The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults.

During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self-reported emotion regulation and reactivity in a sample of typically developed adolescents (n = 37; 13-16 years) and adults (n = 39; 30-40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate Í age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within-group follow-up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age-group differences in gamma-aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA-ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age-related differences in emotion processing.

A Psychometric Evaluation of the Expanded Version of the Inventory of Depression and Anxiety Symptoms (IDAS-II) in Children and Adolescents.

The expanded version of the Inventory of Depression and Anxiety Symptoms (IDAS-II) is a self-report measure of 18 empirically derived internalizing symptom dimensions. The measure has shown good psychometric properties in adults but has never been evaluated in children and adolescents. A Swedish version of the IDAS-II was administered to 633 children and adolescents (Mage =16.6 [SD = 2.0]) and 203 adults (Mage = 35.4 [SD = 12.1]). The model/data fit of the 18-factor structure was excellent in both samples and measurement invariance across age groups was supported. All scales showed good to excellent internal consistency and psychometric properties replicated in the younger youth sample (< 16 years). Among youth, good convergent validity was established for all scales and divergent validity for most scales. The IDAS-II was better at identifying youth with current mental health problems than an internationally recommended scale of internalizing symptoms. In conclusion, the IDAS-II shows promise as a measure of internalizing symptoms in youth.

Pupil dilation during negative prediction errors is related to brain choline concentration and depressive symptoms in adolescents.

Depressive symptoms are associated with altered pupillary responses during learning and reward prediction as well as with changes in neurometabolite levels, including brain concentrations of choline, glutamate and gamma-aminobutyric acid (GABA). However, the full link between depressive symptoms, reward-learning-related pupillary responses and neurometabolites is yet to be established as these constructs have not been assessed in the same individuals. The present pilot study, investigated these relations in a sample of 24 adolescents aged 13 years. Participants completed the Revised Child Anxiety and Depression Scale (RCADS) and underwent a reward learning task while measuring pupil dilation and a single voxel dorsal anterior cingulate cortex (dACC) MEGA-PRESS magnetic resonance spectroscopy scan assessing choline, glutamate and GABA concentrations. Pupil dilation was related to prediction errors (PE) during learning, which was captured by a prediction error-weighted pupil dilation response index (PE-PDR) for each individual. Higher PE-PDR scores, indicating larger pupil dilations to negative prediction errors, were related to lower depressive symptoms and lower dACC choline concentrations. Dorsal ACC choline was positively associated with depressive symptoms, whereas glutamate and GABA were not related to PE-PDR or depressive symptoms. The findings support notions of cholinergic involvement in depressive symptoms and cholinergic influence on reward-related pupillary response, suggesting that pupillary responses to negative prediction errors may hold promise as a biomarker of depressive states.

Surgical or non-surgical treatment of plantar fasciopathy (SOFT): study protocol for a randomized controlled trial.

BACKGROUND: Plantar fasciopathy is the most common reason for complaints of plantar heel pain and one of the most prevalent musculoskeletal conditions with a reported lifetime incidence of 10%. The condition is normally considered self-limiting with persistent symptoms that often last for several months or years. Multiple treatments are available, but no single treatment appears superior to the others. Heavy-slow resistance training and radiofrequency microtenotomy for the treatment of plantar fasciopathy have shown potentially positive effects on short- and long-term outcomes (> 3 months). However, the effect of heavy-slow resistance training compared with a radiofrequency microtenotomy treatment is currently unknown. This trial compares the efficacy of heavy-slow resistance training and radiofrequency microtenotomy treatment with supplemental standardized patient education and heel inserts in improving the Foot Health Status Questionnaire pain score after 6 months in patients with plantar fasciopathy. METHODS: In this randomized superiority trial, we will recruit 70 patients with ultrasound-confirmed plantar fasciopathy and randomly allocate them to one of two groups: (1) heavy-slow resistance training, patient education and a heel insert (n = 35), and (2) radiofrequency microtenotomy treatment, patient education and a heel insert (n = 35). All participants will be followed for 1 year, with the 6-month follow-up considered the primary endpoint. The primary outcome is the Foot Health Status Questionnaire pain domain score. Secondary outcomes include the remaining three domains of the Foot Health Status Questionnaire, a Global Perceived Effect scale, the physical activity level, and Patient Acceptable Symptom State, which is the point at which participants feel no further need for treatment. DISCUSSION: By comparing the two treatment options, we should be able to answer if radiofrequency microtenotomy compared with heavy-slow resistance training is superior in patients with plantar fasciopathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03854682. Prospectively registered on February 26, 2019.

