Spatial Memory in Spontaneously Hypertensive Rats (SHR)

The spontaneously hypertensive rat (SHR) is an established animal model of ADHD. It has been suggested that ADHD symptoms arise from deficits in executive functions such as working memory, attentional control and decision making. Both ADHD patients and SHRs show deficits in spatial working memory. However, the data on spatial working memory deficits in SHRs are not consistent. It has been suggested that the reported cognitive deficits of SHRs may be related to the SHRs’ locomotor activity. We have used a holeboard (COGITAT) to study both cognition and activity in order to evaluate the influence of the activity on the cognitive performance of SHRs. In comparison to Wistar-Kyoto (WKY) rats, SHRs did not have any impairment in spatial working memory and reference memory. When the rats’ locomotor activity was taken into account, the SHRs’ working memory and reference memory were significantly better than in WKY rats. The locomotor activity appears to be a confounding factor in spatial memory tasks and should therefore be controlled for in future studies. In the SHR model of ADHD, we were unable to demonstrate an impairment of working memory which has been reported in patients with ADHD.     

Intraindividual Variability in Inhibitory Function in Adults with ADHD – An Ex-Gaussian Approach

Objective

Attention deficit disorder (ADHD) is commonly associated with inhibitory dysfunction contributing to typical behavioral symptoms like impulsivity or hyperactivity. However, some studies analyzing intraindividual variability (IIV) of reaction times in children with ADHD (cADHD) question a predominance of inhibitory deficits. IIV is a measure of the stability of information processing and provides evidence that longer reaction times (RT) in inhibitory tasks in cADHD are due to only a few prolonged responses which may indicate deficits in sustained attention rather than inhibitory dysfunction. We wanted to find out, whether a slowing in inhibitory functioning in adults with ADHD (aADHD) is due to isolated slow responses.

Methods

Computing classical RT measures (mean RT, SD), ex-Gaussian parameters of IIV (which allow a better separation of reaction time (mu), variability (sigma) and abnormally slow responses (tau) than classical measures) as well as errors of omission and commission, we examined response inhibition in a well-established GoNogo task in a sample of aADHD subjects without medication and healthy controls matched for age, gender and education.

Results

We did not find higher numbers of commission errors in aADHD, while the number of omissions was significantly increased compared with controls. In contrast to increased mean RT, the distributional parameter mu did not document a significant slowing in aADHD. However, subjects with aADHD were characterized by increased IIV throughout the entire RT distribution as indicated by the parameters sigma and tau as well as the SD of reaction time. Moreover, we found a significant correlation between tau and the number of omission errors.

Conclusions

Our findings question a primacy of inhibitory deficits in aADHD and provide evidence for attentional dysfunction. The present findings may have theoretical implications for etiological models of ADHD as well as more practical implications for neuropsychological testing in aADHD.     

Remifentanil added to sufentanil-sevoflurane anesthesia suppresses hemodynamic and metabolic stress responses to intense surgical stimuli more effectively than high-dose sufentanil-sevoflurane alone

Background

Even extremely high-doses of the potent opioid, sufentanil, cannot reliably suppress stress responses to intense surgical stimuli such as sternotomy. The chemically related opioid remifentanil with its different pharmacokinetics and binding affinities for delta- and kappa-opioid receptors might be more effective in attenuating these responses.

Methods

ASA I-III patients scheduled for a surgical procedure with sternotomy under balanced anesthesia (sevoflurane and sufentanil 3 μg.kg^-1 bolus, 0.017 μg.kg^-1.min^-1 infusion) were randomized into two groups. Patients in the study group were supplemented with remifentanil (2 μg.kg^-1 bolus, 2–7 μg.kg^-1.min^-1 infusion) starting ten minutes before sternotomy. Heart rate, arterial blood pressures, cardiac index, ejection fraction, systemic vascular resistance index (SVRI), total body oxygen uptake (VO₂) and electric dermal response were measured and compared between the groups.

Results

62 patients were studied (study group 32, control group 30). Systolic and mean arterial blood pressures, SVRI, VO₂ and skin conductance increased during sternotomy and sternal spread in the control group but not in the study group. Systolic blood pressure increase: 7.5 ± 19 mmHg vs. -3.4 ± 8.9 (p = 0.005); VO₂ increase: 31 ± 46% vs. -0.4 ± 32%; incidence of systolic blood pressure increase greater than 15 percent: 20% vs. 3% (p = 0.035) (control vs. study group).

Conclusion

High-dose remifentanil added to sevoflurane-sufentanil anesthesia suppresses the sympathoadrenergic response to sternotomy and sternal spread better than high-dose sufentanil alone.

Trial registration

Clinical Trial number: DRKS00004327, August 31, 2012

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2253-15-3) contains supplementary material, which is available to authorized users.     

Trends in Longevity in the Americas: Disparities in Life Expectancy in Women and Men, 1965-2010

Objective

We describe trends in life expectancy at birth (LE) and between-country LE disparities since 1965, in Latin America and the Caribbean.

