Evaluation of new antituberculosis drugs in mouse models.
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Animals↗
Biomedical subjects
G R Davies
Publications and source records attributed to G R Davies.
Optimal sampling strategies for early pharmacodynamic measures in tuberculosis.
OBJECTIVES: To evaluate whether methodological optimization of serial sputum colony counting (SSCC) studies, a potentially important component in the drug development process for tuberculosis, could significantly improve their power. METHODS: Simulations were carried out using a model derived from a large SSCC dataset. Variance inflation factors (VIFs) were calculated for model parameters, focusing on the elimination rate constant likely to reflect 'sterilizing' activity and sampling schemes were optimized relative to a scheme of daily sampling during the initial phase of therapy. Corresponding sample sizes required for SSCC studies using different schemes were also computed. RESULTS: Published sampling schemes lacked efficiency with respect to the 'sterilizing' phase. Pragmatic optimized schemes yielding greatest precision were achieved using eleven sampling points around a skeleton of 0, 2, 7, 14 and 56 days. The standard error of the 'sterilizing' rate constant was reduced more than 4-fold, and sample size for realistic treatment effects was effectively halved. Even schemes with a restricted duration of sampling to avoid high proportions of missing data and those with fewer sampling points still achieved significant gains in precision. Sensitivity analysis suggested that such schemes should continue to perform well over the immediately foreseeable range of improvements in therapy. CONCLUSIONS: Methodological improvements in the design of SSCC studies could make them a powerful tool in Phase II development of anti-tuberculosis agents.
Antitubercular Agents↗
Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis.
BACKGROUND AND OBJECTIVE: The onset of multiple sclerosis is relapsing remitting or primary progressive. An improved understanding of the causes of early progressive disability in primary progressive multiple sclerosis (PPMS) could provide mechanistic targets for therapeutic intervention. METHODS: Five magnetic resonance imaging (MRI) parameters that could potentially cause progressive disability were investigated in 43 patients with early PPMS and in 37 patients with early relapsing remitting multiple sclerosis (RRMS): atrophy in brain, both grey matter and white matter; intrinsic abnormality in brain, both grey matter and white matter (measured by the magnetisation transfer ratio (MTR)); and atrophy of the upper cervical spinal cord. Both groups were also compared with controls. RESULTS: Patients with PPMS were older and more likely to be men. Both patient groups had atrophy of brain grey matter and white matter, and intrinsic abnormality in MTR of normal-appearing grey matter and white matter. Cord atrophy was present only in the PPMS (mean cord area: PPMS, 67.8 mm2; RRMS, 72.7 mm2; controls, 73.4 mm2; p = 0.007). This was confirmed by multivariate analysis of all five MRI parameters, age and sex. CONCLUSION: Grey matter and white matter of the brain are abnormal in both early RRMS and PPMS, but cord atrophy is present only in PPMS. This is concordant with myelopathy being the usual clinical presentation of PPMS. Measurement of cord atrophy seems to be clinically relevant in PPMS treatment trials.
Adult↗
Abnormalities in normal appearing tissues in early primary progressive multiple sclerosis and their relation to disability: a tissue specific magnetisation transfer study.
BACKGROUND: Patients with primary progressive multiple sclerosis (PPMS) often develop severe disability despite low levels of abnormality on conventional magnetic resonance imaging (MRI). This may relate to diffuse pathological processes occurring in normal appearing brain tissue (NABT) involving both white matter (NAWM) and grey matter (NAGM). Magnetisation transfer imaging (MTI) is capable of identifying these processes and may be particularly informative when applied to patients with early PPMS. AIM: To assess the relationship between abnormalities in NABT identified by MTI and disability and other radiological data in patients with early PPMS. METHODS: We studied 43 patients within 5 years of disease onset and 43 controls. The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) were scored. Magnetisation transfer ratios (MTR) of NABT, NAWM, and NAGM were calculated and the following MTR parameters were measured: mean, peak height, peak location, and MTR value at the 25th, 50th, and 75th percentiles. Proton density, T2, T1, and gadolinium enhancing lesion loads were also calculated. RESULTS: Differences were found between patients and controls in mean, peak height, and peak location of NAWM and NAGM (p < or = 0.001). Weak to moderate correlations were found between MTR parameters and disability in both NAWM and NAGM. Strong correlations between MTR parameters and lesion loads were found, particularly in NAWM. CONCLUSION: MTR abnormalities are seen in NAWM and NAGM in early PPMS and both are associated with disability. NAWM MTR abnormalities are more closely related to conventional MRI measures than those seen in NAGM.
