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The control of reproductive processes in Rhodnius prolixus involves a variety of neuroactive chemicals. Among these, several studies have suggested that the biogenic amine octopamine (OA), might play an active role in these processes. Here, we investigate the molecular profile of the R. prolixus α adrenergic-like OA receptor 1 (RpOAα1-R) and its role in egg production. Comparative molecular analyses confirm that the RpOAα1-R gene codes for a true OAα1 receptor. The RpOAα1-R transcript is highly expressed in tissues associated with egg production, and after a blood meal, which is the stimulus for full egg production in R. prolixus, the RpOAα1-R transcript is upregulated in the ovaries and spermatheca. After RNAi-mediated RpOAα1-R knockdown, an ovarian phenotype characterized by slow egg development is observed. Furthermore, an altered egg phenotype has been characterized with eggs that are deformed. Interestingly, there is no evidence of disruption in vitellogenin (Vg) synthesis by the fat body or uptake by the oocytes. On the other hand, RpOAα1-R downregulation is correlated with defective choriogenesis in the eggs. These results provide critical information concerning the role of OAα1-R in oogenesis in R. prolixus. [ABSTRACT FROM AUTHOR]

Black Soldier fly (Hermetia illucens) larval (BSFL) frass was examined for its nutrient nitrogen, phosphate and potassium (N:P205:K2O), phytohormone and biogenic amine content, its plant growth promoting activity, and screened to test the hypothesis that bacteria characteristic of the genus Enterococcus (present in the biome of decaying catering waste and the larval gut) are excreted by BSFL in their frass. Frass plant growth promoting activity was measured by comparing the growth of winter wheat berry (Triticum aestivum) in frass treated soil to that of untreated (control) soil. The N:P205:K2O percent dry matter average, biogenic amine and phytohormone content of frass was determined by standard soil analysis, HPLC and HPLC/GC-MS methodologies, respectively. All were at too low of concentrations to account for its plant growth promoting activity. Frass added to soil induced a 11% increase in aerial mass and shoot length in treated plants over controls. Numerous colonies of Enterococci growing out on BEA (bile-esculin-agar) plates were detected in frass collected directly from larvae confirming the hypothesis that viable Enteroccoci are passing from the larval gut into their frass. Since a number of rhizobacteria, including Enterococci, have previously been identified as part of the larval gut biome, the passage of Enterococci from the larval gut into frass in the face of only trace N:P205:K2O percent dry matter averages, biogenic amine and phytohormone content is consistent with the hypothesis that Enterococci exhibiting rhizobacterial activity have a role in conferring to frass its plant growth promoting activity. [ABSTRACT FROM AUTHOR]

How the role of dopamine differs according to the evolution of eusociality and how it is required in the flexible society of Polistes paper wasps need further clarification. In the present study, we compared the storage and usage of dopamine-related substances in brains between the castes of paper wasps. The head widths, lipid stores in the abdomen, and levels of biogenic amines in the brains were measured in newly emerged females before male emergence (workers) and after male emergence (gynes) in four Polistes species. The head widths and the lipid stores were significantly larger in gynes than workers in P. snelleni, P. rothneyi, and P. jokahamae, whereas they did not differ between castes in P. chinensis. The levels of dopamine precursors in the brains were significantly higher in gynes than workers in P. snelleni, P. chinensis, and P. rothneyi, whereas those of dopamine and its metabolites did not differ between castes in these species. In P. jokahamae, the levels of dopamine precursors and dopamine in the brains did not differ between castes, but those of a dopamine metabolite were significantly higher in gynes than workers. Thus, the caste differences in the levels of dopamine-related substances did not always match body sizes and nutritional reserves. Foundresses in P. rothneyi had significantly lower levels of dopamine precursors and higher levels of dopamine and its metabolite than newly emerged gynes. These results suggested that in several Polistes species, dopamine precursors were stored in the brain without dopamine biosynthesis at emergence, and then converted into dopamine in foundresses during colony founding. These neuroendocrinal states in Polistes species largely differed from those in eusocial bees. [ABSTRACT FROM AUTHOR]

Objective: Fermented sausage is popular all over the world for its rich nutrition and unique flavor. Sausage casing is one of the key factors affecting the quality of fermented sausage. However, there is little information involved in this field. Methods: In this study, collagen casings were used as a wrapping material, and natural casings (pig casings) were used as a control. The effects of the two types of casings on biogenic amine content and other quality characteristics of fermented sausage were analyzed with increasing the storage time. Results: The results showed that with storage time increasing, the hardness and gumminess of fermented sausage in collagen casing (CC) group were higher than those in pig casing (PC) group (P<0.05), while the elasticity in CC group was lower than that in PC group (P<0.05). In the processing and storage period, there was no significant difference in the type and content of flavor substances between the two groups. More importantly, the contents of tryptamine, putrescine, cadaverine, histamine, tyramine and phenyethylamine in fermented sausage of CC group were lower than those in PC group (P<0.05). Conclusion: In conclusion, this study revealed that CC could improve the quality characteristics of fermented sausage and reduce the content of biogenic amines in fermented sausage, which provides a theoretical basis for the choice of casings in industrial production in the future. [ABSTRACT FROM AUTHOR]

The last two decades have witnessed a tremendous growth in probiotics and in the numbers of publications on their potential health benefits. Owing to their distinguishing beneficial effects and long history of safe use, species belonging to the Lactobacillus genus are among the most widely used probiotic species in human food and dietary supplements and are finding increased use in animal feed. Here, we isolated, identified, and evaluated the safety of two novel Limosilactobacillus reuteri (L. reuteri) isolates, ATCC PTA-126787 & ATCC PTA-126788. More specifically, we sequenced the genomes of these two L. reuteri strains using the PacBio sequencing platform. Using a combination of biochemical and genetic methods, we identified the two strains as belonging to L. reuteri species. Detailed in silico analyses showed that the two strains do not encode for any known genetic sequences of concern for human or animal health. In vitro assays confirmed that the strains are susceptible to clinically relevant antibiotics and do not produce potentially harmful by-products such as biogenic amines. In vitro bile and acid tolerance studies demonstrated that the two strains have similar survival profiles as the commercial L. reuteri probiotic strain DSM 17938. Most importantly, daily administration of the two probiotic strains to broiler chickens in drinking water for 26 days did not induce any adverse effect, clinical disease, or histopathological lesions, supporting the safety of the strains in an in vivo avian model. All together, these data provide in silico, in vitro and in vivo evidence of the safety of the two novel candidates for potential probiotic applications in humans as well as animals. [ABSTRACT FROM AUTHOR]

Molecular-bacterial vaginosis (BV) is characterized by low levels of vaginal Lactobacillus species and is associated with higher risk of sexually transmitted infections (STI). Perceived psychosocial stress is associated with increased severity and persistence of infections, including STIs. American Indians have the highest rates of stress and high rates of STIs. The prevalence of molecular-BV among American Indian women is unknown. We sought to evaluate measures of psychosocial stress, such as historic loss (a multigenerational factor involving slavery, forced removal from one's land, legally ratified race-based segregation, and contemporary discrimination) and their association with the vaginal microbiota and specific metabolites associated with BV, in 70 Northwestern Plains American Indian women. Demographics, perceived psychosocial stressors, sexual practices, and known BV risk factors were assessed using a modified version of the American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project survey. Self-collected mid-vaginal swabs were profiled for bacterial composition by 16S rRNA gene amplicon sequencing and metabolites quantified by targeted liquid-chromatography mass spectrometry. Sixty-six percent of the participants were classified as having molecular-BV, with the rest being either dominated by L. crispatus (10%) or L. iners (24%). High levels of lifetime trauma were associated with higher odds of having molecular-BV (adjusted Odds Ratio (aOR): 2.5, 95% Credible Interval (CrI): 1.1–5.3). Measures of psychosocial stress, including historic loss and historic loss associated symptoms, were significantly associated with lifestyle and behavioral practices. Higher scores of lifetime trauma were associated with increased concentrations of spermine (aFC: 3.3, 95% CrI: 1.2–9.2). Historic loss associated symptoms and biogenic amines were the major correlates of molecular-BV. Historical loss associated symptoms and lifetime trauma are potentially important underlying factors associated with BV. [ABSTRACT FROM AUTHOR]

In the past, wild edible alimurgic plants became an important alternative food source when poverty, wars or drought made it difficult to access crops. These plants were considered rich in highly nutritional compounds and also frequently used as food-medicine given their health-promoting properties. With the aim of improving our knowledge on the content of beneficial or detrimental compounds in relation with past local dietary and curative traditions, 12 wild food plant species were collected from two study areas selected for their very different degree of industrialization, urbanization, and conservation of local past traditions among the population: the Bologna province (Northern Italy) and the Middle Agri Valley (Southern Italy). Protein, polyphenol flavonoid and biogenic amine (both free and conjugated) contents and antioxidant activity of raw and boiled wild food plant extracts, and of cooking water were analyzed by means of spectrophotometric and high-performance liquid chromatography methods. The results demonstrated that most of the phenolic compounds were released in the cooking water which also showed the highest antioxidant activity. Seventeen different phenolic compounds were identified, of which the health-related luteolin, luteolin-7-glucoside and rutin were the most abundant (e.g., S. pratensis L. and C. intybus L.). On the other hand, biogenic amines were absent or present at very low levels in cooking water of those very same species (e.g., S. pratensis L., T. officinalis Weber, C. vesicaria subsp. taraxacifolia and C. intybus L.) of which traditionally a decoction is used for therapeutic purposes. Free and conjugated spermidine and spermine were generally the most abundant biogenic amines, while none of the known detrimental monoamines (e.g., histamine) was detected. In conclusion, the present results seem to support past local popular traditions which indicated beneficial medical properties of some wild edible plant, as well as of their cooking water. [ABSTRACT FROM AUTHOR]

