Primary male osteoporosis is associated with enhanced glucocorticoid availability

OBJECTIVE: While systemic glucocorticoids compromise bone metabolism, altered intracellular cortisol availability may also contribute to the pathogenesis of primary male osteoporosis (MO). The objective of this study was to assess whether intracellular cortisol availability is increased in MO due to a distorted local cortisol metabolism. METHODS: Forty-one patients with MO were compared with age- and BMI-matched non-osteoporotic subjects after excluding overt systemic hypercortisolism (N = 41). Cortisol, cortisone and the respective tetrahydro-, 5α-tetrahydro- and total cortisol metabolites were analysed by GC-MS in 24 h urine. Apparent 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme activities, excretion of cortisol metabolites and calcium, and fractional urinary calcium excretion were assessed and related to BMD. RESULTS: Fractional and total urinary calcium excretion negatively correlated with BMD at all (P < 0.05) and at three of five (P < 0.05) measurement sites, respectively. While systemic cortisol was unchanged, apparent 11β-HSD enzyme activity in MO patients (P < 0.01) suggested increased intracellular cortisol availability. Total and fractional urinary calcium excretion was higher, with apparent 11β-HSD enzyme activities consistent with an enhanced intracellular cortisol availability (P < 0.05). CONCLUSION: Apparent 11β-HSD enzyme activities consistent with increased intracellular cortisol availability correlated with urinary calcium loss and reduced bone mineral density in MO. The changes in 11β-HSD activity were associated with both the fractional calcium excretion, suggesting altered renal calcium handling, and the absolute urinary calcium excretion. Both mechanisms could result in a marked bone calcium deficiency if insufficiently compensated for by intestinal calcium uptake.

Comparison of pain-resilient working individuals to population-based case controls with/without momentary low back pain

Background: Few studies have examined the 20% of individuals who never experience an episode of low back pain (LBP). To date, no investigation has been undertaken that examines a group who claim to have never experienced LBP in their lifetime in comparison to two population-based case–control groups with and without momentary LBP. This study investigates whether LBP-resilient workers between 50 and 65 years had better general health, demonstrated more positive health behaviour and were better able to achieve routine activities compared with both case–control groups. Methods: Forty-two LBP-resilient participants completed the same pain assessment questionnaire as a population-based LBP sample from a nationwide, large-scale cross-sectional survey in Switzerland. The LBP-resilient participants were pairwise compared to the propensity score-matched case controls by exploring differences in demographic and work characteristics, and by calculating odds ratios (ORs) and effect sizes. A discriminant analysis explored group differences, while the multiple logistic regression analysis specified single indicators which accounted for group differences. Results: LBP-resilient participants were healthier than the case controls with momentary LBP and achieved routine activities more easily. Compared to controls without momentary LBP, LBP-resilient participants had a higher vitality, a lower workload, a healthier attitude towards health and behaved more healthily by drinking less alcohol. Conclusions: By demonstrating a difference between LBP-resilient participants and controls without momentary LBP, the question that arises is what additional knowledge can be attained. Three underlying traits seem to be relevant about LBP-resilient participants: personality, favourable work conditions and subjective attitudes/attributions towards health. These rationales have to be considered with respect to LBP prevention.

Influence of nest site on the behaviour of laying hens

Low rates of nest acceptance by laying hens are a major problem in commercial poultry farming operations with aviary systems, leading to costly manual collection and cleaning of mislaid eggs. To gain knowledge about factors affecting nest use, laying hens' preferences for different nest locations were tested. Nests are normally installed at one of two sites: against a wall of the hen house or integrated into one tier of the aviary rack The preferences of laying hens for different nest sites have never been examined under commercial conditions. The aim of this study is to investigate whether behavioural differences can be detected between the different nest sites. The study consists of two consecutive trials involving 5027 Lohmann Selected Leghorn hens (LSL) and 601 layer hybrids selected for extensive housing conditions (EXT). The hens were randomly assigned to eight compartments per trial in groups of 355-360 LSL or 300 EXT in a laying hen house. Four compartments were equipped with a Volito Voletage (R) aviary system (VV), and four were equipped with a Rihs Bolegell (R) aviary system (RB), both of which contained either integrated or wall-placed nests when the experiments started. A strongly balanced crossover design with four periods was used. At 36, 44 and 52 weeks of age, the nest site in four out of the eight compartments was switched. Before each change, the fronts of half of the nests were videotaped during the light period, and the behaviour throughout the main laying period was analysed. Furthermore, the numbers of nest eggs and mislaid eggs in each compartment were recorded every day. No differences in the number of mislaid eggs between the two nest sites could be detected, except at the age of 20/21 weeks when hens in VV aviaries mislaid more eggs when nests were integrated (P = 0.0012). More hens stood simultaneously in front of the integrated nests than in front of wall-placed nests (P = 0.015). Activity of the laying hens increased (P = 0.0073), and stationary behavioural patterns declined (P = 0.0093), when the nests were placed by the wall. Hens inspected integrated nests for a longer duration than wall-placed nests, but wall-placed nests were visited more frequently. In addition to the nest site, the width of the platform in front of the nest influenced laying hen behaviour. Compared with narrower platforms, balance movements decreased on wider ones. Additionally, the platform design had to be taken into account as well, given that hens could not stand or walk as securely on wooden slats as on a grid floor. (C) 2011 Elsevier B.V. All rights reserved.

