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1.  Identification of new treatments for epilepsy: issues in preclinical methodology 
Epilepsia  2012;53(3):571-582.
Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (a) new symptomatic anti-seizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (b) disease modifying treatments that prevent or ameliorate the epileptogenic state, and (c) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, i.e. age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical anti-epilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis and comorbidities.
PMCID: PMC3551973  PMID: 22292566
anti-seizure drug; anti-epileptoegenesis; disease modification; comorbidities; biomarkers
2.  Comparison of T1 mapping techniques for ECV quantification. Histological validation and reproducibility of ShMOLLI versus multibreath-hold T1 quantification equilibrium contrast CMR 
Myocardial extracellular volume (ECV) is elevated in fibrosis or infiltration and can be quantified by measuring the haematocrit with pre and post contrast T1 at sufficient contrast equilibrium. Equilibrium CMR (EQ-CMR), using a bolus-infusion protocol, has been shown to provide robust measurements of ECV using a multibreath-hold T1 pulse sequence. Newer, faster sequences for T1 mapping promise whole heart coverage and improved clinical utility, but have not been validated.
Multibreathhold T1 quantification with heart rate correction and single breath-hold T1 mapping using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) were used in equilibrium contrast CMR to generate ECV values and compared in 3 ways.
Firstly, both techniques were compared in a spectrum of disease with variable ECV expansion (n=100, 50 healthy volunteers, 12 patients with hypertrophic cardiomyopathy, 18 with severe aortic stenosis, 20 with amyloid). Secondly, both techniques were correlated to human histological collagen volume fraction (CVF%, n=18, severe aortic stenosis biopsies). Thirdly, an assessment of test:retest reproducibility of the 2 CMR techniques was performed 1 week apart in individuals with widely different ECVs (n=10 healthy volunteers, n=7 amyloid patients).
More patients were able to perform ShMOLLI than the multibreath-hold technique (6% unable to breath-hold). ECV calculated by multibreath-hold T1 and ShMOLLI showed strong correlation (r2=0.892), little bias (bias -2.2%, 95%CI -8.9% to 4.6%) and good agreement (ICC 0.922, range 0.802 to 0.961, p<0.0001). ECV correlated with histological CVF% by multibreath-hold ECV (r2= 0.589) but better by ShMOLLI ECV (r2= 0.685). Inter-study reproducibility demonstrated that ShMOLLI ECV trended towards greater reproducibility than the multibreath-hold ECV, although this did not reach statistical significance (95%CI -4.9% to 5.4% versus 95%CI -6.4% to 7.3% respectively, p=0.21).
ECV quantification by single breath-hold ShMOLLI T1 mapping can measure ECV by EQ-CMR across the spectrum of interstitial expansion. It is procedurally better tolerated, slightly more reproducible and better correlates with histology compared to the older multibreath-hold FLASH techniques.
PMCID: PMC3552758  PMID: 23272651
Interstitial space; Fibrosis; CMR
3.  Validity of the McMurray's Test and Modified Versions of the Test: A Systematic Literature Review 
Clinical assessment of meniscal pathology in the knee has proven difficult due to the wide number of tests available and variations in their interpretation and application. The purpose of this paper was to assess the literature investigating the validity and diagnostic accuracy of the McMurray's test (and modifications) for determining meniscal pathology of the knee so that conclusions could be drawn regarding its clinical usefulness as a test. Electronic databases (Medline, CINhAL, AMED, SPORTSDiscus, and SCOPUS) were searched from March 1980 to May 2008. In addition, cited references of relevant articles were examined. Studies were included for analysis if they compared the McMurray's test with a gold standard of knee arthroscopy or magnetic resonance imaging (MRI). Eleven studies met the inclusion criteria. Collectively, these studies indicate that there is little consensus in the reported measures of validity of the McMurray's test and that this is mostly due to limitations in the methodological quality of the studies that were assessed. Methodological scores on the STARD (Standards for Reporting of Diagnostic Accuracy) yielded scores from 10/25 to 20/25. Generally, the McMurray's test has relatively high specificity and low sensitivity. The studies that compared the diagnostic accuracy of the McMurray's test with that of modified versions of the test showed enhanced diagnostic accuracy for the modified tests. This review identified that the McMurray's test is of limited clinical value due to relatively low sensitivity, with modified tests (associated with the traditional McMurray's test) having higher diagnostic accuracy and thus these may be more useful clinically.
PMCID: PMC2704345  PMID: 20046563
Knee; McMurray's; Meniscal; Reliability; Sensitivity; Specificity; Testing; Validity
4.  Treated Choroidal Melanoma with Late Metastases to the Contralateral Orbit 
Choroidal melanoma is the commonest adult primary intraocular tumour,1 and usual sites of secondary spread are to liver, bone and lung. Although delayed recurrence of ipsilateral orbital melanoma is well documented, metastasis to the contralateral orbit is a rarely encountered phenomenon. We describe a case of metastatic spread to the contralateral orbit in a patient 12 years after proton beam radiotherapy of choroidal melanoma.
PMCID: PMC2990236  PMID: 21151543
choroidal melanoma; metastases; orbit; proptosis
5.  Continuous EEG monitoring in Kenyan children with non-traumatic coma 
Archives of Disease in Childhood  2012;97(4):343-349.
The aim of this study was to describe the EEG and clinical profile of seizures in children with non-traumatic coma, compare seizure detection by clinical observations with that by continuous EEG, and relate EEG features to outcome.
This prospective observational study was conducted at the paediatric high dependency unit of Kilifi District Hospital, Kenya. Children aged 9 months to 13 years presenting with acute coma were monitored by EEG for 72 h or until they regained consciousness or died. Poor outcome was defined as death or gross motor deficits at discharge.
82 children (median age 2.8 (IQR 2.0–3.9) years) were recruited. An initial medium EEG amplitude (100–300 mV) was associated with less risk of poor outcome compared to low amplitude (≤100 mV) (OR 0.2, 95% CI 0.1 to 0.7; p<0.01). 363 seizures in 28 (34%) children were observed: 240 (66%) were electrographic and 112 (31%) electroclinical. In 16 (20%) children, electrographic seizures were the only seizure types detected. The majority (63%) of electroclinical seizures had focal clinical features but appeared as generalised (79%) or focal with secondary generalisation (14%) on EEG. Occurrence of any seizure or status epilepticus during monitoring was associated with poor outcome (OR 3.2, 95% CI 1.2 to 8.7; p=0.02 and OR 4.5, 95% CI 1.3 to 15.3; p<0.01, respectively).
Initial EEG background amplitude is prognostic in paediatric non-traumatic coma. Clinical observations do not detect two out of three seizures. Seizures and status epilepticus after admission are associated with poor outcome.
PMCID: PMC3329232  PMID: 22328741

Results 1-5 (5)