During pregnancy, the vaginal microbiome plays an important role in both maternal and neonatal health outcomes. Throughout pregnancy, the vaginal microbial composition undergoes significant changes, including a decrease in overall diversity and enrichment with Lactobacillus spp. In turn, the modifications in the microbial profiles are associated with shifts in the composition of vaginal metabolites. In this study, we characterized the vaginal metabolic profiles throughout pregnancy at two different gestational ages, correlating them with a microscopic evaluation of the vaginal bacterial composition. A total of 67 Caucasian pregnant women presenting to the Family Advisory Health Centres of Ravenna (Italy) were enrolled and a vaginal swab was collected at gestational ages 9–13 weeks (first trimester) and 20–24 weeks (second trimester). The composition of the vaginal microbiome was assessed by Nugent score and women were divided in 'H' (normal lactobacilli-dominated microbiota), 'I' (intermediate microbiota), and 'BV' (bacterial vaginosis) groups. Starting from the cell-free supernatants of the vaginal swabs, a metabolomic analysis was performed by means of a 1H-NMR spectroscopy. From the first to the second trimester, a greater number of women showed a normal lactobacilli-dominated microbiota, with a reduction of cases of dysbiosis. These microbial shifts were associated with profound changes in the vaginal metabolic profiles. Over the weeks, a significant reduction in the levels of BV-associated metabolites (e.g. acetate, propionate, tyramine, methylamine, putrescine) was observed. At the same time, the vaginal metabolome was characterized by higher concentrations of lactate and of several amino acids (e.g. tryptophan, threonine, isoleucine, leucine), typically found in healthy vaginal conditions. Over time, the vaginal metabolome became less diverse and more homogeneous: in the second trimester, women with BV showed metabolic profiles more similar to the healthy/intermediate groups, compared to the first trimester. Our data could help unravel the role of vaginal metabolites in the pathophysiology of pregnancy. [ABSTRACT FROM AUTHOR]

N-hydroxylating flavin-dependent monooxygenases (FMOs) are involved in the biosynthesis of hydroxamate siderophores, playing a key role in microbial virulence. Herein, we report the first structural and kinetic characterization of a novel alkyl diamine N-hydroxylase DesB from Streptomyces sviceus (SsDesB). This enzyme catalyzes the first committed step in the biosynthesis of desferrioxamine B, a clinical drug used to treat iron overload disorders. X-ray crystal structures of the SsDesB holoenzyme with FAD and the ternary complex with bound NADP+ were solved at 2.86 Å and 2.37 Å resolution, respectively, providing a structural view of the active site environment. SsDesB crystallized as a tetramer and the structure of the individual protomers closely resembles the structures of homologous N-hydroxylating FMOs from Erwinia amylovora (DfoA), Pseudomonas aeruginosa (PvdA), and Aspergillus fumigatus (SidA). Using NADPH oxidation, oxygen consumption, and product formation assays, kinetic parameters were determined for various substrates with SsDesB. SsDesB exhibited typical saturation kinetics with substrate inhibition at high concentrations of NAD(P)H as well as cadaverine. The apparent kcat values for NADPH in steady-state NADPH oxidation and oxygen consumption assays were 0.28 ± 0.01 s-1 and 0.24 ± 0.01 s-1, respectively. However, in product formation assays used to measure the rate of N-hydroxylation, the apparent kcat for NADPH (0.034 ± 0.008 s-1) was almost 10-fold lower under saturating FAD and cadaverine concentrations, reflecting an uncoupled reaction, and the apparent NADPH KM was 33 ± 24 μM. Under saturating FAD and NADPH concentrations, the apparent kcat and KM for cadaverine in Csaky assays were 0.048 ± 0.004 s-1 and 19 ± 9 μM, respectively. SsDesB also N-hydroxylated putrescine, spermidine, and L-lysine substrates but not alkyl (di)amines that were branched or had fewer than four methylene units in an alkyl chain. These data demonstrate that SsDesB has wider substrate scope compared to other well-studied ornithine and lysine N-hydroxylases, making it an amenable biocatalyst for the production of desferrioxamine B, derivatives, and other N-substituted products. [ABSTRACT FROM AUTHOR]

In this work, we performed an analysis of the networks of interactions between drugs and their targets to assess how connected the compounds are. For our purpose, the interactions were downloaded from the DrugBank database, and we considered all drugs approved by the FDA. Based on topological analysis of this interaction network, we obtained information on degree, clustering coefficient, connected components, and centrality of these interactions. We identified that this drug-target interaction network cannot be divided into two disjoint and independent sets, i.e., it is not bipartite. In addition, the connectivity or associations between every pair of nodes identified that the drug-target network is constituted of 165 connected components, where one giant component contains 4376 interactions that represent 89.99% of all the elements. In this regard, the histamine H1 receptor, which belongs to the family of rhodopsin-like G-protein-coupled receptors and is activated by the biogenic amine histamine, was found to be the most important node in the centrality of input-degrees. In the case of centrality of output-degrees, fostamatinib was found to be the most important node, as this drug interacts with 300 different targets, including arachidonate 5-lipoxygenase or ALOX5, expressed on cells primarily involved in regulation of immune responses. The top 10 hubs interacted with 33% of the target genes. Fostamatinib stands out because it is used for the treatment of chronic immune thrombocytopenia in adults. Finally, 187 highly connected sets of nodes, structured in communities, were also identified. Indeed, the largest communities have more than 400 elements and are related to metabolic diseases, psychiatric disorders and cancer. Our results demonstrate the possibilities to explore these compounds and their targets to improve drug repositioning and contend against emergent diseases. [ABSTRACT FROM AUTHOR]

This study evaluates whole-genome sequence of Lactobacillus reuteri PNW1 and identifies its safety genes that may qualify it as a putative probiotic. It further extracted the bacteriocin produced by the strain and tested its effectiveness against pathogenic STEC E. coli O177. The genomic DNA was sequenced on illuminal Miseq instrument and the sequenced data was assessed for quality reads before assembled with SPAdes. The draft assembly was annotated with Prokaryotic Genome Annotation Pipeline (PGAP) and Rapid Annotations using Subsystems Technology (RAST). Further downstream analyses were carried out using appropriate bioinformatic tools. Production of biogenic amines was biochemically confirmed through HPLC analysis. The assembled genome was 2,430,215 bp long in 420 contigs with 39% G+C content. Among all known genes, putatively responsible for the production of toxic biochemicals, only arginine deiminase (EC3.5.3.6) was spotted. Coding sequences (CDS) putative for D-lactate dehydrogenase (EC1.1.1.28), L-lactate dehydrogenase (EC1.1.1.27) and bacteriocin helveticin J were found within the genome together with plethora of other probiotic important genes. The strain harbours only resistant genes putative for Lincosamide (lnuC) and Tetracycline resistant genes (tetW). There was no hit found for virulence factors and probability of the strain being a human pathogen was zero. Two intact prophage regions were detected within the genome of L. reuteri PNW1 and nine CDS were identified for insertion sequence by OASIS which are belong to seven different families. Five putative CDS were identified for the CRISPR, each associated with Cas genes. Maximum zone of inhibition exhibited by the bacteriocin produced L. reuteri PNW1 is 20.0±1.00 mm (crude) and 23.3±1.15 mm (at 0.25 mg/ml) after being partially purified. With the strain predicted as non-human pathogen, coupled with many other identified desired features, L. reuteri PNW1 stands a chance of making good and safe candidates for probiotic, though further in-vivo investigations are still necessary. [ABSTRACT FROM AUTHOR]

Ecology studies showed that esophageal and gastric cancers are directly correlated with the consumption of processed foods. The carcinogenicity of traditional Chinese fermented foods such as douchi (fermented black beans or fermented black soybeans) is due to the presence of carcinogenic N-nitroso compounds, which are derived from biogenic amines. Among the various biogenic amines that can act as precursors of N-nitroso compounds, histamine and tyramine are considered to be the most toxic and are of public health concern when present in food. We have examined some douchi products on the market, and significant amounts of histamine and tyramine were found. The use of fermentation starters generated by subculturing fermented products with unknown microbiota would induce the risk of biogenic amines. As the microbiota used in fermentation is a crucial factor in determining the biogenic amines of fermented food, it is hypothesized that the possible harmful effects of douchi can be minimized through the use of fermentation starters composed of probiotic bacteria. This is the first study to investigate the potential of using probiotic bacteria in manufacturing douchi. Lactobacillus rhamnosus GG (LGG), Lactobacillus casei Shirota (LcS) and Escherichia coli Nissle 1917 (EcN) were used to ferment black beans in this study, and no tyramine was detected in black bean samples incubated with these three strains anaerobically at 37°C or 20°C. The starter culture strains, temperature and presence of oxygen during the incubation period were found to be critical to the generation of biogenic amines. The findings of this study can provide evidence-based insights and warrant further investigations on the potential of reducing the harmful compounds in food fermented with probiotic bacteria as well as the sensory evaluation of douchi fermented with probiotic bacteria. [ABSTRACT FROM AUTHOR]