Adult↗
Increasing cord atrophy in early relapsing-remitting multiple sclerosis: a 3 year study.
OBJECTIVES: Previous studies have shown that upper cervical cord atrophy (UCCA) occurs in multiple sclerosis (MS), particularly in those disabled and with primary or secondary progressive disease. It is less clear how early it can be detected in relapsing-remitting (RR) MS, and whether early cord atrophy relates to the concurrent or future clinical course. METHODS: Twenty seven RR MS patients (median disease duration 1.7 years, in all cases <3 years from onset) were recruited along with 20 controls. They were followed for up to 3 years with a yearly assessment of UCCA and clinical function measured by the Expanded Disability Status Scale (EDSS) and MS Functional Composite Score (MSFC). Clinical and MRI correlations were investigated. Statistical models adjusted for covariates including total intracranial volume. RESULTS: Longitudinal analysis showed a significant decrease in UCCA in patients both within the patient cohort (p < 0.001) and in comparison with controls (p = 0.001). There was a significant increase in EDSS (p = 0.008) but no significant change in MSFC. The rate of UCCA loss did not correlate with clinical change or with change in brain volume. CONCLUSIONS: In summary, serial UCCA measurement detects the development of spinal cord atrophy in clinically early RR MS.
Adult↗
Mixture analysis of tuberculin survey data from northern Malawi and critique of the method.
SETTING: Various methods have been used to estimate the prevalence of Mycobacterium tuberculosis infection from tuberculin survey data. All are complicated by prior sensitisation to environmental mycobacteria and bacille Calmette-Guérin (BCG) vaccination. Mixture analysis has recently been proposed as a means of overcoming misclassification and improving infection prevalence estimates. OBJECTIVE: To compare conventional and mixture model estimates of M. tuberculosis infection prevalence. DESIGN: Mixture models with two or three univariate normal components were fitted to the results of 53 909 tuberculin tests conducted in northern Malawi during 1980-1984. Data were stratified by BCG status, sex and age and corrected for digit preference. Prevalence estimates derived from mixture models were compared with those of conventional methods. RESULTS: The optimal model was age-dependent, with three- and one-component solutions preferred in younger and older age groups, respectively. In contrast with findings from elsewhere, a component corresponding to BCG vaccination was indistinguishable from that attributable to environmental mycobacterial exposure, and infection prevalence estimates in younger individuals with a BCG scar were inflated, irrespective of the method used. CONCLUSION: The validity of infection prevalence and incidence estimates based on mixture modelling is probably locale-dependent, and the assumptions underlying mixture models may not realistically reflect underlying immunological processes.
Adolescent↗
Increasing normal-appearing grey and white matter magnetisation transfer ratio abnormality in early relapsing-remitting multiple sclerosis.
Abnormalities within normal-appearing grey and white matter (NAGM and NAWM) occur early in the clinical course of multiple sclerosis (MS) and can be detected in-vivo using the magnetisation transfer ratio (MTR). To better characterize the rates of change in both tissues and to ascertain when such changes begin, we serially studied a cohort of minimally disabled, early relapsing-remitting MS patients, using NAGM and NAWM MTR histograms. Twenty-three patients with clinically definite early relapsing-remitting MS (mean disease duration at baseline 1.9 years), and 19 healthy controls were studied. A magnetisation transfer imaging sequence was acquired yearly for two years. Twenty-one patients and 10 controls completed followup. NAWM and NAGM MTR histograms were derived and mean MTR calculated. A hierarchical regression analysis, adjusting for brain parenchymal fraction,was used to assess MTR change over time. MS NAWM and NAGM MTR were significantly reduced in comparison with controls at baseline and, in patients, both measures decreased further during follow-up: (-0.10 pu/year, p=0.001 and -0.18 pu/year, p<0.001 respectively). The rate of MTR decrease was significantly greater in NAGM than NAWM (p=0.004). Under the assumption that such changes are linear, backward extrapolation of the observed rates of change suggested that NAWM abnormality began before symptom onset. We conclude that increasing MTR abnormalities in NAWM and NAGM are observed early in the course of relapsing-remitting MS. It is now important to investigate whether these measures are predictive of future disability, and consequently, whether MTR could be used as a surrogate marker in therapeutic trials.
Adult↗
Atmosphere-ocean dynamics in the Western Indian Ocean recorded in corals.
