William M. Holmes

Reducing antibiotic use for acute bronchitis in primary care: blinded, randomised controlled trial of patient information leaflet

Abstract Objective: To assess whether sharing the uncertainty of the value of antibiotics for acute bronchitis in the form of written and verbal advice affects the likelihood of patients taking antibiotics. Design: Nested, single blind, randomised controlled trial. Setting: Three suburban general practices in Nottingham. Participants: 259 previously well adults presenting with acute bronchitis. Intervention: In group A, 212 patients were judged by their general practitioner not to need antibiotics that day but were given a prescription to use if they got worse and standard verbal reassurance. Half of them (106) were also given an information leaflet. All patients in group B (47) were judged to need antibiotics and were given a prescription and encouraged to use it. Main outcome measures: Antibiotic use in the next two weeks. Reconsultation for the same symptoms in the next month. Results: In group A fewer patients who received the information leaflet took antibiotics compared with those who did not receive the leaflet (49 v 63, risk ratio 0.76, 95% confidence interval 0.59 to 0.97, P=0.04). Numbers reconsulting were similar (11 v 14). In group B, 44 patients took the antibiotics. Conclusion: Most previously well adults with acute bronchitis were judged not to need antibiotics. Reassuring these patients and sharing the uncertainty about prescribing in a information leaflet supported by verbal advice is a safe strategy and reduces antibiotic use. What is already known on this topic Most adults with acute bronchitis who consult their general practitioner will receive antibiotics For most patients antibiotics do not modify the natural course of the symptoms The widespread belief among patients that infection is the problem and antibiotics the solution has considerable influence on prescribing by general practitioners, even when they judge that antibiotics are not definitely indicated What this study adds General practitioners judged that about four in five adults with acute bronchitis did not definitely need antibiotics on the day they consulted Antibiotic use was reduced by a quarter in such patients, who received verbal and written information and reassurance in addition to a prescription for antibiotics Sharing with the patient the uncertainty about the decision to prescribe seems safe and effective

Interleukin-33 Induces Protective Effects in Adipose Tissue Inflammation During Obesity in Mice

Rationale: Chronic low-grade inflammation involving adipose tissue likely contributes to the metabolic consequences of obesity. The cytokine interleukin (IL)-33 and its receptor ST2 are expressed in adipose tissue, but their role in adipose tissue inflammation during obesity is unclear. Objective: To examine the functional role of IL-33 in adipose tissues and investigate the effects on adipose tissue inflammation and obesity in vivo. Methods and Results: We demonstrate that treatment of adipose tissue cultures in vitro with IL-33 induced production of Th2 cytokines (IL-5, IL-13, IL-10) and reduced expression of adipogenic and metabolic genes. Administration of recombinant IL-33 to genetically obese diabetic (ob/ob) mice led to reduced adiposity, reduced fasting glucose and improved glucose and insulin tolerance. IL-33 also induced accumulation of Th2 cells in adipose tissue and polarization of adipose tissue macrophages toward an M2 alternatively activated phenotype (CD206+), a lineage associated with protection against obesity-related metabolic events. Furthermore, mice lacking endogenous ST2 fed high-fat diet had increased body weight and fat mass and impaired insulin secretion and glucose regulation compared to WT controls fed high-fat diet. Conclusions: In conclusion, IL-33 may play a protective role in the development of adipose tissue inflammation during obesity.

Potential use of oxygen as a metabolic biosensor in combination with T2*-weighted MRI to define the ischemic penumbra

We describe a novel magnetic resonance imaging technique for detecting metabolism indirectly through changes in oxyhemoglobin:deoxyhemoglobin ratios and T2* signal change during ‘oxygen challenge’ (OC, 5 mins 100% O2). During OC, T2* increase reflects O2 binding to deoxyhemoglobin, which is formed when metabolizing tissues take up oxygen. Here OC has been applied to identify tissue metabolism within the ischemic brain. Permanent middle cerebral artery occlusion was induced in rats. In series 1 scanning (n = 5), diffusion-weighted imaging (DWI) was performed, followed by echo-planar T2* acquired during OC and perfusion-weighted imaging (PWI, arterial spin labeling). Oxygen challenge induced a T2* signal increase of 1.8%, 3.7%, and 0.24% in the contralateral cortex, ipsilateral cortex within the PWI/DWI mismatch zone, and ischemic core, respectively. T2* and apparent diffusion coefficient (ADC) map coregistration revealed that the T2* signal increase extended into the ADC lesion (3.4%). In series 2 (n = 5), FLASH T2* and ADC maps coregistered with histology revealed a T2* signal increase of 4.9% in the histologically defined border zone (55% normal neuronal morphology, located within the ADC lesion boundary) compared with a 0.7% increase in the cortical ischemic core (92% neuronal ischemic cell change, core ADC lesion). Oxygen challenge has potential clinical utility and, by distinguishing metabolically active and inactive tissues within hypoperfused regions, could provide a more precise assessment of penumbra.