Happiness, or Subjective Well-Being (SWB), is generally considered as a peaceful and satisfied state accompanied by consistent and optimistic mood. Due to its subjective and elusive nature, however, wellbeing has only been scarcely investigated in the neuroimaging literature. In this study, we investigated its neural substrates by characterizing two different perspectives: self- or other-concerned wellbeing. In the present study, 22 participants evaluated the subjective happiness (with button presses 1 to 4) to 3 categories (intra- and inter-personal and neutral) of pre-rated pictures in a slow event-related fMRI. Because wellbeing is constantly featured by pleasure feelings after self-inspection, we predict that happier conditions, featured by “intra-personal vs. neutral” and “inter-personal vs. neutral” conditions, should yield higher BOLD activities in overlapping reward- and self-related regions. Indeed, medial prefrontal (mPFC), pregenual ACC (pACC), precuneus and posterior cingulate cortex (PCC) were revealed both by General Linear Model (GLM) (categorical contrasts) and parametric modulations (correlations with rating 1-4s), specifically, more connectivity between nucleus accumbens (NAcc) and mPFC, via additional psychophysiological interaction, or PPI, analyses. More interestingly, GLM and multivariate searchlight analyses jointly reveal the subdivision of mPFC and the PCC/precuneus, with anterior mPFC and dorsal PCC/precuneus more for interpersonal, posterior mPFC and ventral PCC/precuneus more for intrapersonal, SWB, respectively. Taken together, these results are not only consistent with the “cortical midline hypothesis of the self”, but also extending the “spatial gradients of self-to-other-concerned processing” from mPFC to including both mPFC and PCC/precuneus, making them two “hubs” of self-to-other-concerned wellbeing network. [ABSTRACT FROM AUTHOR]

Confined hydration and conformational flexibility are some of the challenges encountered for the rational design of selective antagonists of G-protein coupled receptors. We present a set of C3-substituted (-)-stepholidine derivatives as potent binders of the dopamine D3 receptor. The compounds are characterized biochemically, as well as by computer modeling using a novel molecular dynamics-based alchemical binding free energy approach which incorporates the effect of the displacement of enclosed water molecules from the binding site. The free energy of displacement of specific hydration sites is obtained using the Hydration Site Analysis method with explicit solvation. This work underscores the critical role of confined hydration and conformational reorganization in the molecular recognition mechanism of dopamine receptors and illustrates the potential of binding free energy models to represent these key phenomena. [ABSTRACT FROM AUTHOR]

Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and α1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT1A receptors (5-HT1AARs) and α1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1–10 μM) concentration-dependently silenced neurons through activation of 5-HT1AARs. The effect was fully antagonized by the selective 5-HT1A receptor antagonist Way-100635. With 5-HT1A receptors blocked by Way-100635, trazodone (1–10 μM) concentration-dependently inhibited neuron firing facilitated by 1 μM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10–100 μM) indicated competitive antagonism at α1-adrenoceptors. Both effects of trazodone were also observed in slices from Tph2-/- mice that lack synthesis of brain serotonin, showing that the activation of 5-HT1AARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT1AAR-coupled G protein-activated inwardly-rectifying (GIRK) channel conductance with weak partial agonist efficacy (~35%) compared to that of the full agonist 5-CT. Collectively our data show that trazodone, at concentrations relevant to its clinical effects, exerts weak partial agonism at 5-HT1AARs and disfacilitation of firing through α1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α1-adrenoceptor stimulation. [ABSTRACT FROM AUTHOR]

The ventral midbrain supports a variety of functions through the heterogeneity of neurons. Dopaminergic and GABA neurons within this region are particularly susceptible targets of amphetamine-class psychostimulants such as methamphetamine. While this has been evidenced through single-neuron methods, it remains unclear whether and to what extent the local neuronal network is affected and if so, by which mechanisms. Both GABAergic and dopaminergic neurons were heavily featured within the primary ventral midbrain network model system. Using spontaneous calcium activity, our data suggest methamphetamine decreased total network output via a D2 receptor-dependent manner. Over culture duration, functional connectivity between neurons decreased significantly but was unaffected by methamphetamine. However, across culture duration, exposure to methamphetamine significantly altered changes in network assortativity. Here we have established primary ventral midbrain networks culture as a viable model system that reveals specific changes in network activity, connectivity, and topology modulation by methamphetamine. This network culture system enables control over the type and number of neurons that comprise a network and facilitates detection of emergent properties that arise from the specific organization. Thus, the multidimensional properties of methamphetamine can be unraveled, leading to a better understanding of its impact on the local network structure and function. [ABSTRACT FROM AUTHOR]

Gap junctions (GJs), which consist of proteins called connexins, are intercellular channels that allow the passage of ions, second messengers, and small molecules. GJs and connexins are considered as emerging therapeutic targets for various diseases. Previously, we screened numerous compounds using our recently developed iodide yellow fluorescent protein gap junctional intercellular communication (I-YFP GJIC) assay and found that flunarizine (FNZ), used for migraine prophylaxis and as an add-on therapy for epilepsy, inhibits GJIC in LN215 human glioma cells. In this study, we confirmed that FNZ inhibits GJIC using the I-YFP GJIC assay. We demonstrated that FNZ inhibits GJ activities via a mechanism that is independent of calcium channels and dopaminergic D2, histaminergic H1, or 5-HT receptors. In addition, we showed that FNZ significantly increases connexin 43 (Cx43) phosphorylation on the cell surface, but does not alter the total amount of Cx43. The beneficial effects of FNZ on migraines and epilepsy might be related to GJ inhibition. [ABSTRACT FROM AUTHOR]

Biochemical changes in utero may alter normal fetal development, resulting in disease later in life, a phenomenon known as fetal programming. Recent epidemiological studies link fetal programming to negative health outcomes, such as low birth weight and hypertension in adulthood. Here, we used a WKY rat model and studied the molecular changes triggered by prenatal glucocorticoid (GC) exposure on the development of hypertension, and on the regulation of phenylethanolamine N-methyl transferase (PNMT), the enzyme responsible for biosynthesis of epinephrine, and a candidate gene linked to hypertension. Clinically, high doses of the synthetic GC dexamethasone (DEX) are used to treat infant respiratory distress syndrome. Elevated maternal GCs have been correlated with fetal programming of hypertension. The aim of this study was to determine if lower doses of DEX would not lead to detrimental fetal programming effects such as hypertension. Our data suggests that prenatal stress programs for increased expression of PNMT and altered regulation of PNMT in males and females. Importantly, we identified that DEX mediated programming was more apparent in the male rats, and the lower dose 10μg/kg/day of DEX did not lead to changes in blood pressure (BP) in female rats suggesting that this dose is below the threshold for programming of hypertension. Furthermore, sex-specific differences were observed in regards to programming mechanisms that may account for hypertension in males. [ABSTRACT FROM AUTHOR]

Cell-to-cell communication is a key element of microvascular blood flow control, including rapidly carrying signals through the vascular endothelium in response to local stimuli. This cell-to-cell communication is negatively impacted during inflammation through the disruption of junctional integrity. Such disruption is associated with promoting the onset of cardiovascular diseases as a result of altered microvascular blood flow regulation. Therefore, understanding the mechanisms how inflammation drives microvascular dysfunction and compounds that mitigate such inflammation and dysfunction are of great interest for development. As such we aimed to investigate extracts of mushrooms as potential novel compounds. Using intravital microscopy, the medicinal mushroom, Inonotus obliquus was observed, to attenuate histamine-induced inflammation conducted vasodilation in second-order arterioles in the gluteus maximus muscle of C57BL/6 mice. Mast cell activation by C48/80 similarly disrupted endothelial junctions and conducted vasodilation but only histamine was blocked by the histamine antagonist, pyrilamine not C48/80 suggesting the importance of mast cell activation. Data presented here supports that histamine induced inflammation is a major disruptor of junctional integrity, and highlights the important anti-inflammatory properties of Inonotus obliquus focusing future assessment of mast cells as putative target for Inonotus obliquus. [ABSTRACT FROM AUTHOR]

Human fumarylacetoacetate hydrolase (FAH) domain containing protein 1 (FAHD1) is a mitochondrial oxalocatate decarboxylase, the first of its kind identified in eukaryotes. The physiological role of FAHD1 in other eukaryotes is still poorly understood. In C. elegans loss of the FAHD1 ortholog FAHD-1 was reported to impair mitochondrial function, locomotion and egg-laying behavior, yet the underlying mechanisms remained unclear. Using tissue-specific rescue of fahd-1(-) worms, we find that these phenotypic abnormalities are at least in part due to fahd-1’s function in neurons. Moreover, we show that egg-laying defects in fahd-1(-) worms can be fully rescued by external dopamine administration and that depletion of fahd-1 expression induces expression of several enzymes involved in serotonin biosynthesis. Together, our results support a role for fahd-1 in modulating serotonin levels and suggest this protein as a novel link between metabolism and neurotransmitter signaling in the nervous system. Finally, we propose a model to explain how a metabolic defect could ultimately lead to marked changes in neuronal signaling. [ABSTRACT FROM AUTHOR]

