Removal of AMPA receptors (AMPARs) from synapses is preceded by transient endocytosis of extrasynaptic AMPARs

AMPA receptors (AMPARs) are dynamically regulated at synapses, but the time course and location of their exocytosis and endocytosis are not known. Therefore, we have used ecliptic pHluorin-tagged glutamate receptor 2 to visualize changes in AMPAR surface expression in real time. We show that synaptic and extrasynaptic AMPARs respond very differently to NMDA receptor activation; there is a rapid internalization of extrasynaptic AMPARs that precedes the delayed removal of synaptic AMPARs

Decidual cell regulation of trophoblast is altered in pregnancies at risk of pre-eclampsia

Successful implantation and placentation are dependent on the interaction between decidual stromal cells (DSC) and extravillous trophoblast (EVT) cells. The extent of trophoblast invasion relies on communication between the placenta and maternal decidua. The cyclical process of decidualisation induces a transformation of endometrial fibroblasts to secretory DSC; these secreted products have many functions including the control of trophoblast invasion. Inadequate trophoblast invasion and remodelling of the uterine vessels (the spiral arteries) are associated with pregnancy disorders such as pre-eclampsia. Uterine artery Doppler resistance index (RI) in the first trimester of pregnancy can be used as a proxy measure of remodelling. DSC were isolated from pregnancies with normal (normal RI) or impaired (high RI) spiral artery remodelling. Following isolation, DSC were re-decidualised using cAMP and MPA and secretion of the decidualisation markers IGFBP-1 and prolactin assessed. We examined the impact of DSC secreted factors on trophoblast cell function, using the EVT cell line SGHPL-4. We demonstrated that DSC exposed to decidual factors were able to re-decidualise in vitro and that the chemoattraction of trophoblasts by DSC is impaired in pregnancies with high RI. This study provides new insights into the role that DSC play in regulating EVT functions during the first trimester of pregnancy. This is the first study to demonstrate that DSC from pregnancies with impaired vascular remodelling in the first trimester secrete factors that inhibit the directional movement of trophoblast cells. This finding may be important in understanding aberrant trophoblast invasion in pregnancies where vascular remodelling is impaired

Can smoking initiation contexts predict how adult Aboriginal smokers assess their smoking risks? A cross-sectional study using the 'Smoking Risk Assessment Target'

Objectives: Smoking prevalence is slow to reduce among Indigenous Australians of reproductive age. We analysed the relationships between age of smoking initiation, recalled initiation influences and self-assessment of smoking risks in Aboriginal smokers. Design, setting and participants: A community-based cross-sectional survey of Aboriginal smokers aged 18–45 years (N=121; 58 men) was undertaken, using single-item measures. The Smoking Risk Assessment Target (SRAT) as the primary outcome measure enabled self-assessment of smoking risks from 12 options, recategorised into 3 groups. Participants recalled influences on their smoking initiation. Multinomial logistic regression modelling included age, gender, strength of urges to smoke, age at initiation (regular uptake) and statistically significant initiation influences on χ2 tests (‘to be cool’, alcohol and cannabis). Results: Frequent initiation influences included friends (74%; SD 0.44), family (57%; SD 0.5) and alcohol (40%; SD 0.49). 54% (n=65) of smokers had the highest risk perception on the SRAT, selected by those who cared about the smoking risks and intended to quit soon. On multivariate analyses, compared with the highest level of SRAT, male gender, lower age of uptake and strong urges to smoke were significantly associated with the lowest level of SRAT, selected by those who refuted risks or thought they could not quit. Lower age of uptake and alcohol were associated with mid-level of SRAT, selected by those who cared about smoking risks, but did not consider quitting as a priority. Conclusions: Characteristics of smoking initiation in youth may have far-reaching associations with how smoking risks are assessed by adults of reproductive age, and their intentions to quit smoking. Becoming a regular smoker at under the age of 16 years, and influences of alcohol on smoking uptake, were inversely associated with high-level assessment of smoking risks and intention to quit in regional Aboriginal smokers. The SRAT may help tailor approaches to Indigenous smoking cessation

Acute hepatitis in a woman following excessive ingestion of an energy drink: a case report

<p>Abstract</p> <p>Introduction</p> <p>The consumption of energy drinks has increased significantly. We report the case of a patient who presented to our hospital with jaundice, abdominal pain, and markedly increased liver transaminases likely due to the increased consumption of an energy drink. To the best of our knowledge, this is the first case report in the literature linking the development of acute hepatitis to the consumption of an energy drink.</p> <p>Case presentation</p> <p>A 22-year-old Caucasian woman presented to our hospital with epigastric pain, nausea, vomiting, and low-grade fever. She had been drinking 10 cans of an energy drink daily for two weeks prior to presentation. Her physical examination revealed mild epigastric tenderness. Her initial blood tests revealed elevated alanine aminotransferase, aspartate aminotransferase, and total bilirubin. A computed tomographic scan of the abdomen and pelvis was normal, and the patient was discharged to home. She returned to the Emergency Department of our hospital with worsening pain and new-onset jaundice. This time her physical examination revealed epigastric tenderness and icteric sclera. Her aspartate aminotransferase, alanine aminotransferase, and international normalized ratio were markedly elevated. Further radiological studies were non-specific, and she was admitted to our hospital with a diagnosis of acute hepatitis. Her viral serology and toxicology screens were negative. The patient was treated supportively and was discharged after resolution of her symptoms and a marked decrease in her liver enzymes.</p> <p>Conclusion</p> <p>The development of acute hepatitis in this patient was most likely due to the excessive ingestion of an energy drink, and we speculate that niacin was the culprit ingredient.</p