Global prevalent use, trends and practices in haemodiafiltration.

Online haemodiafiltration (HDF) represents today the most advanced and innovative form of renal replacement therapy (RRT). Recent controlled trials tend to prove its superiority over conventional haemodialysis on hard clinical end points provided that the right convective dose was delivered. In this article we report on present prevalent use and epidemiologic trends of HDF worldwide as well as on practice patterns in HDF prescription. In addition we analyze factors that may affect HDF clinical acceptance and more widely its implementation. National and international renal registries provide valuable demographic and epidemiologic information on end stage kidney disease patients on RRT. However, the updating and maintenance of such information system is particularly challenging at a country level and even more so on an international basis. Lag time, incompleteness and/or imprecision of data collection may further hamper precision and validity of data reporting. Fresenius Medical Care (FMC), as a large dialysis care provider operating worldwide, maintains an annually updated database addressing international end stage kidney disease data. Over the last decade, FMC has produced series of precise and reliable reports analyzing RRT trends and practices worldwide. The present overview and analysis is based on our consolidated data from market survey as well as national database registries and databases of recent studies. Online HDF acceptance is growing fast in the two leading regions having approved the method, i.e. Europe and Asia Pacific, with a patient average growth rate of 12 to 24%, being far above the total patient HD growth rate of 6.6%. Today online HDF represents a new paradigm shift in RRT with promising clinical results. Further initiatives (e.g., Kidney Health Initiative, NICE) might provide further push for promoting HDF as a new standard of care in end stage kidney disease patients on a global scale.

Application of Synthetic Peptide Arrays To Uncover Cyclic Di-GMP Binding Motifs.

UNLABELLED: High levels of the universal bacterial second messenger cyclic di-GMP (c-di-GMP) promote the establishment of surface-attached growth in many bacteria. Not only can c-di-GMP bind to nucleic acids and directly control gene expression, but it also binds to a diverse array of proteins of specialized functions and orchestrates their activity. Since its development in the early 1990s, the synthetic peptide array technique has become a powerful tool for high-throughput approaches and was successfully applied to investigate the binding specificity of protein-ligand interactions. In this study, we used peptide arrays to uncover the c-di-GMP binding site of a Pseudomonas aeruginosa protein (PA3740) that was isolated in a chemical proteomics approach. PA3740 was shown to bind c-di-GMP with a high affinity, and peptide arrays uncovered LKKALKKQTNLR to be a putative c-di-GMP binding motif. Most interestingly, different from the previously identified c-di-GMP binding motif of the PilZ domain (RXXXR) or the I site of diguanylate cyclases (RXXD), two leucine residues and a glutamine residue and not the charged amino acids provided the key residues of the binding sequence. Those three amino acids are highly conserved across PA3740 homologs, and their singular exchange to alanine reduced c-di-GMP binding within the full-length protein. IMPORTANCE: In many bacterial pathogens the universal bacterial second messenger c-di-GMP governs the switch from the planktonic, motile mode of growth to the sessile, biofilm mode of growth. Bacteria adapt their intracellular c-di-GMP levels to a variety of environmental challenges. Several classes of c-di-GMP binding proteins have been structurally characterized, and diverse c-di-GMP binding domains have been identified. Nevertheless, for several c-di-GMP receptors, the binding motif remains to be determined. Here we show that the use of a synthetic peptide array allowed the identification of a c-di-GMP binding motif of a putative c-di-GMP receptor protein in the opportunistic pathogen P. aeruginosa. The application of synthetic peptide arrays will facilitate the search for additional c-di-GMP receptor proteins and aid in the characterization of c-di-GMP binding motifs.

