Antibiotic-induced disruption of commensal microbiome linked to increases in binge-like ethanol consumption behavior.

Research focusing on the gut-brain axis is growing, but the interplay of ethanol (alcohol molecule), the gut microbiome, the brain and behavior is poorly understood. In the current study, we remodeled the gut microbiota by providing adult male C57BL/6J mice with a non-absorbable antibiotic cocktail (ABX) in the drinking water and tested ethanol consumption behavior in a binge-like "Drinking in the Dark" model. Notably, 2 weeks of ABX pre-treatment significantly increased ethanol consumption during the 6 weeks of ethanol exposure in the DID paradigm. ABX treatment also appeared to prevent anxiety-like behavior during ethanol withdrawal period. ABX-treated mice expressed reduced bacterial diversity and modified microbiota compositions within cecal samples. There were drastically reduced levels of commensal Firmicutes and increases in the Bacteroidetes and Verrucomicrobia populations. Importantly, the relative abundance of Firmicutes inversely correlated to ethanol intake levels regardless of antibiotic treatment, whereas Bacteroidetes and Verrucomicrobia populations negatively correlated to ethanol intake levels. This is the first report demonstrating that ABX-induced disruption of the gut commensal microbiota leads to increased ethanol consumption in mice. This work reveals an important relationship between the gut microbiota and ethanol consumption behavior and supports the use of microbial-targeted approaches to study gut-brain interactions during alcohol use disorder.

Moxidectin Effects on Gut Microbiota of Wistar-Kyoto Rats: Relevance to Depressive-Like Behavior.

BACKGROUND/AIMS: The prevalent comorbidity between neuropsychiatric and gastrointestinal (GI) disorders is believed to be significantly influenced by gut microbiota (GM). GM may also play a substantial role in comorbidity between substance abuse (e.g. Alcohol Use Disorder, AUD) and depression. The anti-parasitic drug Moxidectin (MOX) has been reported to reduce alcohol intake in male and female mice. This effect is purported to be centrally mediated with a significant contribution linked to purinergic, P2X4 purinergic receptors. However, MOX's effects on GM in animal models of depression is not known. METHODS: Adult male Wistar Kyoto (WKY) rats (5/group) were injected intraperitoneally (i.p.) once daily for 7 days with MOX (2.5mg/kg), or saline as control group. On day 8, approximately 20 h after the last MOX injection, animals were sacrificed, intestinal stools were collected and stored at -80°C DNA was extracted from the samples for 16S rRNA gene-based GM analysis using 16S Metagenomics application. RESULTS: At taxa and species level, MOX affected a number of bacteria including a 30-fold increase in Bifidobacterium cholerium, a bacterium with a strong ability to degrade carbohydrates that resist digestion in the small intestine. There was a minimum of 2-fold increase in: five probiotic species of Lactobacillus, butyrate-forming Rosburia Facies and Butyrivibro proteovlasticus. In contrast, MOX depleted 11 species, including 2 species of Ruminoccus, which are positively associated with severity of irritable bowel syndrome, and 4 species of Provettela, which are closely associated with depressive-like behavior. CONCLUSION: Thus, MOX enhanced probiotic species, and suppressed the opportunistic pathogens. Since overall effect of MOX appears to be promoting GM associated with mood enhancement (e.g. Bifidobacterium and Lactobacillus) and suppressing GM associated with inflammation (e.g. Ruminoccus), potential antidepressant and anti-inflammatory effects of MOX in suitable animal models should be investigated.

Evaluation of a rapid diagnostic test for detection of dengue infection using a single-tag hybridization chromatographic-printed array strip format.

A dipstick DNA chromatography assay, a single-tag hybridization-printed array strip (STH-PAS), was evaluated for its efficacy to detect dengue virus (DENV). Reverse-transcribed DNA was amplified by PCR, and the amplified DNA was detected using the STH-PAS system. The method was evaluated using stored RNA samples previously identified to carry all 4 serotypes of dengue, chikungunya, and influenza viruses. Clinical performance was also assessed in a prospective study using plasma from 269 febrile cases from the Emergency Department of St. Luke's Medical Center, Quezon City, Philippines, and 30 afebrile normal healthy volunteers. A Taqman real-time PCR (RT-PCR) assay and a rapid Dengue NS1 test, SD Bioline, were used for comparison. The STH-PAS system was more sensitive in detecting dengue infection compared to Taqman RT-PCR. For DENV serotypes 1, 2, and 3, the detection was 1 to 2 dilutions (10-fold) higher, and for DENV serotype 4, the detection was 2-4 dilutions higher. In clinical studies, the STH-PAS system showed 100% sensitivity with 88.9% and 86.6% specificities compared to Taqman RT-PCR and SD Dengue Duo NS1 test, respectively. The STH-PAS system was found to have a superior sensitivity than the Taqman system. Further evaluation of its performance in the field may provide important data to extend its usefulness for surveillance and epidemiological research in outbreak situations.

P2X7 Receptor Antagonist A804598 Inhibits Inflammation in Brain and Liver in C57BL/6J Mice Exposed to Chronic Ethanol and High Fat Diet.

