.5ms, 0.55mm in-plane resolution, 2mm slice thickness, 16 slices, 3min scan time) with two different flow suppression techniques (mDIR and MSDE) were obtained separately. For each subject, bilateral arteries were reviewed. One radiologist blinded to time points, flow suppression techniques, and clinical information, measured the arterial lumen area, wall area and total vessel wall area.
Results
Compared to mDIR, the MSDE technique had a smaller inter-scan standard deviation (SD) in lumen (SD: 3.6 vs. 5.2 mm2, p=0.02), wall area measurements (SD: 4.5 vs. 6.4 mm2, p=0.02) and total vessel area measurement (SD: 4.4 vs. 4.9 mm2, p=0.07), and a trend towards smaller SD in total vessel area measurement (SD: 4.4 vs. 4.9 mm2, p=0.07).
Conclusion
The results from this study demonstrated that vessel wall imaging could quantify atherosclerotic plaque measurements more reliably with improved blood suppression technique. This relationship between flow suppression efficiency and reproducibility of plaque measurements is important as more reliable area measurements will be useful in clinical diagnosis and in serial MRI studies that monitor carotid atherosclerotic lesion progression and regression.
doi:10.1002/jmri.22274
PMCID: PMC2915455  PMID: 20677277
Vessel wall MRI; Reproducibility; MSDE; mDIR
13.  Arterial Remodeling in the Subclinical Carotid Artery Disease 
JACC. Cardiovascular imaging  2009;2(12):1381-1389.
OBJECTIVES
We sought to identify clinical and/or plaque characteristics that affect atherosclerotic disease progression and arterial remodeling in the carotid artery with subclinical stenosis.
BACKGROUND
Increasing severity of stenosis has been associated with a higher risk of stroke. Factors that drive subclinical lesions to become stenotic plaques remain ambiguous. Carotid magnetic resonance imaging (MRI) has been validated with histology to accurately quantify in vivo arterial morphology and plaque composition.
METHODS
A total of 67 asymptomatic participants with 16% to 49% carotid stenosis as demonstrated by duplex ultrasonography were imaged at 1.5-T with a carotid MRI protocol at baseline and at 18-month follow-up. Clinical and/or intra-arterial metrics with a significant association with change in plaque burden during multivariate analysis were evaluated for effects on lumen, wall, and total vessel volume.
RESULTS
From multiple regression analysis, intraplaque hemorrhage (IPH) (p < 0.001) and statin therapy (p = 0.015) were identified as key determinants of change in plaque burden. The group with IPH compared with the group without IPH demonstrated luminal narrowing, with a mean ± SD decrease in lumen volume (−24.9 ± 21.1 mm3/year vs. −0.5 ± 26.9 mm3/year; p = 0.005), a larger increase in wall volume (44.1 ± 36.1 mm3/year vs. 0.8 ± 34.5 mm3/year; p < 0.001), and no difference in total vessel volume (19.3 ± 27.4 mm3/year vs. 0.4 ± 42.4 mm3/year; p = 0.15). The nonstatin group compared with the statin group demonstrated outward remodeling, with an increase in wall volume (22.4 ± 35.6 mm3/year3/year vs. 0.9 ± 38.0 mm3/year; p = 0.026) and total vessel volume (19.2 ± 36.9 mm3/year vs. −4.9 ± 40.4 mm3/year; p = 0.019) and no difference in lumen volume (−5.8 ± 26.6 mm3/year vs. −3.2 ± 29.5 mm3/year; p = 0.72).