We showed previously an epinephrine-induced inhibition of the Na+/K+ ATPase in Caco-2 cells mediated via PGE2. This work is an attempt to further elucidate mediators downstream of PGE2 and involved in the observed inhibitory effect. The activity of the Na+/K+ ATPase was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of ouabain, a specific inhibitor of the enzyme. Changes in the protein expression of the Na+/K+ ATPase were investigated by western blot analysis which revealed a significant decrease in the abundance of the ATPase in plasma membranes. Treating the cells with epinephrine or PGE2 in presence of SC19220, a blocker of EP1 receptors abolished completely the effect of the hormone and the prostaglandin while the effect was maintained unaltered in presence of antagonists to all other receptors. Treatment with calphostin C, PTIO, ODQ or KT5823, respective inhibitors of PKC, NO, soluble guanylate cyclase and PKG, abrogated completely the effect of epinephrine and PGE2, suggesting an involvement of these mediators. A significant inhibition of the ATPase was observed when cells were treated with PMA, an activator of PKC or with 8-Br-cGMP, a cell permeable cGMP analogue. PMA did reduce the protein expression of IκB, as shown by western blot analysis, and its effect on the ATPase was not manifested in presence of an inhibitor of NF-κB while that of SNAP, a nitric oxide donor, was not affected. The results infer that NF-κB is downstream PKC and upstream NO. The data support a pathway in which epinephrine induces the production of PGE2 which binds to EP1 receptors and activates PKC and NF-κB leading to NO synthesis. The latter activates soluble guanylate cyclase resulting in cGMP production and activation of PKG which through direct or indirect phosphorylation inhibits the Na+/K+ ATPase by inducing its internalization. [ABSTRACT FROM AUTHOR]

Background: Many patients with major depressive disorder (MDD) fail to respond to antidepressant (AD) pharmacotherapy. The objectives of this study were to characterize MDD and treatment-resistant depression (TRD) at the level of pharmacologically treated episodes and to describe the sequential treatment patterns by lines of therapy (LOT) in the first two episodes. Methods: Adults (≥18 years of age) with continuous enrollment ≥12 months before and after the first MDD diagnosis and treated with an AD, with or without an MDD-indicated antipsychotic (AP), were identified (1/1/2010-12/31/2015). The MDD episode started on the date of MDD diagnosis that was preceded by a clean period without any MDD diagnosis. The MDD episode ended on the last MDD diagnosis or the end of the days’ supply of AD/AP medication, whichever came last. TRD was defined as an MDD episode with ≥3 AD/AP regimens. Measured outcomes included episode duration, number of LOT, relapse hospitalization, and sequential treatment patterns of MDD episode stratified by TRD and non-TRD episodes. Results: Of 48,440 patients who received AD/AP in the 1st MDD episode, 3,317 (6.8%) of episodes were considered TRD. Mean duration of 1st TRD episodes was 571 days, mean number of AD/AP LOTs was 3.47, and 13.7% involved relapse hospitalization. Mean duration of 1st non-TRD episodes was 200 days, mean number of AD/AP LOTs was 1.21, and 9.6% involved relapse hospitalization. Among 1st MDD episodes, 25.5% had a second LOT; 7.3% had a third LOT. Most patients received selective serotonin reuptake inhibitors (SSRIs) as the first LOT (63.0%), and the plurality of regimens were SSRIs in second (44.9%) and third LOT (41.1%). Conclusions: Compared to non-TRD episodes, TRD episodes were longer and more often involved relapse hospitalizations. SSRIs were the most common treatment; treatment changes and potential treatment unresponsiveness were frequent among MDD patients. [ABSTRACT FROM AUTHOR]

Mutations in ATP13A2 cause Kufor-Rakeb syndrome (KRS), a juvenile form of Parkinson’s disease (PD) with dementia. However, the mechanisms by which mutations in ATP13A2 cause KRS is not understood. The mutations lead to misfolding of the translated Atp13a2 protein and its premature degradation in the endoplasmic reticulum, never reaching the lysosome where the protein is thought to function. Atp13a2 is a P-type ATPase, a class of proteins that function in ion transport. Indeed, studies of human, mouse, and yeast Atp13a2 proteins suggest a possible involvement in regulation of heavy metal toxicity. Here we report on the cytoprotective function of Atp13a2 on HeLa cells and dopamine neurons of Caenorhabditis elegans (C. elegans). HeLa cells stably overexpressing V5- tagged Atp13a2Isoform-1 protein were more resistant to elevated manganese exposure and to starvation-induced cell death compared to cells not overexpressing the protein. Because PD is characterized by loss of dopamine neurons, we generated transgenic C. elegans expressing GFP-tagged human Atp13a2 protein in dopamine neurons. The transgenic animals exhibited higher resistance to dopamine neuron degeneration after acute exposure to manganese compared to nematodes that expressed GFP alone. The results suggest Atp13a2 Isoform-1 protein confers cytoprotection against toxic insults, including those that cause PD syndromes. [ABSTRACT FROM AUTHOR]

The neural mechanisms underlying behavioral therapy for vocal acoustic deficits in patients with Parkinson disease is unknown. A primary hypothesis is that voice therapy may modulate mesolimbic brainstem regions, including the ventral tegmental area (VTA). The VTA is implicated in ultrasonic call peak frequency, involved in rewarding behaviors, and impacted by Parkinsonism. We tested the hypothesis that chronic (daily) behavioral vocal exercise of male Pink1-/- rats would alter ultrasonic vocalization acoustics and mesolimbic neurochemistry (catecholamines, GABA, mu-opioid receptor) compared to three different controls: sham-exercised Pink1-/-, unexercised Pink1-/-, and unexercised wildtype (WT) rats. A sub-hypothesis is that sham-exercise rats may exhibit changes to VTA neurochemistry as a result of a type or rewarding intervention. Results demonstrate that average bandwidth (frequency range) of ultrasonic vocalizations did not differ between WT, Pink1-/- no exercise vs. sham and vocal-exercise rats. However, average peak frequency is significantly reduced in vocal-exercised Pink1-/- rats compared to Pink1-/- no exercise, and WT groups. Unexpectedly, there were no significant acoustic differences between the vocal- and sham-exercised groups. There were no differences in catecholamine protein concentrations or tyrosine hydroxylase mRNA expression in the VTA between any of the groups. However, there was significant upregulation of all GABA-related genes in both vocal- and sham-exercised Pink1-/- rats (Gad1, Gad2, Gls, Glul); this finding was confirmed with follow up quantitative Western blotting for GAD. Additionally, there were differential results for mu-opioid receptor quantification in the VTA: vocal-exercised Pink1-/- rats showed increased mRNA expression for mu-opioid receptors whereas Western blotting indicated decreased protein levels in all Pink1-/- rats compared to WT controls suggesting the possible onset of pathology in this model. These data demonstrate modulatory effects of a rewarding behavioral paradigm on ultrasonic vocalization peak frequency. The results suggest that neuromodulators such as GABA and opioid activity, as well as the rewarding aspects of therapy may play a key role in shaping vocal treatments. [ABSTRACT FROM AUTHOR]

Previous research has suggested an association between antidepressants use and clinical restless legs syndrome (RLS) in patients, but there has never been a single study investigating the risk of RLS in irritable bowel syndrome (IBS) patients treated with antidepressants. Hence, we aimed to explore the association between IBS and RLS and to examine the risk of RLS in IBS patients treated with antidepressants. With the use of the National Health Insurance Research Database of Taiwan, 27,437 adults aged ≥ 20 years with newly diagnosed IBS (ICD-9-CM Code 564.1) and gender- and age-matched 54,874 controls without IBS were enrolled between 2000 and 2012. All patients were followed-up until RLS diagnosis, withdrawal from the National Health Insurance program, or end of 2013. We used the Cox proportional hazards model to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of RLS. RLS was more prevalent in IBS patients than in the non-IBS group (7.57 versus 3.36 per 10,000 person-years), with an increased risk of RLS (adjusted HR [aHR], 1.91; 95% CI, 1.52–2.40). Multivariate Cox proportional hazards analysis identified older age (age, 51–65 years; aHR, 1.67; 95% CI, 1.09–2.56; and age > 65; aHR, 1.59; 95% CI, 1.02–2.48), hypothyroidism (aHR, 4.24; 95% CI, 1.92–9.37), CAD (aHR, 1.70; 95% CI, 1.17–2.48), and depression (aHR, 3.15; 95% CI, 2.14–4.64) as independent RLS risk factors in IBS patients. In addition, the male SSRIs users were associated with significantly higher risk of RLS (aHR, 3.05 95% CI, 1.34–6.92). Our study showed that the IBS group has higher risk of RLS. Moreover, SSRIs use may increase the risk of RLS in male IBS patients. [ABSTRACT FROM AUTHOR]

Background: Endotoxin induces an inflammatory response, with secondary release of cytokines, which can progress to shock and multiple organ failure. We explored whether continuous renal replacement therapy (CRRT) using a modified membrane (oXiris) capable of adsorption could reduce endotoxin and cytokine levels in septic patients. Methods: Sixteen patients requiring CRRT for septic shock-associated acute renal failure and who had endotoxin levels >0.03 EU/ml were prospectively randomized in a crossover double-blind design to receive CRRT with an oXiris filter or with a standard filter. Endotoxin and cytokine levels were measured at baseline and 1, 3, 8, 16 and 24 hours after the start of CRRT. Norepinephrine infusion rate and blood lactate levels were monitored. Results: During the first filter treatment period, endotoxin levels decreased in 7 of 9 (77.8%) oXiris filter patients, but in only 1 of 6 (16.7%) standard filter patients (P = 0.02). Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8 and interferon (IFN)γ decreased more with the oXiris filter than with the standard filter. Lactate concentration decreased with oXiris (-1.3[-2.2 to -1.1] mmol/l, P = 0.02), but not with the standard filter (+0.15[-0.95 to 0.6]). The norepinephrine infusion rate was reduced during oXiris CRRT, but not during standard filter CRRT. In the second filter treatment period, there was no significant reduction in endotoxin or cytokine levels in either group. Conclusions: CRRT with the oXiris filter seemed to allow effective removal of endotoxin and TNF-α, IL-6, IL-8 and IFNγ in patients with septic shock-associated acute renal failure. This may be associated with beneficial hemodynamic effects. [ABSTRACT FROM AUTHOR]