Molecular characterization of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome

We report on a father and daughter with hand-foot-genital syndrome (HFGS) with typical skeletal and genitourinary anomalies due to a 14-residue polyalanine expansion in HOXA13. This is the largest (32 residues) polyalanine tract so far described for any polyalanine mutant protein. Polyalanine expansion results in protein misfolding, cytoplasmic aggregation and degradation; however, HOXA13 polyalanine expansions appear to act as loss of function mutations in contrast to gain of function for HOXD13 polyalanine expansions. To address this paradox we examined the cellular consequences of polyalanine expansions on HOXA13 protein using COS cell transfection and immunocytochemistry. HOXA13 polyalanine expansion proteins form cytoplasmic aggregates, and distribution between cytoplasmic aggregates or the nucleus is polyalanine tract size-dependent. Geldanamycin, an Hsp90 inhibitor, reduces the steady-state abundance of all polyalanine-expanded proteins in transfected cells. We also found that wild-type HOXA13 or HOXD13 proteins are sequestered in HOXA13 polyalanine expansion cytoplasmic aggregates. Thus, the difference between HOXA13 polyalanine expansion loss-of-function and HOXD13 polyalanine expansion dominant-negative effect is not the ability to aggregate wild-type group 13 paralogs but perhaps to variation in activities associated with refolding, aggregation or degradation of the proteins.

Extended resection for thyroid disease has less operative morbidity than limited resection

BACKGROUND: Theodor Kocher, surgeon and Nobel laureate, has influenced thyroid surgery all over the world: his treatment for multinodular goiter-subtotal thyroidectomy-has been the "Gold Standard" for more than a century. However, based on a new understanding of molecular growth mechanisms in goitrogenesis, we set out to evaluate if a more extended resection yields better results. METHODS: Four thousand three hundred and ninety-four thyroid gland operations with 5,785 "nerves at risk" were prospectively analyzed between 1972 and 2002. From 1972 to 1990, the limited Kocher resections were performed, and from 1991 to 2002 a more radical resection involving at least a hemithyroidectomy was performed. RESULTS: The incidence of postoperative nerve palsy was 3.6%; in the first study period and 0.9%; in the second (P < 0.001, Fisher's exact). Postoperative hypoparathyroidism decreased from 3.2%; in the first period to 0.64%; in the second (P < 0.01). The rate of reoperation for recurrent disease was 11.1%; from 1972 to 1990 and 8.5%; from 1991 to 2002 (P < 0.01). CONCLUSIONS: Extended resection for multinodular goiter not only significantly reduced morbidity, but also decreased the incidence of operations for recurrent disease. Our findings in a large cohort corroborate the suggestions that Kocher's approach should be replaced by a more radical resection, which actually was his original intention more than 130 years ago.

Filling the Eastern European gap in millennium-long temperature reconstructions

Tree ring–based temperature reconstructions form the scientific backbone of the current global change debate. Although some European records extend into medieval times, high-resolution, long-term, regional-scale paleoclimatic evidence is missing for the eastern part of the continent. Here we compile 545 samples of living trees and historical timbers from the greater Tatra region to reconstruct interannual to centennial-long variations in Eastern European May–June temperature back to 1040 AD. Recent anthropogenic warming exceeds the range of past natural climate variability. Increased plague outbreaks and political conflicts, as well as decreased settlement activities, coincided with temperature depressions. The Black Death in the mid-14th century, the Thirty Years War in the early 17th century, and the French Invasion of Russia in the early 19th century all occurred during the coldest episodes of the last millennium. A comparison with summer temperature reconstructions from Scandinavia, the Alps, and the Pyrenees emphasizes the seasonal and spatial specificity of our results, questioning those large-scale reconstructions that simply average individual sites.

