407-3 Glutathione Peroxidase Prevents the Inactivation of Nitric Oxide and Restores the Inhibition of Platelet Function by S-Nitrosothiols

The interaction of nitric oxide (NO) with reactive oxygen species in the vasculature can inactivate NO leading to potentially adverse vascular consequences. Glutathione peroxidases (GSH-Px), a family of antioxidant enzymes present at reduced concentrations in plasma and platelets of patients with coronary artery disease, catalyze the reduction of hydrogen peroxide and lipid hydroperoxides (LOOH) by glutathione. Given the role of LOOH in platelet eicosanoid metabolism and their presence in atherosclerotic plaque, we investigated the effect of GSH-Px on the inhibition of platelet function by the naturally occurring NO donor, S-nitroso-glutathione (SNO-Glu). Subthreshold inhibitory concentrations of SNO-Glu were added to platelet-rich plasma, and aggregation was induced by arachidonate. The addition of GSHPx (0.2–20U/ml) to this system led to a dose-dependent inhibition of platelet aggregation with an IC50= 0.6U/ml GSH-Px (p < 0.05 by ANOVA). Superoxide dismutase (0.1–200U/ml), catalase (0.1–200U/ml), or GSH-Px without SNO-Glu did not alter platelet aggregation responses. The addi ion of GSH-Px to a subthreshold inhibitory concentration of sodium nitroprusside also did not affect platelet aggregation responses. LOOH increased platelet aggregation in the presence of SNO-Glu, an effect reversed by GSH-Px. Levels of cGMP were measured after platelets were incubated with SNO-Glu, exogenous LOOH, and GSH-Px. SNO-Glu alone increased cGMP levels, and this effect was attenuated by LOOH but restored by the addition of GSH-Px. GSH-Px activity was equivalent with either SNO-Glu or glutathione as cosubstrate. Incubation of SNO-Glu with GSH-Px led to a 48.5% decrease in the concentration of SNO-Glu as determined by HPLC-electrochemical detection. Incubation of SNO-Glu with albumin in the presence of GSH-Px led to increased formation of S-nitroso-albumin, a prevalent reservoir of EDRF in plasma. These results show that GSH-Px, at physiologically relevant concentrations, has a potent effect on NO-induced inhibition of platelet aggregation and that this enzyme may have two functions: (i) metabolism of LOOH, thereby preventing its inactivation of NO; and (ii) metabolism of SNO-Glu, thereby liberating NO and/or supporting further transnitrosation reactions These findings suggest that GSH-Px, in addition to its antioxidant functions, regulates the availability of NO in the vasculature and possibly alters plateletdependent thrombotic events

Change over time in functional capacity and self-perceived health status for patients with chronic musculoskeletal pain: a registry-based longitudinal study.

BACKGROUND AND AIMS Chronic musculoskeletal pain is a major public health problem worldwide. Both self-reported functional capacity and self-perceived health status are reduced in patients with chronic musculoskeletal pain. Previous studies mostly assessed functional capacity through self-reported questionnaires instead of objective measurements. The aim of this study, therefore, is to assess the amount of change over time and its clinical meaningfulness in functional capacity and self-perceived health status of patients with chronic musculoskeletal pain undergoing Bern Ambulatory Interprofessional Rehabilitation (BAI-Reha). METHODS The registry-based longitudinal cohort study with prospectively collected data from a rehabilitation programme took place in a real-life setting. Patients (n = 81) with chronic musculoskeletal pain took part in the BAI-Reha. The main outcomes were the six-minute-walk test (6MWT), the safe maximum floor-to-waist lift (SML) and the European Quality of Life and Health measure visual analogue scale (EQ VAS). Timepoints of measurement were at baseline and post-BAI-Reha (i.e., at 4 months). The quantity of interest was the adjusted time effect (point estimate, 95% confidence interval, and p-value for testing the null hypothesis of no change over time). Statistical significance (α = 0.05) and clinical meaningfulness of the mean value change over time were assessed using predefined thresholds (six-minute-walk test 50 m, SML 7 kg, and EQ VAS 10 points). RESULTS The linear mixed model analysis showed a statistically significant change over time for the six-minute-walk test (mean value change 56.08 m, 95% CI [36.13, 76.03]; p <0.001), SML (mean value change 3.92 kg, 95% CI [2.66, 5.19]; p <0.001), and EQ VAS (mean value change 9.58 points, 95% CI [4.87, 14.28]; p <0.001). Moreover, the improvement in the six-minute-walk test is clinically meaningful (mean value change 56.08 m) and almost clinically meaningful (mean value change 9.58 points) in the EQ VAS. CONCLUSION Patients walk further, lift more weight, and feel healthier after interprofessional rehabilitation when compared to baseline measurement. These findings confirm and add to previous results. IMPLICATIONS We encourage other providers of rehabilitation for patients with chronic musculoskeletal pain to measure functional capacity with objective outcome variables and to use self-reported outcome measures in addition to self-perceived health status. The well-established assessments used in this study are suitable for this purpose

