Fluoride doped γ-Fe2O3 nanoparticles with increased MRI relaxivity.

Iron oxide nanoparticles (IONs) are being actively researched and experimented with as contrast agents for Magnetic Resonance Imaging (MRI), as well as image-directed delivery of therapeutics. The efficiency of an MRI contrast agent can be described by its longitudinal and transverse relaxivities, r1 and r2. γ-Fe2O3 nanoparticles - doped with fluoride in a controlled manner and functionalised with citric acid - showed a 3-fold increase in r1 and a 17-fold increase in r2 in a magnetic field of 3 T and almost 6-fold increase in r1 and a 14-fold increase in r2 at 11 T. Following fluorination, PXRD shows that the crystal structure of γ-Fe2O3 is maintained, Mössbauer spectroscopy shows that the oxidation state of the Fe cation is unchanged and HREM shows that the particle size does not vary. However, magnetisation curves show a large increase in the coercive field, pointing towards a large increase in the magnetic anisotropy for the fluorinated nanoparticles compared to the un-doped γ-Fe2O3 nanoparticles. Therefore, a chemically induced increase in magnetic anisotropy appears to be the most relevant parameter responsible for the large increase in relaxivity for γ-Fe2O3 nanoparticles.

A Bayesian approach to estimate changes in condom use from limited human immunodeficiency virus prevalence data.

Evaluation of large-scale intervention programmes against human immunodeficiency virus (HIV) is becoming increasingly important, but impact estimates frequently hinge on knowledge of changes in behaviour such as the frequency of condom use over time, or other self-reported behaviour changes, for which we generally have limited or potentially biased data. We employ a Bayesian inference methodology that incorporates an HIV transmission dynamics model to estimate condom use time trends from HIV prevalence data. Estimation is implemented via particle Markov chain Monte Carlo methods, applied for the first time in this context. The preliminary choice of the formulation for the time varying parameter reflecting the proportion of condom use is critical in the context studied, because of the very limited amount of condom use and HIV data available. We consider various novel formulations to explore the trajectory of condom use over time, based on diffusion-driven trajectories and smooth sigmoid curves. Numerical simulations indicate that informative results can be obtained regarding the amplitude of the increase in condom use during an intervention, with good levels of sensitivity and specificity performance in effectively detecting changes. The application of this method to a real life problem demonstrates how it can help in evaluating HIV interventions based on a small number of prevalence estimates, and it opens the way to similar applications in different contexts.

Who mixes with whom among men who have sex with men? Implications for modelling the HIV epidemic in southern India.

In India, the identity of men who have sex with men (MSM) is closely related to the role taken in anal sex (insertive, receptive or both), but little is known about sexual mixing between identity groups. Both role segregation (taking only the insertive or receptive role) and the extent of assortative (within-group) mixing are known to affect HIV epidemic size in other settings and populations. This study explores how different possible mixing scenarios, consistent with behavioural data collected in Bangalore, south India, affect both the HIV epidemic, and the impact of a targeted intervention. Deterministic models describing HIV transmission between three MSM identity groups (mostly insertive Panthis/Bisexuals, mostly receptive Kothis/Hijras and versatile Double Deckers), were parameterised with behavioural data from Bangalore. We extended previous models of MSM role segregation to allow each of the identity groups to have both insertive and receptive acts, in differing ratios, in line with field data. The models were used to explore four different mixing scenarios ranging from assortative (maximising within-group mixing) to disassortative (minimising within-group mixing). A simple model was used to obtain insights into the relationship between the degree of within-group mixing, R0 and equilibrium HIV prevalence under different mixing scenarios. A more complex, extended version of the model was used to compare the predicted HIV prevalence trends and impact of an HIV intervention when fitted to data from Bangalore. With the simple model, mixing scenarios with increased amounts of assortative (within-group) mixing tended to give rise to a higher R0 and increased the likelihood that an epidemic would occur. When the complex model was fit to HIV prevalence data, large differences in the level of assortative mixing were seen between the fits identified using different mixing scenarios, but little difference was projected in future HIV prevalence trends. An oral pre-exposure prophylaxis (PrEP) intervention was modelled, targeted at the different identity groups. For intervention strategies targeting the receptive or receptive and versatile MSM together, the overall impact was very similar for different mixing patterns. However, for PrEP scenarios targeting insertive or versatile MSM alone, the overall impact varied considerably for different mixing scenarios; more impact was achieved with greater levels of disassortative mixing.

Differences between seven measures of self-reported numbers of clients of female sex workers in southern India: implications for individual- and population-level analysis.

