Alien Registration- Brickley, Ellen M. (Portland, Cumberland County)

https://digitalmaine.com/alien_docs/24606/thumbnail.jp

Synchronizing retinal activity in both eyes disrupts binocular map development in the optic tectum

Spatiotemporal correlations in the pattern of spontaneous and evoked retinal ganglion cell (RGC) activity are believed to influence the topographic organization of connections throughout the developing visual system. We have tested this hypothesis by examining the effects of interfering with these potential activity cues during development on the functional organization of binocular maps in the Xenopus frog optic tectum. Paired recordings combined with cross-correlation analyses demonstrated that exposing normal frogs to a continuous 1 Hz of stroboscopic illumination synchronized the firing of all three classes of RGC projecting to the tectum and induced similar patterns of temporally correlated activity across both lobes of the nucleus. Embryonic and eye-rotated larval animals were reared until early adulthood under equivalent stroboscopic conditions. The maps formed by each RGC class in the contralateral tectum showed normal topography and stratification after strobe rearing, but with consistently enlarged multiunit receptive fields. Maps of the ipsilateral eye, formed by crossed isthmotectal axons, showed significant disorder and misalignment with direct visual input from the retina, and in the eye-rotated animals complete compensatory reorientation of these maps usually induced by this procedure failed to occur. These findings suggest that refinement of retinal arbors in the tectum and the ability of crossed isthmotectal arbors to establish binocular convergence with these retinal afferents are disrupted when they all fire together. Our data thus provide direct experimental evidence that spatiotemporal activity patterns within and between the two eyes regulate the precision of their developing connections

Urbanisation and asthma in low-income and middle-income countries: a systematic review of the urban-rural differences in asthma prevalence.

BACKGROUND: Urbanisation has been associated with temporal and geographical differences in asthma prevalence in low-income and middle-income countries (LMICs). However, little is known of the mechanisms by which urbanisation and asthma are associated, perhaps explained by the methodological approaches used to assess the urbanisation-asthma relationship. OBJECTIVE: This review evaluated how epidemiological studies have assessed the relationship between asthma and urbanisation in LMICs, and explored urban/rural differences in asthma prevalence. METHODS: Asthma studies comparing urban/rural areas, comparing cities and examining intraurban variation were assessed for eligibility. Included publications were evaluated for methodological quality and pooled OR were calculated to indicate the risk of asthma in urban over rural areas. RESULTS: Seventy articles were included in our analysis. Sixty-three compared asthma prevalence between urban and rural areas, five compared asthma prevalence between cities and two examined intraurban variation in asthma prevalence. Urban residence was associated with a higher prevalence of asthma, regardless of asthma definition: current-wheeze OR:1.46 (95% CI:1.22 to 1.74), doctor diagnosis OR:1.89 (95% CI:1.47 to 2.41), wheeze-ever OR:1.44 (95% CI:1.15 to 1.81), self-reported asthma OR:1.77 (95% CI:1.33 to 2.35), asthma questionnaire OR:1.52 (95% CI:1.06 to 2.16) and exercise challenge OR:1.96 (95% CI:1.32 to 2.91). CONCLUSIONS: Most evidence for the relationship between urbanisation and asthma in LMICs comes from studies comparing urban and rural areas. These studies tend to show a greater prevalence of asthma in urban compared to rural populations. However, these studies have been unable to identify which specific characteristics of the urbanisation process may be responsible. An approach to understand how different dimensions of urbanisation, using contextual household and individual indicators, is needed for a better understanding of how urbanisation affects asthma. PROSPERO REGISTRATION NUMBER: CRD42017064470

The contribution of δ subunit-containing GABAA receptors to phasic and tonic conductance changes in cerebellum, thalamus and neocortex

We have made use of the delta subunit-selective allosteric modulator DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide) to assay the contribution of delta-GABAARs to tonic and phasic conductance changes in the cerebellum, thalamus and neocortex. In cerebellar granule cells, an enhancement of the tonic conductance was observed for DS2 and the orthosteric agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol). As expected, DS2 did not alter the properties of GABAA receptor-mediated inhibitory postsynaptic synaptic currents (IPSCs) supporting a purely extrasynaptic role for delta-GABAARs in cerebellar granule cells. DS2 also enhanced the tonic conductance recorded from thalamic relay neurons of the visual thalamus with no alteration in IPSC properties. However, in addition to enhancing the tonic conductance DS2 also slowed the decay of IPSCs recorded from layer II/III neocortical neurons. A slowing of the IPSC decay also occurred in the presence of the voltage-gated sodium channel blocker TTX. Moreover, under conditions of reduced GABA release the ability of DS2 to enhance the tonic conductance was attenuated. These results indicate that delta-GABAARs can be activated following vesicular GABA release onto neocortical neurons and that the actions of DS2 on the tonic conductance may be influenced by the ambient GABA levels present in particular brain regions

Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial

Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the α1-blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The α1-blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16 mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators. Forty-one AD individuals were randomized, 30 (doxazosin = 15) completed the treatment phase and 28 (doxazosin = 14) also completed the follow-up. There were no significant differences between groups on DPW and HDD per week. With FHDA as a moderator, there were significant FHDA × medication interactions for both DPW (pcorrected = 0.001, d = 1.18) and HDD (pcorrected = 0.00009, d = 1.30). Post hoc analyses revealed that doxazosin significantly reduced alcohol drinking in AD patients with high FHDA and by contrast increased drinking in those with low FHDA. Doxazosin may be effective selectively in AD patients with high FHDA. This study provides preliminary evidence for personalized medicine using α1-blockade to treat AD. However, confirmatory studies are required

Cord Blood Hepcidin: Cross-Sectional Correlates and Associations with Anemia, Malaria, and Mortality in a Tanzanian Birth Cohort Study.

Hepcidin, the master regulator of bioavailable iron, is a key mediator of anemia and also plays a central role in host defense against infection. We hypothesized that measuring hepcidin levels in cord blood could provide an early indication of interindividual differences in iron regulation with quantifiable implications for anemia, malaria, and mortality-related risk. Hepcidin concentrations were measured in cord plasma from a birth cohort (N = 710), which was followed for up to 4 years in a region of perennial malaria transmission in Muheza, Tanzania (2002-2006). At the time of delivery, cord hepcidin levels were correlated with inflammatory mediators, iron markers, and maternal health conditions. Hepcidin levels were 30% (95% confidence interval [CI]: 12%, 44%) lower in children born to anemic mothers and 48% (95% CI: 11%, 97%) higher in placental malaria-exposed children. Relative to children in the lowest third, children in the highest third of cord hepcidin had on average 2.5 g/L (95% CI: 0.1, 4.8) lower hemoglobin levels over the duration of follow-up, increased risk of anemia and severe anemia (adjusted hazard ratio [HR] [95% CI]: 1.18 [1.03, 1.36] and 1.34 [1.08, 1.66], respectively), and decreased risk of malaria and all-cause mortality (adjusted HR [95% CI]: 0.78 [0.67, 0.91] and 0.34 [0.14, 0.84], respectively). Although longitudinal measurements of hepcidin and iron stores are required to strengthen causal inference, these results suggest that hepcidin may have utility as a biomarker indicating children's susceptibility to anemia and infection in early life

Measuring urbanicity as a risk factor for childhood wheeze in a transitional area of coastal Ecuador: a cross-sectional analysis.

BACKGROUND: The urbanisation process has been associated with increases in asthma prevalence, an observation supported largely by studies comparing urban with rural populations. The nature of this association remains poorly understood, likely because of the limitations of the urban-rural approach to understand what a multidimensional process is. OBJECTIVE: This study explored the relationship between the urbanisation process and asthma prevalence using a multidimensional and quantitative measure of urbanicity. METHODS: A cross-sectional analysis was conducted in 1843 children living in areas with diverse levels of urbanisation in the district of Quinindé, Ecuador in 2013-2015. Categorical principal components analysis was used to generate an urbanicity score derived from 18 indicators measured at census ward level based on data from the national census in 2010. Indicators represent demographic, socioeconomic, built environment and geographical dimensions of the urbanisation process. Geographical information system analysis was used to allocate observations and urban characteristics to census wards. Logistic random effects regression models were used to identify associations between urbanicity score, urban indicators and three widely used definitions for asthma. RESULTS: The prevalence of wheeze ever, current wheeze and doctor diagnosis of asthma was 33.3%, 13% and 6.9%, respectively. The urbanicity score ranged 0-10. Positive significant associations were observed between the urbanicity score and wheeze ever (adjusted OR=1.033, 95% CI 1.01 to 1.07, p=0.05) and doctor diagnosis (adjusted OR=1.06, 95% CI 1.02 to 1.1, p=0.001). For each point of increase in urbanicity score, the prevalence of wheeze ever and doctor diagnosis of asthma increased by 3.3% and 6%, respectively. Variables related to socioeconomic and geographical dimensions of the urbanisation process were associated with greater prevalence of wheeze/asthma outcomes. CONCLUSIONS: Even small increases in urbanicity are associated with a higher prevalence of asthma in an area undergoing the urban transition. The use of a multidimensional urbanicity indicator has greater explanatory power than the widely used urban-rural dichotomy to improve our understanding of how the process of urbanisation affects the risk of asthma