Methods & Findings

LE trends since 1965 are described for three geographical sub-regions: the Caribbean, Central America, and South America. LE disparities are explored using a suite of absolute and relative disparity metrics, with measurement consensus providing confidence to observed differences. LE has increased throughout Latin America and the Caribbean. Compared to the Caribbean, LE has increased by an additional 6.6 years in Central America and 4.1 years in South America. Since 1965, average reductions in between-country LE disparities were 14% (absolute disparity) and 23% (relative disparity) in the Caribbean, 55% and 51% in Central America, 55% and 52% in South America.

Conclusions

LE in Latin America and the Caribbean is exceeding ‘minimum standard’ international targets, and is improving relative to the world region with the highest human longevity. The Caribbean, which had the highest LE and the lowest between-country LE disparities in Latin America and the Caribbean in 1965-70, had the lowest LE and the highest LE disparities by 2005-10. Caribbean Governments have championed a collaborative solution to the growing burden of non-communicable disease, with 15 territories signing on to the Declaration of Port of Spain, signalling regional commitment to a coordinated public-health response. The persistent LE inequity between Caribbean countries suggests that public health interventions should be tailored to individual countries to be most effective. Between- and within-country disparity monitoring for a range of health metrics should be a priority, first to guide country-level policy initiatives, then to contribute to the assessment of policy success.     

Rare Large Scale Subdomain Motions in Prion Protein can Initiate Aggregation

Abstract

The prion protein is thought to induce prion diseases by changing its conformation from the cellular form, PrP^c, into the infectious Scrapie-form, PrP^Sc. Little is known about the structural and dynamical features of this conformational change. We here introduce a novel concept that involves rare large scale motions between the subdomains βl-αl-β2 and α2-α3 in the carboxy-terminal, globular part of PrP. The interface between these two subdomains carries most pathogenic mutations known to be associated with prion diseases. Based on computational simulations as well as experimental results we propose that such a large scale motion subsequently destabilizes large parts of the cellular conformer PrP^c, thus, rendering it prone to structural rearrangements, including aggregation of now partially unfolded parts of the PrP sequence. We hypothesize that such large scale motions occur as a rare event even under equilibrium conditions and that the interaction of such partially destabilized PrP^c-conformers, which we named PrP^c*, contributes to the formation of pathogenic oligomeric species of the prion protein.     

Post-fire recovery of ant communities in Submediterranean Pinus nigra forests

This study analyzes the variations in the structure and composition of ant communities in burned Pinus nigra forests in central Catalonia (NE Spain). Pinus nigra forests do not recover after fire, changing to shrublands and oak coppices. For this reason, we suggest that ant communities of burned P. nigra forests will change after fire, because the post‐fire scenario, in particular with the increase of open areas, is different to the unburned one, and more favourable for some species than for others. In four locations previously occupied by P. nigra forests where different fires occurred 1, 5, 13 and 19 yr before the sampling, we sampled the structure and composition of ant communities with pitfall traps, tree traps and net sweeping in unburned plots and in plots affected by canopy and understory fire. The results obtained suggest that canopy and understory fire had little effect on the structure of ant communities. Thus, many variables concerning ant communities were not modified either by fire type (understory or canopy fire) or by time since fire. However, a number of particular species were affected, either positively or negatively, by canopy fire: three species characteristic of forest habitats decreased after fire, while eight species characteristic of open habitats increased in areas affected by canopy fire, especially in the first few years after fire. These differences in ant community composition between burned and unburned plots imply that the maximum richness is achieved when there is a mixture of unburned forests and areas burned with canopy fire. Moreover, as canopy cover in P. nigra forests burned with canopy fire is not completed in the period of time studied, the presence of the species that are characteristic of burned areas remains along the chronosequence studied, while the species that disappear after fire do not recover in the period of time considered. Overall, the results obtained indicate that there is a persistent replacement of ant species in burned P. nigra forests, as is also the case with vegetation.     

Crystal structure of the nucleotide-binding subunit DhaL of the Escherichia coli dihydroxyacetone kinase