Handling and consumption of Campylobacter-contaminated poultry meat is the most common cause of human campylobacteriosis. While many studies deal with interventions to reduce Campylobacter spp. on chicken carcasses, studies on other poultry species are rare. In the present study, a spray treatment with peracetic acid (PAA) on turkey carcasses was evaluated. For this, parts of breast fillets with skin and Campylobacter (C.) jejuni DSM 4688 (108 cfu/ml) inoculated drumsticks were sprayed for 30 s with PAA (1200 ppm) or water as control solution. Samples were packaged under modified atmosphere and stored at 4°C until analysis on day 1, 6 and 12. The breast fillets were used for determination of the total viable count, sensory and meat quality examination as well as myoglobin content and biogenic amines. The drumsticks were used for C. jejuni counts. PAA had a significant effect in reducing total viable counts on all days by up to 1.2 log10 compared to the untreated control. Treatment with water alone showed no effect. C. jejuni counts were significantly reduced by PAA (0.9–1.3 log10), while water achieved a 0.5 log10 reduction on C. jejuni counts on day 1. No differences in sensory, pH, electrical conductivity and myoglobin content could be found. The skin of the PAA treated fillets had lower redness values than the water control on day 1, whereas on day 12 parts of the water treated muscles were lighter than the untreated control. A lower putrescine content of the water sprayed fillets in comparison to the control sample on day 12 was the only significant difference concerning the biogenic amines. Results from this study indicate that a spray treatment with 1200 ppm PAA would be a useful measure to lower the Campylobacter spp. counts on turkey carcasses without having a negative influence on product quality. [ABSTRACT FROM AUTHOR]

Objective: Traumatic brain injury (TBI) is common and associated with a marked increased risk of developing epilepsy. Animal studies indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the risk of epilepsy after TBI. The aim of this study was to investigate whether use of SSRIs modifies the risk of epilepsy after TBI. Methods: This was a cohort study of 205,715 persons, who suffered a TBI in Denmark from 1996 to 2013. For each person with TBI, we matched 10 reference persons (N = 2,057,150) who were alive on the day of TBI and who had the same age and gender but had no history of TBI. We used a stratified Cox regression to calculate the relative risk of epilepsy after TBI for persons exposed to TBI, SSRI or both after adjustment for income, civil status, medical and neurological comorbidities, severe mental disease, and substance abuse. Results: The risk of epilepsy was 5.61 times higher for persons who used SSRI at time of TBI (adjusted Hazard Ratio (aHR): 5.61 (95% CI: 4.88; 6.45)), 3.23 times higher for persons who had a TBI but did not use SSRI at time of TBI (aHR: 3.23 (95% CI: 3.12;3.35)), and 1.31 times higher for persons who used SSRI but had no TBI (aHR: 1.31 (95% CI: 1.18; 1.45)) compared to persons unexposed to both TBI and SSRI. Conclusions: This large population based cohort study showed that people using SSRI at the time of a TBI had higher risk of developing epilepsy compared to people not using SSRI at the time of TBI. The results are in line with those of animal studies and calls for further studies to evaluate whether the association is due to SSRIs or to the underlying disease (e.g. depression or anxiety). [ABSTRACT FROM AUTHOR]

In acidosis, catecholamines are attenuated, and higher doses are often required to improve cardiovascular function. Colforsin activates adenylate cyclase in cardiomyocytes without beta-adrenoceptor. Here, six beagles were administered colforsin or dobutamine four times during eucapnia (partial pressure of arterial carbon dioxide 35–40 mm Hg; normal) and hypercapnia (ibid 90–110 mm Hg; acidosis) conditions. The latter was induced by CO2 inhalation. Anesthesia was induced with propofol and maintained with isoflurane. Cardiovascular function was measured by thermodilution and a Swan-Ganz catheter at baseline and 60 min after 0.3 μg/kg/min (low), 0.6 μg/kg/min (middle), and 1.2 μg/kg/min (high) colforsin administration. The median pH was 7.38 [range 7.33–7.42] and 7.01 [range 6.96–7.08] at baseline in the Normal and Acidosis conditions, respectively. Endogenous adrenaline and noradrenaline levels at baseline were significantly (P < 0.05) higher in the Acidosis than in the Normal condition. Colforsin induced cardiovascular effects similar to those caused by dobutamine. Colforsin increased cardiac output in the Normal condition (baseline: 3.9 ± 0.2 L/kg/m2 [mean ± standard error], low: 5.2 ± 0.4 L/kg/min2, middle: 7.0 ± 0.4 L/kg/m2, high: 9.4 ± 0.2 L/kg/m2; P < 0.001) and Acidosis condition (baseline: 6.1 ± 0.3 L/kg/m2, low: 6.2 ± 0.2 L/kg/m2, middle: 7.2 ± 0.2 L/kg/m2, high: 8.3 ± 0.2 L/kg/m2; P < 0.001). Colforsin significantly increased heart rate and decreased systemic vascular resistance compared to values at baseline. Both drugs increased pulmonary artery pressure, but colforsin (high: 13.3 ± 0.6 mmHg in Normal and 20.1 ± 0.2 mmHg in Acidosis) may have lower clinical impact on the pulmonary artery than dobutamine (high: 19.7 ± 0.6 in Normal and 26.7 ± 0.5 in Acidosis). Interaction between both drugs and experimental conditions was observed in terms of cardiovascular function, which were similarly attenuated with colforsin and dobutamine under acute respiratory acidosis. [ABSTRACT FROM AUTHOR]

The human serotonin transporter hSERT facilitates the reuptake of its endogenous substrate serotonin from the synaptic cleft into presynaptic neurons after signaling. Reuptake regulates the availability of this neurotransmitter and therefore hSERT plays an important role in balancing human mood conditions. In 2016, the first 3D structures of this membrane transporter were reported in an inhibitor-bound, outward-open conformation. These structures revealed valuable information about interactions of hSERT with antidepressant drugs. Nevertheless, the question remains how serotonin facilitates the specific conformational changes that open and close pathways from the synapse and to the cytoplasm as required for transport. Here, we present a serotonin-bound homology model of hSERT in an outward-occluded state, a key intermediate in the physiological cycle, in which the interactions with the substrate are likely to be optimal. Our approach uses two template structures and includes careful refinement and comprehensive computational validation. According to microsecond-long molecular dynamics simulations, this model exhibits interactions between the gating residues in the extracellular pathway, and these interactions differ from those in an outward-open conformation of hSERT bound to serotonin. Moreover, we predict several features of this state by monitoring the intracellular gating residues, the extent of hydration, and, most importantly, protein-ligand interactions in the central binding site. The results illustrate common and distinct characteristics of these two transporter states and provide a starting point for future investigations of the transport mechanism in hSERT. [ABSTRACT FROM AUTHOR]

In this study, we report a ligand-guided homology modeling approach allowing the analysis of relevant binding site residue conformations and the identification of two novel histamine H3 receptor ligands with binding affinity in the nanomolar range. The newly developed method is based on exploiting an essential charge interaction characteristic for aminergic G-protein coupled receptors for ranking 3D receptor models appropriate for the discovery of novel compounds through virtual screening. [ABSTRACT FROM AUTHOR]

Roux-en-Y gastric bypass surgery (RYGB) is the most common and effective weight loss procedure for severe obesity. However, a significant increase in addictive behaviors and new-onset substance use disorder (SUD) are sometimes observed post-surgery. The endogenous opioid system is known to play a major role in motivated behavior and reward, as well as the abuse of substances, including alcohol, tobacco, opioids and highly palatable foods. Here, we examined the effects of RYGB on mu-opioid receptor levels in the brain. Male Sprague-Dawley rats were assigned to one of four groups: standard diet with sham surgery (control), ad libitum high-energy high-fat (HF) diet with sham surgery, calorie restricted HF diet with sham surgery (Sham-FR), or HF diet with RYGB surgery. Control and HF groups were fed their respective diets for 8 weeks, with surgery performed on the eighth week. After 9 weeks on their respective diets post-surgery, animals were sacrificed for mu-opioid receptor autoradiography using the [3H] [D-Ala2,N-Me-Phe4-Gly5-ol]- enkephalin (DAMGO) ligand. Rats with RYGB showed reduced DAMGO binding in the central amygdala compared to sham-operated HF diet controls, and in the hypothalamus compared to high-fat fed Sham-FR. Diet alone did not change [3H] DAMGO binding in any region. These findings show that RYGB surgery, independent of diet or caloric restriction, decreases mu opioid signaling in specific regions important for stress and energy regulation. Thus, RYGB surgery may lead to greater stress sensitivity via downregulated mu opioid signaling in the central amygdala, which may contribute to the observed increased risk in some subjects for addictive behavior. [ABSTRACT FROM AUTHOR]

