Is there an association between angiotensin-converting enzyme gene variants and chronic nonproductive cough?

Background: It is unclear why some patients develop a chronic nonproductive cough. Angiotensin-converting enzyme (ACE) inactivates tussive peptides in the airways such as bradykinin and tachykinins. An insertion/deletion polymorphism in the ACE gene accounts for variation in ACE levels, and patients with the II genotype have lowest serum ACE levels compared with ID and DD genotypes. We hypothesized that the II genotype would be associated with increased risk of developing a chronic cough.

Materials and methods: We recruited 47 patients (33 women), referred for evaluation of cough (median cough duration, 24 months; range, 2 to 240 months). Cough patients were evaluated using a comprehensive diagnostic protocol, and cough reflex sensitivity was measured using a capsaicin inhalation challenge. ACE genotyping was performed on DNA samples from patients using the polymerase chain reaction followed by agarose gel electrophoresis. ACE genotypes in patients with chronic cough were compared with those in 199 healthy control subjects. Serum ACE levels were determined using a colorimetric assay.

Results: Genotype frequencies for the ACE gene were similar between patients and control subjects. There was no correlation between capsaicin sensitivity and ACE genotypes or serum ACE levels.

Conclusion: Susceptibility to develop chronic cough is not associated with ACE genotype.

Identification of tone duration, line length and letter position: An experimental approach to timing and working memory deficits in schizophrenia.

Patients with schizophrenia display numerous cognitive deficits, including problems in working memory, time estimation, and absolute identification of stimuli. Research in these fields has traditionally been conducted independently. We examined these cognitive processes using tasks that are structurally similar and that yield rich error data. Relative to healthy control participants (n = 20), patients with schizophrenia (n = 20) were impaired on a duration identification task and a probed-recall memory task but not on a line-length identification task. These findings do not support the notion of a global impairment in absolute identification in schizophrenia. However, the authors suggest that some aspect of temporal information processing is indeed disturbed in schizophrenia.

Accelerated apoptosis in SLE neutrophils cultured with anti-dsDNA antibody isolated from SLE patient serum: a pilot study.

Increased numbers of apoptotic neutrophils are found in SLE, related to disease activity and levels of anti-dsDNA antibody. The mechanism of increased apoptosis is not clear, but anti-dsDNA antibody has been shown to induce apoptosis in neutrophils from normal subjects and in certain cell lines. In this study, polyclonal anti-dsDNA antibody was isolated from the serum of a patient with active SLE, and was shown to substantially accelerate apoptosis in neutrophils from SLE patients as compared with neutrophils from healthy control or rheumatoid arthritis subjects.

Distinctive effects of G-CSF, GM-CSF and TNFalpha on neutrophil apoptosis in systemic lupus erythematosus.

OBJECTIVE: To investigate the influence of culture with G-CSF GM-CSF and TNFalpha on neutrophil apoptosis, comparing neutrophils from SLE patients with rheumatoid arthritis (RA) patients and healthy control subjects. METHODS: Neutrophils were isolated from SLE (n= 10), RA (n= 10) and healthy control subjects (n= 10), and cultured with two different concentrations of G-CSF, GM-CSF and TNFalpha. Proportion of apoptotic neutrophils at T=0, T=2hrs and T=24hrs was measured using FITC-labelled annexinV and flow cytometry. RESULTS: Significantly more neutrophils were apoptotic at T=0 in the SLE subjects than in the other groups (median, range--Control 3.5% (0.3-7.9) SLE 9.5% (2.9-29.1) RA 3.0% (0.4-23.0) p

The CTLA4 + 49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland

Rheumatoid and juvenile idiopathic arthritis (RA, JIA) are chronic inflammatory arthropathies with an autoimmune background. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation. We analyzed the CTLA4 +49A/G and CT60 polymorphisms in cohorts of Northern Irish RA and JIA patients and healthy control subjects using restriction fragment length polymorphism methods. The +49 A allele was increased in RA (61.2%; P=0.02; OR=1.28; 95% C.I.=1.04-1.58) and JIA (61.8%; P=0.14) patients compared to the control population (55.3%). No significant association was observed for the CT60 polymorphism. Haplotype analysis revealed a significantly different distribution of +49 A/G-CT60 haplotypes in RA and JIA patients compared to controls (P value

