Brugia malayi infection in ferrets - A small mammal model of lymphatic filariasis.

BACKGROUND: The lack of effective short-course therapies for treatment of the adult stage of filarial worms is a major limitation in the global effort to eliminate lymphatic filariasis. Studies using current small mammal models of lymphatic filariasis are limited by difficulties in quantifying adult worm numbers and in assessing lymphatic anatomy and function. METHODOLOGY/PRINCIPAL FINDINGS: Here, we re-established Brugia malayi infection of ferrets as a model for lymphatic filariasis and demonstrated parasitological, immunological, and histological parallels with human infection. Subcutaneous injection of L3 larvae into a hind-footpad resulted in a mean of 18 adult worms recovered 16 weeks post-infection, primarily from the draining inguinal and femoral lymphatics of the injected limb. Infected ferrets developed microfilaremia, with patency lasting from 12-26 weeks post-infection. Quantitative PCR assessing cytokine transcription by antigen-stimulated lymph node cells demonstrated a mixed Th1/Th2 response occurring during early infection. Immunoregulation with production of down-regulatory cytokine IL-10 occurred just prior to peak microfilaremia. Histological analysis revealed progressive inflammation of the lymphatic vessel walls, with intimal thickening and disorganization of collagen fibers. Inflammation was observed as early as 8 weeks post-infection and extended into the perivascular and subcutaneous tissues by 16 weeks post-infection. Finally, we developed a novel ferret PET/CT lymphoscintigraphy method demonstrating substantial changes in lymphatic anatomy and function as early as 3 weeks post-infection, with progression over the course of infection. CONCLUSIONS/SIGNIFICANCE: B. malayi infection of ferrets is a robust model of human lymphatic filariasis that can be utilized to study efficacy of novel antifilarial agents against adult worms residing within lymphatic vessels. In conjunction with PET/CT lymphoscintigraphy, this model can also be used to investigate pathogenesis of lymphatic dysfunction in lymphatic filariasis and efficacy of medications aimed at reversing lymphatic dysfunction after clearance of adult worms.

Microstructural white matter alterations in preclinical Alzheimer's disease detected using free water elimination diffusion tensor imaging.

Brain changes associated with Alzheimer's disease (AD) begin decades before disease diagnosis. While ß-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and synaptic pathology are closely related to the cognitive dysfunction. Brain imaging methods that are tuned to assess degeneration of myelinated nerve fibers in the brain (collectively called white matter) include diffusion tensor imaging (DTI) and related techniques, and are expected to shed light on disease-related loss of structural connectivity. Participants (N = 70, ages 47-76 years) from the Wisconsin Registry for Alzheimer's Prevention study underwent DTI and hybrid diffusion imaging to determine a free-water elimination (FWE-DTI) model. The study assessed the extent to which preclinical AD pathology affects brain white matter. Preclinical AD pathology was determined using cerebrospinal fluid (CSF) biomarkers. The sample was enriched for AD risk (APOE ε4 and parental history of AD). AD pathology assessed by CSF analyses was significantly associated with altered microstructure on both DTI and FWE-DTI. Affected regions included frontal, parietal, and especially temporal white matter. The f-value derived from the FWE-DTI model appeared to be the most sensitive to the relationship between the CSF AD biomarkers and microstructural alterations in white matter. These findings suggest that white matter degeneration is an early pathological feature of AD that may have utility both for early disease detection and as outcome measures for clinical trials. More complex models of microstructural diffusion properties including FWE-DTI may provide increased sensitivity to early brain changes associated with AD over standard DTI.

Effects of isoflurane anesthesia and intravenous morphine self-administration on regional glucose metabolism ([18 F]FDG-PET) of male Sprague-Dawley rats.