CONCLUSIONS
IPH may represent an indication of accelerated plaque growth and impending luminal compromise in the subclinical carotid artery. Statin therapy may stabilize lesions by slowing or halting lesion progression. This phase of plaque stenosis (16% to 49%) may be a critical stage for intrinsic and extrinsic factors to affect the atherosclerotic disease process.
doi:10.1016/j.jcmg.2009.08.007
PMCID: PMC2830091  PMID: 20083072
atherosclerosis; carotid arteries; magnetic resonance imaging; remodeling
14.  Hemorrhage and large lipid-rich necrotic cores are independently associated with thin or ruptured fibrous caps: An In vivo 3T MRI study 
Objective
Histological studies suggest associations between hemorrhage and large lipid-rich/necrotic cores with thin or ruptured fibrous caps in advanced atherosclerosis. We investigated these associations in carotid arteries with mild to severe stenosis by in-vivo 3T MRI.
Methods and results
Seventy-seven patients with ≥50% carotid stenosis in at least one side by duplex ultrasound underwent bilateral multi-contrast carotid MRI scans. Measurements for wall and lipid-rich/necrotic core sizes, presence of hemorrhage and fibrous cap status (classified as intact thick, intact thin or ruptured) were recorded. Arteries with poor image quality, occlusion or no detectable lipid-rich/necrotic core were excluded. For the 798 MRI slices included, multivariate ordinal regression analysis demonstrated larger %lipid-rich/necrotic core (odds ratio for 10% increase, 1.49; p=0.02) and presence of hemorrhage (odds ratio, 5.91; p<0.001) were independently associated with a worse (intact thin or ruptured) stage of fibrous cap status. For artery-based multivariate analysis, a larger maximum %lipid-rich/necrotic core and presence of hemorrhage independently associated with worse fibrous cap status (p<0.001, for both). No hemorrhage was detected in arteries with thick fibrous caps.
Conclusion
Hemorrhage and larger %lipid-rich/necrotic core were independently associated with a thin or ruptured fibrous cap status at an early to advanced stage of carotid atherosclerosis.
doi:10.1161/ATVBAHA.109.192179
PMCID: PMC2750883  PMID: 19608971
magnetic resonance imaging; carotid artery; fibrous cap rupture; hemorrhage; lipid-rich necrotic core
15.  Contrast Enhanced MR Imaging of Carotid Atherosclerosis: Dependence on Contrast Agent 
Purpose
To investigate the dependence of contrast-enhanced MRI of carotid artery atherosclerotic plaque on use of gadobenate dimeglumine versus gadodiamide.
Materials and Methods
15 subjects with carotid atherosclerotic plaque were imaged with 0.1 mmol/kg of each agent. For arteries with interpretable images, the areas of the lumen, wall, and necrotic core and overlying fibrous cap (when present) were measured, as were the percent enhancement and contrast-to-noise ratio (CNR). A kinetic model was applied to dynamic imaging results to determine the fractional plasma volume vp and contrast agent transfer constant Ktrans.
Results
For 12 subjects with interpretable images, the agent used did not significantly impact any area measurements or the presence or absence of necrotic core (p>0.1 for all). However, the percent enhancement was greater for the fibrous cap (72% vs. 54%; p<0.05) necrotic core (51% vs. 42%; p=0.12), and lumen (42% vs. 63%; p<0.05) when using gadobenate dimeglumine, although no apparent difference in CNR was found. Additionally, Ktrans was lower when using gadobenate dimeglumine (0.0846 min−1 vs. 0.101 min−1; p<0.01), although vp showed no difference (9.5% vs. 10.1%; p=0.39).
Conclusion
Plaque morphology measurements are similar with either contrast agent, but quantitative enhancement characteristics, such as percent enhancement and Ktrans, differ.
doi:10.1002/jmri.21826
PMCID: PMC2757078  PMID: 19557844
contrast-enhanced MRI; atherosclerosis; gadobenate dimeglumine; gadodiamide; dynamic MRI
16.  How effective are mental health nurses in A&E departments? 
Emergency Medicine Journal : EMJ  2006;23(9):687-692.
Background
A&E departments are key points of contact for many people with mental health problems. Various models of care have been developed in A&E departments for delivering mental health services, but few have been assessed for effectiveness. The present study aimed to assess the impact of a dedicated A&E psychiatric nurse service on several outcomes relevant to patients and clinicians.