The Moldable Debugger: A Framework for Developing Domain-Specific Debuggers

Debuggers are crucial tools for developing object-oriented software systems as they give developers direct access to the running systems. Nevertheless, traditional debuggers rely on generic mechanisms to explore and exhibit the execution stack and system state, while developers reason about and formulate domain-specific questions using concepts and abstractions from their application domains. This creates an abstraction gap between the debugging needs and the debugging support leading to an inefficient and error-prone debugging effort. To reduce this gap, we propose a framework for developing domain-specific debuggers called the Moldable Debugger. The Moldable Debugger is adapted to a domain by creating and combining domain-specific debugging operations with domain-specific debugging views, and adapts itself to a domain by selecting, at run time, appropriate debugging operations and views. We motivate the need for domain-specific debugging, identify a set of key requirements and show how our approach improves debugging by adapting the debugger to several domains.

Drilling into debris-rich basal ice at the bottom of the NEEM (Greenland) borehole

After the NEEM (Greenland) deep ice-core drilling was declared terminated with respect to developing stratigraphic climate reconstructions, efforts were turned toward collecting basal ice-sheet debris and, if possible, drilling into the bedrock itself. In 2010, several meters of banded debris-rich ice were obtained under normal ice-drilling operations with the NEEM version of the Hans Tausen (HT) drill, but further penetration was obstructed by a rock in the path of the drill head at 2537.36 m. During short campaigns in 2011 and 2012, attempts were made to penetrate further using various reinforced ice cutters mounted on the HT drill head, tailored to cut through rock. These had some success in penetrating coarse material, but produced severely damaged cutters. Additionally a 51 mm diameter diamond cutting tipped rock drill was adapted to fit the NEEM drill. With this device, several additional meters of core containing subglacial sediments, rocks and rock fragments were collected. With these tools 1.39 m of additional material were obtained during the 2011 field season, and 7.1 m during 2012. Subglacial water refreezing into the newly formed borehole hindered further penetration, and the bedrock interface was not reached before final closure of the NEEM Camp.

CYP17A1 Enzyme Activity Is Linked to Ambulatory Blood Pressure in a Family-Based Population Study

BACKGROUND Genome-wide association studies have linked CYP17A1 coding for the steroid hormone synthesizing enzyme 17α-hydroxylase (CYP17A1) to blood pressure (BP). We hypothesized that the genetic signal may translate into a correlation of ambulatory BP (ABP) with apparent CYP17A1 activity in a family-based population study and estimated the heritability of CYP17A1 activity. METHODS In the Swiss Kidney Project on Genes in Hypertension, day and night urinary excretions of steroid hormone metabolites were measured in 518 participants (220 men, 298 women), randomly selected from the general population. CYP17A1 activity was assessed by 2 ratios of urinary steroid metabolites: one estimating the combined 17α-hydroxylase/17,20-lyase activity (ratio 1) and the other predominantly 17α-hydroxylase activity (ratio 2). A mixed linear model was used to investigate the association of ABP with log-transformed CYP17A1 activities exploring effect modification by urinary sodium excretion. RESULTS Daytime ABP was positively associated with ratio 1 under conditions of high, but not low urinary sodium excretion (P interaction <0.05). Ratio 2 was not associated with ABP. Heritability estimates (SE) for day and night CYP17A1 activities were 0.39 (0.10) and 0.40 (0.09) for ratio 1, and 0.71 (0.09) and 0.55 (0.09) for ratio 2 (P values <0.001). CYP17A1 activities, assessed with ratio 1, were lower in older participants. CONCLUSIONS Low apparent CYP17A1 activity (assessed with ratio 1) is associated with elevated daytime ABP when salt intake is high. CYP17A1 activity is heritable and diminished in the elderly. These observations highlight the modifying effect of salt intake on the association of CYP17A1 with BP.

Practical domain-specific debuggers using the Moldable Debugger framework

Understanding the run-time behavior of software systems can be a challenging activity. Debuggers are an essential category of tools used for this purpose as they give developers direct access to the running systems. Nevertheless, traditional debuggers rely on generic mechanisms to introspect and interact with the running systems, while developers reason about and formulate domain-specific questions using concepts and abstractions from their application domains. This mismatch creates an abstraction gap between the debugging needs and the debugging support leading to an inefficient and error-prone debugging effort, as developers need to recover concrete domain concepts using generic mechanisms. To reduce this gap, and increase the efficiency of the debugging process, we propose a framework for developing domain-specific debuggers, called the Moldable Debugger, that enables debugging at the level of the application domain. The Moldable Debugger is adapted to a domain by creating and combining domain-specific debugging operations with domain-specific debugging views, and adapts itself to a domain by selecting, at run time, appropriate debugging operations and views. To ensure the proposed model has practical applicability (i.e., can be used in practice to build real debuggers), we discuss, from both a performance and usability point of view, three implementation strategies. We further motivate the need for domain-specific debugging, identify a set of key requirements and show how our approach improves debugging by adapting the debugger to several domains.