We present a set of Porites coral oxygen isotope records from the tropical and subtropical Western Indian Ocean covering the past 120-336 years. All records were thoroughly validated for proxy response to regional climate factors and their relation to large-scale climate modes. The records show markedly different imprints of regional climate factors. At the same time, all coral records show clear teleconnections between the Western Indian Ocean and the El Nino-Southern Oscillation (ENSO). The multi-proxy site analysis enables the detection of the covariance structure between individual records and climate modes such as ENSO. This method unravels shifts in ENSO teleconnectivity of the Western and Central Indian Ocean on multi-decadal time-scales (after 1976). The Seychelles record shows a stationary correlation with ENSO, Chagos corals show evidence for non-stationary delta18O/ENSO relationships and the Southwestern Indian Ocean corals show a strong relationship with ENSO when the forcing is strong (1880-1920, 1970 to present). Our results indicate that the coral delta18O, in combination with other proxies, can be used to monitor temporal and spatial variations in the sea-surface temperature and the fresh water balance within the Indian Ocean on interannual to interdecadal time-scales.
Animals↗
Correlation of apparent myelin measures obtained in multiple sclerosis patients and controls from magnetization transfer and multicompartmental T2 analysis.
Two relatively new techniques purport to give measures of the myelin content of brain tissue. These measures are the myelin water fraction from multicompartmental T(2) analysis, and the semisolid proton fraction from analysis of magnetization transfer (MT). The myelin water fraction is the fraction of signal with a T(2) of less than 50 ms measured from a 32-echo sequence. It is believed to originate from water trapped between the myelin bilayers. The semisolid proton fraction is thought to include protons within phospholipid bilayers and macromolecular protons, and may also be a measure of myelin content. Multicompartmental T(2) and MT imaging were carried out on controls and patients with multiple sclerosis (MS), and estimates of the semisolid proton and myelin water fractions were obtained from white matter (WM), gray matter (GM), and MS lesions. These were then correlated for each tissue and subject group. Positive correlations were seen for MS lesions (r approximately 0.2) and in WM in patients (r = 0.6). A negative correlation (r approximately -0.3) was seen for GM. These results indicate that the two techniques measure, to some extent, the same thing (most likely myelin content), but that other factors, such as inflammation, mean they may provide complementary information.
Adult↗
Eating disorders and oral health: a review of the literature.
This article is a review of the recent literature pertaining to the oral sequelae of eating disorders (EDs). Dentists are recognized as being some of the first health care professionals to whom a previously undiagnosed eating disorder patient (EDP) may present. However, despite the prevalence (up to 4 per cent) of such conditions in teenage girls and young adult females, there is relatively little published in the recent literature regarding the oral sequelae of EDs. This compares unfavourably with the attention given recently in the dental literature to conditions such as diabetes mellitus, which have a similar prevalence in the adult population. The incidence of EDs is increasing and it would be expected that dentists who treat patients in the affected age groups would encounter more individuals exhibiting EDs. Most of the reports in the literature concentrate on the obvious clinical features of dental destruction (perimolysis), parotid swelling and biochemical abnormalities particularly related to salivary and pancreatic amylase. However, there is no consistency in explanation of the oral phenomena and epiphenomena seen in EDs. Many EDPs are nutritionally challenged; there is a relative lack of information pertaining to non-dental, oral lesions associated with nutritional deficiencies.
Adolescent↗
Emergence of thalamic magnetization transfer ratio abnormality in early relapsing-remitting multiple sclerosis.
While there is now evidence for thalamic abnormality in established secondary progressive and relapsing-remitting multiple sclerosis (MS), it remains unclear when such abnormality begins. This study investigated the emergence of thalamic abnormality in relapsing-remitting MS by assessing the thalamic magnetization transfer ratio (MTR) in a cohort with clinically early disease. Twenty-three patients with early relapsing-remitting MS (mean age 37; mean disease duration 1.9 years; Expanded Disability Status Scale (EDSS) range 0-3) and 19 healthy controls (mean age 34) were imaged yearly with a magnetization transfer imaging sequence. Twenty-two MS patients and 14 controls completed two-year follow-up. Regions of interest were placed in both thalami and mean thalamic MTR calculated. At baseline, significant differences between patient and control thalamic MTR were not observed. However, at years one and two, the thalamic MTR in patients was significantly lower than control MTR. Although baseline lesion volume did not correlate with baseline thalamic MTR, at year one, an association between baseline lesion volume and year one thalamic MTR emerged. There was also a significant inverse correlation between EDSS and thalamic MTR (r = -0.47, P = 0.02). The study suggests that thalamic involvement occurs within the first five years of MS onset, when most patients are still minimally disabled.
