Senescence in cell oxidative status in two bird species with contrasting life expectancy.

Oxidative stress occurs when the production of reactive oxygen species (ROS) by an organism exceeds its capacity to mitigate the damaging effects of the ROS. Consequently, oxidative stress hypotheses of ageing argue that a decline in fecundity and an increase in the likelihood of death with advancing age reported at the organism level are driven by gradual disruption of the oxidative balance at the cellular level. Here, we measured erythrocyte resistance to oxidative stress in the same individuals over several years in two free-living bird species with contrasting life expectancy, the great tit (known maximum life expectancy is 15.4 years) and the Alpine swift (26 years). In both species, we found evidence for senescence in cell resistance to oxidative stress, with patterns of senescence becoming apparent as subjects get older. In the Alpine swift, there was also evidence for positive selection on cell resistance to oxidative stress, the more resistant subjects being longer lived. The present findings of inter-individual selection and intra-individual deterioration in cell oxidative status at old age in free-living animals support a role for oxidative stress in the ageing of wild animals.

Acquired antibody responses against Plasmodium vivax infection vary with host genotype for duffy antigen receptor for chemokines (DARC).

BACKGROUND: Polymorphism of the Duffy Antigen Receptor for Chemokines (DARC) is associated with susceptibility to and the severity of Plasmodium vivax malaria in humans. P. vivax uses DARC to invade erythrocytes. Individuals lacking DARC are 'resistant' to P. vivax erythrocytic infection. However, susceptibility to P. vivax in DARC+ individuals is reported to vary between specific DARC genotypes. We hypothesized that the natural acquisition of antibodies to P. vivax blood stages may vary with the host genotype and the level of DARC expression. Furthermore, high parasitemia has been reported to effect the acquisition of immunity against pre-erythrocytic parasites. We investigated the correlation between host DARC genotypes and the frequency and magnitude of antibodies against P. vivax erythrocytic stage antigens. METHODOLOGY/FINDINGS: We assessed the frequencies and magnitudes of antibody responses against P. vivax and P. falciparum sporozoite and erythrocytic antigens in Colombian donors from malaria-endemic regions. The frequency and level of naturally-acquired antibodies against the P. vivax erythrocytic antigens merozoite surface protein 1 (PvMSP1) and Duffy binding protein (PvDBP) varied with the host DARC genotypes. Donors with one negative allele (FY*B/FY*Bnull and FY*A/FY*Bnull) were more likely to have anti-PvMSP1 and anti-PvDBP antibodies than those with two positive alleles (FY*B/FY*B and FY*A/FY*B). The lower IgG3 and IgG1 components of the total IgG response may account for the decreased responses to P. vivax erythrocytic antigens with FY*A/FY*B and FY*B/FY*B genotypes. No such association was detected with P. falciparum erythrocytic antigens, which does not use DARC for erythrocyte invasion. CONCLUSION/SIGNIFICANCE: Individuals with higher DARC expression, which is associated with higher susceptibility to P. vivax infection, exhibited low frequencies and magnitudes of P. vivax blood-stage specific antibody responses. This may indicate that one of the primary mechanisms by which P. vivax evades host immunity is through DARC indirectly down-regulating humoral responses against erythrocytic invasion and development.

Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study.

BACKGROUND: Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. METHODS: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. FINDINGS: 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0.94, 95% CI 0.60-1.45) or after IAT (adjusted RR 1.29, 0.97-1.72) but had a worse outcome after IAT compared with IVT (adjusted RR 1.49, 1.00-2.23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0.88, 0.76-1.01) or IAT (adjusted RR 0.94, 0.86-1.02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1.06, 0.91-1.22). INTERPRETATION: Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. FUNDING: Department of Neurology, University Medical Center Utrecht.

Discriminating irritable bowel syndrome from inflammatory bowel disease: what is the role of biomarkers in daily practice?

