Age correction in dementia--matching to a healthy brain

In recent research, many univariate and multivariate approaches have been proposed to improve automatic classification of various dementia syndromes using imaging data. Some of these methods do not provide the possibility to integrate possible confounding variables like age into the statistical evaluation. A similar problem sometimes exists in clinical studies, as it is not always possible to match different clinical groups to each other in all confounding variables, like for example, early-onset (age<65 years) and late-onset (age≥65) patients with Alzheimer's disease (AD). Here, we propose a simple method to control for possible effects of confounding variables such as age prior to statistical evaluation of magnetic resonance imaging (MRI) data using support vector machine classification (SVM) or voxel-based morphometry (VBM). We compare SVM results for the classification of 80 AD patients and 79 healthy control subjects based on MRI data with and without prior age correction. Additionally, we compare VBM results for the comparison of three different groups of AD patients differing in age with the same group of control subjects obtained without including age as covariate, with age as covariate or with prior age correction using the proposed method. SVM classification using the proposed method resulted in higher between-group classification accuracy compared to uncorrected data. Further, applying the proposed age correction substantially improved univariate detection of disease-related grey matter atrophy using VBM in AD patients differing in age from control subjects. The results suggest that the approach proposed in this work is generally suited to control for confounding variables such as age in SVM or VBM analyses. Accordingly, the approach might improve and extend the application of these methods in clinical neurosciences.     

Sex-dependent influences of obesity on cerebral white matter investigated by diffusion-tensor imaging

Several studies have shown that obesity is associated with changes in human brain function and structure. Since women are more susceptible to obesity than men, it seems plausible that neural correlates may also be different. However, this has not been demonstrated so far. To address this issue, we systematically investigated the brain''s white matter (WM) structure in 23 lean to obese women (mean age 25.5 y, std 5.1 y; mean body mass index (BMI) 29.5 kg/m², std 7.3 kg/m²) and 26 lean to obese men (mean age 27.1 y, std 5.0 y; mean BMI 28.8 kg/m², std 6.8 kg/m²) with diffusion-weighted magnetic resonance imaging (MRI). There was no significant age (p>0.2) or BMI (p>0.7) difference between female and male participants. Using tract-based spatial statistics, we correlated several diffusion parameters including the apparent diffusion coefficient, fractional anisotropy (FA), as well as axial (λ_∥) and radial diffusivity (λ_⊥) with BMI and serum leptin levels. In female and male subjects, the putative axon marker λ_∥ was consistently reduced throughout the corpus callosum, particularly in the splenium (r = −0.62, p<0.005). This suggests that obesity may be associated with axonal degeneration. Only in women, the putative myelin marker λ_⊥ significantly increased with increasing BMI (r = 0.57, p<0.005) and serum leptin levels (r = 0.62, p<0.005) predominantly in the genu of the corpus callosum, suggesting additional myelin degeneration. Comparable structural changes were reported for the aging brain, which may point to accelerated aging of WM structure in obese subjects. In conclusion, we demonstrate structural WM changes related to an elevated body weight, but with differences between men and women. Future studies on obesity-related functional and structural brain changes should therefore account for sex-related differences.     

Tularemia in Alaska, 1938 - 2010

Background

A major challenge in sheep farming during the grazing season along the coast of south-western Norway is tick-borne fever (TBF) caused by the bacteria Anaplasma phagocytophilum that is transmitted by the tick Ixodes ricinus.

Methods

A study was carried out in 2007 and 2008 to examine the prevalence of A. phagocytophilum infection and effect on weaning weight in lambs. The study included 1208 lambs from farms in Sunndal Ram Circle in Møre and Romsdal County in Mid-Norway, where ticks are frequently observed. All lambs were blood sampled and serum was analyzed by an indirect fluorescent antibody assay (IFA) to determine an antibody status (positive or negative) to A. phagocytophilum infection. Weight and weight gain and possible effect of infection were analyzed using ANOVA and the MIXED procedure in SAS.

Results

The overall prevalence of infection with A. phagocytophilum was 55%. A lower weaning weight of 3% (1.34 kg, p < 0.01) was estimated in lambs seropositive to an A. phagocytophilum infection compared to seronegative lambs at an average age of 137 days.

Conclusions

The results show that A. phagocytophilum infection has an effect on lamb weight gain. The study also support previous findings that A. phagocytophilum infection is widespread in areas where ticks are prevalent, even in flocks treated prophylactic with acaricides.     

H1-antihistamine up-dosing in chronic spontaneous urticaria: patients' perspective of effectiveness and side effects--a retrospective survey study

Background

The guidelines recommend that first line treatment of chronic spontaneous urticaria should be second generation non-sedating H₁-antihistamines with a positive recommendation against the use of old sedating first generation antihistamines. If standard dosing is not effective, increasing the dosage up to four-fold is recommended. The objective of this study was to obtain the chronic spontaneous urticaria-patient perspective on the effectiveness and unwanted effects of H₁-antihistamines in standard and higher doses.

