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1.  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.
PMCID: PMC3572924  PMID: 23413262
nemaline; myopathies; muscle and nerve pathology; mutation; neuromuscular disorders
2.  Sustained acceleration in carotid atherosclerotic plaque progression with intraplaque hemorrhage: A long-term time course study 
JACC. Cardiovascular imaging  2012;5(8):798-804.
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.
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.
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.
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.
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.
PMCID: PMC3422506  PMID: 22897993
carotid arteries; intraplaque hemorrhage; atherosclerosis; magnetic resonance imaging
3.  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.
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.
To describe an automated method for operator-independent quantification of LGE that correlates with colocated endocardial voltage and clinical outcomes.
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.
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).
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.
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
4.  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.
PMCID: PMC3358131  PMID: 20363022
Calcification; Alginate; Microencapsulation; Adipose stem cell microbeads; Bone tissue engineering
5.  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.
PMCID: PMC3008309  PMID: 21029782
bound pool fraction; cross-relaxation imaging; glioma; magnetization transfer ratio; myelin; quantitative magnetization transfer; rat brain
6.  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.
PMCID: PMC3269908  PMID: 17499219
7.  How effective are mental health nurses in A&E departments? 
Emergency Medicine Journal : EMJ  2006;23(9):687-692.
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.
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.
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.
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.
PMCID: PMC2564209  PMID: 16921080
liaison psychiatric services; mental health; psychiatric assessment and treatment; psychiatric nursing
8.  The added value of longitudinal black-blood cardiovascular magnetic resonance angiography in the cross sectional identification of carotid atherosclerotic ulceration 
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.
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.
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.
The addition of longitudinal BB CMR angiography to multisequence cross-sectional CMR images increases accuracy in the identification of carotid atherosclerotic ulceration.
PMCID: PMC2737539  PMID: 19689816
9.  Differences in carotid arterial morphology and composition between individuals with and without obstructive coronary artery disease: A cardiovascular magnetic resonance study 
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.
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.
PMCID: PMC2440371  PMID: 18549502
10.  Exercise and manual auricular acupuncture: a pilot assessor-blind randomised controlled trial. (The acupuncture and personalised exercise programme (APEP) Trial) 
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.
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.
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.
PMCID: PMC2322991  PMID: 18325114
11.  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.
PMCID: PMC2362081  PMID: 15685241
Bcl-2 family; cervix carcinoma; prognosis; metastasis; radiotherapy
12.  Cocaine/heroin induced rhabdomyolysis and ventricular fibrillation 
Emergency Medicine Journal : EMJ  2002;19(3):264-265.
PMCID: PMC1725859  PMID: 11971848
13.  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.
PMCID: PMC525738  PMID: 15546001
14.  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
PMCID: PMC2363353  PMID: 10735502
cervix carcinoma; apoptosis; hypoxia; reoxygenation; radiotherapy
15.  A controlled evaluation of tuned-aperture computed tomography applied to digital spot mammography 
Journal of Digital Imaging  2000;13(2):90-97.
The purpose of this work was to compare the detection accuracy of 3-dimensional (3D) modalities of tuned-aperture computed tomography (TACT) with that of conventional 2-dimensional (2D) digital spot mammograms. A standardized mammographic phantom was placed beneath cadaveric breast tissues of varying densities. Five radiologists were asked to detect as many objects (specks, fibers, and lowcontrast masses) as possible from 90 displays in a controlled and factorially balanced multivariate experiment. Radiographic exposure was varied systematically, and projections were averaged to ensure stochastic comparability. Scores were weighted to eliminate task-specific bias and were analyzed by multivariate analyses of variance. All display modalities based on the linear application of the 3D TACT reconstruction method yielded significantly higher detection scores for all tasks than did conventional 2D digital spot mammography, which served as the scientific control modality. This effect was found to be statistically significant (P<.001) in spite of significant variations between tissues (P<.001), observers (P<.001), and exposures (P<.01). TACT may be a promising alternative or enhancement to conventional 2D digital mammography for tasks well simulated by this experimental design.