Background and Aims: Discriminating irritable bowel syndrome (IBS) from inflammatorybowel disease (IBD) can be a clinical challenge as symptoms can overlap. We and othershave recently shown that fecal calprotectin (FC) is more accurate for discriminating IBSfrom IBD compared to C-reactive protein (CRP) and blood leukocytes. Data on the biomarkersused in daily gastroenterological practice are lacking. We therefore aimed to assess whichbiomarkers are used by gastroenterologists in their daily practice for discriminating IBSfrom IBD.Methods: A questionnaire was sent to all board certified gastroenterologists inSwitzerland focusing on demographic informations, number of IBS patients treated in thetime period from May 2009 to April 2010, and the specific biomarkers evaluated fordiscriminating IBS from IBD.Results: Response rate was 57% (153/270). Mean physician'sage was 50±9years, mean duration of gastroenterologic practice 14±8years, 52% of themwere working in private practice and 48% in hospitals. Thirty-nine percent had taken careof more than 100 IBS patients in the last 12 months, 37% had seen 41-100 and 24% hadseen 1-40 IBS patients. Gastroenterologists in private practice more frequently took care ofat least 40 IBS patients in a year compared to hospital-based gastroenterologists (P<0.001).The following biomarkers were determined for discriminating IBS from IBD: CRP 100%,FC 79%, hematogram (red blood cells and leukocytes) 70%, iron status (ferritin, transferrinsaturation) 59%, erythrocyte sedimentation rate 2.7%, protein electrophoresis 0.7%, andalpha-1 antitrypsin clearance 0.7%. There was a trend for using FC more often in privatepractice than in hospital (P = 0.08). Twenty-four percent of gastroenterologists had usedFC in the workup of more than 70% of patients classified as IBS, 22% had used FC in 30-70% of IBS patients, 39% in less than 30%, and 15% had never used FC for the work-upof suspected IBS. Eighty-nine percent of gastroenterologists considered FC to be superiorto CRP for discriminating IBS from IBD, 87% thought that patient's compliance for fecalsampling is high, and 51% judged the fee of USD 60 for a FC test as appropriate.Conclusions:FC is widely used in clinical practice to discriminate IBS from IBD. In accordance with thescientific evidence, the majority of gastroenterologists consider FC to be more accurate thanCRP for discriminating IBS from IBD. Gastroenterologists in private practice take care ofsignificantly more IBS patients than colleagues in hospital.

Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal cord injury.

Limiting the development of secondary damage represents one of the major goals of neuroprotective therapies after spinal cord injury. Here, we demonstrate that specific JNK inhibition via a single intraperitoneal injection of the cell permeable peptide D-JNKI1 6h after lesion improves locomotor recovery assessed by both the footprint and the BMS tests up to 4 months post-injury in mice. JNK inhibition prevents c-jun phosphorylation and caspase-3 cleavage, has neuroprotective effects and results in an increased sparing of white matter at the lesion site. Lastly, D-JNKI1 treated animals show a lower increase of erythrocyte extravasation and blood brain barrier permeability, thus indicating protection of the vascular system. In total, these results clearly point out JNK inhibition as a promising neuroprotective strategy for preventing the evolution of secondary damage after spinal cord injury.

Investigating the genetic variation underlying episodicity in major depressive disorder: Suggestive evidence for a bipolar contribution.

BACKGROUND: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. METHODS: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. RESULTS: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. LIMITATIONS: Episode count was self-reported and, therefore, subject to recall bias. CONCLUSIONS: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.

Prophylaxis of experimental endocarditis with antiplatelet and antithrombin agents : a role for long-term prevention of infective endocarditis in humans?

BACKGROUND: Infective endocarditis (IE) mostly occurs after spontaneous low-grade bacteremia. Thus, IE cannot be prevented by circumstantial antibiotic prophylaxis. Platelet activation following bacterial-fibrinogen interaction or thrombin-mediated fibrinogen-fibrin polymerization is a critical step in vegetation formation. We tested the efficacy of antiplatelet and antithrombin to prevent experimental IE. METHODS: A rat model of experimental IE following prolonged low-grade bacteremia mimicking smoldering bacteremia in humans was used. Prophylaxis with antiplatelets (aspirin, ticlopidine [alone or in combination], eptifibatide, or abciximab) or anticoagulants (antithrombin dabigatran etexilate or anti-vitamin K acenocoumarol) was started 2 days before inoculation with Streptococcus gordonii or Staphylococcus aureus. Valve infection was assessed 24 hours later. RESULTS: Aspirin plus ticlopidine, as well as abciximab, protected 45%-88% of animals against S. gordonii and S. aureus IE (P < .05). Dabigatran etexilate protected 75% of rats against IE due to S. aureus (P < .005) but failed to protect against S. gordonii (<30% protection). Acenocoumarol was ineffective. CONCLUSIONS: Antiplatelet and direct antithrombin agents may be useful in the prophylaxis of IE in humans. In particular, the potential dual benefit of dabigatran etexilate might be reconsidered for patients with prosthetic valves, who require life-long anticoagulation and in whom S. aureus IE is associated with high mortality.