Chronic low-grade neuroinflammation is increasingly implicated in organ damage caused by alcohol abuse. Purinergic P2X7 receptors (P2X7Rs) play an important role in the generation of inflammatory responses during a number of CNS pathologies as evidenced from studies using pharmacological inhibition approach. P2X7Rs antagonism has not been tested during chronic alcohol abuse. In the present study, we tested the potential of P2X7R antagonist A804598 to reduce/abolish alcohol-induced neuroinflammation using chronic intragastric ethanol infusion and high-fat diet (Hybrid) in C57BL/6J mice. We have previously demonstrated an increase in neuroinflammatory response in 8 weeks of Hybrid paradigm. In the present study, we found neuroinflammatory response to 4 weeks of Hybrid exposure. A804598 treatment reversed the changes in microglia and astrocytes, reduced/abolished increases in mRNA levels of number of inflammatory markers, including IL-1ß, iNOS, CXCR2, and components of inflammatory signaling pathways, such as TLR2, CASP1, NF-kB1 and CREB1, as well in the protein levels of pro-IL-1ß and Nf-kB1. The P2X7R antagonist did not affect the increase in mRNA levels of fraktalkine (CX3CL1) and its receptor CX3CR1, an interaction that plays a neuroprotective role in neuron-glia communication. P2X7R antagonism also resulted in reduction of the inflammatory markers but did not alter steatosis in the liver. Taken together, these findings demonstrate how P2X7R antagonism suppresses inflammatory response in brain and liver but does not alter the neuroprotective response caused by Hybrid exposure. Overall, these findings support an important role of P2X7Rs in inflammation in brain and liver caused by combined chronic alcohol and high-fat diet. Graphical Abstract ᅟ.

Functional Impairment Variability in Children With ADHD Due to Emotional Impulsivity.

OBJECTIVE: The present study utilized ecological momentary assessment (EMA) to examine the effects of emotional impulsivity on overall functional impairment and functional impairment variability (FIV) of children with and without ADHD. METHOD: Parents of 74 children, 8- to 12-year-olds (42 with ADHD, 32 without ADHD), completed EMA assessment protocol ratings of their child's mood (3 times daily) and functional impairment (1 time daily) over the course of 28 days. RESULTS: Hierarchical regression analyses supported the interaction of ADHD diagnostic status and greater EMA-derived emotional impulsivity in the estimation of total functional impairment (Total FI) and FIV. Thus, greater emotional impulsivity was found to be related to greater Total FI and FIV among children with ADHD but not among children without ADHD. CONCLUSION: This study suggests that children with ADHD and greater emotional impulsivity demonstrate greater overall levels of functional impairment, with the severity of their impairment varying significantly over time.

The Relation of Poor Emotional Awareness and Externalizing Behavior Among Children With ADHD.

OBJECTIVE: Children with ADHD often demonstrate poor emotional self-awareness and higher levels of externalizing behavior problems relative to unaffected children. This study examined the relation of deficient emotional self-awareness to externalizing behavior problems in children with ADHD, and the role of emotional reactivity in this relationship. METHOD: Fifty-one 8- to 12-year-old children with ADHD and their parents completed measures of the children's emotional and behavioral functioning, as well as a diagnostic structured interview. RESULTS: Logistic regression suggested that more impaired emotional self-awareness was strongly associated with the diagnosis of a comorbid externalizing disorder. Hierarchical regression analyses strongly supported the relation of poor emotional awareness to reactivity-driven externalizing behavior, but not to proactive externalizing behavior. These effects were evident across reporters. CONCLUSION: This study suggested that poor emotional self-awareness is significantly linked to externalizing problems in children with ADHD, and that dysregulated emotional reactivity plays an important role in this relationship.

Regulation of the extrarenal CYP27B1-hydroxylase.

Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune responses, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-γ, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN-α and IFN-ß, block the hydroxylation reaction. The Type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a confined disease phenotype is enabled by the presence of sufficient extracellular 25OHD to modulate IFN-γ-promoted and substrate 25OH-driven intracellular synthesis of 1,25(OH)2D. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Slits affect the timely migration of neural crest cells via Robo receptor.

BACKGROUND: Neural crest cells emerge by delamination from the dorsal neural tube and give rise to various components of the peripheral nervous system in vertebrate embryos. These cells change from non-motile into highly motile cells migrating to distant areas before further differentiation. Mechanisms controlling delamination and subsequent migration of neural crest cells are not fully understood. Slit2, a chemorepellant for axonal guidance that repels and stimulates motility of trunk neural crest cells away from the gut has recently been suggested to be a tumor suppressor molecule. The goal of this study was to further investigate the role of Slit2 in trunk neural crest cell migration by constitutive expression in neural crest cells. RESULTS: We found that Slit gain-of-function significantly impaired neural crest cell migration while Slit loss-of-function favored migration. In addition, we observed that the distribution of key cytoskeletal markers was disrupted in both gain and loss of function instances. CONCLUSIONS: These findings suggest that Slit molecules might be involved in the processes that allow neural crest cells to begin migrating and transitioning to a mesenchymal type.

Early intervention for hearing impairment: appropriate, accessible and affordable.

Before the onset of universal newborn hearing screening, children with hearing loss are not identified until they fail to meet important speech and language milestones at 2 years old and beyond. With the current widespread implementation of universal newborn hearing screening programmes, more infants with hearing loss can now be identified in the first few weeks of life and be fitted with amplification within the first few months. This presentation aims to discuss the adverse effects of hearing loss in a child's development. More importantly, it will highlight the value of early identification and early intervention and how these can maximise a child's healthy development of speech, language, academic, emotional and psychosocial skills, thereby facilitating his/her successful integration into mainstream society. In Singapore, universal newborn hearing screening is in place in major hospitals and polyclinics with childbirth services, making it accessible to all families with newborn babies. There are also a number of early intervention programmes that provide rehabilitation services focusing on the development of communication skills of children with hearing impairment. With the availability of services and abundant government support, any child with hearing loss should be identified as soon as possible and provided with early, appropriate intervention. A hearing impairment is said to be an "invisible disability," yet it is the most common major birth defect. In Singapore, one in 1000 babies are born with severe to profound hearing loss and about 5 in 1000 with lesser degrees of hearing loss. Several surveys indicate that between 1 and 3 percent of all children suffer from hearing loss.