PMCID: PMC3453191  PMID: 10843254
computed tomography; three-dimensional; observer performance; digital radiography; breast radiography; tomosynthesis
16.  Tumour vascularity is a significant prognostic factor for cervix carcinoma treated with radiotherapy: independence from tumour radiosensitivity 
British Journal of Cancer  1999;81(2):354-358.
The aim of the study was to investigate the relationship between intrinsic radiosensitivity and vascularity in carcinoma of the cervix given radiotherapy, and assess whether more refined prognostic information can be gained by combining the two parameters. A retrospective study was carried out on 74 patients with locally advanced carcinoma of the cervix. Formalin-fixed, paraffin-embedded tumour biopsies were stained with anti-factor VIII using immunohistochemistry. Vascularity was scored using the intra-tumour microvessel density (IMD), or ‘hot-spot’, technique. For the same patients, the measurement of intrinsic radiosensitivity (SF2) had been made previously on the same pretherapy samples. Patients were stratified by the median IMD and SF2 scores. Women with radioresistant and highly vascular tumours had poorer 5-year survival (P = 0.0005, P = 0.035 respectively) and local control (P = 0.012, P = 0.077 respectively) than those with radiosensitive and poorly vascular tumours. No significant correlation was seen between IMD and SF2. Multivariate analysis (including tumour stage and patient age) showed that only SF2 and IMD were significant prognostic factors for survival. Patients with both a radioresistant and highly vascular tumour had a 5-year survival level of 18% compared to 77% for those patients with a radiosensitive and poorly vascularized tumour. Tumour angiogenesis and cellular radiosensitivity are independent prognostic factors for cervix carcinoma treated with radiotherapy. Allowing for tumour radiosensitivity increases the prognostic significance of vascularity measurements in cervix tumours. © 1999 Cancer Research Campaign
PMCID: PMC2362853  PMID: 10496365
angiogenesis; SF2; predictive assays
17.  Cytokine profile suggesting that murine cerebral malaria is an encephalitis. 
Infection and Immunity  1997;65(11):4883-4887.
Cerebral malaria (CM) remains a poorly understood and life-threatening complication of malaria caused by the parasite Plasmodium falciparum. The discovery that murine CM caused by Plasmodium berghei ANKA and human CM are both characterized by production of inflammatory cytokines, especially tumor necrosis factor alpha (TNF-alpha), led to a revival of the suggestion that P. berghei CM may have value as a model of the human disease. In this study, quantitative reverse transcription-PCR was used to measure levels of message for 18S rRNA of P. berghei and 10 cytokines in the brains, livers, and spleens of mice during the induction and course of CM. A coordinated increase in RNA of parasite and proinflammatory cytokines was observed in the brains of mice in parallel with onset of CM. Levels of message for parasite, TNF-alpha, and gamma interferon increased in the brains of mice from day 5 to death on day 7. These changes were observed only in the brain, and message for other cytokines remained near baseline levels. This demonstrated that parasite sequestration does take place in the brains of mice with CM. Histologically, CM was characterized by widespread damage to the microvasculature in the brain with focal infiltration of inflammatory cells. The pattern of cytokine production in the brain is characteristic of other murine encephalitides.
PMCID: PMC175703  PMID: 9353082
18.  Alzheimer's disease in the United Kingdom: developing patient and carer support strategies to encourage care in the community. 
Quality in Health Care  1997;6(3):146-152.
