Influence of chronic and acute spinal cord injury on skeletal muscle Na+-K+-ATPase and phospholemman expression in humans

Na(+)-K(+)-ATPase is an integral membrane protein crucial for the maintenance of ion homeostasis and skeletal muscle contractibility. Skeletal muscle Na(+)-K(+)-ATPase content displays remarkable plasticity in response to long-term increase in physiological demand, such as exercise training. However, the adaptations in Na(+)-K(+)-ATPase function in response to a suddenly decreased and/or habitually low level of physical activity, especially after a spinal cord injury (SCI), are incompletely known. We tested the hypothesis that skeletal muscle content of Na(+)-K(+)-ATPase and the associated regulatory proteins from the FXYD family is altered in SCI patients in a manner dependent on the severity of the spinal cord lesion and postinjury level of physical activity. Three different groups were studied: 1) six subjects with chronic complete cervical SCI, 2) seven subjects with acute, complete cervical SCI, and 3) six subjects with acute, incomplete cervical SCI. The individuals in groups 2 and 3 were studied at months 1, 3, and 12 postinjury, whereas individuals with chronic SCI were compared with an able-bodied control group. Chronic complete SCI was associated with a marked decrease in [(3)H]ouabain binding site concentration in skeletal muscle as well as reduced protein content of the α(1)-, α(2)-, and β(1)-subunit of the Na(+)-K(+)-ATPase. In line with this finding, expression of the Na(+)-K(+)-ATPase α(1)- and α(2)-subunits progressively decreased during the first year after complete but not after incomplete SCI. The expression of the regulatory protein phospholemman (PLM or FXYD1) was attenuated after complete, but not incomplete, cervical SCI. In contrast, FXYD5 was substantially upregulated in patients with complete SCI. In conclusion, the severity of the spinal cord lesion and the level of postinjury physical activity in patients with SCI are important factors controlling the expression of Na(+)-K(+)-ATPase and its regulatory proteins PLM and FXYD5.     

Effects of prenatal stress exposure on soluble Aβ and brain-derived neurotrophic factor signaling in male and female APPswe/PS1dE9 mice

Chronic stress and stress-related disorders, such as major depression (MD), have been shown to increase the risk for developing Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF) has been postulated as a neurophysiological link between these illnesses. Our previous research has indicated that exposing the APPswe/PS1dE9 mouse model of AD to prenatal maternal stress (PS) induced a depressive-like phenotype, specifically in female mice. Considering the role of BDNF in depressive-like behavior and its interactions with amyloid-β (Aβ), our aim was to explore whether these mice would also exhibit alterations in soluble Aβ, mature BDNF (mBDNF), proBDNF, and the receptors TrkB and p75(NTR) in comparison to non-stressed animals. Our results demonstrate that female APPswe/PS1dE9 mice have higher levels of hippocampal proBDNF and soluble Aβ as compared to their male littermates. Additionally, a tendency was observed for PS to lower mBDNF protein levels in the hippocampus, but only in female mice, while receptor levels remained unaltered by sex or PS exposure. Given that female mice both have higher proBDNF and Aβ levels, these findings suggest an underlying role for BDNF signaling and Aβ production in the selective vulnerability of women for MD and AD development.     

Timing in a fluctuating environment: environmental variability and asymmetric fitness curves can lead to adaptively mismatched avian reproduction

Adaptation in dynamic environments depends on the grain, magnitude and predictability of ecological fluctuations experienced within and across generations. Phenotypic plasticity is a well-studied mechanism in this regard, yet the potentially complex effects of stochastic environmental variation on optimal mean trait values are often overlooked. Using an optimality model inspired by timing of reproduction in great tits, we show that temporal variation affects not only optimal reaction norm slope, but also elevation. With increased environmental variation and an asymmetric relationship between fitness and breeding date, optimal timing shifts away from the side of the fitness curve with the steepest decline. In a relatively constant environment, the timing of the birds is matched with the seasonal food peak, but they become adaptively mismatched in environments with temporal variation in temperature whenever the fitness curve is asymmetric. Various processes affecting the survival of offspring and parents influence this asymmetry, which collectively determine the 'safest' strategy, i.e. whether females should breed before, on, or after the food peak in a variable environment. As climate change might affect the (co)variance of environmental variables as well as their averages, risk aversion may influence how species should shift their seasonal timing in a warming world.     