Although certain drugs of abuse are known to disrupt brain glucose metabolism (BGluM), the effects of opiates on BGluM are not well characterized. Moreover, preclinical positron emission tomography (PET) studies anesthetize animals during the scan, which limits clinical applications. We investigated the effects of (i) isoflurane anesthesia and (ii) intravenous morphine self-administration (MSA) on BGluM in rats. Jugular vein cannulated adult male Sprague-Dawley rats self-administered either saline (SSA) or morphine (0.5 mg/kg/infusion, 4 h/day for 12 days). All animals were scanned twice with [18 F]-fluoro-deoxy-glucose (FDG)-PET/CT at a baseline and at 2-day withdrawal from self-administration. After the IV injection of FDG, one batch of animals (n = 14) was anesthetized with isoflurane and the other batch (n = 16) was kept awake during the FDG uptake (45 min). After FDG uptake, all animals were anesthetized in order to perform a PET/CT scan (30 min). Isoflurane anesthesia, as compared to the awake condition, reduced BGluM in the olfactory, cortex, thalamus, and basal ganglia, while increasing BGluM in the midbrain, hypothalamus, hippocampus, and cerebellum. Morphine self-administered animals exhibited withdrawal signs (piloerection and increased defecation), drug seeking, and locomotor stimulation to morphine (0.5 mg/kg) during the 2 day withdrawal. The BGluM in the striatum was increased in the MSA group as compared to the SSA group; this effect was observed only in the isoflurane anesthesia, not the awake condition. These findings suggest that the choice of the FDG uptake condition may be important in preclinical PET studies and increased BGluM in the striatum may be associated with opiate seeking in withdrawal.

Which young people in England are most at risk of an alcohol-related revolving-door readmission career?

BACKGROUND: This research investigated what Hospital Episode Statistics (HES) records could reveal about the development of problematic drinking careers among young people in England. METHODS: A cohort of 7286 young people (aged 12-18) who had an index alcohol-related emergency admission between April 2003 and March 2004 were investigated for subsequent alcohol-related readmission. Regressions of patient and visit characteristics were performed against measures of readmission. RESULTS: A total of 677 patients (9.3% of the cohort) were readmitted during the following 3.75 years, and this group had on average 1.52 readmissions following their index admission. Predictors of having a first readmission included living in a deprived area at index admission (B = -.081, OR = .923, 95% CI = .894 to .952, df = 1, p < .001); having another substance use diagnosis (B = .302, OR = 1.352, 95% CI = 1.017 to 1.798, df = 1, p < .05), or a comorbid mental health diagnosis (B = .441, OR = 1.555, 95% CI = 1.147 to 2.108, df = 1, p < .01), or a diagnosis of self-harm (B = .316, OR = 1.371, 95% CI = 1.082 to 1.738, df = 1, p < .01) at index admission. These last three results were also associated with the readmission rate being higher for young women than young men (B = -.250, OR = .779, 95% CI = .656 to .925, df = 1, p < .01). Patients who had an injury diagnosis alongside their alcohol diagnosis were less likely to be readmitted in the future (B = -.439, OR = .645, 95% CI = .475 to .876, df = 1, p < .01) On average, each subsequent admission featured a longer hospital stay; was progressively more likely to occur on a non-traditional drinking day; and occurred after a progressively smaller number of days since previous admission. CONCLUSIONS: This study illustrates ways in which problematic drinking careers can be analysed using routinely collected health information, and the results from this analysis may be useful in informing the process of hospital screening and treatment referral. The effects of poverty and comorbid conditions on the initiation of a drinking career are suggested by these results.

Free water elimination diffusion tractography: A comparison with conventional and fluid-attenuated inversion recovery, diffusion tensor imaging acquisitions.

PURPOSE: White matter tractography reconstructions using conventional diffusion tensor imaging (DTI) near cerebrospinal fluid (CSF) spaces are often adversely affected by CSF partial volume effects (PVEs). This study evaluates the ability of free water elimination (FWE) DTI methods to minimize the PVE of CSF for deterministic tractography applications. MATERIALS AND METHODS: Ten healthy individuals were scanned with "traditional," FLAIR (fluid-attenuated inversion recovery), and FWE DTI scans. The fornix, corpus callosum, and cingulum bundles were reconstructed using deterministic tractography. The FWE DTI scan was performed twice to separately match total acquisition time (long FWE) and number of measurements (encoding directions, short FWE) to the FLAIR and "traditional" DTI scans. PVE resolution was determined based on reconstructed tract volume. All reconstructions underwent blinded review for anatomical correctness, symmetry, and completeness. RESULTS: Reconstructions of the fornix demonstrated that the FWE and FLAIR scans produce more complete, anatomically plausible reconstructions than "traditional" DTI. Additionally, the tract reconstructions using FWE-DTI were significantly larger than when FLAIR was used with DTI (P < 0.0005). FLAIR and the FWE methods led to signal-to-noise ratio (SNR) reductions of 33% and 11%, respectively, compared with conventional DTI. The long and short FWE acquisitions did not significantly (P ≥ 0.31) differ from one another for any of the reconstructed tracts. CONCLUSION: The FWE diffusion model overcomes CSF PVE without the time, SNR, and volumetric coverage penalties inherent to FLAIR DTI.