Alzheimer's disease is a growing challenge for care providers and purchasers. With the shift away from the provision of long term institutional care in most developed countries, there is a growing tendency for patients with Alzheimer's disease to be cared for at home. In the United Kingdom, this change of direction contrasts with the policies of the 1980s and 90s which focused more attention on controlling costs than on assessment of the needs of the patient and carer and patient management. In recent years, the resources available for management of Alzheimer's disease have focused on institutional care, coupled with drug treatment to control difficult behaviour as the disease progresses. For these reasons, the current system has led to crisis management rather than preventive support--that is, long term care for a few rather than assistance in the home before the crises occur and institutional care is needed. Despite recent innovations in the care of patients with Alzheimer's disease, the nature of the support that patients and carers receive is poorly defined and sometimes inadequate. As a result of the shift towards care in the community, the informal carer occupies an increasingly central role in the care of these patients and the issue of how the best quality of care may be defined and delivered is an issue which is now ripe for review. The objective of this paper is to redefine the type of support that patients and carers should receive so that the disease can be managed more effectively in the community. The needs of patients with Alzheimer's disease and their carers are many and this should be taken into account in defining the quality and structure of healthcare support. This paper shows how new initiatives, combined with recently available symptomatic drug treatment, can allow patients with Alzheimer's disease to be maintained at home for longer. This will have the dual impact of raising the quality of care for patients and improving the quality of life for their carers. Moreover, maintaining patients in a home environment will tend to limit public and private expenditure on institutional care due to a possible delay in the need for it.
PMCID: PMC1055476  PMID: 10173772
19.  The Belfast Cord Blood Bank. 
The Ulster Medical Journal  1997;66(1):9-12.
The first cord blood bank in the British Isles was established in Belfast in June 1993. Cord blood (CB) is rich in haematopoietic progenitor cells and has been used successfully as a substitute for bone marrow transplants in over 200 patients world-wide. Most have received CB from a histocompatible sibling, but reports include several unrelated HLA matched transplants. In addition to the cryopreservation of 400 units of donated CB in the Cord Blood Bank, we have stored eight CB collections from siblings of children with leukaemia in Northern Ireland. A pilot study in collaboration with the maternity unit in the Mater Infirmorum Hospital confirmed the feasibility of a CB banking programme and highlighted many issues relating to Good Manufacturing Practice (GMP). The authors describe experience of collecting 824 units of CB over three years and discuss a few of the wider implications of this innovation in the management of patients requiring myeloablative therapy.
PMCID: PMC2448714  PMID: 9185483
20.  The independence of intrinsic radiosensitivity as a prognostic factor for patient response to radiotherapy of carcinoma of the cervix. 
British Journal of Cancer  1997;76(9):1184-1190.
A study was made of the prognostic value of pretreatment measurements of tumour radiosensitivity (surviving fraction at 2 Gy, SF2) in 128 patients with stage I-III carcinomas of the uterine cervix undergoing radiotherapy. The median follow-up time was 47 months. In a univariate analysis stratifying patients according to the median value, radiosensitivity was a significant prognostic factor for overall survival, local control and metastasis-free survival. The 5-year survival rate for tumours with SF2 values below the median was 81% and was significantly greater than the rate of 51% for those with SF2 values above the median. In bivariate analyses, SF2 was shown to be independent of disease stage, tumour grade, patient age, colony-forming efficiency and tumour diameter. In a multivariate analysis, radiosensitivity was the most important variable and, after allowing for this, only stage was a significant independent predictor of treatment outcome. These data indicate that, in carcinoma of the cervix treated with radiotherapy, pretreatment tumour intrinsic radiosensitivity is an important prognostic parameter and contributes to prognosis independently of other established and putative parameters.
PMCID: PMC2228123  PMID: 9365167
21.  Activities of poloxamer CRL8131 against Mycobacterium tuberculosis in vitro and in vivo. 
A poloxamer surfactant, CRL8131, was evaluated for activity against Mycobacterium tuberculosis (Erdman) by itself and in combination with antibiotics in broth culture, in a macrophage cell line assay, and in testing with mice. In the broth culture, CRL8131 suppressed the growth of M. tuberculosis and produced synergistic effects in combination with isoniazid, rifampin, and streptomycin. It also displayed synergy with isoniazid and rifampin against two drug-resistant isolates. In the macrophage cell line assay, CRL8131 produced a synergistic effect on intracellular killing of M. tuberculosis by isoniazid, rifampin, streptomycin, pyrazinamide, thiacetazone, D-cycloserine, ethionamide, amikacin, clindamycin, and p-aminosalicylic acid. It demonstrated no synergy or antagonism with ethambutol, gentamicin, kanamycin, ciprofloxacin, or nalidixic acid. Finally, with C57BL/6 mice infected with M. tuberculosis, a combination of CRL8131 and either thiacetazone or pyrazinamide produced 100% survival at 40 days whereas the antibiotics produced only 33% survival and CRL8131 produced 0% survival when used as single agents. This improved survival rate was associated with a significant reduction in the number of organisms in the lungs and spleens of infected mice.