Methods
A crossover design was used to introduce a dedicated psychiatric nurse service (comprising four experienced community psychiatric nurses) into two busy UK A&E departments. Standardised assessments were completed for each patient, and a random sample of these independently assessed for quality. Data were also collected on the number of patients assessed, psychiatric nurse time employed, waiting times, onward referrals, repeat attendances, patient satisfaction, and staff views.
Results
A&E staff referred about a third of patients judged to have mental health problems to the psychiatric nurse service; approximately half of those assessed had a psychiatric history. On average, assessments took 60 min and over 90% of the formulated management plans were judged appropriate by independent assessors. The psychiatric nurse intervention had little impact on waiting times or satisfaction levels for mental health patients, although there was evidence of a change in onward referral patterns.
Comment
Psychiatric nurse assessment services have been introduced in many A&E departments, although the evidence base for the effectiveness of this development is not well established. This study presents evidence that psychiatric nurses can provide an accurate assessment and referral service with advantages for patient care.
doi:10.1136/emj.2005.033175
PMCID: PMC2564209  PMID: 16921080
liaison psychiatric services; mental health; psychiatric assessment and treatment; psychiatric nursing
17.  The added value of longitudinal black-blood cardiovascular magnetic resonance angiography in the cross sectional identification of carotid atherosclerotic ulceration 
Background
Carotid atherosclerotic ulceration is a significant source of stroke. This study evaluates the efficacy of adding longitudinal black-blood (BB) cardiovascular magnetic resonance (CMR) angiography to cross-sectional CMR images in the identification of carotid atherosclerotic ulceration.
Methods
Thirty-two subjects (30 males and two females with ages between 48 and 83 years) scheduled for carotid endarterectomy were imaged on a 1.5T GE Signa scanner using multisequence [3D time-of-flight, T1, proton density, T2, contrast enhanced T1], cross-sectional CMR images and longitudinal BB CMR angiography (0.625 × 0.625 mm/pixel). Two rounds of review (round 1: cross-sectional CMR images alone and round 2: cross-sectional CMR images plus longitudinal BB CMR angiography) were conducted for the presence and volume measurements of ulceration. Ulceration was defined as a distinct depression into the plaque containing blood flow signal on cross-sectional CMR and longitudinal BB CMR angiography.
Results
Of the 32 plaques examined by histology, 17 contained 21 ulcers. Using the longitudinal BB CMR angiography sequence in addition to the cross-sectional CMR images in round 2, the sensitivity improved to 80% for ulcers of at least 6 mm3 in volume by histology and 52.4% for all ulcers, compared to 30% and 23.8% in round 1, respectively. There was a slight decline in specificity from 88.2% to 82.3%, though both the positive and negative predictive values increased modestly from 71.4% to 78.6% and from 48.4% to 58.3%, respectively.
Conclusion
The addition of longitudinal BB CMR angiography to multisequence cross-sectional CMR images increases accuracy in the identification of carotid atherosclerotic ulceration.
doi:10.1186/1532-429X-11-31
PMCID: PMC2737539  PMID: 19689816
18.  Differences in carotid arterial morphology and composition between individuals with and without obstructive coronary artery disease: A cardiovascular magnetic resonance study 
Objective
We sought to determine differences with cardiovascular magnetic resonance (CMR) in the morphology and composition of the carotid arteries between individuals with angiographically-defined obstructive coronary artery disease (CAD, ≥ 50% stenosis, cases) and those with angiographically normal coronaries (no lumen irregularities, controls).