Adult↗
Evidence for grey matter MTR abnormality in minimally disabled patients with early relapsing-remitting multiple sclerosis.
OBJECTIVES: To establish whether magnetisation transfer ratio (MTR) histograms are sensitive to change in normal appearing grey matter (NAGM) in early relapsing-remitting multiple sclerosis (RRMS) in the absence of significant disability; and to assess whether grey or white matter MTR measures are associated with clinical measures of impairment in early RRMS METHODS: 38 patients were studied (mean disease duration 1.9 years (range 0.5 to 3.7); median expanded disability status scale (EDSS) 1.5 (0 to 3)), along with 35 healthy controls. MTR was determined from proton density weighted images with and without MT presaturation. SPM99 was used to generate normal appearing white matter (NAWM) and NAGM segments of the MTR map, and partial voxels were minimised with a 10 pu threshold and voxel erosions. Mean MTR was calculated from the tissue segments. Atrophy measures were determined using a 3D fast spoiled gradient recall sequence from 37 patients and 17 controls. RESULTS: Mean NAGM and NAWM MTR were both reduced in early RRMS (NAGM MTR: 31.9 pu in patients v 32.2 pu in controls; p<0.001; NAWM MTR: 37.9 v 38.3 pu, p = 0.001). Brain parenchymal fraction (BPF) correlated with NAGM MTR, but when BPF was included as a covariate NAGM MTR was still lower in the patients (p = 0.009). EDSS correlated with NAGM MTR (r = 0.446 p = 0.005). CONCLUSIONS: In early RRMS, grey matter MTR abnormality is apparent. The correlation with mild clinical impairment (in this essentially non-disabled cohort) suggests that NAGM MTR could be a clinically relevant surrogate marker in therapeutic trials.
Adult↗
Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis.
Brain atrophy appears to occur in patients with multiple sclerosis (MS) in excess of that associated with normal ageing, and may be observed early in the clinical course of the disease. The dynamics and tissue specificity of this process remain unclear This preliminary study explored the evolution of brain grey matter (GM) and white matter (WM) volume loss (as fractions of total intracranial volumes) in 13 subjects with relapsing-remitting MS (mean disease duration 1.9 years at first scan), compared with nine normal control (NC) subjects. Subjects were scanned every six months for 18 months. In MS compared with NC subjects, significant differences in WM fractional volumes were observed at baseline (mean - 5.8%, P = 0.008) but no apparent progressive WM tissue loss was detected. In contrast, while no significant differences in GM fractional volumes were observed at baseline, there was significantly greater time-related volume loss in MS compared with NC subjects over the follow-up period (circa - 0.0086 per year in MS subjects, - 0.0021 per year in the NC subjects, difference P = 0.010). These results suggest that while both GM and WM atrophy are seen early in the clinical course of MS, they may not occur concurrently and may evolve at different rates.
Adult↗
Estimation of the macromolecular proton fraction and bound pool T2 in multiple sclerosis.
This study used a model for magnetization transfer (MT) to estimate two underlying parameters: the macromolecular proton fraction (f) and the bound pool T2 (T2b) in patients with multiple sclerosis (MS). Sixty patients with clinically definite MS and 27 healthy controls were imaged using: (1) a dual echo fast spin echo sequence, (2) a MT sequence (with ten MT power and offset frequency combinations) and (3) proton density and T1 weighted sequences (for T1 relaxation time estimation). Fourteen normal-appearing white matter (NAWM) regions of interest (ROI) and six normal-appearing gray matter (NAGM) ROIs were outlined in all subjects. Lesions were also contoured in subjects affected by MS. The model was fitted to the data leading to estimates of T2b and f. Results showed that T2b was increased in lesions whereas f was reduced. In NAWM, f was decreased while T2b was only increased in secondary progressive MS. NAWM f correlated modestly with disability. Further studies are needed to investigate the pathological basis of the abnormalities observed.
Adult↗
Diffusion tensor imaging of early relapsing-remitting multiple sclerosis with histogram analysis using automated segmentation and brain volume correction.