Culture and end of life care: a scoping exercise in seven European countries

Aim

Culture is becoming increasingly important in relation to end of life (EoL) care in a context of globalization, migration and European integration. We explore and compare socio-cultural issues that shape EoL care in seven European countries and critically appraise the existing research evidence on cultural issues in EoL care generated in the different countries.

Methods

We scoped the literature for Germany, Norway, Belgium, the Netherlands, Spain, Italy and Portugal, carrying out electronic searches in 16 international and country-specific databases and handsearches in 17 journals, bibliographies of relevant papers and webpages. We analysed the literature which was unearthed, in its entirety and by type (reviews, original studies, opinion pieces) and conducted quantitative analyses for each country and across countries. Qualitative techniques generated themes and sub-themes.

Results

A total of 868 papers were reviewed. The following themes facilitated cross-country comparison: setting, caregivers, communication, medical EoL decisions, minority ethnic groups, and knowledge, attitudes and values of death and care. The frequencies of themes varied considerably between countries. Sub-themes reflected issues characteristic for specific countries (e.g. culture-specific disclosure in the southern European countries). The work from the seven European countries concentrates on cultural traditions and identities, and there was almost no evidence on ethnic minorities.

Conclusion

This scoping review is the first comparative exploration of the cultural differences in the understanding of EoL care in these countries. The diverse body of evidence that was identified on socio-cultural issues in EoL care, reflects clearly distinguishable national cultures of EoL care, with differences in meaning, priorities, and expertise in each country. The diverse ways that EoL care is understood and practised forms a necessary part of what constitutes best evidence for the improvement of EoL care in the future.     

State of degradation in archeological oak from the 17th century vasa ship: substantial strength loss correlates with reduction in (holo)cellulose molecular weight

In 1628, the Swedish warship Vasa capsized on her maiden voyage and sank in the Stockholm harbor. The ship was recovered in 1961 and, after polyethylene glycol (PEG) impregnation, it was displayed in the Vasa museum. Chemical investigations of the Vasa were undertaken in 2000, and extensive holocellulose degradation was reported at numerous locations in the hull. We have now studied the longitudinal tensile strength of Vasa oak as a function of distance from the surface. The PEG-content, wood density, and cellulose microfibril angle were determined. The molar mass distribution of holocellulose was determined as well as the acid and iron content. A good correlation was found between the tensile strength of the Vasa oak and the average molecular weight of the holocellulose, where the load-bearing cellulose microfibril is the critical constituent. The mean tensile strength is reduced by approximately 40%, and the most affected areas show a reduction of up to 80%. A methodology is developed where variations in density, cellulose microfibril angle, and PEG content are taken into account, so that cell wall effects can be evaluated in wood samples with different rate of impregnation and morphologies.     

Collagen-binding proteins in age-dependent changes in renal collagen turnover: microarray analysis of mRNA expression

Aging is associated with progressive structural and functional deterioration of the kidney. Among the morphological changes associated with renal aging is an accumulation of extracellular matrix (ECM) in the glomeruli and tubuloinsterstitium, which may ultimately lead to the development of renal fibrosis. The mechanisms governing the regulation of ECM metabolism during renal aging are only incompletely defined. We present data from a genome-wide mRNA expression study on renal tissue from 90 wk old male Wistar rats and 10 wk old controls using Illumina BeadArray cDNA microarray. Regulation of candidate gene products was verified by real-time PCR. Morphological changes were evaluated by routine histological methods. Activated fibroblasts were identified by their expression of alpha-smooth muscle actin and collagen I. Morphological analysis demonstrated an expansion of the tubulointerstitial compartment with increased amounts of fibrous collagen but no overt glomerular or tubular damage in the aged rats. Activated fibroblasts were readily detectable in the adventitial layer of large renal vessels in controls and were not found in the old animals. In agreement with this finding, gene expression analysis revealed significant downregulation of collagen I mRNA along with numerous other ECM components. Concomitantly, collagen-stabilizing proteins were induced, whereas matrix metalloproteinase 9, an enzyme involved in collagen breakdown, was reduced. In conclusion, our results suggest that ECM expansion during renal aging results from an augmented stabilization in conjunction with a reduced breakdown of collagen fibers. Collagen stabilizing proteins may be essential for the control of renal ECM turnover and the pathogenesis of kidney fibrosis.     

