Pain interferes with daily activities, emotions and sleep in adults with severe, moderate and mild haemophilia: A national cross-sectional survey.

INTRODUCTION: Pain is a major issue in people with haemophilia (PwH). Few studies comprehensively assessed pain in PwH using a biopsychosocial framework and studies in mild PwH are lacking. AIM: To assess pain prevalence, pain interference and their relationship with health-related quality of life (HR-QoL) in male adults with haemophilia. METHODS: A survey was initiated by the Belgian national member organisation. Pain in the last 24 h, pain severity (BPI-PS) and pain interference (BPI-PI) scores were obtained with the Brief Pain Inventory short-form (BPI). HR-QoL was evaluated with the EQ-5D-3L, giving the health utility index (EQ-HUI). Associations between EQ-HUI, BPI-PS and BPI-PI were analysed using Pearson's correlation test. A multiple regression analysed the relationship between HR-QoL and BPI-PS, with age and haemophilia severity as confounding factors. RESULTS: Within 185 respondents (97, 31 and 57 respectively severe, moderate and mild PwH), 67% (118/177) reported pain. In severe, moderate and mild PwH, respectively 86% (79/92), 71% (22/31) and 32% (17/54) reported pain. Median [IQR] BPI-PS, BPI-PI and EQ-HUI scores were respectively 1.5 [.0; 4.0], 1.6 [.0; 3.6] and .81 [.69; 1.00]. PwH reported pain interference with general activity (56% (99/176)), psychosocial factors such as mood (53% (93/175)), and sleep (51% (90/177)). Moderate correlations were found between EQ-HUI, BPI-PS and BPI-PI. After adjusting for age and haemophilia severity, BPI-PS explained 14% of HR-QoL variance. CONCLUSIONS: Pain is a major issue amongst PwH, including people with mild haemophilia. Pain interferes with activities, emotions, sleep and HR-QoL, arguing for a comprehensive biopsychosocial approach of pain.

The combined relationship of occupational and leisure-time physical activity with all-cause mortality among men, accounting for physical fitness.

The aim of this study was to assess the combined relationship of occupational physical activity and leisure-time physical activity with all-cause mortality among men, while accounting for physical fitness. The prospective Belgian Physical Fitness Study included 1,456 male workers aged 40-55 years who were free of coronary heart disease at baseline. Baseline data were collected through questionnaires and clinical examinations from 1976 to 1978. To estimate physical fitness, a submaximal graded exercise test was performed on a bicycle ergometer. Total mortality was registered during a mean follow-up period of 16.9 years. Main results were obtained through Cox proportional hazards regression analysis. A total of 145 deaths were registered during follow-up. After adjustment for confounders, a significantly increased mortality rate was observed in workers who had low levels of both physical activity types (hazard ratio = 2.07, 95% confidence interval: 1.03, 4.19) but also in workers combining high occupational physical activity and low leisure-time physical activity (hazard ratio = 2.04, 95% confidence interval: 1.07, 3.91); the latter finding was particularly pronounced among workers with a low physical fitness level. The present results confirm the existence of a complex interplay among different physical activity settings and fitness levels in predicting mortality.

The perception of work stressors is related to reduced parasympathetic activity.

PURPOSE: The aim was to examine the perception of work stressors in relation to ambulatory measures of heart rate variability (HRV). METHODS: Results are based on a sample of 653 healthy male workers aged 40-55 from the Belgian Physical Fitness Study conducted in 1976-1978. Data were collected by means of self-administered questionnaires and bio-clinical examinations. An index of physical and psychosocial work stressors containing five items was constructed based on the job stress questionnaire. Data on HRV were collected by means of 24-h ambulatory ECG recordings on a working day. Both time and frequency domain measures of HRV were calculated. Associations between work stressors and HRV measures were assessed by means of correlations, multiple linear regression analysis and analysis of (co)variance. RESULTS: The work stressor index was significantly associated with lower pNN50 (the percentage of differences between adjacent normal RR intervals > 50 ms), lower high frequency power and a higher ratio of low frequency over high frequency power. Very similar results were obtained after adjusting for age, language, occupation, smoking, body mass index, total cholesterol, systolic blood pressure and leisure time physical activity. No significant associations were found with SDNN (the standard deviation of all normal RR intervals) and low frequency power. CONCLUSIONS: The perception of work stressors was related to reduced parasympathetic activity in a sample of 653 healthy male workers. These findings support the idea that particularly the parasympathetic component of the autonomic nervous system is related to work stress.