Cochlin in the eye: Functional implications

Aqueous humor is actively produced in the ciliary epithelium of the anterior chamber and has important functions for the eye. Under normal physiological conditions, the inflow and outflow of the aqueous humor are tightly regulated, but in the pathologic state this balance is lost. Aqueous outflow involves structures of the anterior chamber and experiences most resistance at the level of the trabecular meshwork (TM) that acts as a filter. The modulation of the TM structure regulates the filter and its mechanism remains poorly understood. Proteomic analyses have identified cochlin, a protein of poorly understood function, in the glaucomatous TM but not in healthy control TM from human cadaver eyes. The presence of cochlin has subsequently been confirmed by Western and immunohistochemical analyses. Functionally, cochlin undergoes multimerization induced by shear stress and other changes in the microenvironment. Cochlin along with mucopolysaccharide deposits have been found in the TM of glaucoma patients and in the inner ear of subjects affected by the hearing disorder DNFA9, a late onset, progressive disease that also involves alterations in fluid shear regimes. In vitro, cochlin induces aggregation of primary TM cells suggesting a role in cell adhesion, possibly in mechanosensation, and in modulation of the TM filter.

Molecular detection of exercise-induced free radicals following ascorbate prophylaxis in type 1 diabetes mellitus: a randomised controlled trial

Aims/hypothesis: Patients with type 1 diabetes mellitus are more susceptible than healthy individuals to exercise-induced oxidative stress and vascular endothelial dysfunction, which has important implications for the progression of disease. Thus, in the present study, we designed a randomised double-blind, placebo-controlled trial to test the original hypothesis that oral prophylaxis with vitamin C attenuates rest and exercise-induced free radical-mediated lipid peroxidation in type 1 diabetes mellitus. Methods: All data were collected from hospitalised diabetic patients. The electron paramagnetic resonance spectroscopic detection of spin-trapped a-phenyl-tert-butylnitrone (PBN) adducts was combined with the use of supporting markers of lipid peroxidation and non-enzymatic antioxidants to assess exercise-induced oxidative stress in male patients with type 1 diabetes (HbA1c 7.9±1%, n=12) and healthy controls (HbA1c 4.6±0.5%, n=14). Following participant randomisation using numbers in a sealed envelope, venous blood samples were obtained at rest, after a maximal exercise challenge and before and 2 h after oral ingestion of 1 g ascorbate or placebo. Participants and lead investigators were blinded to the administration of either placebo or ascorbate treatments. Primary outcome was the difference in changes in free radicals following ascorbate ingestion. Resuts: Six diabetic patients and seven healthy control participants were randomised to each of the placebo and ascorbate groups. Diabetic patients (n=12) exhibited an elevated concentration of PBN adducts (p<0.05 vs healthy, n=14), which were confirmed as secondary, lipid-derived oxygen-centred alkoxyl (RO•) radicals (a nitrogen=1.37 mT and aßhydrogen=0.18 mT). Lipid hydroperoxides were also selectively elevated and associated with a depression of retinol and lycopene (p<0.05 vs healthy). Vitamin C supplementation increased plasma vitamin C concentration to a similar degree in both groups (p<0.05 vs pre-supplementation) and attenuated the exercise-induced oxidative stress response (p<0.05 vs healthy). There were no selective treatment differences between groups in the primary outcome variable. Conclusions/ interpretation: These findings are the first to suggest that oral vitamin C supplementation provides an effective prophylaxis against exercise-induced free radical-mediated lipid peroxidation in human diabetic blood.

Dysregulated apoptosis and NFkappaB expression in COPD subjects.

Background
The abnormal regulation of neutrophil apoptosis may contribute to the ineffective resolution of inflammation in chronic lung diseases. Multiple signalling pathways are implicated in regulating granulocyte apoptosis, in particular, NF?B (nuclear factor-kappa B) signalling which delays constitutive neutrophil apoptosis. Although some studies have suggested a dysregulation in the apoptosis of airway cells in chronic obstructive pulmonary disease (COPD), no studies to date have directly investigated if NF?B is associated with apoptosis of airway neutrophils from COPD patients. The objectives of this study were to examine spontaneous neutrophil apoptosis in stable COPD subjects (n = 13), healthy smoking controls (n = 9) and non-smoking controls (n = 9) and to investigate whether the neutrophil apoptotic process in inflammatory conditions is associated with NF?B activation.