PMCID: PMC162740  PMID: 7574529
22.  Enhancement of antibiotic susceptibility and suppression of Mycobacterium avium complex growth by poloxamer 331. 
The resistance of Mycobacterium avium complex (MAC) to antibiotics is thought to be enhanced by its outer glycolipid layer, which protects the organisms from antibiotics and host defense mechanisms. We hypothesized that surfactants which disrupt the lipid barrier might be of therapeutic value. We evaluated the ability of 10 poloxamer surfactants to inhibit the growth of MAC organisms and to potentiate antimycobacterial drug activity in broth culture using a radiometric assay. Very large, small, or hydrophilic poloxamers had little or no effect. However, certain hydrophobic poloxamers, especially P331, retarded the growth of most isolates of MAC and produced a synergistic effect with rifampin. The MIC of rifampin required to inhibit the growth of MAC was reduced from a mean of 14.6 micrograms/ml (range, 4 to > 32 micrograms/ml) to 1.4 micrograms/ml (range, < 1.125 to 4 micrograms/ml) by 1.0 mg of P331 per ml (P < 0.01). Enhancement of antibiotic susceptibility was observed with concentrations of poloxamer as low as 10 micrograms/ml. These studies suggest that P331 might be useful in increasing the effectiveness of antibiotic therapy of MAC infections.
PMCID: PMC162556  PMID: 7726511
23.  Characterization of the trehalose 6,6'-dimycolate surface monolayer by scanning tunneling microscopy. 
Infection and Immunity  1994;62(2):754-756.
The toxicity of trehalose 6,6'-dimycolate (TDM), a glycolipid of mycobacteria, requires presentation as a surface monolayer. Our model of the structure of the TDM monolayer was confirmed and extended by scanning tunneling microscopy. It consists of linear arrays with a periodicity of approximately 90 A (9 nm) that clustered in groups of four to form secondary structures with a periodicity of 360 A (36 nm).
PMCID: PMC186174  PMID: 8300239
25.  Intrinsic radiosensitivity and prediction of patient response to radiotherapy for carcinoma of the cervix. 
British Journal of Cancer  1993;68(4):819-823.
The intrinsic radiosensitivity of cervical carcinoma has been measured using a soft agar clonogenic assay. All patients received radical radiotherapy alone with a minimum of 2 years post-treatment follow-up. Only women with stage I, II and III disease were included in the analysis. Values for cell surviving fraction at 2 Gy (SF2) were obtained for 88 tumours with an assay success rate of 73%. The 53 patients alive and well at the time of analysis had tumours with a mean SF2 that was significantly lower than the value from the 22 patients with locoregional failure (P < 0.01). Patients with radioresistant tumours (SF2 > 0.40, the median) had a significantly lower 3 year survival level than those with sensitive tumours (SF2 < or = 0.40) (P = 0.002). Also the frequency of local recurrence was higher (P = 0.001) whether these were central (P = 0.009) or peripheral (P = 0.046). Cell surviving fraction at 3.5 Gy was obtained for 46 tumours and the 3 year patient survival rate was significantly higher for those with SF3.5 values less than the median (P = 0.043). There was, however, no difference in the level of local recurrence (P = 0.24). The ability to grow in culture was not associated with significantly poorer patient survival (P = 0.56) or failure to control the primary disease (P = 0.17). While high colony forming efficiencies were associated with an increased rate of local recurrence (P = 0.029) they did not predict for overall patient survival (P = 0.32). These data suggest that, for cervical carcinoma treated with radical radiotherapy, intrinsic radiosensitivity is important in determining treatment outcome.
PMCID: PMC1968626  PMID: 8398714

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