Significance of the factor analysis due to decreasing anthropogenic pollution--exemplified by river sediments.

Environmental datasets often consist of numerous features analyzed in many investigated samples. Therefore, the evaluation of those datasets is difficult. Chemometric methods like the factor analysis are useful tools to handle big datasets. In this paper, we discussed the relation between the geogenic background (noise) and anthropogenic pollution (source) for the suitability of environmental datasets for factor analytical methods. Thus, computed test datasets with different sources, diverse maximum of the sources, and various geogenic backgrounds were generated. Afterward, the maximum of the source was decreased stepwise, a factor analysis was computed, and the corresponding results were investigated in respect of the credibility. The major impacts on the evaluation of a feature are the mean value of the noise and the standard deviation of the noise. With the help of these two parameters, a pollution index can be calculated. The maximum of the source has to exceed that index in order to be usefully evaluable with the factor analyses. The evaluation of the results of the factor analysis would become increasingly complicated if the variability of a dataset decreases due to reduced maximum values or geogenic/anthropogenic sources which correspond to increasing environmental quality.

Cyclic nucleotide mapping of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a central role in the regulation of cardiac and neuronal firing rate, and these channels can be dually activated by membrane hyperpolarization and by binding of cyclic nucleotides. cAMP has been shown to directly bind HCN channels and modulate their activity. Despite this, while there are selective inhibitors that block the activation potential of the HCN channels, regulation by cAMP analogs has not been well investigated. A comprehensive screen of 47 cyclic nucleotides with modifications in the nucleobase, ribose moiety, and cyclic phosphate was tested on the three isoforms HCN1, HCN2, and HCN4. 7-CH-cAMP was identified to be a high affinity binder for HCN channels and crosschecked for its ability to act on other cAMP receptor proteins. While 7-CH-cAMP is a general activator for cAMP- and cGMP-dependent protein kinases as well as for the guanine nucleotide exchange factors Epac1 and Epac2, it displays the highest affinity to HCN channels. The molecular basis of the high affinity was investigated by determining the crystal structure of 7-CH-cAMP in complex with the cyclic nucleotide binding domain of HCN4. Electrophysiological studies demonstrate a strong activation potential of 7-CH-cAMP for the HCN4 channel in vivo. So, this makes 7-CH-cAMP a promising activator of the HCN channels in vitro whose functionality can be translated in living cells.

Period prevalence of self-reported headache in the general population in Germany from 1995-2005 and 2009: results from annual nationwide population-based cross-sectional surveys.

BACKGROUND: Although primary headache is the most frequent neurological disorder and there is some evidence that the prevalence rates have increased in recent years, no long-term data on the annual prevalence of headache are available for Germany. The objective of the study was therefore to obtain long-term data on the period prevalence of headache in the general population in Germany by means of population-based cross-sectional annual surveys (1995-2005 and 2009). METHODS: These surveys were conducted as face-to-face paper-and-pencil interviews from 1995 through 2004, and from 2005 onwards as computer-aided personal interviews. The reported headaches were self-diagnosed by the interviewees. Per year, approximately 640 trained interviewers interviewed between 10,898 and 12,538 German-speaking individuals aged 14 and older and living in private households in the whole of Germany (response rate: 67.4% and 73.1%, gross samples: 16,026 to 18,176 subjects). A total of more than 146,000 face-to-face interviews were analyzed. RESULTS: The one-year headache prevalence remained stable over the entry period, with 58.9% (95%CI 57.7-60.1) to 62.5% (95%CI 61.3-63.7) (p=0.07). Women showed consistently higher prevalence rates than men (females: 67.3 (95%CI 65.7-68.9) to 70.7% (95%CI 69.1-72.3), males: 48.4% (95%CI 46.5-50.3) to 54.3% (95%CI 52.4-56.2)), and both sexes showed a bell-shaped age dependence with peaks in the 30-39 age group. A stable slightly higher prevalence was observed in urban versus rural areas (p<0.0001), and there was also a significant trend towards higher prevalence rates in groups with a monthly household income larger than 3,500 € (p=0.03). CONCLUSION: The overall headache prevalence remained stable in Germany in the last 15 years.