Protein and lipid binding parameters in rainbow trout (Oncorhynchus mykiss) blood and liver fractions to extrapolate from an in vitro metabolic degradation assay to in vivo bioaccumulation potential of hydrophobic organic chemicals

Binding of hydrophobic chemicals to colloids such as proteins or lipids is difficult to measure using classical microdialysis methods due to low aqueous concentrations, adsorption to dialysis membranes and test vessels, and slow kinetics of equilibration. Here, we employed a three-phase partitioning system where silicone (polydimethylsiloxane, PDMS) serves as a third phase to determine partitioning between water and colloids and acts at the same time as a dosing device for hydrophobic chemicals. The applicability of this method was demonstrated with bovine serum albumin (BSA). Measured binding constants (K(BSAw)) for chlorpyrifos, methoxychlor, nonylphenol, and pyrene were in good agreement with an established quantitative structure-activity relationship (QSAR). A fifth compound, fluoxypyr-methyl-heptyl ester, was excluded from the analysis because of apparent abiotic degradation. The PDMS depletion method was then used to determine partition coefficients for test chemicals in rainbow trout (Oncorhynchus mykiss) liver S9 fractions (K(S9w)) and blood plasma (K(bloodw)). Measured K(S9w) and K(bloodw) values were consistent with predictions obtained using a mass-balance model that employs the octanol-water partition coefficient (K(ow)) as a surrogate for lipid partitioning and K(BSAw) to represent protein binding. For each compound, K(bloodw) was substantially greater than K(S9w), primarily because blood contains more lipid than liver S9 fractions (1.84% of wet weight vs 0.051%). Measured liver S9 and blood plasma binding parameters were subsequently implemented in an in vitro to in vivo extrapolation model to link the in vitro liver S9 metabolic degradation assay to in vivo metabolism in fish. Apparent volumes of distribution (V(d)) calculated from the experimental data were similar to literature estimates. However, the calculated binding ratios (f(u)) used to relate in vitro metabolic clearance to clearance by the intact liver were 10 to 100 times lower than values used in previous modeling efforts. Bioconcentration factors (BCF) predicted using the experimental binding data were substantially higher than the predicted values obtained in earlier studies and correlated poorly with measured BCF values in fish. One possible explanation for this finding is that chemicals bound to proteins can desorb rapidly and thus contribute to metabolic turnover of the chemicals. This hypothesis remains to be investigated in future studies, ideally with chemicals of higher hydrophobicity.

Identification of novel rhoptry proteins in Neospora caninum by LC/MS-MS analysis of subcellular fractions

Apicomplexan parasites possess an apical complex that is composed of two secretory organelles recognized as micronemes and rhoptries. Rhoptry contents are secreted into the parasitophorous vacuole during the host cell invasion process. Several rhoptry proteins have been identified in Toxoplasma gondii and seem to be involved in host-pathogen interactions and some of them are considered to be important virulence factors. Only one rhoptry protein, NcROP2, has been identified and extensively characterized in the closely related parasite Neospora caninum, and this has showed immunoprotective properties. Thus, with the aim of increasing knowledge of the rhoptry protein repertoire in N. caninum, a subcellular fractionation of tachyzoites was performed to obtain fractions enriched for this secretory organelle. 2-D SDS-PAGE followed by MS and LC/MS-MS were applied for fraction analysis and 8 potential novel rhoptry components (NcROP1, 5, 8, 30 and NcRON2, 3, 4, 8) and several kinases, proteases and phosphatases proteins were identified with a high homology to those previously found in T. gondii. Their existence in N. caninum tachyzoites suggests their involvement in similar events or pathways that occur in T. gondii. These novel proteins may be considered as targets that could be useful in the future development of immunoprophylactic measures.