Methods and results
191 participants (50.3% female; 50.8% CAD cases) were imaged with a multi-sequence, carotid CMR protocol at 1.5T. For each segment of the carotid, lumen area, wall area, total vessel area (lumen area + wall area), mean wall thickness and the presence or absence of calcification and lipid-rich necrotic core were recorded bilaterally. In male CAD cases compared to male controls, the distal bulb had a significantly smaller lumen area (60.0 ± 3.1 vs. 79.7 ± 3.2 mm2, p < 0.001) and total vessel area (99.6 ± 4.0 vs. 119.8 ± 4.1 mm2; p < 0.001), and larger mean wall thickness (1.25 ± 0.03 vs. 1.11 ± 0.03 mm; p = 0.002). Similarly, the internal carotid had a smaller lumen area (37.5 ± 1.8 vs. 44.6 ± 1.8 mm2; p = 0.006) and smaller total vessel area (64.0 ± 2.3 vs. 70.9 ± 2.4 mm2; p = 0.04). These metrics were not significantly different between female groups in the distal bulb and internal carotid or for either gender in the common carotid. Male CAD cases had an increased prevalence of lipid-rich necrotic core (49.0% vs. 19.6%; p = 0.003), while calcification was more prevalent in both male (46.9% vs. 17.4%; p = 0.002) and female (33.3% vs. 14.6%; p = 0.031) CAD cases compared to controls.
Conclusion
Males with obstructive CAD compared to male controls had carotid bulbs and internal carotid arteries with smaller total vessel and lumen areas, and an increased prevalence of lipid-rich necrotic core. Carotid calcification was related to CAD status in both males and females. Carotid CMR identifies distinct morphological and compositional differences in the carotid arteries between individuals with and without angiographically-defined obstructive CAD.
doi:10.1186/1532-429X-10-31
PMCID: PMC2440371  PMID: 18549502
19.  Exercise and manual auricular acupuncture: a pilot assessor-blind randomised controlled trial. (The acupuncture and personalised exercise programme (APEP) Trial) 
Background
Evidence supports the use of exercise for chronic low back pain (CLBP); however, adherence is often poor due to ongoing pain. Auricular acupuncture is a form of pain relief involving the stimulation of points on the outer ear corresponding with specific body parts. It may be a useful adjunct to exercise in managing CLBP; however, there is only limited evidence to support its use with this patient group.
Methods/Design
This study was designed to test the feasibility of an assessor-blind randomised controlled trial which assess the effects on clinical outcomes and exercise adherence of adding manual auricular acupuncture to a personalised and supervised exercise programme (PEP) for CLBP. No sample size calculation has been carried out as this study aims to identify CLBP referral rates within the catchment area of the study site. The researchers aim to recruit four cohorts of n = 20 participants to facilitate a power analysis for a future randomised controlled trial. A computer generated random allocation sequence will be prepared centrally and used to allocate participants by cohort to one of the following interventions: 1) six weeks of PEP plus manual auricular acupuncture; 2) six weeks of PEP alone. Both groups will also complete a further six weeks of self-paced exercise with telephone follow-up support. In addition to a baseline and exit questionnaire at the beginning and end of the study, the following outcomes will be collected at baseline, and after 7, 13 and 25 weeks: pain frequency and bothersomeness, back-specific function, objective assessment and recall of physical activity, use of analgesia, perceived self-efficacy, fear avoidance beliefs, and beliefs about the consequences of back pain. Since this is a feasibility study, significance tests will not be presented, and treatment effects will be represented by point estimates and confidence intervals. For each outcome variable, analysis of covariance will be performed on the data, conditioning on the baseline value.
Discussion
The results of this study investigating the adjuvant effects of auricular acupuncture to exercise in managing CLBP will be used to inform the design of a future multi-centre randomised controlled trial.
Trial Registration
Current Controlled Trials ISRCTN94142364.
doi:10.1186/1471-2474-9-31
PMCID: PMC2322991  PMID: 18325114
20.  No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix 
British Journal of Cancer  2006;94(1):115-120.