Dihydroxyacetone (Dha) kinases are a family of sequence-related enzymes that utilize either ATP or phosphoenolpyruvate (PEP) as source of high energy phosphate. The PEP-dependent Dha kinase of Escherichia coli consists of three subunits. DhaK and DhaL are homologous to the Dha and nucleotide-binding domains of the ATP-dependent kinase of Citrobacter freundii. The DhaM subunit is a multiphosphorylprotein of the PEP:sugar phosphotransferase system (PTS). DhaL contains a tightly bound ADP as coenzyme that gets transiently phosphorylated in the double displacement of phosphate between DhaM and Dha. Here we report the 2.6A crystal structure of the E.coli DhaL subunit. DhaL folds into an eight-helix barrel of regular up-down topology with a hydrophobic core made up of eight interlocked aromatic residues and a molecule of ADP bound at the narrower end of the barrel. The alpha and beta phosphates of ADP are complexed by two Mg2+ and by a hydrogen bond to the imidazole ring of an invariant histidine. The Mg ions in turn are coordinated by three gamma-carboxyl groups of invariant aspartate residues. Water molecules complete the octahedral coordination sphere. The nucleotide is capped by an alpha-helical segment connecting helices 7 and 8 of the barrel. DhaL and the nucleotide-binding domain of the C.freundii kinase assume the same fold but display strongly different surface potentials. The latter observation and biochemical data indicate that the domains of the C.freundii Dha kinase constitute one cooperative unit and are not randomly interacting and independent like the subunits of the E.coli enzyme.     

Correlating calcium binding, Förster resonance energy transfer, and conformational change in the biosensor TN-XXL

Genetically encoded calcium indicators have become instrumental in imaging signaling in complex tissues and neuronal circuits in vivo. Despite their importance, structure-function relationships of these sensors often remain largely uncharacterized due to their artificial and multimodular composition. Here, we describe a combination of protein engineering and kinetic, spectroscopic, and biophysical analysis of the Förster resonance energy transfer (FRET)-based calcium biosensor TN-XXL. Using fluorescence spectroscopy of engineered tyrosines, we show that two of the four calcium binding EF-hands dominate the FRET output of TN-XXL and that local conformational changes of these hands match the kinetics of FRET change. Using small-angle x-ray scattering and NMR spectroscopy, we show that TN-XXL changes from a flexible elongated to a rigid globular shape upon binding calcium, thus resulting in FRET signal output. Furthermore, we compare calcium titrations using fluorescence lifetime spectroscopy with the ratiometric approach and investigate potential non-FRET effects that may affect the fluorophores. Thus, our data characterize the biophysics of TN-XXL in detail and may form a basis for further rational engineering of FRET-based biosensors.     

RHYTHM-AF: design of an international registry on cardioversion of atrial fibrillation and characteristics of participating centers

Background

Cigarette exposure increases brain oxidative stress. The literature showed that increased brain oxidative stress affects cardiovascular regulation. However, no previous study investigated the involvement of brain oxidative stress in animals exposed to cigarette and its relationship with cardiovascular regulation. We aimed to evaluate the effects of central catalase inhibition on baroreflex and cardiovascular responses in rats exposed to sidestream cigarette smoke (SSCS).

Methods

We evaluated males Wistar rats (320-370 g), which were implanted with a stainless steel guide cannula into the fourth cerebral ventricle (4th V). Femoral artery and vein were cannulated for mean arterial pressure (MAP) and heart rate (HR) measurement and drug infusion, respectively. Rats were exposed to SSCS during three weeks, 180 minutes, 5 days/week (CO: 100-300 ppm). Baroreflex was tested with a pressor dose of phenylephrine (PHE, 8 ??g/kg, bolus) to induce bradycardic reflex and a depressor dose of sodium nitroprusside (SNP, 50 ??g/kg, bolus) to induce tachycardic reflex. Cardiovascular responses were evaluated before, 5, 15, 30 and 60 minutes after 3-amino-1,2,4-triazole (ATZ, catalase inhibitor, 0.001 g/100 ??L) injection into the 4th V.

Results

Central catalase inhibition increased basal HR in the control group during the first 5 minutes. SSCS exposure increased basal HR and attenuated bradycardic peak during the first 15 minutes.

Conclusion

We suggest that SSCS exposure affects cardiovascular regulation through its influence on catalase activity.     

Stigma in attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a frequently diagnosed disorder in child- and adulthood with a high impact affecting multiple facets of social life. Therefore, patients suffering from ADHD are at high risk to be confronted with stigma, prejudices, and discrimination. A review of the empirical research in the field of ADHD with regard to stigma was performed. The findings of investigations in this field were clustered in different categories, including stigma in children with ADHD, stigma in adults with ADHD, stigma in relatives or in people close to a patient with ADHD, and the influence of stigma on authorities' attitudes toward patients with ADHD. Variables identified to contribute to stigma in ADHD are public's uncertainty concerning the reliability/validity of an ADHD diagnosis and the related diagnostic assessment, public's perceived dangerousness of individuals with ADHD, socio-demographical factors as age, gender, and ethnicity of the respondent or the target individual with ADHD, stigmatization of ADHD treatment, for example public's skepticism toward ADHD medication and disclosure of diagnostic status as well as medication status of the individual with ADHD. The contribution of stigma associated with ADHD can be conceptualized as an underestimated risk factor, affecting treatment adherence, treatment efficacy, symptom aggravation, life satisfaction, and mentally well-being of individuals affected by ADHD. Public as well as health professionals' concepts about ADHD are highly diverse, setting individuals with an ADHD diagnosis at greater risk to get stigmatized.