Quantifying sexual activity of sub-populations with high-risk sexual behaviour is important in understanding HIV epidemiology. This study examined inconsistency of seven outcomes measuring self-reported clients per month (CPM) of female sex workers (FSWs) in southern India and implications for individual/population-level analysis. Multivariate negative binomial regression was used to compare key social/environmental factors associated with each outcome. A transmission dynamics model was used to assess the impact of differences between outcomes on population-level FSW/client HIV prevalence. Outcomes based on 'clients per last working day' produced lower estimates than those based on 'clients per typical day'. Although the outcomes were strongly correlated, their averages differed by approximately two-fold (range 39.0-79.1 CPM). The CPM measure chosen did not greatly influence standard epidemiological 'risk factor' analysis. Differences across outcomes influenced HIV prevalence predictions. Due to this uncertainty, we recommend basing population-based estimates on the range of outcomes, particularly when assessing the impact of interventions.

Breast MRI at 3.0 T in a high-risk familial breast cancer screening cohort: comparison with 1.5 T screening studies.

OBJECTIVES: The sensitivity of X-ray mammography for the detection of breast malignancy in younger females is lower than that of breast MRI; consequently, guidelines recommend annual MRI for patients with a significantly elevated lifetime risk. The improved signal-to-noise ratio obtainable at 3.0 T should result in data superior to those obtainable at 1.5 T. However, breast imaging on higher field strength systems poses specific problems. As a result, caution has been urged in the implementation of breast MRI at 3.0 T. The aim of this study was to determine if it is appropriate to use 3.0 T MRI in the screening of patients by comparing the summary statistics achieved by this 3.0 T MRI programme against the published results of 1.5 T screening studies. METHODS: Over a 20-month period, 291 patients referred with an elevated familial risk of breast cancer were examined at 3.0 T. Resulting images were scored based on the Royal College of Radiologists Breast Group imaging classification. The reference standard was a combination of histology and follow-up imaging. RESULTS: Follow-up data were available in 267 patients. Analysis revealed positive and negative post-test probabilities of 28% [95% confidence intervals (CI); range, 10-60%] and 1% (95% CI; range, 0-2%), respectively. These results compared favourably against those of a recent meta-analysis [25.3% (95% CI; range, 18.4-33.8%) and 0.4% (95% CI; range, 0.2-0.9%), respectively]. CONCLUSION: Given the similar summary statistics between this work and the 1.5 T results, it would appear that screening of high-risk patients at 3.0 T has potential. Further studies should be undertaken to verify this result.

In vivo magnetic resonance spectroscopy of gynaecological tumours at 3.0 Tesla.

BACKGROUND: Magnetic resonance spectroscopy (MRS) uses the same hardware as MR imaging and allows us to analyse the biochemistry of tissues in vivo. Published data for gynaecological lesions are limited and are largely based on MRS carried out at the lower magnetic field strength of 1.5 Tesla (T). OBJECTIVE: The purpose of this study was to determine whether in vivo proton MRS could be performed at the higher magnetic field strength of 3 T to characterise the spectra of a variety of benign and malignant gynaecological lesions. DESIGN: Prospective, non-randomised study. SETTING: MRI department within a tertiary referral centre for gynaecological cancers. SAMPLE: All women with a pelvic mass under going 3T MRI. METHODS: We carried out MRS on nonrandomised women undergoing routine 3 T MRI within our MRI department during investigation for gynaecological lesions from February 2006 to April 2008. Only those women for whom histopathological data were available were included. MAIN OUTCOME MEASURES: The presence of choline detected by in vivo 3T MRS. RESULTS: Eighty-seven women underwent MRS, 57 of whom had newly diagnosed neoplasms. MRS data for 39 of these new women (18 were excluded because of technical errors or missing data) were used to detect the presence of choline, an indicator of basement membrane turnover. Overall, choline was present in 13 of the 14 ovarian cancers, 8 of the 11 cervical tumours and all 4 of the uterine cancers. There was no statistical significant difference between choline levels in various lesion types (P=0.735) or between benign and malignant disease (P=0.550). CONCLUSIONS: In vivo MRS can be performed at 3 T to provide biochemical information on pelvic lesions. The way in which this information can be utilised is less clear but may be incorporated into monitoring tissue response in cancer treatments.

The measurement of enamel wear by four toothpastes.

