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"THOMPSON, David G"
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Control of enhanced Raman scattering using a DNA-based assembly process of dye-coded nanoparticles
Enhanced Raman scattering from metal surfaces has been investigated for over 30 years
1
. Silver surfaces are known to produce a large effect, and this can be maximized by producing a roughened surface, which can be achieved by the aggregation of silver nanoparticles
2
,
3
,
4
. However, an approach to control this aggregation, in particular through the interaction of biological molecules such as DNA, has not been reported. Here we show the selective turning on of the surface enhanced resonance Raman scattering
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effect on dye-coded, DNA-functionalized, silver nanoparticles through a target-dependent, sequence-specific DNA hybridization assembly that exploits the electromagnetic enhancement mechanism for the scattering. Dye-coded nanoparticles that do not undergo hybridization experience no enhancement and hence do not give surface enhanced resonance Raman scattering. This is due to the massive difference in enhancement from nanoparticle assemblies compared with individual nanoparticles. The electromagnetic enhancement is the dominant effect and, coupled with an understanding of the surface chemistry, allows surface enhanced resonance Raman scattering nanosensors to be designed based on a natural biological recognition process.
Base-pairing drives the assembly of dye-functionalized nanoparticles that have complementary DNA strands attached. This aggregation leads to a massive enhancement of the resonant Raman signal, which may prove useful for sensing applications.
Journal Article
Predicting Aspiration After Hemispheric Stroke from Timing Measures of Oropharyngeal Bolus Flow and Laryngeal Closure
Deglutitive aspiration is common after stroke, affecting up to 50% of patients and predisposing them to pneumonia, yet it is virtually impossible to predict those patients at greatest risk. The aim of this study was to develop a robust predictive model for aspiration after stroke. Swallowing was assessed by digital videofluoroscopy (VF) in 90 patients following hemispheric stroke. Lesion characteristics were determined by computerized tomography (CT) brain scan using the Alberta Stroke Programme Early CT Score (ASPECTS). Aspiration severity was measured using a validated penetration-aspiration scale. The probability of aspiration was then determined from measures of swallowing pathophysiology and lesion location by discriminant analysis. Aspiration was observed in 47 (52%) patients, yet despite disrupted swallowing physiology, intrasubject aspiration scores were variable. The best discriminant model combined pharyngeal transit time, swallow response time, and laryngeal closure duration to predict 73.11% of those aspirating (sensitivity = 66.54, specificity = 80.22,
p
> 0.001). The addition of lesion location did not add anything further to the predictive model. We conclude that the pathophysiology of poststroke aspiration is multifactorial but in most cases can be predicted by three key swallowing measurements. These measurements, if translatable into clinical bedside evaluation, may assist with the development of novel measurement and intervention techniques to detect and treat poststroke aspiration.
Journal Article
Explaining oropharyngeal dysphagia after unilateral hemispheric stroke
Oropharyngeal dysphagia occurs in up to a third of patients presenting with a unilateral hemiplegic stroke, yet its neurophysiological basis remains unknown. To explore the relation between cortical motor function of swallowing and oropharyngeal dysphagia, mylohyoid, pharyngeal, and thenar electromyographic responses to stimulation of affected and unaffected hemispheres were recorded in dysphagic and non-dysphagic patients.
The 20 patients studied had unilateral hemispheric stroke confirmed by computed tomography. Eight of them had associated swallowing difficulties. Electromyographic responses were recorded after suprathreshold transcranial magneto-electric stimulation of affected and unaffected hemispheres with a figure-of-eight coil.
Stimulation of the unaffected hemisphere evoked smaller pharyngeal responses in dysphagic patients than in non-dysphagic patients (mean 64 μV, median 48, interquartile range 44–86 vs 118 μV, 81, 73–150) (p < 0·02). With stimulation of the affected hemisphere, the pharyngeal responses were smaller than for the unaffected hemisphere but similar between the two patient groups (26 μV, 0, 0·48 vs 54 μV, 0, 0·80). Dysphagic and non-dysphagic patients showed similar mylohyoid and thenar responses to stimulation of the unaffected hemisphere as well as to stimulation of the affected hemisphere– unaffected mylohyoid (269 μV, 239, 89–372 vs 239 μV, 163, 133–307), thenar (572 μV, 463, 175–638 vs 638 μV, 485, 381–764); affected mylohyoid (60 μV, 41, 0–129 vs 96 μV, 0, 0–195); thenar (259 μV, 258, 0–538 vs 451 μV, 206, 8–717).
The findings indicate that dysphagia after unilateral hemispheric stroke is related to the magnitude of pharyngeal motor representation in the unaffected hemisphere.
Journal Article
Mapping glucose-mediated gut-to-brain signalling pathways in humans
Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role.
Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded.
Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex.
Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway.
