Effect of inhaled corticosteroids on symptom severity and sputum mediator levels in chronic persistent cough

BACKGROUND: Chronic cough often lasts for more than 1 year and is associated with airway inflammation. The effect of inhaled corticosteroids on symptom severity and inflammatory mediator levels in these patients is unknown. OBJECTIVE: We sought to determine whether inhaled corticosteroids reduce cough severity and sputum mediator concentrations in patients with chronic persistent cough. METHODS: We performed a double-blind, randomized, placebo-controlled crossover study with inhaled fluticasone, 500 microg twice daily, and placebo for 14 days in 88 patients with cough for more than 1 year, with normal chest radiography and spirometry results. Outcome measures were a daily cough visual analogue scale and induced sputum concentrations of eosinophilic cationic protein (ECP), myeloperoxidase, leukotriene B(4) (LTB(4)), leukotrienes C(4)/D(4)/E(4) (cysteinyl leukotrienes [Cys-LTs]), prostaglandin E(2) (PGE(2)), IL-8, and TNF-alpha. Sputum cell counts, exhaled nitric oxide levels, and carbon monoxide levels were also measured. RESULTS: There was a significant improvement in the cough visual analogue scale after inhaled fluticasone compared with placebo (mean difference, 1.0; 95% CI, 0.4-1.5; P <.001). LTB(4), Cys-LT, and PGE(2) levels were increased in all causes of cough. Sputum ECP counts, exhaled nitric oxide levels, and carbon monoxide levels decreased significantly after inhaled fluticasone. There was no change in sputum cell counts and other mediator concentrations. CONCLUSION: Cough severity and sputum ECP levels are modestly reduced by inhaled corticosteroids in patients with chronic cough persisting for more than 1 year. LTB(4), Cys-LT, PGE(2), IL-8, myeloperoxidase, and TNF-alpha levels are unaltered by this therapy. This raises the possibility that drugs targeted to reduce the effects of these mediators might be of benefit in chronic persistent cough.     

Microcomputer Automated System for Measuring Systolic Time Intervals in Response to Exercise and a Psychophysiological Task

A microcomputer automated system for measuring systolic time intervals is described. Electrocardiogram, phonocardiogram, and carotid pulse tracings were measured in 38 healthy male subjects during baseline conditions and during either exercise on a bicycle ergometer or a video-game task. These measurements were recorded on both a traditional 3-channel ECG recorder and the computerized system. Both methods of recording systolic time intervals were independently scored by two different experimenters. In this way, interrater reliability of hand-scoring, intermethod reliability between hand-scoring versus computer-scoring, and interrater reliability of computer-scoring could be assessed. The interrater reliabilities of hand-scored systolic time intervals were generally above .90, ranging from .73 for left ventricular ejection time to .99 for R-R intervals of the ECG, with a mean of .92. The intermethod reliability of the computer versus hand-scored systolic time intervals also proved to be generally above .90, ranging from .76 for S1-S2 components of the phonocardiogram to .99 for R-R, with a mean of .94. The interrater reliabilities of the computer-scored systolic time intervals were all above .90, ranging from .93 for S1-S2 to .99 for R-R, with a mean of .98. These data indicate that the computerized method of scoring systolic time intervals is at least as reliable as the more traditional scoring of paper tracing.     

Randomised controlled trial of near-patient testing for glycated haemoglobin in people with type 2 diabetes mellitus

BACKGROUND: Tight glycaemic control in people with type 2 diabetes can lead to a reduction in microvascular and possibly macrovascular complications. The use of near-patient (rapid) testing offers a potential method to improve glycaemic control. AIM: To assess the effect and costs of rapid testing for glycated haemoglobin (HbA1c) in people with type 2 diabetes. DESIGN OF STUDY: Pragmatic open randomised controlled trial. SETTING: Eight practices in Leicestershire, UK. METHOD: Patients were randomised to receive instant results for HbA1c or to routine care. The principal outcome measure was the proportion of patients with an HbA1c <7% at 12 months. We also assessed costs for the two groups. RESULTS: Of the 681 patients recruited to the study 638 (94%) were included in the analysis. The mean age at baseline was 65.7 years (SD = 10.8 years) with a median (interquartile range) duration of diabetes of 4(1-8) years. The proportion of patients with HbA1c < 7% did not differ significantly between the intervention and control groups (37 versus 38%, odds ratio 0.95 [95% confidence interval = 0.69 to 1.31]) at 12 months follow up. The total cost for diabetes-related care was 390 UK pounds per patient for the control group and 370 UK pounds for the intervention group. This difference was not statistically significant. CONCLUSION: Near-patient testing for HbA1c alone does not lead to outcome or cost benefits in managing people with type 2 diabetes in primary care. Further research is required into the use of rapid testing as part of an optimised patient management model including arrangements for patient review and testing.     