OBJECTIVES: To determine the enamel abrasivity of three whitening toothpastes and a silica toothpaste and to measure the brushing forces used. METHODS: Polished human enamel blocks were indented with a Knoop diamond and attached to dentures of adult volunteers. The blocks were brushed ex vivo, twice per day with either a whitening toothpaste containing Perlite (White System), a commercial whitening toothpaste (A and B) or a silica toothpaste. After four and twelve-weeks, one block per subject was removed and the Knoop indent remeasured. From the changes in the indent length, the amount of enamel wear was calculated. RESULTS: The mean enamel wear (sd) for White System, silica toothpaste, whitening toothpaste A and B after four-weeks was 0.14 (0.15), 0.09 (0.16), 0.14 (0.12) and 0.89 (0.93) and after twelve-weeks was 0.24 (0.21), 0.37 (0.73), 0.36 (0.52) and 1.04 (0.98) microm respectively. After four-weeks, the differences in enamel wear between whitening toothpaste B and all other toothpastes were of statistical significance (p < 0.003), but not after twelve-weeks. The mean ex vivo normal brushing force (sd) was 2.67 (1.33) N. CONCLUSIONS: All three whitening toothpastes did not give significantly more enamel wear than a silica toothpaste after twelve-weeks in situ with ex vivo brushing.

Evaluating large-scale HIV prevention interventions: study design for an integrated mathematical modelling approach.

BACKGROUND: There is an urgent need to evaluate HIV prevention interventions, thereby improving our understanding of what works, under what circumstances and what is cost effective. OBJECTIVES: To describe an integrated mathematical evaluation framework designed to assess the population-level impact of large-scale HIV interventions and applied in the context of Avahan, the Indian AIDS Initiative, in southern India. The Avahan Initiative is a large-scale HIV prevention intervention, funded by the Bill & Melinda Gates Foundation, which targets high-risk groups in selected districts of the six states most affected by the HIV/AIDS epidemic (Maharashtra, Karnataka, Tamil Nadu, Andhra Pradesh, Nagaland and Manipur) and along the national highways. METHODS: One important component of the monitoring and evaluation of Avahan relies on an integrated mathematical framework that combines empirical biological and behavioural data from different subpopulations in the intervention areas, with the use of tailor-made transmission dynamics models embedded within a Bayesian framework. RESULTS: An overview of the Avahan Initiative and the objectives of the monitoring and evaluation of the intervention is given. The rationale for choosing this evaluation design compared with other possible designs is presented, and the different components of the evaluation framework are described and its advantages and challenges are discussed, with illustrated examples. CONCLUSIONS: This is the first time such an approach has been applied on such a large scale. Lessons learnt from the CHARME project could help in the design of future evaluations of large-scale interventions in other settings, whereas the results of the evaluation will be of programmatic and public health relevance.

A simple solution for reducing artefacts due to conductive and dielectric effects in clinical magnetic resonance imaging at 3T.

The quality of imaging obtained at high magnetic field strengths can be degraded by various artefacts due to conductive and dielectric effects, which leads to loss of signal. Various methods have been described and used to improve the quality of the image affected by such artefacts. In this article, we describe the construction and use of a simple solution that can be used to diminish artefacts due to conductive and dielectric effects in clinical imaging at 3T field strength and thereby improve the diagnostic quality of the images obtained.

Neoadjuvant chemotherapy in breast cancer: early response prediction with quantitative MR imaging and spectroscopy.

A prospective study was undertaken in women undergoing neoadjuvant chemotherapy for locally advanced breast cancer in order to determine the ability of quantitative magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to predict ultimate tumour response (percentage decrease in volume) or to detect early response. Magnetic resonance imaging and MRS were carried out before treatment and after the second of six treatment cycles. Pharmacokinetic parameters were derived from T1-weighted dynamic contrast-enhanced MRI, water apparent diffusion coefficient (ADC) was measured, and tissue water:fat peak area ratios and water T2 were measured using unsuppressed one-dimensional proton spectroscopic imaging (30 and 135 ms echo times). Pharmacokinetic parameters and ADC did not detect early response; however, early changes in water:fat ratios and water T2 (after cycle two) demonstrated substantial prognostic efficacy. Larger decreases in water T2 accurately predicted final volume response in 69% of cases (11/16) while maintaining 100% specificity and positive predictive value. Small/absent decreases in water:fat ratios accurately predicted final volume non-response in 50% of cases (3/6) while maintaining 100% sensitivity and negative predictive value. This level of accuracy might permit clinical application where early, accurate prediction of non-response would permit an early change to second-line treatment, thus sparing patients unnecessary toxicity, psychological morbidity and delay of initiation of effective treatment.

Abrasion of human enamel and dentine caused by toothpastes of differing abrasivity determined using an in situ wear model.