The expression of hypoxia-regulated genes promotes an aggressive tumour phenotype and is associated with an adverse cancer treatment outcome. Thymidine phosphorylase (TP) levels increase under hypoxia, but the protein has not been studied in association with hypoxia in human tumours. An investigation was made, therefore, of the relationship of tumour TP with hypoxia, the expression of other hypoxia-associated markers and clinical outcome. This retrospective study was carried out in patients with locally advanced cervical carcinoma who underwent radiotherapy. Protein expression was evaluated with immunohistochemistry. Hypoxia was measured using microelectrodes and the level of pimonidazole binding. There was no relationship of TP expression with tumour pO2 (r=−0.091, P=0.59, n=87) or pimonidazole binding (r=0.13, P=0.45, n=38). There was no relationship between TP and HIF-1α, but there was a weak borderline significant relationship with HIF-2α expression. There were weak but significant correlations of TP with the expression of VEGF, CA IX and Glut-1. In 119 patients, the presence of TP expression predicted for disease-specific (P=0.032) and metastasis-free (P=0.050) survival. The results suggest that TP is not a surrogate marker of hypoxia, but is linked to the expression of hypoxia-associated genes and has weak prognostic power.
doi:10.1038/sj.bjc.6602882
PMCID: PMC2361082  PMID: 16317434
thymidine phosphorylase; hypoxia; hypoxia-inducible factor; cervix
21.  Expression of the proapoptotic protein Bid is an adverse prognostic factor for radiotherapy outcome in carcinoma of the cervix 
British Journal of Cancer  2005;92(3):449-458.
The Bcl-2 family of apoptotic regulators is thought to play an essential role in cancer development and influence the sensitivity of tumour cells to radiotherapy. Bid is an abundantly expressed Bcl-2 family protein playing a central role in various pathways of apoptosis by integrating and converging signals at the mitochondria. The relevance of apoptotic modulation by Bcl-2 and related proteins in tumour development and radiation response for human tumours remains undefined. Therefore, a study was made regarding the expression of Bid in patients with locally advanced cervix carcinoma who received radiotherapy. Bid expression was assessed using immunohistochemistry in pretreatment archival biopsies from 98 patients. The data were correlated with clinicopathologic characteristics and treatment outcome. Pretreatment tumour radiosensitivity data were available for 60 patients. Strong Bid expression was associated with a patient age less than the median of 52 years (P=0.034) and poor metastasis-free survival. In multivariate analysis, after allowing for stage, Bid expression was a significant prognostic factor for both disease-specific and metastasis-free survival (P=0.026). It is concluded that strong tumour Bid expression is associated with poor outcome following radiotherapy regardless of intrinsic tumour cell radiosensitivity, and is adverse prognostic for disease-specific and metastasis-free survival in younger patients.
doi:10.1038/sj.bjc.6602344
PMCID: PMC2362081  PMID: 15685241
Bcl-2 family; cervix carcinoma; prognosis; metastasis; radiotherapy
22.  Cocaine/heroin induced rhabdomyolysis and ventricular fibrillation 
Emergency Medicine Journal : EMJ  2002;19(3):264-265.
doi:10.1136/emj.19.3.264
PMCID: PMC1725859  PMID: 11971848
23.  Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy 
Journal of Clinical Investigation  2004;114(10):1504-1511.
The intracellular signals that mediate skeletal muscle protein loss and functional deficits due to muscular disuse are just beginning to be elucidated. Previously we showed that the activity of an NF-κB–dependent reporter gene was markedly increased in unloaded muscles, and p50 and Bcl-3 proteins were implicated in this induction. In the present study, mice with a knockout of the p105/p50 (Nfkb1) gene are shown to be resistant to the decrease in soleus fiber cross-sectional area that results from 10 days of hindlimb unloading. Furthermore, the marked unloading-induced activation of the NF-κB reporter gene in soleus muscles from WT mice was completely abolished in soleus muscles from Nfkb1 knockout mice. Knockout of the B cell lymphoma 3 (Bcl3) gene also showed an inhibition of fiber atrophy and an abolition of NF-κB reporter activity. With unloading, fast fibers from WT mice atrophied to a greater extent than slow fibers. Resistance to atrophy in both strains of knockout mice was demonstrated clearly in fast fibers, while slow fibers from only the Bcl3–/– mice showed atrophy inhibition. The slow-to-fast shift in myosin isoform expression due to unloading was also abolished in both Nfkb1 and Bcl3 knockout mice. Like the soleus muscles, plantaris muscles from Nfkb1–/– and Bcl3–/– mice also showed inhibition of atrophy with unloading. Thus both the Nfkb1 and the Bcl3 genes are necessary for unloading-induced atrophy and the associated phenotype transition.