Shear banding phenomena in ultrasoft colloidal glasses

We explore the nonlinear rheological response of a soft gel formed by a crowded colloidal star polymer and focus on the occurrence of a stress plateau, marked hysteresis, and yield stress in its flow curve. With the aid of nuclear magnetic resonance velocimetry we find evidence for fluctuations in the flow behavior across the gap of the concentric cylindrical Couette device, in association with a degree of apparent slip at the inner wall. The time scale of the these fluctuations appears rapid (with respect to the measurement time per shear rate in the flow curve), on the order of tens to hundreds of milliseconds, with the speed of fluctuations associated with the flow history of the sample. Our velocity profile analysis suggests a qualitative model in which intermittent changes due to jamming/unjamming transitions occur, analogous to cage dynamics in colloidal glasses.

Rheo-NMR phenomena of wormlike micelles

Using a combination of rheology and nuclear magnetic resonance (NMR) spectroscopy/velocimetry we demonstrate the existence of shear banding fluctuations under Couette flow of the micellar system 10% w/v cetylpyridinium chloride and sodium salicylate (CPyCl-NaSal) molar ratio 2 : 1 in 0.5 M NaCl in either HO or HO, using both time-averaged and real-time measurements. These shear banding fluctuations are consistent not only with the shear stress fluctuations observed in rheological measurements but also with fluctuations in the change of the constrained fraction of the amphiphile chain (Δ) observed in H-NMR spectroscopy experiments. Using H-NMR spectroscopy on a deuterated probe molecule (-decane) located in the wormlike micellar interior, direct measurement of the shear-induced nematic phase transition is reported.

T2*-weighted magnetic resonance imaging with hyperoxia in acute ischemic stroke

We describe the first clinical application of transient hyperoxia (“oxygen challenge”) during T2*‐weighted magnetic resonance imaging (MRI), to detect differences in vascular deoxyhemoglobin between tissue compartments following stroke.

Penumbra Detection using PWI/DWI Mismatch MRI in a Rat Stroke Model with and without Comorbidity: Comparison of Methods

Perfusion-diffusion (perfusion-weighted imaging (PWI)/diffusion-weighted imaging (DWI)) mismatch is used to identify penumbra in acute stroke. However, limitations in penumbra detection with mismatch are recognized, with a lack of consensus on thresholds, quantification and validation of mismatch. We determined perfusion and diffusion thresholds from final infarct in the clinically relevant spontaneously hypertensive stroke-prone (SHRSP) rat and its normotensive control strain, Wistar-Kyoto (WKY) and compared three methods for penumbra calculation. After permanent middle cerebral artery occlusion (MCAO) (WKY n=12, SHRSP n=15), diffusion-weighted (DWI) and perfusion-weighted (PWI) images were obtained for 4 hours post stroke and final infarct determined at 24 hours on T2 scans. The PWI/DWI mismatch was calculated from volumetric assessment (perfusion deficit volume minus apparent diffusion coefficient (ADC)-defined lesion volume) or spatial assessment of mismatch area on each coronal slice. The ADC-derived lesion growth provided the third, retrospective measure of penumbra. At 1 hour after MCAO, volumetric mismatch detected smaller volumes of penumbra in both strains (SHRSP: 31±50 mm3, WKY: 22±59 mm3, mean±s.d.) compared with spatial assessment (SHRSP: 36±15 mm3, WKY: 43±43 mm3) and ADC lesion expansion (SHRSP: 41±45 mm3, WKY: 65±41 mm3), although these differences were not statistically significant. Spatial assessment appears most informative, using both diffusion and perfusion data, eliminating the influence of negative mismatch and allowing the anatomical location of penumbra to be assessed at given time points after stroke.