Epidermal growth factor (EGF) stimulation of cultured brain cells. I. Enhancement of the developmental increase in glial enzymatic activity.

Serum-free aggregating cell cultures of fetal rat telencephalon grown in the presence of 3 ng/ml (5 X 10(-10) M) epidermal growth factor (EGF) until day 12 showed 2- to 3-fold increased activities in the two glial enzymes, glutamine synthetase (GLU-S) and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase). This effect was concentration-dependent, with maximal stimulation in cultures treated daily with 3 ng/ml EGF. Addition of EGF during the first 10 culture days was sufficient to produce a maximal stimulation of both GLU-S and CNPase on day 19, whereas treatments starting on day 12 were ineffective. The stimulation of GLU-S preceded that of CNPase. The EGF-induced increase in GLU-S activity was not directly dependent on the presence of insulin, triiodothyronine, or hydrocortisone in the medium, whereas insulin was required for the stimulation of CNPase. A single dose of 5 ng/ml EGF on day 2 caused a slight but significant decrease in DNA synthesis after day 6. The present results indicate that in serum-free aggregating cell cultures of fetal rat telencephalon EGF partially inhibits DNA synthesis, and stimulates an early step in glial differentiation.

Role of Particle Shape on the Stress Propagation in Granular Packings

We present an experimental and numerical study on the influence that particle aspect ratio has on the mechanical and structural properties of granular packings. For grains with maximal symmetry (squares), the stress propagation in the packing localizes forming chainlike forces analogous to the ones observed for spherical grains. This scenario can be understood in terms of stochastic models of aggregation and random multiplicative processes. As the grains elongate, the stress propagation is strongly affected. The interparticle normal force distribution tends toward a Gaussian, and, correspondingly, the force chains spread leading to a more uniform stress distribution reminiscent of the hydrostatic profiles known for standard liquids

The neuronal adhesion protein D2 in differentiating aggregates of brain cells.

The D2-protein is a high molecular weight protein involved in interneuronal adhesion. The concentration of D2-protein was measured both in aggregates of fetal rat telencephalic cells cultured in a chemically defined medium and in developing forebrain. Both the concentration of the D2-protein and the degree of sialylation were changed in the cultures in parallel with the corresponding values obtained from postnatal forebrain. In the cultures the highest specific concentration of D2-protein was observed after 12 days in culture. This value was 2.7 times higher than the average value of adult rat forebrain. Antibodies to D2-protein have previously been shown to inhibit fasciculation of neuritic fibers extending from cultured explants of sympathetic ganglia. We investigated the effect of such antibodies on the differentiation of aggregating telencephalic cells. By adding surplus antibodies to the cultures from day 11 to day 16 we were able to decrease the specific concentration of D2-protein on the neurons by 53% measured at day 19. The decrease was not compensated fully even after further 10 days in the culture. Although the concentration of D2-protein was decreased during the period of synaptogenesis no change was found in the specific concentration of a marker of mature synapses, the D3-protein. Thus, in this culture system synaptogenesis could proceed to an unimpaired extent in the presence of a decreased concentration of a putatively involved adhesion molecule. However, the specific concentration of two markers of myelination, 2',3'-cyclic nucleotide 3'-phosphodiesterase and myelin basic protein, were both increased, suggesting an antibody-induced stimulation of myelination in the cultured aggregates.

Efectos de la aplicación de cenizas de caldera de biomasa en el modelo jerárquico de agregación de un suelo forestal bajo condiciones oceánicas

Se ha estudiado los efectos que tiene la aplicación de cenizas de caldera de biomasa, en el modelo jerárquico de agregación (Tisdall y Oades, 1982) y en la estabilización del C orgánico en un suelo forestal situado en la zona templada del País Vasco. Para ello, se aplicaron 3 tratamientos con diferentes dosis de ceniza en muestras de suelo tamizadas a 250 μm procedentes de un huerto semillero de pinus radiata. Estas muestras fueron incubadas durante 3 meses y fraccionadas los días 29, 44, 64, 78 y 92 con la intención de separar los macroagregados grandes (LMagg), de los macroagregados pequeños (Magg), microagregados (magg), limos (silt) y arcillas (clay). Todas las fracciones fueron analizadas para determinar su contenido en C orgánico. Los resultados mostraron que con la aplicación de cenizas, el modelo jerárquico de agregación de suelo se cumple para las fracciones LMagg, Magg y magg, pero no para la fracción silt. Además se ha observado que las cenizas promueven la formación de microagregados aumentado así la capacidad de secuestro de C del suelo, pero en cambio disminuye la proporción de macroagregados, hecho que podría acarrear una disminución en la calidad estructural del suelo.