OBJECTIVES: To determine the rates of enamel and dentine wear in situ during tooth brushing with a range of five toothpastes of differing RDA and REA values. METHODS: Enamel/dentine inserts were placed in the buccal aspects of full upper dentures of human volunteers. Enamel wear was determined by change in Knoop indent length and dentine wear was determined from the enamel-dentine step height, measured using optical profilometry. RESULTS: Significant differences between the test products were found for both enamel and dentine (p < 0.05). However for the conventional toothpastes the rate of wear was similar and differences between the products were not generally statistically significant for either enamel or dentine, despite the fact that their RDA values differed by more than a factor of two. The rate of wear was found to decrease throughout the duration of the study. CONCLUSIONS: The study demonstrated that the methodology used is capable of assessing enamel and dentine wear in situ within a relatively short period of time. The data suggest that whilst in vitro tests have value in understanding differences in abrasivity between products, they cannot be used to predict in vivo effects.

The measurement of enamel and dentine abrasion by tooth whitening products using an in situ model.

OBJECTIVES: To determine the enamel and dentine wear of two whitening toothpastes using an in situ model with ex vivo brushing. METHODS: Human enamel/dentine (approximately 50:50) blocks (approximately 4 x 4mm) were placed in the upper buccal aspects of full or partial dentures of a group of 25 subjects. Subjects brushed the specimens ex vivo with either a calcium carbonate/perlite or silica containing whitening toothpaste under exaggerated conditions as compared to normal for 30 s, twice per day. Specimens were removed after 4, 8 and 12 weeks and the wear to the enamel and dentine was determined. Enamel wear was determined by change in Knoop indent length and dentine wear was determined from the enamel-dentine step height, measured using optical profilometry. RESULTS: The mean wear after 12 weeks was for enamel 0.27 and 0.19 microns, and for dentine 34.3 and 61.1 microns, for the calcium carbonate/perlite and silica toothpastes respectively. There were no significant differences between products after 12 weeks. The rate of wear was found to decrease throughout the duration of the study. CONCLUSION: There were no significant differences between the two whitening toothpastes in terms of enamel and dentine wear after 12 weeks brushing.

In vitro efficacy of a whitening toothpaste containing calcium carbonate and perlite.

OBJECTIVES: The studies described in this paper aimed to assess the stain removal efficacy, fluoride efficacy and abrasivity to enamel and dentine of a new whitening toothpaste containing calcium carbonate and perlite, using appropriate in vitro models. METHODS: Stain removal efficacy was assessed using the pellicle cleaning ratio (PCR) method. Fluoride efficacy was assessed using remineralisation, demineralisation and fluoride-uptake methods. Abrasivity was assessed using an enamel and dentine wear method. RESULTS: The results showed that the new whitening toothpaste was able to remove extrinsic tooth stain more effectively than three commercially available toothpaste formulations. The fluoride efficacy was superior to a non-fluoridated control and was not significantly different to a clinically tested fluoride-containing toothpaste. The abrasivity data showed that the calcium carbonate/perlite toothpaste is no more abrasive to enamel or dentine than two other commercially available whitening toothpastes. CONCLUSIONS: The studies show that the new whitening toothpaste is effective in extrinsic stain removal, has an efficacious fluoride source and does not have an undue degree of abrasivity to enamel or dentine compared to other relevant commercially available products.

Investigation of erosion and abrasion on enamel and dentine: a model in situ using toothpastes of different abrasivity.

BACKGROUND: Studies in vitro suggest that abrasion and erosion may act synergistically to produce wear of enamel and dentine. Methods in situ are recently available to study separately erosion and abrasion of dental tissues. The aim of this study was to combine two in situ protocols to study the interplay between erosion and abrasion of enamel and dentine. METHOD: The study was a single-blind, randomised, five-treatment cross-over design involving 15 healthy volunteers. During each 10-day study period, subjects wore from 0900 to 1700 h an upper removable acrylic appliance holding one polished enamel and one polished dentine specimen. The specimen treatment regimens were: 1. Drinking water and brushing with toothpaste A. 2. Drinking water and brushing with toothpaste B. 3. Drinking orange juice. 4. Drinking orange juice and brushing with toothpaste A. 5. Drinking orange juice and brushing with toothpaste B. Drinking and brushing times were around 0900, 1100, 1300 and 1500 h. Drinks were consumed as 250 ml over 10 min and brushing ex vivo for 1 min to each specimen. Measurement of tissue loss was made on days 5 and 10 of each period using a profilometer. RESULTS: All treatments produced increasing tissue loss over time, which was considerably greater for dentine than enamel. For enamel, the data at days 5 and 10 showed a significant effect for erosion (i.e. orange juice was significantly more erosive than water), but no significant effect for abrasion (i.e. no significant difference between the two toothpaste treatments). The combined orange juice and toothpaste effects were directional for synergy but did not reach significance. For dentine at day 10, many specimens exceeded the 50 microm set limit of the profilometer and only day 5 data were considered. There were significant effects for erosion (orange juice produced significantly more erosion than water) and for abrasion (paste A was significantly more abrasive to dentine than paste B). The synergy effect could not be examined for dentine due to the truncation effect as the set limit of the profilometer was exceeded. CONCLUSIONS: Erosion increases the susceptibility of enamel to toothpaste abrasion. Dentine is considerably more susceptible than enamel to erosion and abrasion alone or combined. Dentine loss appears to correlate with toothpaste abrasivity (RDA value).