The stellate ganglia are the predominant source of sympathetic innervation to the heart. Remodeling of sympathetic nerves projecting to the heart has been observed in several cardiovascular diseases, and sympathetic dysfunction contributes to cardiac pathology. Wistar Kyoto rats are a common model for the study of cardiovascular diseases, but we lack a profile of the baseline transcriptomic and neurochemical characteristics of their cardiac sympathetic neurons. Most studies of cardiovascular disease have used male animals only, but in the future both male and female animals will be used for these types of studies; therefore, we sought to characterize the transcriptome of male and female stellate ganglia and to correlate that with catecholamine and acetylcholine content in the heart. We have generated a dataset of baseline RNA expression in male and female Wistar Kyoto rat stellate ganglia using RNA-seq, and have measured neurotransmitter levels in heart and stellate ganglia using HPLC and mass spectrometry. We identified numerous gene expression differences between male and female stellates, including genes encoding important developmental factors, receptors and neuropeptides. Female hearts had significantly higher neurotransmitter content than male hearts; however, no significant differences were detected in expression of the genes encoding neurotransmitter synthetic enzymes. Similarly, no statistically significant differences were identified between the sexes in cardiac tyrosine hydroxylase levels. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase receptor type Z (PTPRZ) is preferentially expressed in the central nervous system as two transmembrane receptor isoforms PTPRZ-A/B and one secretory isoform PTPRZ-S. Ptprz-knockout mice lacking the expression of all three isoforms show behavioral, learning, and neurological abnormalities, including increased exploratory activities to novelty, deficits in spatial and contextual learning, and reduced responses to methamphetamine, relative to wild-type mice. To investigate whether PTPRZ isoforms play distinct physiological roles, we herein performed behavioral studies on two knock-in mouse lines: One expresses the catalytically inactive Cys-1930 to Ser (CS) mutants of PTPRZ-A/B, while the other generated in the present study expresses catalytically active mutants of PTPRZ-A/B lacking the negative regulatory PTP-D2 domain and C-terminal PDZ-binding motif (ΔD2) instead of wild-type PTPRZ-A/-B. In contrast to Ptprz-knockout mice, neither increased responses to novelty in the open field nor memory impairments in the inhibitory-avoidance task were observed in Ptprz-CS or Ptprz-ΔD2 mice. However, the effects of methamphetamine on locomotor activity were significantly weaker in Ptprz-KO mice and CS mutant mice than in wild-type mice, but were normal in ΔD2 mutant mice. Furthermore, microdialysis experiments revealed that methamphetamine-evoked dopamine release in the nucleus accumbens was reduced in Ptprz-KO mice and CS mutant mice. These results suggest that the extracellular region of PTPRZ, including the secretory isoform, is crucial for behavioral responses to novelty and the formation of aversive memories, whereas the PTPase activities of PTPRZ receptor isoforms are involved in regulating the dopaminergic system. [ABSTRACT FROM AUTHOR]

Antibiotics induced acute kidney injury (AKI) risk in critically ill patients is not well known. This study aimed to evaluate the AKI development and clinical outcomes in critically ill adult patients treated with vancomycin (VAN) or combined with piperacillin-tazobactam (TZP) or meropenem (MEM). This was a retrospective study on critically ill adult patients who were given VAN, TZP or MEM and maintained for at least 48 h. The risk of AKI development and clinical outcomes were compared using the simple analysis and multivariate logistic regression. Three hundred forty patients were eligible. The incidence of any AKI was significantly higher in patients treated with VAN + TZP than those with VAN + MEM or VAN alone (52.7% vs. 27.7% vs. 25.7%; p < .0001). The adjusted odds of AKI increased 2.43-fold in VAN + TZP versus VAN, but not different in VAN + MEM versus VAN. However, AKI duration and recovery rate were not statistically different. In addition, all-cause death within 30 days after AKI onset was not significantly associated with antibiotic regimens. AKI incidence is higher in critically ill patients administered with VAN + TZP than those with VAN + MEM or VAN. However, no obvious evidence was found to prove that antibiotic-induced AKI leads to poor clinical outcomes. [ABSTRACT FROM AUTHOR]

Subsets of small-diameter dorsal root ganglia (DRG) neurons detect pruritogenic (itch-causing) and algogenic (pain-causing) stimuli and can be activated or sensitized by chemical mediators. Many of these chemical mediators activate receptors that are coupled to lipid hydrolysis and diacylglycerol (DAG) production. Diacylglycerol kinase iota (DGKI) can phosphorylate DAG and is expressed at high levels in small-diameter mouse DRG neurons. Given the importance of these neurons in sensing pruritogenic and algogenic chemicals, we sought to determine if loss of DGKI impaired responses to itch- or pain-producing stimuli. Using male and female Dgki-knockout mice, we found that in vivo sensitivity to histamine—but not other pruritogens—was enhanced. In contrast, baseline pain sensitivity and pain sensitization following inflammatory or neuropathic injury were equivalent between wild type and Dgki-/- mice. In vitro calcium responses in DRG neurons to histamine was enhanced, while responses to algogenic ligands were unaffected by Dgki deletion. These data suggest Dgki regulates sensory neuron and behavioral responses to histamine, without affecting responses to other pruritogenic or algogenic agents. [ABSTRACT FROM AUTHOR]

Background: A significant percentage of patients suffering from Parkinson’s Disease (PD) experience Impulse Control Disorders (ICDs), contributing to reduced quality of life. As they can be managed by reducing the dopamine dosage, the detection of their presence is crucial for PD treatment plan. Nevertheless, they tend to be under-recognized in clinical practice, since routine screening is not common–despite existing instruments that may support clinicians. This work presents a systematic review on the psychometric properties of instruments measuring ICDs in PD, to test whether clinicians dispose of valid tools that may help them in clinical assessment. Method: A systematic literature search in three databases (EMBASE, MEDLINE, and PsycINFO) was conducted. Quality of the instruments’ psychometric properties was evaluated with Terwee et al.’s criteria, and methodological quality of the studies was evaluated with the COSMIN Checklist. Results: Ten studies examining seven instruments were selected. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) and the Ardouin Scale of Behavior in Parkinson’s Disease (ASBPD) resulted to be the best from a psychometric point of view. Conclusions: Though the gold standard for diagnosis remains a detailed diagnostic interview, this review will encourage clinicians to use validated tools to accurately assess ICDs. [ABSTRACT FROM AUTHOR]

Theoretical models of time perception suggest a simple bottom-up relationship between physiological arousal and perceived duration. Increases in physiological arousal lengthen the perceived duration of events whereas decreases in physiological arousal reduce them. Whilst this relationship has been demonstrated for highly arousing negatively valenced stimuli, it has not been demonstrated for other classes of distorting stimuli (e.g. positively valenced or low arousal stimuli). The current study tested the effect of valence (positive and negative) and arousal level (high and low) on the relationship between physiological arousal and perceived duration. Sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS) activity was measured during a verbal estimation task in which participants judged the duration of high and low arousal, positive, negative and neutrally valenced IAPS images. SNS and PSNS activity were indexed by measuring Pre-Ejection Period (PEP) and High Frequency Heart-rate Variability (HF-HRV) respectively. SNS reactivity was predicative of perceived duration, but only for high arousal negatively valenced stimuli, with decreases in PEP being associated with longer duration estimates. SNS and PSNS activity was not predictive of perceived duration for the low arousal negative stimuli or the low and high arousal positive stimuli. We therefore propose a new model suggesting that emotional distortions to time result from a combination of bottom-up (physiological arousal) and top-down (threat detection) factors. [ABSTRACT FROM AUTHOR]

Abnormal red blood cell (RBC) adhesion to endothelial αvβ3 plays a crucial role in triggering vaso-occlusive episodes in sickle cell disease (SCD). It is known that epinephrine, a β-adrenergic receptor (β-AR) stimulator, increases the RBC surface density of active intercellular adhesion molecule-4 (ICAM-4) which binds to the endothelial αvβ3. It has also been demonstrated that in human embryonic kidney 293 cells, mouse cardiomyocytes, and COS-7 cell lines, the β-adrenergic and renin-angiotensin systems are interrelated and that there is a direct interaction and cross-regulation between β-AR and angiotensin II type 1 receptor (AT1R). Selective blockade of AT1R reciprocally inhibits the downstream signaling of β-ARs, similar to the inhibition observed in the presence of a β-AR-blocker. However, it is not known if this mechanism is active in human RBCs. Here, we studied the effect of valsartan, an AT1R blocker, on the surface density of active ICAM-4 receptors in normal, sickle cell trait, and homozygous sickle RBCs. We applied single molecule force spectroscopy to detect active ICAM-4 receptors on the RBC plasma membrane with and without the presence of valsartan and epinephrine. We found that epinephrine significantly increased whereas valsartan decreased their surface density. Importantly, we found that pretreatment of RBCs with valsartan significantly impeded the activation of ICAM-4 receptors induced by epinephrine. The observed reduced expression of active ICAM-4 receptors on the RBC plasma membrane leads us to conjecture that valsartan may be used as a supporting remedy for the prevention and treatment of vaso-occlusive crisis in SCD. [ABSTRACT FROM AUTHOR]