Diffusion tensor magnetic resonance imaging (DTI) reveals measurable abnormalities in normal-appearing brain tissue (NABT) in established multiple sclerosis (MS). However, it is unclear how early this occurs. Recent studies have employed whole brain histogram analysis to improve sensitivity, but concern exists regarding reliability of tissue/cerebrospinal fluid segmentation and possible intersubject brain volume differences, which can introduce partial volume error: To address this, 28 early relapsing-remitting MS subjects [median disease duration 1.6 years; median Expanded Disability Status Scale (EDSS) score 1.5] and 20 controls were compared with whole brain histogram analysis using an automated segmentation algorithm to improve reproducibility. Brain parenchymal volumes (BPV) were estimated for each subject in the analysis. The mean, peak height and peak location were calculated for DTI parameters [fractional anisotropy (FA), mean diffusivity and volume ratio]. An increased FA peak height in MS subject NABT was observed (P = 0.02) accounting for age, gender and BPV. Removing BPV revealed additional abnormalities in NABT. The main conclusions are i) FA peak height is increased in NABT in early MS, ii) partial volume edge effects may contribute to apparent NABT histogram abnormalities, and iii) correction for brain volume differences should reduce potential partial volume edge effects.
Adult↗
Quantitative magnetization transfer mapping of bound protons in multiple sclerosis.
Quantitative analysis of magnetization transfer images has the potential to allow a more thorough characterization of the protons, both bound and free, in a tissue by extracting a number of parameters relating to the NMR properties of the protons and their local environment. This work develops previously presented techniques to produce estimates of parameters such as the bound proton fraction, f, and the transverse relaxation time of the bound pool, T(2B), for the whole brain in a clinically acceptable imaging time. This is achieved by limiting the number of data collected (typically to 10); to collect 28 5-mm slices with a reconstructed resolution of 0.94 x 0.94 mm. The protocol takes 82 sec per data point. The fitting technique is assessed against previous work and for fitting failures. Maps and analysis are presented from a group of seven controls and 20 multiple sclerosis patients. The maps show that the parameters are sensitive to tissue-specific differences and can detect pathological change within lesions. Statistically significant differences in parameters such as T(2B) and f are seen between normal-appearing white matter, multiple sclerosis lesions, and control white matter. Whole-brain histograms of these parameters are also presented, showing differences between patients and controls.
Adolescent↗
Sales of over-the-counter remedies as an early warning system for winter bed crises.
OBJECTIVES: To evaluate the pattern of emergency adult medical admissions during the winter period and the usefulness of sales of over-the-counter cough/cold remedies as a predictor of these. METHODS: The databases of a single NHS trust acute unit and pharmacy outlets in its catchment area were analyzed retrospectively, comparing numbers of emergency admissions, ICD-10 discharge codes, local electronic point-of-sale (EPOS) and national sales data. RESULTS: Over nine consecutive winter periods from 1992/3, peak admissions always occurred within a defined ten-day period from 29th December to 9th January. Emergency admissions increased significantly during this period (P = 0.0002). Pharmaceutical/retail data were available for three consecutive winters 1998/99, 1999/2000 and 2000/2001, none of which coincided with increased influenza activity nationally. Acute respiratory illness as defined by International Classification of Diseases, 10th edition (ICD-10) discharge coding did not appear to contribute to the increase in admissions at the peak. However, National and Local EPOS sales were positively correlated with admissions and the rate of EPOS sales exceeded an empiric threshold of 1000 units per week two weeks prior to the admissions peak in each year. CONCLUSIONS: Emergency admissions over the winter period are increasing and can be expected within a period of only ten days each year. No firm relationship between acute respiratory illness and admissions could be defined but local EPOS data may give up to two weeks warning of the peak in admissions and merits further prospective evaluation.
Antitussive Agents↗
Preliminary magnetic resonance study of the macromolecular proton fraction in white matter: a potential marker of myelin?
We report on a new quantitative magnetization transfer (MT) technique that allows for the in vivo estimation of the macromolecular proton fraction (f) and the bound pool T2 relaxation time (T2b), whilst permitting whole brain coverage. In this pilot study, five subjects with multiple sclerosis (MS) and five healthy controls were studied. Both f and T2b were significantly different between MS lesions and normal control white matter (WM). Relationships between f and T1 relaxation time [Spearmans rank correlation coefficient (r(s)) = -0.97, P < 0.001] and f and the magnetization transfer ratio (MTR; r(s) = 0.80, P < 0.001) were observed. Compared with MTR, f and T2b have the potential advantage of relative independence from MT acquisition protocol while offering more pathologically specific information. In particular, f may provide a more direct indication of myelin content in WM.
Adult↗