Methods
Analysis of apoptosis in induced sputum was carried out by 3 methods; light microscopy, Annexin V/Propidium iodide and the terminal transferase-mediated dUTP nick end-labeling (TUNEL) method. Activation of NF?B was assessed using a flow cytometric method and the phosphorylation state of I?Ba was carried out using the Bio-Rad Bio-Plex phosphoprotein I?Ba assay.

Results
Flow cytometric analysis showed a significant reduction in the percentage of sputum neutrophils undergoing spontaneous apoptosis in healthy smokers and subjects with COPD compared to non-smokers (p < 0.001). Similar findings were demonstrated using the Tunel assay and in the morphological identification of apoptotic neutrophils. A significant increase was observed in the expression of both the p50 (p = 0.006) and p65 (p = 0.006) subunits of NF?B in neutrophils from COPD subjects compared to non-smokers.

Conclusion
These results demonstrate that apoptosis is reduced in the sputum of COPD subjects and in healthy control smokers and may be regulated by an associated activation of NF?B.

Association of VEGF-1499C -> T polymorphism with diabetic nephropathy in type 1 diabetes mellitus

Vascular endothelial growth factor (VEGF) is reported to be implicated in the development of diabetic nephropathy. We performed a case-control study to determine if VEGF-2578C -> A, VEGF-1499C -> T, and VEGF-635G -> C single-nucleotide polymorphisms (SNPs) in the VEGF gene are associated with predisposition to diabetic nephropathy in type I diabetes. Genomic DNA was obtained from Irish type I diabetic individuals with nephropathy (cases, n=242) and those without nephropathy (controls, n=301), in addition to 400 healthy control samples. These samples were genotyped for the three SNPs using TaqMan or Pyrosequencing technology. Chi-squared analyses revealed no significant differences in genotype or allele frequencies in cases versus controls for VEGF-2578C -> A (genotype, P=.58; allele, P=.52) and VEGF-635G -> C (genotype, P=.58; allele, P=.33). However, a positive association with diabetic nephropathy was observed for the VEGF-1499T allele in the Northern Ireland population (P

Identification of MRP-8 (calgranulin A) as a major responsive protein in chronic periodontitis

The purpose of the study was to analyse how the protein composition of the inflammatory exudate associated with chronic periodontitis differed from the exudate in periodontal health. Gingival crevicular fluid (GCF) was collected from sites with chronic periodontal inflammation and from non-diseased sites in healthy control subjects. Microbore HPLC analysis revealed one major difference in GCF protein profiles between healthy controls and periodontitis patients. The protein enhanced in periodontitis patients was identified as migration inhibitory factor-related protein-8 (MRP-8) by a combination of N-terminal amino acid sequencing, mass spectrometry, and SDS-PAGE. Together, these data demonstrate, for the first time, the presence of monomeric MRP-8 in an inflammatory exudate. Whether monomeric MRP-8 is a unique feature of chronic periodontal inflammation is not yet clear, but the chemotactic properties of this peptide support a functional role for MRP-8 in periodontal inflammation. Copyright (C) 2000 John Wiley & Sons, Ltd.

Functional management of ankle sprains: what volume and intensity of walking is undertaken in the first week postinjury:what volume and intensity of walking is undertaken in the first week postinjury

BACKGROUND: Acute ankle sprains are usually managed functionally, with advice to undertake progressive weight-bearing and walking. Mechanical loading is an important modular of tissue repair; therefore, the clinical effectiveness of walking after ankle sprain may be dose dependent. The intensity, magnitude and duration of load associated with current functional treatments for ankle sprain are unclear.

AIM: To describe physical activity (PA) in the first week after ankle sprain and to compare results with a healthy control group.

METHODS: Participants (16-65 years) with an acute ankle sprain were randomised into two groups (standard or exercise). Both groups were advised to apply ice and compression, and walk within the limits of pain. The exercise group undertook additional therapeutic exercises. PA was measured using an activPAL accelerometer, worn for 7 days after injury. Comparisons were made with a non-injured control group.

