Can mutations in ELA2, neutrophil elastase expression or differential cell toxicity explain sulphasalazine-induced agranulocytosis?

BACKGROUND: Drug-induced agranulocytosis, a severe side effect marked by a deficit or absolute lack of granulocytic white blood cells, is a rare side-effect of the anti-inflammatory drug sulphasalazine. Mutations in the human neutrophil elastase gene (ELA2), causing increased intracellular concentration of this serine protease, inhibits neutrophil differentiation in severe congenital neutropenia (SCN). Since the clinical symptoms of agranulocytosis and SCN are similar, we hypothesized that it may origin from a common genetic variation in ELA2 or that sulphasalazine may affect human neutrophil elastase activity and protein expression. METHODS: We screened for genetic differences in ELA2 in DNA from 36 patients who had suffered from sulphasalazine-induced agranulocytosis, and compared them with 72 patients treated with sulphasalazine without blood reactions. We also performed in vitro studies of the blood cell lines HL60 and U937 after sulphasalazine exposure with respect to cell survival index, neutrophil elastase protein expression and activity. RESULTS: None of the mutations in ELA2, which previously have been reported to be associated with SCN, was found in this material. Protein expression of human neutrophil elastase in lymphoma U937 cells was not affected by treatment with concentrations equivalent to therapeutic doses. Cell survival of lymphoma U937 and promyelocytic leukemia HL-60 cells was not affected in this concentration range, but exhibited a decreased proliferative capacity with higher sulphasalazine concentrations. Interestingly the promyelocytic cells were more sensitive to sulphasalazine than the lymphoma cell line. CONCLUSION: Neutrophil elastase expression and ELA2 mutations do, however, not seem to be involved in the etilogy of sulphasalazine-induced agranulocytosis. Why sulphasalazine is more toxic to promyelocytes than to lymphocytes remains to be explained

Gravidity, parity and knee breadth at midlife:a population-based cohort study

Abstract Gestation increases the biomechanical loading of lower extremities. Gestational loading may influence anthropometrics of articular surfaces in similar means as bone diaphyseal properties. This study aimed to investigate whether gravidity (i.e. number of pregnancies) and parity (i.e. number of deliveries) is associated with knee breadth among middle-aged women. The study sample comprised 815 women from the Northern Finland Birth Cohort 1966. The median parity count of our sample was 2 and the median gravidity count 3. At the age of 46, questionnaires were used to enquire gravidity and parity, and posteroanterior knee radiographs were used to obtain two knee breadth parameters (tibial plateau mediolateral breadth (TPML) and femoral condylar mediolateral breadth (FCML)) as representatives of articular size. The associations of gravidity and parity with knee breadth were analyzed using general linear models with adjustments for height, weight, leisure-time physical activity, smoking, and education years. Individuals with osteoarthritic changes were excluded from our sample. The mean TPML in our sample was 70.3 mm and the mean FCML 71.6 mm respectively. In the fully adjusted models, gravidity and parity showed positive associations with knee breadth. Each pregnancy was associated with 0.11–0.14% larger knee breath (p < 0.05), and each delivery accounted for an increase of 0.20% in knee breadth (p < 0.01). Between-group comparisons showed that multiparous women had 0.68–1.01% larger knee breath than nulli- and primiparous women (p < 0.05). Pregnancies and deliveries seem to increase the mediolateral breadth of the knee. This increase is potentially associated with increased biomechanical loadings during gestation

Body mass estimation from dimensions of the fourth lumbar vertebra in middle-aged Finns