Optimization of a free water elimination two-compartment model for diffusion tensor imaging.

Diffusion tensor imaging is used to measure the diffusion of water in tissue. The diffusion properties carry information about the relative organization and structure of the underlying tissue. In the case of a single voxel containing both tissue and a fast diffusing component such as free water, a single diffusion tensor is no longer appropriate. A two-tensor free water elimination model has previously been proposed to correct for the case of volume mixing. Here, this model was implemented in a straightforward but novel manner without the use of spatial constraints. The optimal acquisition parameters were investigated through Monte Carlo simulations and human brain imaging studies. At a signal-to-noise ratio of 40 with 64 diffusion-weighted encoding images, the most accurate estimates of fast diffusion signal were obtained with two diffusion-weighted shells (b-value in s/mm(2)×number of directions) of 500×32 and 1500×32. The potential bias in fractional anisotropy induced by this two-compartment model was more than an order of magnitude less than the error of using the single diffusion tensor model in the presence of partial volume effects with free water. This strategy may be useful for characterizing the diffusion of tissues adjacent to cerebral spinal fluid (CSF), tissues affected by edema, and removing artifacts from blurring and ghosting of the CSF signal.

Measuring the influence of colleagues on a consultant team's use of breast conserving surgery.

OBJECTIVES: The aim of this study was to examine potential reasons why the use of breast conserving surgery (BCS) for breast cancer varies substantially between hospital teams in England, and in particular to examine whether colleague influence has a role in influencing BCS rates locally. METHODS: Routinely collected Hospital Episode Statistics (HES) data relating to 420 surgical teams in England who performed more than ten breast cancer operations during the financial year 2006/07 were used to identify predictors of team BCS use. Team BCS rates (as a proportion of all types of breast excision surgery) were subject to a regression analysis that incorporated, as independent variables, a range of patient, organizational, and local demographic factors, as well as the BCS rate of colleagues working alongside them in the same hospitals(s). RESULTS: After adjusting for the effects of other variables, BCS use by colleagues working in the same hospital(s) was a significant predictor of a team's own BCS rate (standardized b = 0.224; p < .001), denoting a typical 3 percent increase in a team's BCS rate for every 10 percent increase in the BCS rate of colleagues. CONCLUSIONS: The practice of colleagues seems to have a measurable influence upon a surgical team's BCS usage. Guidance from HTA organizations can set national standards about the use of new techniques and innovations, but dissemination can be either slowed down or accelerated by the influence of local colleagues. A strategy of disseminating guidance through professional networks or "local champions" could be a powerful avenue for change.

Influence of expert clinical adviser characteristics on opinions about interventional procedures.

OBJECTIVES: The aim of this study was to examine potential associations between the professional background and experience of expert clinicians and their opinions about the clinical utility of interventional procedures. METHODS: A retrospective survey of expert clinician characteristics and their opinions was conducted. Information was collected on expert clinical adviser self-declared "operator," "researcher," and conflict of interest status. Associations were sought between expert clinical adviser characteristics and their opinions on whether procedures were "established," "efficacious," and "safe." The setting was the Interventional Procedures Programme of the UK's National Institute for Health and Clinical Excellence (NICE). A total of 598 expert clinician questionnaires relating to 182 different interventional procedures were analyzed. RESULTS: Expert clinical advisers with operative experience of procedures were significantly more likely to consider them as established (odds ratio [OR] 3.93; 95 percent confidence interval [CI], 2.43 to 6.36; p < .001), efficacious (OR 1.76; 95 percent CI, 1.00 to 3.08; p = .049), and safe (OR 2.28; 95 percent CI, 1.43 to 3.65; p = .001). Once adjusted for other characteristics, there was no association between either researcher or conflict of interest status and opinions about the clinical utility of procedures. CONCLUSIONS: Expert clinical advisers are an important source of information for decision makers producing guidance about the use of procedures, especially when published evidence is sparse or of poor quality. This study suggests that those who are operators, but not those who are researchers or declare a conflict of interest, are more likely to have a favorable opinion of a procedure's clinical utility. Use of expert clinical advisers with a variety of experience and backgrounds seems a reasonable approach to obtaining authoritative opinions about interventional procedures, to supplement and help interpret evidence from published data.