1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one inhibits neurite outgrowth and causes neurite retraction in PC12 cells independently of soluble guanylyl cyclase.

The effect of the potent soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) on neurite outgrowth and retraction was investigated in PC12 cells and SH-SY5Y human neuroblastoma cells. ODQ inhibited neurite outgrowth and triggered neurite retraction in the cells stimulated with nerve growth factor (NGF), staurosporine, or Y-27632. The nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO) had little effect on neurite outgrowth induced by Y-27632 or staurosporine. In the presence of ODQ, treatment of the cells with the cell-permeable cGMP analogue 8-bromo-cGMP failed to retrigger Y-27632- and staurosporine-induced neurite outgrowth. Furthermore, the depletion of sGC by RNA interference failed to prevent Y-27632- and staurosporine-induced neurite outgrowth. These results indicate that the NO/sGC/cGMP signaling cascade is not critically involved in ODQ-induced neurite remodeling. The MEK inhibitor PD98059 did not inhibit neurite outgrowth, and Y-27632 and staurosporine did not induce ERK phosphorylation, suggesting that the inhibitory effect of ODQ on neurite outgrowth is independent of the ERK signaling pathway. In contrast, pretreatment with dithionite or a hemin-glutathione mixture reversed the inhibitory effect of ODQ on Y-27632- and staurosporine-induced neurite outgrowth, indicating that ODQ might act on an intracellular redox-sensitive molecule. We conclude that ODQ inhibits Y-27632- and staurosporine-induced neurite outgrowth and triggers neurite retraction in an sGC-independent manner in neuronal cells and suggest that oxidation of unidentified redox-sensitive protein could be responsible for these effects.

A truncation in the RYR1 gene associated with central core lesions in skeletal muscle fibres.

A novel single-nucleotide deletion in exon 100 of the RYR1 gene, corresponding to deletion of nucleotide 14,510 in the human RyR1 mRNA (c14510delA), was identified in a man with malignant hyperthermia and in his two daughters who were normal for malignant hyperthermia. This deletion results in a RyR1 protein lacking the last 202 amino acid residues. All three subjects heterozygotic for the mutated allele presented with a prevalence of type 1 fibres with central cores, although none experienced clinical signs of myopathy. Expression of the truncated protein resulted in non-functional RYR1 calcium release channels. Expression of wild-type and RyR1(R4836fsX4838) proteins resulted in heterozygotic release channels with overall functional properties similar to those of wild-type RyR1 channels. Nevertheless, small differences in sensitivity to calcium and caffeine were observed in heterotetrameric channels, which also presented an altered assembly/stability in sucrose-gradient centrifugation analysis. Altogether, these data suggest that altered RYR1 tetramer assembly/stability coupled with subtle chronic changes in Ca2+ homoeostasis over the long term may contribute to the development of core lesions and incomplete malignant hyperthermia susceptibility penetrance in individuals carrying this novel RYR1 mutation.