RESULTS: The standard group were significantly less active (1.2 ± 0.4 h activity/day; 5621 ± 2294 steps/day) than the exercise (1.7 ± 0 .7 h/day, p=0.04; 7886 ± 3075 steps/day, p=0.03) and non-injured control groups (1.7 ± 0.4 h/day, p=0.02; 8844 ± 2185 steps/day, p=0.002). Also, compared with the non-injured control group, the standard and exercise groups spent less time in moderate (38.3 ± 12.7 min/day vs 14.5 ± 11.4 min/day, p=0.001 and 22.5 ± 15.9 min/day, p=0.003) and high-intensity activity (4.1 ± 6.9 min/day vs 0.1 ± 0.1 min/day, p=0.001 and 0.62 ± 1.0 min/day p=0.005).

CONCLUSION: PA patterns are reduced in the first week after ankle sprain, which is partly ameliorated with addition of therapeutic exercises. This study represents the first step towards developing evidence-based walking prescription after acute ankle sprain.

Deficiencies of folate and vitamin B-6 exert distinct effects on homocysteine, serine, and methionine kinetics

Folate and vitamin B-6 act in generating methyl groups for homocysteine remethylation, but the kinetic effects of folate or vitamin B-6 deficiency are not known. We used an intravenous primed, constant infusion of stable isotope-labeled serine, methionine, and leucine to investigate one-carbon metabolism in healthy control (n = 5), folate-deficient (n = 4), and vitamin B-6-deficient (n = 5) human subjects. The plasma homocysteine concentration in folate-deficient subjects [15.9 +/-2.1 (SD) mu mol/l] was approximately two times that of control (7.4 +/-1.7 mmol/l) and vitamin B-6-deficient (7.7 +/-2.1 mmol/l) subjects. The rate of methionine synthesis by homocysteine remethylation was depressed (P = 0.027) in folate deficiency but not in vitamin B-6 deficiency. For all subjects, the homocysteine remethylation rate was not significantly associated with plasma homocysteine concentration (r = -0.44, P = 0.12). The fractional synthesis rate of homocysteine from methionine was positively correlated with plasma homocysteine concentration (r = 0.60, P = 0.031), and a model incorporating both homocysteine remethylation and synthesis rates closely predicted plasma homocysteine levels (r = 0.85, P = 0.0015). Rates of homocysteine remethylation and serine synthesis were inversely correlated (r = -0.89, P < 0.001). These studies demonstrate distinctly different metabolic consequences of vitamin B-6 and folate deficiencies.

Volume reduction of the corpus callosum and its relationship with deficits in interhemispheric transfer of information in recent-onset psychosis

The present study aimed to investigate the presence of corpus callosum (CC) volume deficits in a population-based recent-onset psychosis (ROP) sample, and whether CC volume relates to interhemispheric communication deficits. For this purpose, we used voxel-based morphometry comparisons of magnetic resonance imaging data between ROP (n = 122) and healthy control (n = 94) subjects. Subgroups (38 ROP and 39 controls) were investigated for correlations between CC volumes and performance on the Crossed Finger Localization Test (CFLT). Significant CC volume reductions in ROP subjects versus controls emerged after excluding substance misuse and non-right-handedness. CC reductions retained significance in the schizophrenia subgroup but not in affective psychoses subjects. There were significant positive correlations between CC volumes and CFLT scores in ROP subjects, specifically in subtasks involving interhemispheric communication. From these results, we can conclude that CC volume reductions are present in association with ROP. The relationship between such deficits and CFLT performance suggests that interhemispheric communication impairments are directly linked to CC abnormalities in ROP. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q(84)-M(86)-K(88), W(108)-M(112)-R(116), and L(144)-M(148)-R(149). These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met(86), Met(112), and Met(148)) in diabetic patients. The increase in Met(O) in the diabetic group did not correlate with other biomarkers of oxidative stress, such as N(epsilon)-malondialdehyde-lysine or N(epsilon)-(carboxymethyl)lysine, in plasma or lipoproteins. The higher Met(O) content in apoA-I from diabetic patients is consistent with increased levels of lipid peroxidation products in plasma in diabetes. Using the methods developed here, future studies can address the relationship between Met(O) in apoA-I and the risk, development, or progression of the vascular complications of diabetes.