Background: Increasing exercise reinforcement, or decreasing sedentary reinforcement, may reduce sedentary activity and promote habitual exercise. Repeated exposures to a reinforcer may increase its reinforcing value (i.e., incentive sensitization). It is not yet known whether incentive sensitization occurs for exercise or factors associated with incentive sensitization for exercise reinforcement. The purpose was to determine whether exercise exposures increase exercise reinforcement relative to a sedentary alternative and whether this sensitization of exercise reinforcement would alter physical or sedentary behavior. This work also determined whether exercise dose, intensity, and preference and tolerance for exercise intensity were associated with incentive sensitization of exercise. Methods: 104 sedentary men and women were randomized to exercise training groups with 89 completing the study. Groups included exercise exposures of 150 (n = 35) or 300 kcal/session (n = 34), 3 sessions/week for 6 weeks, or a non-exercise control group (n = 35). Assessments for exercise and sedentary behavior reinforcement (primary dependent variables) and activity and tolerance for exercise intensity were performed at baseline (week 0), post training (week 6), and post washout (week 10). Results: The control group reduced (P = 0.022) relative reinforcing value of exercise, such that the 150 kcal group had a greater relative reinforcing value of exercise after the exercise treatment 150 kcal: 0.69 ± 0.07 to 0.74 ± 0.07; 300 kcal: 0.72 ± 0.07 to 0.63 ± 0.08, control: 0.72 ± 0.07 to 0.57 ± 0.08 mean ± SE. Increases in tolerance for exercise intensity discomfort were associated with increases in relative reinforcing value of exercise. Sedentary behavior reinforcement decreased in both exercise groups (150 kcal: 5.4 ± 4.3 to 1.8 ± 1.3; 300 kcal: 5.4 ± 4.3 to 3.1 ± 2.4, P<0.05), but remained unchanged in the control group (5.1 ± 4.0 to 6.1 ± 4.9, P>0.05). Sedentary activity decreased baseline to post-training in the 300 kcal group (546.5 ± 10.7 to 503.8 ± 11.8 minutes, P<0.01). Conclusion: Small amounts of regular exercise may reduce the reinforcing value sedentary behavior. The process of incentive sensitization of exercise may include reducing the reinforcing value of competing sedentary activities. Developing tolerance to exercise discomfort of exercise may be critical to increasing exercise reinforcement. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is caused mostly by mutations in polycystin-1 or polycystin-2. Fluid flow leads to polycystin-dependent calcium influx and nuclear export of histone deacetylase 5 (HDAC5), which facilitates the maintenance of renal epithelial architecture by de-repression of MEF2C target genes. Here, we screened a small-molecule library to find drugs that promotes nuclear export of HDAC5. We found that dopamine receptor antagonists, domperidone and loxapine succinate, stimulate export of HDAC5, even in Pkd1–/–cells. Domperidone targets Drd3 receptor to modulate the phosphorylation of HDAC5. Domperidone treatment increases HDAC5 phosphorylation likely by reducing protein phosphatase 2A (PP2A) activity, thus shifting the equilibrium towards HDAC5-P and export from the nucleus. Treating Pkd1–/–mice with domperidone showed significantly reduced cystic growth and cell proliferation. Further, treated mice displayed a reduction in glomerular cyst and increased body weight and activity. These results suggest that HDAC5 nucleocytoplasmic shuttling may be modulated to impede disease progression in ADPKD and uncovers an unexpected role for a class of dopamine receptors in renal epithelial morphogenesis. [ABSTRACT FROM AUTHOR]

Plant extracts and phytochemicals may prevent chronic diseases via activation of adaptive cellular stress response pathways including induction of antioxidant and phase II detoxifying enzymes. The regulatory regions of these inducible genes encode the electrophile-response element (EpRE). This study tested the EpRE induction ability of Maerua subcordata (fruit, leaf, root, seed) methanol extracts and selected candidate constituents thereof, identified by liquid chromatography coupled with multistage mass spectroscopy, employing an EpRE luciferase reporter gene assay using hepa-1c1c7 mouse hepatoma cells. A parallel Cytotox CALUX assay using human osteosarcoma U2OS cells was used to monitor any non-specific changes in luciferase activity or cytotoxicity. Results showed that fruit, root, and seed extracts were non-cytotoxic up to a concentration of 30 gram dry weight per litre but the leaf extract exhibited some cytotoxicity and that the leaf (despite some cytotoxicity), fruit, and seed extracts showed strong induction of EpRE mediated gene expression while induction by the root extract was minimal. Selected candidates included glucosinolates, isothiocyanates, and some biogenic amines. Subsequent studies showed that methyl-, ethyl-, isopropyl-, isobutyl- isothiocyanates, and sec-butyl thiocyanate as well as glucobrassicin induced concentration (1–100 μM) dependent EpRE-mediated gene expression while the biogenic amines stachydrine and trigonelline acted as inhibitors of EpRE-mediated gene expression at 100 μM. The identification of glucolepidiin, glucobrassicin, glucocapparin, stachydrine, and trigonelline in all extracts was confirmed using standards and based on multiple reaction monitoring; yet, glucobrassicin level in the root extract was negligible. In conclusion, this study provided a first report on EpRE mediated gene expression effects of M. subcordata; and despite detection of different glucosinolates in all extracts, those containing glucobrassicin particularly displayed high EpRE induction. Because EpRE inducers are cytoprotective and potential chemopreventive agents while inhibitors are suggested adjuvants of chemotherapy, results of this study imply that process manipulation of this plant may result in herbal preparations that may be used as chemopreventive agents or adjuvants of chemotherapies. [ABSTRACT FROM AUTHOR]

Objective: Whether the cardiovascular (CV) outcomes of second-generation limus-eluting stents (LESs) differ from those of paclitaxel-eluting stents (PESs) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) is still unclear. Methods: We used the Taiwan National Health Insurance Research Database to analyse data of 516 patients with AMI and CS diagnosed from January 2007 to December 2011. We used propensity score matching to adjust for the imbalance in covariate baseline values between these two groups. We evaluated clinical outcomes by comparing 197 subjects who used second-generation LESs to 319 matched subjects who used PESs. Results: The risk of the primary composite outcomes (i.e., myocardial infarction, coronary revascularisation or CV death) was significantly lower in the second-generation LES group than in the PES group [37.3% vs. 51.8%; hazard ratio (HR), 0.73; 95% CI: 0.56–0.95] at the 12-month follow-up. The patients who received second-generation LESs had a lower risk of coronary revascularisation (HR 0.62; 95% CI: 0.41–0.93) than those who used PESs. However, the risks of myocardial infarction (HR 0.56; 95% CI: 0.26–1.24), ischemic stroke (HR 0.73; 95% CI: 0.23–2.35), or CV death (HR 0.90; 95% CI: 0.63–1.28) were not significantly different between the two groups. Conclusions: Among patients with CS-complicating AMI, second-generation LES implantation significantly reduced the risk of coronary revascularisation and composite CV events compared to PES implantation at the 12-month follow-up. [ABSTRACT FROM AUTHOR]

Background: Hyperglycemia is common and associated with increased mortality after out-of-hospital cardiac arrest (OHCA) and return of spontaneous circulation (ROSC). Mechanisms behind ultra-acute hyperglycemia are not well known. We performed an explorative study to describe the changes in glucose metabolism mediators during the prehospital postresuscitation phase. Methods: We included patients who were successfully resuscitated from out-of-hospital cardiac arrest in two physician-staffed units. Insulin, glucagon, and glucagon-like peptide 1 (GLP-1) were measured in prehospital and hospital admission samples. Additionally, interleukin-6 (IL-6), cortisol, and HbA1c were measured at hospital admission. Results: Thirty patients participated in the study. Of those, 28 cases (71% without diabetes) had sufficient data for analysis. The median time interval between prehospital samples and hospital admission samples was 96 minutes (IQR 85–119). At the time of ROSC, the patients were hyperglycemic (11.2 mmol/l, IQR 8.8–15.7), with insulin and glucagon concentrations varying considerably, although mostly corresponding to fasting levels (10.1 mU/l, IQR 4.2–25.2 and 141 ng/l, IQR 105–240, respectively). GLP-1 increased 2- to 8-fold with elevation of IL-6. The median glucose change from prehospital to hospital admission was -2.2 mmol/l (IQR -3.6 to -0.2). No significant correlations between the change in plasma glucose levels and the changes in insulin (r = 0.30, p = 0.13), glucagon (r = 0.29, p = 0.17), or GLP-1 levels (r = 0.32, p = 0.15) or with IL-6 (r = (-0.07), p = 0.75), cortisol (r = 0.13, p = 0.52) or HbA1c levels (r = 0.34, p = 0.08) were observed. However, in patients who did not receive exogenous epinephrine during resuscitation, changes in blood glucose correlated with changes in insulin (r = 0.59, p = 0.04) and glucagon (r = 0.65, p = 0.05) levels, demonstrating that lowering glucose values was associated with a simultaneous lowering of insulin and glucagon levels. Conclusions: Hyperglycemia is common immediately after OHCA and cardiopulmonary resuscitation. No clear hormonal mechanisms were observed to be linked to changes in glucose levels during the postresuscitation phase in the whole cohort. However, in patients without exogenous epinephrine treatment, the correlations between glycemic and hormonal changes were more obvious. These results call for future studies examining the mechanisms of postresuscitation hyperglycemia and the metabolic effects of the global ischemic insult and medical treatment. [ABSTRACT FROM AUTHOR]

