Resting-state glutamate level in the anterior cingulate predicts blood-oxygen level-dependent response to cognitive control

The dorsal anterior cingulate cortex (dACC) is a core structure for the governing of cognitive control, and recent studies have shown that interindividual differences in dACC anatomy are associated with corresponding differences in the ability for cognitive control. However, individuals differ not only in anatomical features of dACC, but also exhibit substantial variability regarding the biochemical characteristics of the dACC. In this study, we combined magnetic resonance spectroscopy ((1)H-MRS) and functional magnetic resonance imaging (fMRI), finding that interindividual differences of glutamate levels in the dACC during resting-state predict the strength of the blood-oxygen level-dependent (BOLD) response to a task requiring cognitive control. This relationship was observed in the retrosplenial cortex, the orbitofrontal cortex, the inferior parietal lobe, and the basal ganglia. More specifically, individuals with low resting-state glutamate levels in the dACC showed an increased BOLD response when the task demands were high, whereas high-glutamate individuals showed the opposite pattern of an increased BOLD response when the task demands were low. Thus, we show here that individual variability of glutamate levels is directly related to how the brain implements cognitive control.     

Epidemiology and population structure of Staphylococcus aureus in various population groups from a rural and semi urban area in Gabon, Central Africa

Little data is available on the epidemiology of Staphylococcus aureus in Africa. In the present study we aim at characterizing the population structure of S. aureus in healthy subjects from a rural and a semi-urban area in Lambaréné, Gabon as well as in hospital staff and inpatients. In total, 500 subjects were screened for S. aureus colonization of the nares, axillae and inguinal region. Overall, 146 (29%) were positive. We found 46 different spa types. The most frequent spa types were t084 (35%) and the agr II was the most prevalent subtype of the accessory gene regulator (56%, n=82). Five isolates (3%) were methicillin resistant S. aureus (MRSA). Carriage rates of S. aureus in Gabon are comparable to developed countries. MRSA is for the first time described and could pose a significant health threat in this region with limited access to microbiological laboratory facilities and to adequate antimicrobial agents.     

The effects of background noise on dichotic listening to consonant-vowel syllables: An fMRI study

The present fMRI study attempts to identify brain areas that may underlie the effect of different background noises on functional brain asymmetry in a dichotic listening task. Previous studies have shown that the prominent right ear advantage in dichotic listening to consonant-vowel syllables is affected by background noise. To explore the underlying neuronal processes, haemodynamic brain responses using fMRI were recorded while participants performed the dichotic listening task in two different noisy backgrounds (conversational “babble” and traffic noise). The behavioural results showed a reduction of the right ear advantage in the background noise conditions, especially in the traffic noise condition. The behavioural results are discussed in terms of alertness-attentional mechanisms. The effects of background noise on brain activation involved significant activations in a speech-processing network. Specifically the changes in activations in the peri-Sylvian region of the superior temporal gyrus and in the temporo-parietal junction part in the left hemisphere, as well as in the superior temporal gyrus/sulcus area in the right hemisphere may mirror the effects of noise on behavioural performance. The effects of noise on brain activation are discussed with regard to pre-activation mechanisms.     

Adaptive Smoothing as Inference Strategy

Although spatial smoothing of fMRI data can serve multiple purposes, increasing the sensitivity of activation detection is probably its greatest benefit. However, this increased detection power comes with a loss of specificity when non-adaptive smoothing (i.e. the standard in most software packages) is used. Simulation studies and analysis of experimental data was performed using the R packages neuRosim and fmri. In these studies, we systematically investigated the effect of spatial smoothing on the power and number of false positives in two particular cases that are often encountered in fMRI research: (1) Single condition activation detection for regions that differ in size, and (2) multiple condition activation detection for neighbouring regions. Our results demonstrate that adaptive smoothing is superior in both cases because less false positives are introduced by the spatial smoothing process compared to standard Gaussian smoothing or FDR inference of unsmoothed data.     