Methodology/Principal Findings

This was a questionnaire based survey, initially completed by 368 individuals. 319 (248 female, 71 male, median age 42 years) had a physician-confirmed diagnosis of chronic spontaneous urticaria and were included in the results. Participants believed standard doses (manufacturers recommended dose) of second generation antihistamines to be significantly (P<0.005) more effective than first generation drugs. Furthermore, they believed that second generation drugs caused significantly (P<0.001) fewer unwanted effects and caused significantly (P<0.001) less sedation than first generation antihistamines. Three-quarters of the patients stated that they had up-dosed with antihistamines with 40%, 42% and 54% reporting significant added benefit from taking 2, 3 or 4 tablets daily respectively. The number of reports of unwanted effects and sedation following up-dosing were not significantly different from those reported for standard doses.

Conclusions

This survey supports the urticaria guidelines recommendations that the first line treatment for chronic spontaneous urticaria should be second generation rather than first generation H₁-antihistamines and that, if standard dosing is not effective, the dosage should be increased up to four-fold.     

Translation initiation factor 3 antagonizes authentic start codon selection on leaderless mRNAs

In this study, we have examined the influence of initiation factors on translation initiation of leaderless mRNAs whose 5'-terminal residues are the A of the AUG initiating codon. A 1:1 ratio of initiation factors to ribosomes abolished ternary complex formation at the authentic start codon of different leaderless mRNAs. Supporting this observation, in vitro translation assays using limiting ribosome concentrations with competing leaderless λ c I and Escherichia coli ompA mRNAs, the latter containing a canonical ribosome binding site, revealed reduced cI synthesis relative to OmpA in the presence of added initiation factors. Using in vitro toeprinting and in vitro translation assays, we show that this effect can be attributed to IF3. Moreover, in vivo studies revealed that the translational efficiency of a leaderless reporter gene is decreased with increased IF3 levels. These studies are corroborated by the observed increased translational efficiency of a leaderless reporter construct in an infC mutant strain unable to discriminate against non-standard start codons. These results suggest that, in the absence of a leader or a Shine–Dalgarno sequence, the function(s) of IF3 limits stable 30S ternary complex formation.     

Geographic and between-generation variation in the parasitoid communities associated with an invading gallwasp,Andricus quercuscalicis (Hymenoptera: Cynipidae)

The knopper gallwasp Andricus quercuscalicis Burgsdorf 1783 (Hymenoptera: Cynipidae) has invaded western and northern Europe from southern and eastern Europe over the last 400 years. A. quercuscalicis has two alternating generations, which differ in phenology, structure, and host oak species. This study describes geographic variation in the community in the tiny catkin galls of the sexual generation on Turkey oak, Quercus cerris, and compares the patterns obtained with those in the community attacking the alternate agamic generation. As predicted from considerations of parasitoid recruitment to the communities of invading phytophagous insects (Cornell and Hawkins 1993), in its native range the sexual generation shows (1) higher parasitoid community species richness, (2) higher total mortality due to parasitoid attack and (3) a higher ratio of specialist to generalist parasitoid species than is evident in the invaded range. Counter to predictions, there is no indication that parasitoid community richness in the invaded range has increased with time since the arrival of the new host. Higher host mortality in the native range is due principally to a single specialist, Aulogymnus obscuripes Mayr 1877 (Hymenoptera: Eulophidae), and is not distributed evenly among parasitoid species which attack the gall-former only in this area. This contrasts with the community in Britain, where three principal generalist parasitoids cause approximately equal mortalities. The agamic gall contains a taxonomically and structurally diverse guild of parasitoid and inquiline species, associated with the changing resource provided by a large, long-lived, complex gall. In contrast, the sexual community includes a taxonomically and structurally narrow guild, associated with a resource which is structurally simple, small in size and short-lived. No parasitoid species attacks the gall-former in both generations. Surprisingly, in spite of these differences in the nature of the gall resource in the two generations, over their entire range (native and invaded) the parasitoid guilds of the two are equally species rich.     

New Approaches for Absolute Quantification of Stable‐Isotope‐Labeled Peptide Standards for Targeted Proteomics Based on a UV Active Tag

Targeted proteomics depends on the availability of stable isotope labeled (SIL) peptide standards, which for absolute protein quantification need to be absolutely quantified. In the present study, three new approaches for absolute quantification of SIL peptides are developed. All approaches rely on a quantification tag (Qtag) with a specific UV absorption. The Qtag is attached to the peptide during synthesis and is removed by tryptic digestion under standard proteomics workflow conditions. While one quantification method (method A) is designed to allow the fast and economic production of absolutely quantified SIL peptides, two other methods (methods B and C) are developed to enable the straightforward re‐quantification of SIL peptides after reconstitution to control and monitor known problems related to peptide solubility, precipitation, and adhesion to vials. All methods yield consistent results when compared to each other and when compared to quantification by amino acid analysis. The precise quantitation methods are used to characterize the in vivo specificity of the H3 specific histone methyltransferase EZH2.     

PPARalpha /gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly

Peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARalpha/gamma agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARalpha agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARgamma agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P < 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels (P < 0.01). We conclude that the PPARalpha/gamma agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARgamma ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARalpha activation, but without hepatomegaly.