Leukocyte populations and mRNA expression of inflammatory factors in quarter milk fractions at different somatic cell score levels in dairy cows

The effect of somatic cell count (SCC) and milk fraction on milk composition, distribution of cell populations, and mRNA expression of various inflammatory parameters was studied. Therefore, quarter milk samples were defined as cisternal (C), first 400 g of alveolar (A1), and remaining alveolar milk (A2) during the course of milking. Quarters were assigned to 4 groups according to their total SCC: 1) <12 x 10(3)/mL, 2) 12 to 100 x 10(3)/mL, 3) 100 to 350 x 10(3)/mL, and 4) >350 x 10(3)/mL. Milk constituents of interest were SCC, fat, protein, lactose sodium, and chloride ions as well as electrical conductivity. Cell populations were classified into lymphocytes, macrophages, and neutrophils (PMN). The mRNA expression of the inflammatory factors tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, lactoferrin, and lysozyme was measured via real-time, quantitative reverse transcription PCR. Somatic cell count decreased from highest levels in C to lowest levels in A1 and increased thereafter to A2 in all groups. Fat content increased from C to A2 and with increasing SCC level. Lactose decreased with increasing SCC level but remained unchanged during milking. Concentrations of sodium and chloride, and electrical conductivity increased with increasing SCC but were higher in C than in A1 and A2. Protein was not affected by milk fraction or SCC level. The distribution of leukocytes was dramatically influenced by milk fraction and SCC. Lymphocytes were the dominating cell population in group 1, but the proportion of lymphocytes was low in groups 2, 3, and 4. Macrophage proportion was highest in group 2 and decreased in groups 3 and 4, whereas that of PMN increased from group 2 to 4. The content of macrophages decreased during milking in all SCC groups whereas that of PMN increased. The proportion of lymphocytes was not affected by milk fraction. The mRNA expression of all inflammatory factors showed an increase with increasing SCC but minor changes occurred during milking. In conclusion, milk fraction and SCC level have a crucial influence on the distribution of leukocyte populations and several milk constituents. The surprisingly high content of lymphocytes and concomitantly low mRNA expression of inflammatory factors in quarters with SCC <12 x 10(3)/mL indicates a different and possibly reduced readiness of the immune system to respond to invading pathogens.

Weber fractions and time-order errors for long and short durations: Implications for modeling

Using a weighted up-down procedure, in each of eight conditions 28 participants compared durations of auditory (noise bursts) or visual (LED flashes) intervals; filled or unfilled with 3-ms markers; with or without feedback. Standards (Sts) were 100 and 1000 ms, and the ISI 900 ms. Intermixedly, presentation orders were St-Comparison (Co) and Co-St. TOEs were positive for St=100-ms and negative for St=1000 ms. Weber fractions (WFs, JND/St) were lowered by feedback. For visual-filled and visual-empty, WFs were highest for St=100 ms. For auditory-filled and visual-empty, St interacted with Order: lowest WFs occurred for St-Co with St=1000 ms, but for Co-St with St=100 ms. Lowest average WFs occurred with St-Co for visual-filled, but with Co-St for visual-empty. The results refute the generalization of better discrimination with St-Co than with Co-St (”type-B effect”), and support the notion of sensation weighting: flexibly differential impact weights of the compared durations in generating the response.

Fossil and Non-Fossil Sources of Different Carbonaceous Fractions in Fine and Coarse Particles by Radiocarbon Measurement

Radiocarbon offers a unique possibility for unambiguous source apportionment of carbonaceous particles due to a direct distinction of non-fossil and fossil carbon. In this work, particulate matter of different size fractions was collected at 4 sites in Switzerland to examine whether fine and coarse carbonaceous particles exhibit different fossil and contemporary sources. Elemental carbon (EC) and organic carbon (OC) as well as water-soluble OC (WSOC) and water-insoluble OC (WINSOC) were separated and determined for subsequent 14C measurement. In general, both fossil and non-fossil fractions in OC and EC were found more abundant in the fine than in the coarse mode. However, a substantial fraction (~20 ± 5%) of fossil EC was found in coarse particles, which could be attributed to traffic-induced non-exhaust emissions. The contribution of biomass burning to coarse-mode EC in winter was relatively high, which is likely associated to the coating of EC with organic and/or inorganic substances emitted from intensive wood burning. Further, fossil OC (i.e. from vehicle emissions) was found to be smaller than non-fossil OC due to the presence of primary biogenic OC and/or growing in size of wood-burning OC particles during aging processes. 14C content in WSOC indicated that the second organic carbon rather stems from non-fossil precursors for all samples. Interestingly, both fossil and non-fossil WINSOC concentrations were found to be higher in fine particles than in coarse particles in winter, which is likely due to primary wood burning emissions and/or secondary formation of WINSOC.