Abstract Although body mass is not a stable trait over the lifespan, information regarding body size assists the forensic identification of unknown individuals. In this study, we aimed to study the potential of using the fourth lumbar vertebra (L4) for body mass estimation among contemporary Finns. Our sample comprised 1158 individuals from the Northern Finland Birth Cohort 1966 who had undergone measurements of body mass at age 31 and 46 and lumbar magnetic resonance imaging (MRI) at age 46. MRI scans were used to measure the maximum and minimum widths, depths, and heights of the L4 body. Their means and sum were calculated together with vertebral cross-sectional area (CSA) and volume. Ordinary least squares (OLS) and reduced major axis (RMA) regression was used to produce equations for body mass among the full sample (n = 1158) and among normal-weight individuals (n = 420). In our data, body mass was associated with all the L4 size parameters (R = 0.093–0.582, p ≤ 0.019 among the full sample; R = 0.243–0.696, p ≤ 0.002 among the normal-weight sample). RMA regression models seemed to fit the data better than OLS, with vertebral CSA having the highest predictive value in body mass estimation. In the full sample, the lowest standard errors were 6.1% (95% prediction interval ±9.6 kg) and 7.1% (±9.1 kg) among men and women, respectively. In the normal-weight sample, the lowest errors were 4.9% (±6.9 kg) and 4.7% (±5.7 kg) among men and women, respectively. Our results indicate that L4 dimensions are potentially useful in body mass estimation, especially in cases with only the axial skeleton available

Accelerometer-measured physical activity is associated with knee breadth in middle-aged Finns:a population-based study

Abstract Background: Articular surface size is traditionally considered to be a relatively stable trait throughout adulthood. Increased joint size reduces bone and cartilage tissue strains. Although physical activity (PA) has a clear association with diaphyseal morphology, the association between PA and articular surface size is yet to be confirmed. This cross-sectional study aimed to clarify the role of moderate-to-vigorous PA (MVPA) in knee morphology in terms of tibiofemoral joint size. Methods: A sample of 1508 individuals from the population-based Northern Finland Birth Cohort 1966 was used. At the age of 46, wrist-worn accelerometers were used to monitor MVPA (≥3.5 METs) during a period of two weeks, and knee radiographs were used to obtain three knee breadth measurements (femoral biepicondylar breadth, mediolateral breadth of femoral condyles, mediolateral breadth of the tibial plateau). The association between MVPA and knee breadth was analyzed using general linear models with adjustments for body mass index, smoking, education years, and accelerometer weartime. Results: Of the sample, 54.8% were women. Most individuals were non-smokers (54.6%) and had 9—12 years of education (69.6%). Mean body mass index was 26.2 (standard deviation 4.3) kg/m2. MVPA was uniformly associated with all three knee breadth measurements among both women and men. For each 60 minutes/day of MVPA, the knee breadth dimensions were 1.8—2.0% (or 1.26—1.42 mm) larger among women (p < 0.001) and 1.4—1.6% (or 1.21—1.28 mm) larger among men (p < 0.001). Conclusions: Higher MVPA is associated with larger tibiofemoral joint size. Our findings indicate that MVPA could potentially increase knee dimensions through similar biomechanical mechanisms it affects diaphyseal morphology, thus offering a potential target in reducing tissue strains and preventing knee problems. Further studies are needed to confirm and investigate the association between articulation area and musculoskeletal health

Finite-Tree Analysis for Constraint Logic-Based Languages

Logic languages based on the theory of rational, possibly infinite, trees have much appeal in that rational trees allow for faster unification (due to the safe omission of the occurs-check) and increased expressivity (cyclic terms can provide very e#cient representations of grammars and other useful objects). Unfortunately, the use of infinite rational trees has problems. For instance, many of the built-in and library predicates are ill-defined for such trees and need to be supplemented by run-time checks whose cost may be significant. Moreover, some widely-used program analysis and manipulation techniques are correct only for those parts of programs working over finite trees. It is thus important to obtain, automatically, a knowledge of the program variables (the finite variables) that, at the program points of interest, will always be bound to finite terms. For these reasons, we propose here a new dataflow analysis, based on abstract interpretation, that captures such information. We present a parametric domain where a simple component for recording finite variables is coupled, in the style of the open product construction of Cortesi et al., with a generic domain (the parameter of the construction) providing sharing information. The sharing domain is abstractly specified so as to guarantee the correctness of the combined domain and the generality of the approach. This finite-tree analysis domain is further enhanced by coupling it with a domain of Boolean functions, called finite-tree dependencies, that precisely captures how the finiteness of some variables influences the finiteness of other variables. We also summarize our experimental results showing how finite-tree analysis, enhanced with finite-tree dependencies, is a practical means of obtaining precise finitenes..