Effect of vaccines and antivirals during the major 2009 A(H1N1) pandemic wave in Norway--and the influence of vaccination timing

To evaluate the impact of mass vaccination with adjuvanted vaccines (eventually 40% population coverage) and antivirals during the 2009 influenza pandemic in Norway, we fitted an age-structured SEIR model using data on vaccinations and sales of antivirals in 2009/10 in Norway to Norwegian ILI surveillance data from 5 October 2009 to 4 January 2010. We estimate a clinical attack rate of approximately 30% (28.7-29.8%), with highest disease rates among children 0-14 years (43-44%). Vaccination started in week 43 and came too late to have a strong influence on the pandemic in Norway. Our results indicate that the countermeasures prevented approximately 11-12% of potential cases relative to an unmitigated pandemic. Vaccination was found responsible for roughly 3 in 4 of the avoided infections. An estimated 50% reduction in the clinical attack rate would have resulted from vaccination alone, had the campaign started 6 weeks earlier. Had vaccination been prioritized for children first, the intervention should have commenced approximately 5 weeks earlier in order to achieve the same 50% reduction. In comparison, we estimate that a non-adjuvanted vaccination program should have started 8 weeks earlier to lower the clinical attack rate by 50%. In conclusion, vaccination timing was a critical factor in relation to the spread of the 2009 A(H1N1) influenza. Our results also corroborate the central role of children for the transmission of A(H1N1) pandemic influenza.     

MRI of arterial flow reserve in patients with intermittent claudication: feasibility and initial experience

Objectives

The aim of this work was to develop a MRI method to determine arterial flow reserve in patients with intermittent claudication and to investigate whether this method can discriminate between patients and healthy control subjects.

Methods

Ten consecutive patients with intermittent claudication and 10 healthy control subjects were included. All subjects underwent vector cardiography triggered quantitative 2D cine MR phase-contrast imaging to obtain flow waveforms of the popliteal artery at rest and during reactive hyperemia. Resting flow, maximum hyperemic flow and absolute flow reserve were determined and compared between the two groups by two independent MRI readers. Also, interreader reproducibility of flow measures was reported.

Results

Resting flow was lower in patients compared to controls (4.9±1.6 and 11.1±3.2 mL/s in patients and controls, respectively (p<0.01)). Maximum hyperemic flow was 7.3±2.9 and 16.4±3.2 mL/s (p<0.01) and the absolute flow reserve was 2.4±1.6 and 5.3±1.3 mL/s (p<0.01), respectively in patients and controls. The interreader coefficient of variation was below 10% for all measures in both patients and controls.

Conclusions

Quantitative 2D MR cine phase-contrast imaging is a promising method to determine flow reserve measures in patients with peripheral arterial disease and can be helpful to discriminate patients with intermittent claudication from healthy controls.     

Vitamin k-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype

Background

Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE^−/− model of atherosclerosis.

Methodology/Principal Findings

A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE^−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K₁ (VK₁, 1.5 mg/g) or vitamin K₁ and warfarin (VK₁&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.

Conclusions/Significance

VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE^−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.     

Electrophysiological evidence for immature processing capacity and filtering in visuospatial working memory in adolescents

The present study investigated the development of visuospatial working memory (VSWM) capacity and the efficiency of filtering in VSWM in adolescence. To this end, a group of IQ-matched adults and adolescents performed a VSWM change detection task with manipulations of WM-load and distraction, while performance and electrophysiological contralateral delay activity (CDA) were measured. The CDA is a lateralized ERP marker of the number of targets and distracters that are selectively encoded/maintained in WM from one hemifield of the memory display. Significantly lower VSWM-capacity (Cowan's K) was found in adolescents than adults, and adolescents' WM performance (in terms of accuracy and speed) also suffered more from the presence of distracters. Distracter-related CDA responses were partly indicative of higher distracter encoding/maintenance in WM in adolescents and were positively correlated with performance measures of distracter interference. This correlation suggests that the higher interference of distracters on WM performance in adolescents was caused by an inability to block distracters from processing and maintenance in WM. The lower visuospatial WM-capacity (K) in adolescents in the high load (3 items) condition was accompanied by a trend (p<.10) towards higher CDA amplitudes in adolescents than adults, whereas CDA amplitudes in the low load (1 item) condition were comparable between adolescents and adults. These findings point to immaturity of frontal-parietal WM-attention networks that support visuospatial WM processing in adolescence.