Efectos de la aplicación de biochar en el modelo jerárquico de agregación de un suelo forestal bajo condiciones oceánicas

El objetivo del presente proyecto ha sido estudiar los efectos del biochar en el modelo jerárquico de agregación del suelo. Para estudiar estas propiedades se ha realizado una incubación de tres tratamientos de biochar Miscanthus (biochar 10t/ha (B10), 2t/ha (B2) y 10t/ha+Nitrógeno (BN), durante 91 días, realizando fraccionamientos en húmedo de las muestras los días 28, 43, 63, 77 y 91. En estos fraccionamientos se han separado las fracciones macroagregrado (LMagg+Magg), microagregados (magg), limos (Silt) y arcillas (Clay). Por último se determinó el C orgánico de todas las fracciones de los tratamientos obtenidos con el objeto de obtener información sobre el efecto que puede tener la aplicación del biochar sobre la estabilización de C en las fracciones del suelo. Los resultados obtenidos indican que con la aplicación de biochar, la teoría jerárquica de agregación propuesta por Tisdall y Oades (1982), no se cumple en la dinámica de agregación del suelo, si bien se puede observar una jerarquía en la estabilización del C orgánico en los macroagregados y microagregados. Además las dosis altas de biochar producen mayor cantidad de microagregados, favoreciendo el secuestro de C en el suelo. Por otro lado, con dosis altas de biochar se aprecia una disminución de la fracción de macroagregados, hecho que puede influir negativamente en la estructura del suelo.

Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies.

BACKGROUND: In sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer's disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau. RESULTS: Using a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild-type one. CONCLUSION: Taken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading.

Red blood cell microparticles and blood group antigens: an analysis by flow cytometry.

BACKGROUND: The storage of blood induces the formation of erythrocytes-derived microparticles. Their pathogenic role in blood transfusion is not known so far, especially the risk to trigger alloantibody production in the recipient. This work aims to study the expression of clinically significant blood group antigens on the surface of red blood cells microparticles. MATERIAL AND METHODS: Red blood cells contained in erythrocyte concentrates were stained with specific antibodies directed against blood group antigens and routinely used in immunohematology practice. After inducing erythrocytes vesiculation with calcium ionophore, the presence of blood group antigens was analysed by flow cytometry. RESULTS: The expression of several blood group antigens from the RH, KEL, JK, FY, MNS, LE and LU systems was detected on erythrocyte microparticles. The presence of M (MNS1), N (MNS2) and s (MNS4) antigens could not be demonstrated by flow cytometry, despite that glycophorin A and B were identified on microparticles using anti-CD235a and anti-MNS3. DISCUSSION: We conclude that blood group antigens are localized on erythrocytes-derived microparticles and probably keep their immunogenicity because of their capacity to bind specific antibody. Selective segregation process during vesiculation or their ability to elicit an immune response in vivo has to be tested by further studies.

Experimental and computational study on the synthesis and characterization of self-assembling meso/macroporous materials in highly concentrated emulsions

Report for the scientific sojourn carried out at Massachusetts General Hospital Cancer Center-Harvard Medical School, Estats Units, from 2010 to 2011. The project aims to study the aggregation behavior of amphiphilic molecules in the continuous phase of highly concentrated emulsions, which can be used as templates for the synthesis of meso/macroporous materials. At this stage of the project, we have investigated the self-assembly of diblock and triblock surfactants under the effect of a confined geometry being surrounded by the droplets of the dispersed phase. These droplets limit the growth of the aggregates, deeply modify their orientation and hence alter their spatial arrangement as compared to the self-assembly taking place far enough from any boundary surface, that is in the bulk. By performing Monte Carlo simulations, we have showed that the interface between the dispersed and continuous phases as well as its shape has a significant impact on the structural order of the resulting aggregates and hence on the potential applications of highly concentrated emulsions as reaction media, drug delivery systems, or templates for meso/macroporous materials. Due to the combined effect of symmetry breaking and morphological frustration, very intriguing structures, such as square columnar liquid crystals, twisted X-shaped aggregates, and helical phases of cylindrical aggregates, never observed in the bulk for the same model surfactant, have been found. The presence of other more conventional structures, such as micelles and cubic and hexagonal liquid crystals, formed at low and high amphiphilic concentrations, respectively, further enhance the interest on this already rich aggregation behavior.