doi:10.1172/JCI200421696
PMCID: PMC525738  PMID: 15546001
24.  Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix 
British Journal of Cancer  2000;83(5):620-625.
The aim of the study was to evaluate VEGF expression in tumour biopsies as a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. A retrospective study was carried out on 100 patients. Pre-treatment tumour VEGF expression was examined immunohistochemically in formalin-fixed, paraffin-embedded biopsies using a widely available commercial antibody. A semi-quantitative analysis was made using a scoring system of 0, 1, 2, and 3, for increasing intensity of staining. High VEGF expression was associated with a poor prognosis. A univariate log rank analysis found a significant relationship with overall survival (P = 0.0008) and metastasis-free survival (P = 0.0062), but not local control (P = 0.23). There was no correlation between VEGF expression and disease stage, tumour differentiation, patient age, or tumour radiosensitivity (SF2). In a Cox multivariate analysis of survival VEGF expression was the most significant independent prognostic factor (P = 0.001). After allowing for VEGF only SF2 was a significant prognostic factor (P = 0.003). In conclusion, immunohistochemical analysis of VEGF expression is a highly significant and independent prognostic indicator of overall and metastasis-free survival for patients treated with radiotherapy for advanced carcinoma of the cervix. It is also a rapid and easy method that could be used in the clinical setting, to identify patients at high risk of failure with conventional radiotherapy who may benefit from novel approaches or chemoradiotherapy. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.2000.1319
PMCID: PMC2363503  PMID: 10944602
cervical carcinoma; vascular endothelial growth factor (VEGF); immunohistochemistry; prognosis
25.  Pretreatment apoptosis in carcinoma of the cervix correlates with changes in tumour oxygenation during radiotherapy 
British Journal of Cancer  2000;82(6):1177-1182.
A relationship between hypoxia and apoptosis has been identified in vitro and in experimental tumours. The aim of this study was to investigate the relationship between apoptosis, hypoxia and the change in oxygenation during radiotherapy in human squamous cell carcinoma of the cervix. Forty-two patients with locally advanced disease underwent pretreatment evaluation of tumour oxygenation using an Eppendorf computerized microneedle electrode. Twenty-two of these patients also had a second evaluation of tumour oxygenation after receiving 40–45 Gy external beam radiotherapy. Paraffin-embedded histological sections were obtained from random pretreatment biopsies for all 42 patients. Apoptotic index (AI) was quantified by morphology on TUNEL stained sections. No correlation was found between pretreatment measures of AI and either the median pO2(r = 0.12, P = 0.44) or percentage of values < 5 mmHg (r = –0.02, P = 0.89). A significant positive correlation was found between AI and the change in tumour oxygenation (ratio of pre:post-treatment % values < 5 mmHg) following radiotherapy (r = 0.61, P = 0.002). The lack of correlation between apoptosis and hypoxia may occur because the Eppendorf measures both acute and chronic hypoxia, and the relative ability of acute hypoxia to induce apoptosis is unknown. These results indicate that cell death via apoptosis may be a mechanism of tumour reoxygenation during radiotherapy. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.1999.1059
PMCID: PMC2363353  PMID: 10735502
cervix carcinoma; apoptosis; hypoxia; reoxygenation; radiotherapy

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