Electrochemical functionalization of gold and silicon surfaces by a maleimide group as a biosensor for immunological application

In the present study we investigated the preparation of biofunctionalized surfaces using the direct electrochemical grafting of maleimidophenyl molecules with subsequent covalent immobilization of specific peptide to detect target antibody, thereby extending the application of the biosensing systems towards immunodiagnostics. Para-maleimidophenyl (p-MP) functional groups were electrochemically grafted on gold and silicon surfaces from solutions of the corresponding diazonium salt. A specially synthesized peptide modified with cysteine (Cys-peptide) was then immobilized on the p-MP grafted substrates by cross-linking between the maleimide groups and the sulfhydryl group of the cysteine residues. Accordingly, the Cys-peptide worked as an antigen that was able to bind specifically the target antibody (anti-GST antibody), while it was non-sensitive to a negative contrast antibody (i.e. anti-Flag β). The immobilization of both specific and non-specific antibodies on the Cys-peptide-modified surfaces was monitored by infrared spectroscopic ellipsometry, a quartz crystal microbalance integrated in flow injection analysis system and potentiometric response. The results obtained clearly demonstrated that the direct modification of a surface with maleimidophenyl provides a very simple and reliable way of preparing biofunctionalized surfaces suitable for the construction of immunological biosensors.     

Biomarkers for Type 2 Diabetes and Impaired Fasting Glucose Using a Nontargeted Metabolomics Approach

Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39–1.95], P = 8.46 × 10⁻⁹) and was moderately heritable (h² = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34–2.11], P = 6.52 × 10⁻⁶) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27–2.75], P = 1 × 10⁻³). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.Currently, stratification of individuals at risk for type 2 diabetes (T2D) within the general population is based on well-established factors such as age, BMI, and fasting glucose (1). Although these factors contribute considerably to disease risk, they may not identify at-risk individuals before the disease process is well under way.Recently, a number of studies have found several metabolites to be correlated with insulin resistance and T2D (2–6), and T2D-associated metabolic profiles have been identified 10–15 years before the diagnosis/onset of the disease (7–9). To help preventive strategies, and maximize the potential for existing effective interventions, it is important to characterize the molecular changes that take place in the development of T2D.We aim to understand other biochemical changes, in addition to hyperglycemia, that take place at the onset of T2D using the largest metabolomic screening approach to date. We assessed >400 metabolites to determine which metabolomic profiles are correlated with T2D and impaired fasting glucose (IFG) in a large cohort of females from TwinsUK with independent replication.     

Inclusion of CYP3A5 genotyping in a nonparametric population model improves dosing of tacrolimus early after transplantation

Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C₀ concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three‐compartment model with first‐order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat‐free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3‐4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation.     

A non-randomized controlled clinical trial on autologous chondrocyte implantation (ACI) in cartilage defects of the medial femoral condyle with or without high tibial osteotomy in patients with varus deformity of less than 5°

Purpose

High tibial osteotomy (HTO) is a recommended concomitant surgery when treating cartilage lesions of the medial femoral condyle (MFC). Varus deformities of 5° and more were considered an indication for HTO in patients with cartilage defects. This study compares clinical outcome in patients with ACI and concomitant varus deformity of <5° with or without additional HTO.

Methods

43 patients with isolated cartilage defect of the MFC and varus deformity between 1° and 5° (mean age 39.14 ± 8.35 years; mean varus deformity 2.84 ± 1.19°) were included (follow-up 71.88 ± 23.99 months). Group A (n = 19) was treated with ACI and additional HTO; group B (n = 24) received ACI only. Survival rate in terms of absence of the need of reintervention was defined as main outcome parameter. In the subgroup without reintervention, functional outcome (KOOS and WOMAC) was evaluated.

Results

Overall rate of reintervention was 12 (27.9 %). Survival was significantly higher in group A (group A 89.5 %, group B 58.33 %; p = 0.023). Although a trend for better clinical outcome was observed for group A in the subgroup without reintervention, this observation lacked statistical significance (KOOS_symptoms group A 73.23, group B 59.64; p = 0.274).

Conclusion

While there is general consensus for treating varus deformities of >5° in patients with cartilage lesions of the medial femoral condyle, HTO also leads to a reduced rate of reinterventions and longer survival rates in patients with varus deformities of <5°.