Functional MRI of visuospatial working memory in schizotypal personality disorder: a region-of-interest analysis

BACKGROUND: Functional MRI studies have begun to identify neural networks implicated in visuo-spatial working memory in healthy volunteers and patients with schizophrenia. The study of schizotypal personality disorder (SPD) provides regional analysis in unmedicated patients in the schizophrenia spectrum. METHOD: Unmedicated patients with SPD by DSM-IV criteria and normal controls were assessed with fMRI while performing a visuo-spatial working-memory task. It required the subjects to retain the location of three dots located on the circumference of an imaginary circle and then respond to a query display in which one dot was presented and the subject required to press a button to indicate whether the probe dot location was previously displayed. Subject groups did not differ significantly in spatial memory scores. The exact Talairach and Tournoux coordinates of brain areas previously reported to show activation with spatial memory tasks were assessed. RESULTS: The majority of these locations showed BOLD response activation significantly less in patients during the memory retention period, including the left ventral prefrontal cortex, superior frontal gyrus, intraparietal cortex and posterior inferior gyrus. Regions in the right middle prefrontal and prestriate cortex showed greater activation at a trend level for patients with SPD than for normal controls. In addition, we replicated the findings of increased activation with the task in healthy volunteers in the premotor areas, ventral prefrontal cortex and parietal cortex. CONCLUSIONS: SPD patients show decreased activation compared to healthy volunteers in key frontal regions and we also provided a partial replication of findings reported in healthy subjects.     

The role of antigen-presenting cells and interleukin-12 in the priming of antigen-specific CD4+ T cells by immune stimulating complexes

Immune stimulating complexes (ISCOMs) containing the saponin adjuvant Quil A are vaccine adjuvants that promote a wide range of immune responses in vivo, including delayed-type hypersensitivity (DTH) and the secretion of both T helper 1 (Th1) and Th2 cytokines. However, the antigen-presenting cell (APC) responsible for the induction of these responses has not been characterized. Here we have investigated the role of dendritic cells (DC), macrophages (Mφ) and B cells in the priming of antigen-specific CD4⁺ T cells in vitro by ISCOMs containing ovalbumin (OVA). OVA ISCOMs pulsed bone marrow (BM)-derived DC but not BM Mφ, nor naïve B cells prime resting antigen-specific CD4⁺ T cells, and this response is greatly enhanced if DC are activated with lipopolysaccharide (LPS). Of the APC found in the spleen, only DC had the capacity to prime resting antigen specific CD4⁺ T cells following exposure to OVA ISCOMs in vitro, while Mφ and B cells were ineffective. DC, but not B cells purified from the draining lymph nodes of mice immunized with OVA ISCOMs also primed resting antigen-specific CD4⁺ T cells in vitro, suggesting that DC are also critical in vivo. Using DC and T cells from interleukin (IL)-12 p40^−/− mice, we also identified a crucial role for IL-12 in the priming of optimal CD4⁺ T cell responses by OVA ISCOMs. We suggest that DC are the principal APC responsible for the priming of CD4⁺ T cells by ISCOMs in vivo and that directed targeting of these vectors to DC may enhance their efficancy as vaccine adjuvants.     

Patterns of expression of fibrinolytic genes and matrix metalloproteinase-9 in dissecting aortic aneurysms.

Although extensive tissue remodeling occurs during the various phases of aortic dissection, the underlying proteinases remain to be identified. Matrix metalloproteinase-9 (MMP-9) and components of the fibrinolytic system have been implicated in numerous tissue remodeling events and were therefore analyzed in surgical specimens of acute (n = 9), subacute (n = 4), and chronic (n = 7) aortic dissection by in situ hybridization. In the acute phase, intense plasminogen activator inhibitor 1 (PAI-1) gene expression was apparent in areas interfacing the dissecting hematoma, but no tissue-type PA (t-PA), urokinase-type PA (u-PA), or MMP-9 mRNAs were detected. Although PAI-1 mRNA was still present in the subacute phase, t-PA, u-PA, and MMP-9 mRNAs were now obvious, with PA gene expression co-localizing with areas of PAI-1 gene expression. In the chronic phase, PAI-1 mRNA was demonstrated around erythrocyte extravasations and surrounding bands of medial degeneration. However, there was little expression of PAs in these areas, and no MMP-9 was detected. Thus, fibrinolytic genes and MMP-9 are differentially expressed during the progression of aortic dissections. The kinetics of expression are consistent with acute fibrinolytic shutdown in response to the initial injury, a secondary subacute phase with active proteolysis, and finally, a chronic hypofibrinolytic state. Extensive neovascularization in the chronic phase may further reduce the physical stability of the dissected wall.     

Posture, Place, and Mood Effects on Ambulatory Blood Pressure

Ambulatory blood pressure was studied as a function of posture, place, and mood in 131 subjects classified according to race, gender, and hypertensive status. The effect of posture was significant and explained a substantial proportion of within-subject variability. After controlling for posture, significant place and mood effects were observed when subjects were sitting but not when they were standing. Home vs. work differences in both systolic and diastolic blood pressure were significantly greater in Whites than in Blacks. Similar differences in systolic blood pressure were greater in mild hypertensive than in normotensive subjects. The results of this study underscore the need to control for effects of posture when interpreting ambulatory blood pressure readings.     

Aortic nerve-activated cardioinhibitory neurons and interneurons.

Unit activity evoked by electrical stimulation of the aortic and vagus nerves was recorded in the dorsal motor nucleus and nucleus solitarius of unanesthetized rabbits. Cardioinhibitory cells which showed antidromic activation to stimulation of the vagus nerve and synaptic activation to stimulation of the aortic nerve were localized in lateral dorsal motor nucleus 0.5-0.8 mm anterior of the obex. Additionally, units were found that appeared to be interneurons in the medullary pathway subserving baroreceptor reflex effects on cardioinhibitory neurons. These cells were activated by aortic, and usually vagus, nerve stimulation, appeared to be polysynaptically activated, and were located in medial nucleus solitarius rostral to the obex. Neurons reflecting a cardiac rhythm but not activated by aortic nerve stimulation were also observed.