G37R SOD1 mutant alters mitochondrial complex I activity, Ca(2+) uptake and ATP production.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu/Zn superoxide dismutase-1 (SOD1) cause familial ALS but the molecular mechanisms whereby these mutations induce motor neuron death remain controversial. Here, we show that stable overexpression of mutant human SOD1 (G37R) - but not wild-type SOD1 (wt-SOD1) - in mouse neuroblastoma cells (N2a) results in morphological abnormalities of mitochondria accompanied by several dysfunctions. Activity of the oxidative phosphorylation complex I was significantly reduced in G37R cells and correlated with lower mitochondrial membrane potential and reduced levels of cytosolic ATP. Using targeted chimeric aequorin we further analyzed the consequences of mitochondrial dysfunction on cellular Ca(2+) handling. Mitochondrial Ca(2+) uptake, elicited by IP(3)-induced Ca(2+) release from endoplasmic reticulum (ER) was significantly reduced in G37R cells, while uptake induced by a brief Ca(2+) pulse was not affected in permeabilized cells. The decreased mitochondrial Ca(2+) uptake resulted in increased cytosolic Ca(2+) transients, whereas ER Ca(2+) load and resting cytosolic Ca(2+) levels were not affected. Together, these findings suggest that the mechanism linking mutant G37R SOD1 and ALS involves mitochondrial respiratory chain deficiency resulting in ATP loss and impairment of mitochondrial and cytosolic Ca(2+) homeostasis.

Reconstruction of ripped-up documents using fragment stack analysis procedures.

Reconstruction of ripped-up documents can be a very time-consuming task for forensic experts. Currently, this task is often carried out using various homespun or loosely defined procedures. Under the main assumption that a (partially) ordered set of fragments can be recovered, we propose and discuss a more formal analysis methodology for this type of reconstruction problem. We discuss several complications that can occur in real-life problems and illustrate the efficiency of the proposed methods. Although several avenues for further research remain, we show that the proposed approach offers both a better understanding of the problem, as well as important strategies for devising very fast manual and semi-automatic fragment reassembly procedures.

Experimental evaluation of the impact of seating depth variations on observed marks on primers.

Although the examination of bullet and primer striae patterns is still a very important task in forensic ballistics, a fundamental explanation or theoretical model for reasoning about the (ir)reproducibility of the observed marks is still non-existing. More specifically, it is still unclear which ammunition production or firing condition parameters may play an important role in the striae and marks formation process. From a practical point of view this situation is unfortunate because a proper knowledge of these parameters and conditions could help underpin and explain certain differences found in actual casework investigations. Additionally, a proper understanding of these issues could allow examiners to select or develop a near-optimal test firing procedure by using more detailed and controlled variations of certain intra- and/or inter-ammunition parameters than the ones that are in use today. In this paper, we discuss the results of an experiment aimed at evaluating the impact of primer seating depth variations on observed primer striae and other marks. First, three sets of cartridge cases with different seating depth intervals were selected. Second, each of these sets were fired consecutively using a selected pistol. Finally, the cartridge cases were examined using both traditional optical microscopes and three-dimensional (3D) profilometer techniques. The results reported in this paper show that in our experiments no important impact of the initial primer seating depth on the observed primer striae patterns could be found, but that the firing pin impression does seem to change if the initial seating depth is larger than a certain threshold.

Testing two methods to create comparable scale scores between the Job Content Questionnaire (JCQ) and JCQ-like questionnaires in the European JACE Study.

BACKGROUND: Scale comparative properties of "JCQ-like" questionnaires with respect to the JCQ have been little known. PURPOSE: Assessing validity and reliability of two methods for generating comparable scale scores between the Job Content Questionnaire (JCQ) and JCQ-like questionnaires in sub-populations of the large Job Stress, Absenteeism and Coronary Heart Disease European Cooperative (JACE) study: the Swedish version of Demand-Control Questionnaire (DCQ) and a transformed Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Project (MONICA) questionnaire. METHOD: A random population sample of all Malmo males and females aged 52-58 (n = 682) years was given a new test questionnaire with both instruments (the JCQ and the DCQ). Comparability-facilitating algorithms were created (Method I). For the transformed Milan MONICA questionnaire, a simple weighting system was used (Method II). RESULTS: The converted scale scores from the JCQ-like questionnaires were found to be reliable and highly correlated to those of the original JCQ. However, agreements for the high job strain group between the JCQ and the DCQ, and between the JCQ and the DCQ (Method I applied) were only moderate (Kappa). Use of a multiple level job strain scale generated higher levels of job strain agreement, as did a new job strain definition that excludes the intermediate levels of the job strain distribution. CONCLUSION: The two methods were valid and generally reliable.