Investigating the interaction of x-ray free electron laser radiation with grating structure.

The interaction of free electron laser pulses with grating structure is investigated using 4.6±0.1 nm radiation at the FLASH facility in Hamburg. For fluences above 63.7±8.7 mJ/cm2, the interaction triggers a damage process starting at the edge of the grating structure as evidenced by optical and atomic force microscopy. Simulations based on solution of the Helmholtz equation demonstrate an enhancement of the electric field intensity distribution at the edge of the grating structure. A procedure is finally deduced to evaluate damage threshold.

A chemical proteomics approach to identify c-di-GMP binding proteins in Pseudomonas aeruginosa.

In many bacteria, high levels of the ubiquitous second messenger c-di-GMP have been demonstrated to suppress motility and to promote the establishment of surface-adherent biofilm communities. While molecular mechanisms underlying the synthesis and degradation of c-di-GMP have been comprehensively characterized, little is known about how c-di-GMP mediates its regulatory effects. In this study, we have established a chemical proteomics approach to identify c-di-GMP interacting proteins in the opportunistic pathogen Pseudomonas aeruginosa. A functionalized c-di-GMP analog, 2'-aminohexylcarbamoyl-c-di-GMP (2'-AHC-c-di-GMP), was chemically synthesized and following its immobilization used to perform affinity pull down experiments. Enriched proteins were subsequently identified by high-resolution mass spectrometry. 2'-AHC-c-di-GMP was also employed in surface plasmon resonance studies to evaluate and quantify the interaction of c-di-GMP with its potential target molecules in vitro. The biochemical tools presented here may serve the identification of novel classes of c-di-GMP effectors and thus contribute to a better characterization and understanding of the complex c-di-GMP signaling network.

Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually activated by hyperpolarization and binding of cAMP to their cyclic nucleotide binding domain (CNBD). HCN isoforms respond differently to cAMP; binding of cAMP shifts activation of HCN2 and HCN4 by 17 mV but shifts that of HCN1 by only 2-4 mV. To explain the peculiarity of HCN1, we solved the crystal structures and performed a biochemical-biophysical characterization of the C-terminal domain (C-linker plus CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations, whereas those of HCN2 and HCN4 require cAMP saturating levels. Therefore, HCN1 responds less markedly than HCN2 and HCN4 to cAMP increase because its CNBD is already partly tetrameric. This is confirmed by voltage clamp experiments showing that the right-shifted position of V(½) in HCN1 is correlated with its propensity to tetramerize in vitro. These data underscore that ligand-induced CNBD tetramerization removes tonic inhibition from the pore of HCN channels.

The Pseudomonas aeruginosa chemotaxis methyltransferase CheR1 impacts on bacterial surface sampling.

The characterization of factors contributing to the formation and development of surface-associated bacterial communities known as biofilms has become an area of intense interest since biofilms have a major impact on human health, the environment and industry. Various studies have demonstrated that motility, including swimming, swarming and twitching, seems to play an important role in the surface colonization and establishment of structured biofilms. Thereby, the impact of chemotaxis on biofilm formation has been less intensively studied. Pseudomonas aeruginosa has a very complex chemosensory system with two Che systems implicated in flagella-mediated motility. In this study, we demonstrate that the chemotaxis protein CheR1 is a methyltransferase that binds S-adenosylmethionine and transfers a methyl group from this methyl donor to the chemoreceptor PctA, an activity which can be stimulated by the attractant serine but not by glutamine. We furthermore demonstrate that CheR1 does not only play a role in flagella-mediated chemotaxis but that its activity is essential for the formation and maintenance of bacterial biofilm structures. We propose a model in which motility and chemotaxis impact on initial attachment processes, dispersion and reattachment and increase the efficiency and frequency of surface sampling in P. aeruginosa.