High-resolution diffusion tensor imaging of fixed brain in a mouse model of Pelizaeus–Merzbacher disease: comparison with quantitative measures of white matter pathology

Diffusion tensor imaging (DTI) is a powerful technique for the noninvasive assessment of the central nervous system. To facilitate the application of this technique to in vivo studies, we characterised a mouse model of the leukodystrophy, Pelizaeus–Merzbacher disease (PMD), comparing high‐resolution ex vivo DTI findings with quantitative histological analysis of selected areas of the brain. The mice used in this study (Plp1‐transgenic) carry transgenic copies of the Plp1 gene and are models for PMD as a result of gene duplication. Plp1 transgenic mice display a mild ataxia and experience frequent seizures around the time at which they were imaged. Axial (λ1) and radial (RD) diffusivities and fractional anisotropy (FA) data were analysed using an exploratory whole‐brain voxel‐based method, a voxel‐based approach using tract‐based spatial statistics (TBSS), and by application of conventional region of interest (ROI) analyses to selected white matter tracts. Raw t value maps and TBSS analyses indicated widespread changes throughout the brain of Plp1‐transgenic mice compared with the wild‐type. ROI analyses of the corpus callosum, anterior commissure and hippocampal fimbria showed that FA was reduced significantly, whereas λ1 and RD were increased significantly, in Plp1‐transgenic mice compared with the wild‐type. The DTI data derived from ROI analyses were subsequently compared with histological measures taken in the same regions. These revealed an almost complete absence of myelin, preservation of axons, marked astrocytosis and increased or unchanged cell densities. These data contribute to our growing understanding of the basis of anisotropic water diffusion in the normal and diseased nervous system. Copyright

Stroke penumbra defined by an MRI-based oxygen challenge technique: 1. Validation using [14C]2-deoxyglucose autoradiography

Accurate identification of ischemic penumbra will improve stroke patient selection for reperfusion therapies and clinical trials. Current magnetic resonance imaging (MRI) techniques have limitations and lack validation. Oxygen challenge T*2 MRI (T*2 OC) uses oxygen as a biotracer to detect tissue metabolism, with penumbra displaying the greatest T*2 signal change during OC. [14C]2-deoxyglucose (2-DG) autoradiography was combined with T*2 OC to determine metabolic status of T*2-defined penumbra. Permanent middle cerebral artery occlusion was induced in anesthetized male Sprague-Dawley rats (n = 6). Ischemic injury and perfusion deficit were determined by diffusion- and perfusion-weighted imaging, respectively. At 147 ± 32 minutes after stroke, T*2 signal change was measured during a 5-minute 100% OC, immediately followed by 125 μCi/kg 2-DG, intravenously. Magnetic resonance images were coregistered with the corresponding autoradiograms. Regions of interest were located within ischemic core, T*2-defined penumbra, equivalent contralateral structures, and a region of hyperglycolysis. A T*2 signal increase of 9.22% ± 3.9% (mean ± s.d.) was recorded in presumed penumbra, which displayed local cerebral glucose utilization values equivalent to contralateral cortex. T*2 signal change was negligible in ischemic core, 3.2% ± 0.78% in contralateral regions, and 1.41% ± 0.62% in hyperglycolytic tissue, located outside OC-defined penumbra and within the diffusion abnormality. The results support the utility of OC-MRI to detect viable penumbral tissue following stroke.

Magnetic Resonance Imaging of Structure, Diffusivity, and Copper Immobilization in a Phototrophic Biofilm

ABSTRACT Magnetic resonance imaging (MRI) was used to spatially resolve the structure, water diffusion, and copper transport of a phototrophic biofilm and its fate. MRI was able to resolve considerable structural heterogeneity, ranging from classical laminations ∼500 μm thick to structures with no apparent ordering. Pulsed-field gradient (PFG) analysis spatially resolved water diffusion coefficients which exhibited relatively little or no attenuation (diffusion coefficients ranged from 1.7 × 10−9 m2 s−1 to 2.2 × 10−9 m2 s−1). The biofilm was then reacted with a 10-mg liter−1 Cu2+ solution, and transverse-parameter maps were used to spatially and temporally map copper immobilization within the biofilm. Significantly, a calibration protocol similar to that used in biomedical research successfully quantified copper concentrations throughout the biofilm. Variations in Cu concentrations were controlled by the biofilm structure. Copper immobilization was most rapid (∼5 mg Cu liter−1 h−1) over the first 20 to 30 h and then much slower for the remaining 60 h of the experiment. The transport of metal within the biofilm is controlled by both diffusion and immobilization. This was explored using a Bartlett and Gardner model which examined both diffusion and adsorption through a hypothetical film exhibiting properties similar to those of the phototrophic biofilm. Higher adsorption constants (K) resulted in longer lag times until the onset of immobilization at depth but higher actual adsorption rates. MRI and reaction transport models are versatile tools which can significantly improve our understanding of heavy metal immobilization in naturally occurring biofilms.