Asymmetric Thermal Lineshape Broadening in a Gapped 3-Dimensional Antiferromagnet - Evidence for Strong Correlations at Finite Temperature

It is widely believed that magnetic excitations become increasingly incoherent as temperature is raised due to random collisions which limit their lifetime. This picture is based on spin-wave calculations for gapless magnets in 2 and 3 dimensions and is observed experimentally as a symmetric Lorentzian broadening in energy. Here, we investigate a three-dimensional dimer antiferromagnet and find unexpectedly that the broadening is asymmetric - indicating that far from thermal decoherence, the excitations behave collectively like a strongly correlated gas. This result suggests that a temperature activated coherent state of quasi-particles is not confined to special cases like the highly dimerized spin-1/2 chain but is found generally in dimerized antiferromagnets of all dimensionalities and perhaps gapped magnets in general

Quantum spin chain as a potential realization of the Nersesyan-Tsvelik model

It is well established that long-range magnetic order is suppressed in magnetic systems whose interactions are low-dimensional. The prototypical example is the S-1/2 Heisenberg antiferromagnetic chain (S-1/2 HAFC) whose ground state is quantum critical. In real S-1/2 HAFC compounds interchain coupling induces long-range magnetic order although with a suppressed ordered moment and reduced N\'eel temperature compared to the Curie-Weiss temperature. Recently, it was suggested that order can also be suppressed if the interchain interactions are frustrated, as for the Nersesyan-Tsvelik model. Here, we study the new S-1/2 HAFC, (NO)[Cu(NO3)3]. This material shows extreme suppression of order which furthermore is incommensurate revealing the presence of frustration consistent with the Nersesyan-Tsvelik model

RAD51C – a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC)

INTRODUCTION: Head and neck squamous cell carcinomas (HNSSCs) are one of the leading causes of cancer-associated death worldwide. Although certain behavioral risk factors are well recognized as tumor promoting, there is very little known about the presence of predisposing germline mutations in HNSCC patients. METHODS: In this study, we analyzed 121 individuals with HNSCCs collected at our institution for germline alterations in the newly identified cancer susceptibility gene RAD51C. RESULTS: Sequencing of all exons and the adjacent introns revealed five distinct heterozygous sequence deviations in RAD51C in seven patients (5.8%). A female patient without any other risk factors carried a germline mutation that disrupted the canonical splice acceptor site of exon 5 (c.706-2A>G). CONCLUSIONS: As there are only a few publications in the literature identifying germline mutations in head and neck cancer patients, our results provide the first indication that paralogs of RAD51, recently described as mutated in breast and ovarian cancer patients, might also be candidates for genetic risk factors in sporadic squamous cell carcinomas of the head and neck

An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome

<p>Abstract</p> <p>Background</p> <p>A combined aplasia, hypoplasia or atresia of lacrimal points and salivary glands is rarely diagnosed. Those patients suffer from epiphora, xerostomia and severe dental caries. This phenotype represents the autosomal-dominant aplasia of lacrimal and salivary glands syndrome (ALSG). Recently, aberrations of the <it>Fibroblast Growth Factor 10 </it>(<it>FGF10</it>) gene have been identified to be causative for this disorder.</p> <p>Methods</p> <p>We performed a sequence analysis of the <it>FGF10 </it>gene of a patient with ALSG-syndrome and his also affected brother as well as 193 controls. The FGF10 transcript was analyzed using RNA extracted from primary fibroblasts of the patient's mucosa.</p> <p>Results</p> <p>We detected a novel heterozygous sequence variation in intron 2 (c.430-1, G > A) causing the ALSG syndrome. The alteration derogates the regular splice acceptor site and leads to the use of a new splice acceptor site 127 bp upstream of exon 3. The aberration was detected in the genomic DNA derived from two affected brothers, but not in 193 control individuals. Furthermore, no diseased member of the family displayed additional abnormalities that are indicative for the clinically overlapping lacrimo-auriculo-dento-digital syndrome (LADD).</p> <p>Conclusion</p> <p>This family-based approach revealed an intronic variation of the <it>FGF10 </it>gene causing ALSG-syndrome. Our results expand the mutational and clinical spectrum of the ALSG syndrome.</p