•We have identified two distinct CNS responses to glucose in man.•A CCK1 receptor (CCK1R)-dependent BOLD signal increase in the motor cortex.•A CCK1R-independent BOLD signal decrease in the brainstem and hypothalamus.•The BOLD signal decrease was mediated by changes in blood glucose and insulin,
Journal Article
Awareness of Dysphagia by Patients Following Stroke Predicts Swallowing Performance
Patients' awareness of their disability after stroke represents an important aspect of functional recovery. Our study aimed to assess whether patient awareness of the clinical indicators of dysphagia, used routinely in clinical assessment, related to an appreciation of \"a swallowing problem\" and how this awareness influenced swallowing performance and outcome in dysphagic stroke patients. Seventy patients were studied 72 h post hemispheric stroke. Patients were screened for dysphagia by clinical assessment, followed by a timed water swallow test to examine swallowing performance. Patient awareness of dysphagia and its significance were determined by detailed question-based assessment. Medical records were examined at three months. Dysphagia was identified in 27 patients, 16 of whom had poor awareness of their dysphagic symptoms. Dysphagic patients with poor awareness drank water more quickly (5 ml/s vs. <1 ml/s, p = 0.03) and took larger volumes per swallow (10 ml vs. 6 ml, p = 0.04) than patients with good awareness. By comparison, neither patients with good awareness or poor awareness perceived they had a swallowing problem. Patients with poor awareness experienced numerically more complications at three months. Stroke patients with good awareness of the clinical indicators of dysphagia modify the way they drink by taking smaller volumes per swallow and drink more slowly than those with poor awareness. Dysphagic stroke patients, regardless of good or poor awareness of the clinical indicators of dysphagia, rarely perceive they have a swallowing problem. These findings may have implications for longer-term outcome, patient compliance, and treatment of dysphagia after stroke.
Journal Article
Guided self-management and patient-directed follow-up of ulcerative colitis: a randomised trial
Ulcerative colitis is managed mainly in secondary care by regular outpatient reviews done by specialist clinicians. Alternatives would be to discharge patients to primary care or to provide open-access clinics, but neither of these options reduce patients' dependency on doctors or allow patients' involvement in disease management. We did a randomised controlled trial to assess an alternative to traditional outpatient care.
We randomly assigned 203 patients with ulcerative colitis who were undergoing hospital follow-up to receive patient-centred self-management training and follow-up on request (intervention group), or normal treatment and follow-up (control group). The main outcome was the interval between relapse and treatment, and secondary outcomes were rates of primary and secondary care consultation, quality of life, and acceptability to patients. Analysis was by intention to treat.
Intervention patients had relapses treated within a mean of 14·8 h (SD 19·1) compared with 49·6 h (65·1) in controls (difference 34·8 h [95% Cl 16·4–60·2]). Furthermore, intervention patients compared with controls made significantly fewer visits to hospital (0·9 vs 2·9 per patient per year, difference 2·0 [1·6–2·7]) and to the primary-care physician (0·3 vs 0·9 per patient per year, difference 0·6 [0·2–1·1], p < 0·006). Only two patients in the intervention group preferred traditional management. Health-related quality-of-life scores were unchanged in both groups.
Self-management of ulcerative colitis accelerates treatment provision and reduces doctor visits, and does not increase morbidity. This approach could be used in long-term management of many other chronic diseases to improve health-service provision and use, and to reduce costs.
Journal Article
Functional neuroimaging demonstrates that ghrelin inhibits the central nervous system response to ingested lipid
Objective Gut-derived humoural factors activate central nervous system (CNS) mechanisms controlling energy intake and expenditure, and autonomic outflow. Ghrelin is secreted from the stomach and stimulates food intake and gastric emptying, but the relevant mechanisms are poorly understood. Nutrient-activated CNS systems can be studied in humans by physiological/pharmacological MRI (phMRI). This method has been used to examine the CNS responses to exogenous ghrelin. Design phMRI was used to study the CNS responses in healthy people to a ghrelin bolus (0.3 nmol/kg, intravenous) in the post-prandial state, and an intravenous infusion of ghrelin (1.25 pmol/kg/min) alone and after intragastric lipid (dodecanoate, C12) in people who have fasted. Results A ghrelin bolus decreased the blood oxygenation level dependent (BOLD) signal detected by phMRI in feeding-activated areas of the CNS in the post-prandial state. Infusion of ghrelin reversed the effect of C12 in delaying gastric emptying but had no effect on hunger. Intragastric C12 caused strong bilateral activation of a matrix of CNS areas, including the brain stem, hypothalamus and limbic areas which was attenuated by exogenous ghrelin. Ghrelin infusion alone had a small but significant stimulatory effect on CNS BOLD signals. Conclusion Ghrelin inhibits activation of the hypothalamus and brain stem induced by ingested nutrients, suggesting a role in suppression of gut-derived satiety signals in humans.
Journal Article
Contribution of central sensitisation to the development of non-cardiac chest pain
Non-cardiac chest pain mimics angina pectoris but generally originates from the oesophagus. Visceral hypersensitivity may contribute, but its neurophysiological basis is unclear. We investigated whether central sensitisation, an activity-dependent amplification of sensory transfer in the central nervous system, underlies visceral pain hypersensitivity and non-cardiac chest pain.
We studied 19 healthy volunteers and seven patients with non-cardiac chest pain. Acid was infused into the lower oesophagus. Sensory responses to electrical stimulation were monitored within the acid-exposed lower oesophagus, the non-exposed upper oesophagus, and the cutaneous area of pain referral, before and after the infusion.
In healthy volunteers, acid infusion into the lower oesophagus lowered the pain threshold in the upper oesophagus (mean decrease 18.2% [95% CI 10.4 to 26.0]; p=0.01) and on the chest wall (24.5% [10.2 to 38.7]; p=0.01). Patients with non-cardiac chest pain had a lower resting oesophageal pain threshold than healthy controls (45 [30 to 58] vs 64 [49 to 81] mA; p=0.04). In response to acid infusion, their pain threshold in the upper oesophagus fell further and for longer (mean fall in area under threshold/time curve 26.7 [11.0 to 42.3] vs 5.8 [2.8 to 8.8] units; p=0.04).
The finding of secondary viscerovisceral and viscerosomatic pain hypersensitivity suggests that central sensitisation may contribute to visceral pain disorders. The prolonged visceral pain hypersensitivity in patients with non-cardiac chest pain suggests a central enhancement of sensory transfer. New therapeutic opportunities are therefore possible.
Journal Article