Development of a method in situ to study toothpaste abrasion of dentine. Comparison of 2 products.

BACKGROUND/AIMS: The abrasivity of toothpastes is usually determined using in vitro methods; as such, the clinical significance of the findings is uncertain. The aim of the present study was to develop and evaluate a method in situ to study abrasion of dentine by two toothpastes of different Relative Dentine Abrasivity (RDA). METHOD: The study was a single blind, randomised, 2 way cross over design involving 10 healthy dentate volunteers. Subjects wore an maxillary removable acrylic appliance containing two flat human dentine specimens, taped to expose a window of tissue, from 9 am to 4 pm during the two 10 working day study periods. No food or drink was consumed when the appliance was in place. On five occasions each day, the appliances were removed and the dentine windows brushed ex vivo with the allocated paste for 60 s each. Dentine abrasion at days 5 and 10 was measured using a profilometer. RESULTS: Both toothpastes produced measurable abrasion in all subjects and the depth increased in most subjects between 5 and 10 days. There was significant subject and specimen variation both within and between toothpastes. There was significantly increased abrasion by the toothpaste with the higher RDA value and in mean terms the ratio of abrasion between the two pastes was similar to the ratio of the RDA values. CONCLUSION: The method in situ, already used to study dental hard tissue erosion, appears ideally suitable to study dental abrasion alone and the interaction between aetiological factors involved in tooth wear.

American families with Crohn's disease have strong evidence for linkage to chromosome 16 but not chromosome 12.

BACKGROUND & AIMS: Two European genome-wide screens for inflammatory bowel disease have identified two significant regions of linkage on chromosomes 16 (IBD1) and 12 (IBD2) and two regions with suggestive levels of significance (chromosomes 3p and 7q). The aim of this study was to determine if there was evidence for linkage to these regions in non-Jewish and Ashkenazi Jewish families multiplex for Crohn's disease from the United States. METHODS: One hundred forty-eight affected relative pairs, 34% Ashkenazim, were genotyped with 10-14 highly polymorphic markers overlying each candidate region. Nonparametric multipoint and two-point linkage analyses were performed. RESULTS: Significant evidence for replication of linkage was found only for the chromosome 16 locus, IBD1, maximal at D16S769 (nonparametric linkage score [NPL], 2.49; P = 0.007). Analysis by ethnicity showed stronger evidence for Ashkenazim (D16S769; NPL = 2. 52; P = 0.007) than for non-Jewish white populations (D16S401; NPL = 1.40; P = 0.082). There was no significant evidence for replication on chromosome 12 (IBD2). Minimal evidence for extension of linkage evidence was observed for the chromosomes 3p and 7q regions. CONCLUSIONS: American families, particularly Ashkenazim, have significant evidence for the Crohn's disease susceptibility locus, IBD1, on chromosome 16, but not for IBD2 on chromosome 12.

Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1.

The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic differences in familial risks have established that CD and UC are complex, non-Mendelian, related genetic disorders. We performed a genome-wide screen using 377 autosomal markers, on 297 CD, UC, or mixed relative pairs from 174 families, 37% Ashkenazim. We observed evidence for linkage at 3q for all families (multipoint logarithm of the odds score (MLod) = 2.29, P = 5.7 x 10(-4)), with greatest significance for non-Ashkenazim Caucasians (MLod = 3.39, P = 3.92 x 10(-5)), and at chromosome 1p (MLod = 2.65, P = 2.4 x 10(-4)) for all families. In a limited subset of mixed families (containing one member with CD and another with UC), evidence for linkage was observed on chromosome 4q (MLod = 2.76, P = 1.9 x 10(-4)), especially among Ashkenazim. There was confirmatory evidence for a CD locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (MLod = 1.69, P = 2.6 x 10(-3)), particularly among Ashkenazim (MLod = 1.51, P = 7.8 x 10(-3)); however, positive MLod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.016) evidence for linkage. This screen provides strong evidence that there are several major susceptibility loci contributing to the genetic risk for CD and UC.