Executive dysfunction is common in Parkinson's disease (PD) patients. The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been proposed to affect executive functions (EFs) in the prefrontal cortex. The present study attempted to explore the influence of the COMT polymorphism on EFs in patients with PD. Fifty-four PD patients were recruited and underwent neuropsychological assessments for three core EFs. The COMT polymorphism was genotyped using the TaqMan SNP Genotyping Assay. Participants were divided into three study groups: Val homozygotes, heterozygotes, and Met homozygotes. The three COMT genotype groups had significantly different performances in set-shifting [χ2 (2, 54) = 9.717, p = 0.008] and working memory tasks [χ2 (2, 54) = 7.806, p = 0.020]. Post-hoc analyses revealed that PD Val homozygotes performed significantly poorer in the set-shifting task than did either the PD Met homozygotes (z = -2.628, p = 0.009) or PD heterozygotes (z = -2.212, p = 0.027). Our explorative results suggest that the putative level of prefrontal dopamine influenced set-shifting through a "cane-shaped" dopamine level-response relationship. Our results have clinical implications, which may influence PD treatment with dopamine in the future because the optimal dopamine level to maximize EFs may vary based on the clinical course and COMT polymorphism status. Further study recruiting a larger number of participants is needed to confirm our preliminary findings. [ABSTRACT FROM AUTHOR]

Sense of agency refers to the feeling of control over one’s own actions. The strength of this sense varies inter-individually. This means that people differ in their perception concerning the intensity of their intentions and actions. The current study aims to determine the factors influencing this sense of agency on a personality level. Furthermore, it gives insight into the correlative relation between the strength of the sense of agency and substance use. The study involved 210 participants who were tested for the experiment (intentional binding paradigm for sense of agency, hand paradigm for intentionality bias, questionnaires FAD-Plus, NI-20, substance use). Significant determinants in personality were narcissism (vulnerable subtype) and substance use (consumption in general beyond cannabis, and particularly for the substances cannabis, ecstasy, and cocaine). Both personality types were associated with a weaker sense of agency compared to controls. For both results, alterations in the dopaminergic system need to be discussed. The present results confirm prior hypotheses that dopamine seems to play a crucial role in perception of agency. Possibly a higher accessibility of dopamine increases sense of agency (hyper-binding), whereas a lower accessibility of dopamine decreases sense of agency (hypo-binding). A second aim of the study was to see whether there is a connection between sense of agency and intentionality bias. The perception of intention in others differs widely; some people tend to see arbitrary or accidental actions as unintentional, and others quickly label actions as ‘intentional’ although the information is not distinct for a categorization. This cognitive error is called intentionality bias. Results could not confirm a relationship between the two constructs—one’s own intention and judging intention in others. This may be due to a lack of connection between the two constructs or to methodological aspects. Further directions and limitations are discussed. [ABSTRACT FROM AUTHOR]

Background: Obsessive-compulsive disorder (OCD) is a chronic, incapacitating, early onset psychiatric disorder that is characterized by obsessions and compulsions originating from a disturbance in the cortico-striato-thalamico-cortical circuit. We implemented the preclinical quinpirole (QP) rat model for compulsive checking in OCD to analyse the behaviour and visualize the D2R, mGluR5 and GLT1 density in order to contribute to the understanding of the neuroreceptor kinetics. Methods: Animals (n = 14) were exposed to either saline (1 mL/kg) or QP (dopamine D2-agonist, 0.5 mg/kg) twice-weekly during 7 weeks. After each injection animals were placed on an open field test. After model setup, animals were placed in a behavioural cage equipped with tracking software and hardware in order to analyse the behaviour. Subsequently, sagittal slides were made of the CP in the right hemisphere and a staining was done with the D2R, mGluR5 and GLT-1 antibody to visualize the corresponding receptor. Results: The QP animals displayed a strong increase in travelled distance (+596.70%) and in the number of homebase visits (+1222.90%) compared to the control animals. After chronic exposure to QP, animals had a significantly (p < 0.05) higher percentage of D2R density in the CP (7.92% ± 0.48%) versus 6.66% ± 0.28% in animals treated with saline. There were no differences for mGluR5 and GLT1 receptor density. Conclusions: Chronic exposure to QP leads to hyperlocomotion and an increase in D2R density. Furthermore, as mGluR5 and GLT1 density did not seem to be directly affected, decreased levels of glutamate might have influenced the binding potential in earlier reports. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies described impaired microvascular perfusion and tissue oxygenation as reliable predictors of Multiple Organ Failure in major trauma. However, this relationship has been incompletely investigated. The objective of this analysis is to further evaluate the association between organ dysfunction and microcirculation after trauma. Materials and methods: This is a retrospective subgroup analysis on 28 trauma patients enrolled for the Microcirculation DAIly MONitoring in critically ill patients study (NCT 02649088). Patients were divided in two groups according with their Sequential Organ Failure Assessment (SOFA) score at day 4. At admission and every 24 hours, the sublingual microcirculation was evaluated with Sidestream Darkfield Imaging (SDF) and peripheral tissue perfusion was assessed with Near Infrared Spectroscopy (NIRS) and Vascular Occlusion Test (VOT). Simultaneously, hemodynamic, clinical/laboratory parameters and main organ supports were collected. Results: Median SOFA score at Day 4 was 6.5. Accordingly, patients were divided in two groups: D4-SOFA ≤6.5 and D4-SOFA >6.5. The Length of Stay in Intensive Care was significantly higher in patients with D4-SOFA>6.5 compared to D4-SOFA≤6.5 (p = 0.013). Total Vessel Density of small vessels was significantly lower in patients with high D4-SOFA score at Day 1 (p = 0.002) and Day 2 (p = 0.006) after admission; the Perfused Vessel Density was lower in patients with high D4-SOFA score at Day 1 (p = 0.007) and Day 2 (p = 0.033). At Day 1, NIRS monitoring with VOT showed significantly faster tissue oxygen saturation downslope (p = 0.018) and slower upslope (p = 0.04) in patients with high D4-SOFA. Discussion: In our cohort of major traumas, sublingual microcirculation and peripheral microvascular reactivity were significantly more impaired early after trauma in those patients who developed more severe organ dysfunctions. Our data would support the hypothesis that restoration of macrocirculation can be dissociated from restoration of peripheral and tissue perfusion, and that microvascular alterations can be associated with organ failure. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and release of norepinephrine (NE). As sympathetic innervation of the GI tract modulates motility, blood flow, and immune function, changes in NE signaling may alter the risk of developing IBD. Dopamine beta-hydroxylase (DβH), the enzyme responsible for NE production, has been suggested to play a critical role in IBD, however the exact mechanism is unknown. We hypothesized that genetic variants of DβH could increase the risk of IBD. We performed genetic analysis on 45 IBD patients and 74 controls. IBD patients were screened by targeted exome sequencing and compared with NeuroX DβH single nucleotide polymorphism (SNP) genotyping data of the controls. Serum DβH protein levels for 15 IBD patients and 13 controls were evaluated using immunoblots and competitive ELISA. Seven SNPs were observed from DβH targeted exome sequencing in the 45 IBD patients. A single non-synonymous SNP, rs6271 (Arg549Cys), had a significant association with IBD patients; the odds ratio was a 5.6 times higher SNP frequency in IBD patients compared to controls (p = 0.002). We also examined the function and availability of the protein in both the IBD and control patients’ sera bearing DβH Arg549Cys. Both control and IBD subjects bearing the heterozygote allele had statistically lower DβH protein levels while the intrinsic enzyme activity was higher. This is the first report of a noradrenergic genetic polymorphism (rs6271; Arg549Cys) associated with IBD. This polymorphism is associated with significantly lower levels of circulating DβH. [ABSTRACT FROM AUTHOR]

Objective: Antidepressant medication is commonly used for the prevention of depression recurrence in the perinatal period, yet it is unknown what vulnerability markers may play a role in recurrence. The objective of the current study was to provide a descriptive overview of the associated characteristics of women who experienced a perinatal recurrence of depression despite ongoing antidepressant use, and further, to identify clinically measurable vulnerability markers associated with recurrence. Methods: Eighty-five pregnant women with a history of depression who used antidepressants (e.g. Selective Serotonin Reuptake Inhibitors or Serotonin and Noradrenaline Reuptake Inhibitors) at the start of the study were included. Clinical features, including information on psychiatric history and antidepressant use, were collected throughout the perinatal period (in this study defined as the period between 12 weeks of pregnancy untill three months postpartum). The clinical features of women experiencing recurrence of depression were described in detail. To identify vulnerability markers associated with recurrence of depression, we performed exploratory univariable logistic regression analyses. Results: Eight women (9.4%) experienced a recurrence of depression; two during pregnancy and six in the first 12 weeks postpartum. All women with recurrence of depression had first onset of depression during childhood or adolescence and had at least 2 psychiatric co-morbidities. Identification of vulnerability markers associated with recurrence of depression yielded associations with depressive symptoms around 16 weeks of pregnancy (OR 1.28, 95%CI 1.08–1.52), number of psychiatric co-morbidities (OR 1.89, 95%CI 1.16–3.09) and duration of antidepressant use (OR 1.01, 95%CI 1.00–1.02). Conclusion: Implementing adequate risk assessment in pregnant women who use antidepressants can help identify predictors for recurrence of depression in future studies and thus ultimately lead to improved care. [ABSTRACT FROM AUTHOR]