Posterior Vitreous Detachment and the Posterior Hyaloid Membrane

PURPOSE: Despite posterior vitreous detachment being a common ocular event affecting most individuals in an aging population, there is little consensus regarding its precise anatomic definition. We investigated the morphologic appearance and molecular composition of the posterior hyaloid membrane to determine whether the structure clinically observed enveloping the posterior vitreous surface after posterior vitreous detachment is a true basement membrane and to postulate its origin. Understanding the relationship between the vitreous (in both its attached and detached state) and the internal limiting membrane of the retina is essential to understanding the cause of rhegmatogenous retinal detachment and vitreoretinal interface disorders, as well as potential future prophylactic and treatment strategies. DESIGN: Clinicohistologic correlation study. PARTICIPANTS: Thirty-six human donor globes. METHODS: Vitreous bodies identified to have posterior vitreous detachment were examined with phase-contrast microscopy and confocal microscopy after immunohistochemically staining for collagen IV basement membrane markers, in addition to extracellular proteins that characterize the vitreoretinal junction (fibronectin, laminin) and vitreous gel (opticin) markers. The posterior retina similarly was stained to evaluate the internal limiting membrane. Findings were correlated to the clinical appearance of the posterior hyaloid membrane observed during slit-lamp biomicroscopy after posterior vitreous detachment and compared with previously published studies. MAIN OUTCOME MEASURES: Morphologic appearance and molecular composition of the posterior hyaloid membrane. RESULTS: Phase-contrast microscopy consistently identified a creased and distinct glassy membranous sheet enveloping the posterior vitreous surface, correlating closely with the posterior hyaloid membrane observed during slit-lamp biomicroscopy in patients with posterior vitreous detachment. Immunofluorescent confocal micrographs demonstrated the enveloping membranous structure identified on phase-contrast microscopy to show positive stain results for type IV collagen. Immunofluorescence of the residual intact internal limiting membrane on the retinal surface also showed positive stain results for type IV collagen. CONCLUSIONS: The results of this study provide immunohistochemical evidence that the posterior hyaloid membrane is a true basement membrane enveloping the posterior hyaloid surface. Because this membranous structure is observed only after posterior vitreous detachment, the results of this study indicate that it forms part of the internal limiting membrane when the vitreous is in its attached state

The phenotype of decidual CD56+ lymphocytes is influenced by secreted factors from decidual stromal cells but not macrophages in the first trimester of pregnancy

During the first trimester of pregnancy the decidua is comprised of decidual stromal cells (DSC), invading fetal trophoblast cells and maternal leukocytes, including decidual natural killer (dNK) cells and macrophages. dNK cells are distinct from peripheral blood NK cells and have a role in regulating trophoblast invasion and spiral artery remodelling. The unique phenotype of dNK cells results from the decidual environment in which they reside, however the interaction and influence of other cells in the decidua on dNK phenotype is unknown. We isolated first trimester DSC and decidual macrophages and investigated the effect that DSC and decidual macrophage secreted factors have on CD56+ decidual lymphocyte receptor expression and cytokine secretion (including dNK cells). We report that DSC secreted factors induce the secretion of the cytokines IL-8 and IL-6 from first trimester CD56+ cells. However, neither DSC nor decidual macrophage secreted factors changed CD56+ cell receptor expression. These results suggest that secreted factors from DSC influence CD56+ decidual lymphocytes during the first trimester of pregnancy and therefore may play a role in regulating the unique phenotype and function of dNK cells during placentation

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

Hazy Blue Worlds:A Holistic Aerosol Model for Uranus and Neptune, Including Dark Spots

We present a reanalysis (using the Minnaert limb-darkening approximation) of visible/near-infrared (0.3 - 2.5 micron) observations of Uranus and Neptune made by several instruments. We find a common model of the vertical aerosol distribution that is consistent with the observed reflectivity spectra of both planets, consisting of: 1) a deep aerosol layer with a base pressure > 5-7 bar, assumed to be composed of a mixture of H2S ice and photochemical haze; 2) a layer of photochemical haze/ice, coincident with a layer of high static stability at the methane condensation level at 1-2 bar; and 3) an extended layer of photochemical haze, likely mostly of the same composition as the 1-2-bar layer, extending from this level up through to the stratosphere, where the photochemical haze particles are thought to be produced. For Neptune, we find that we also need to add a thin layer of micron-sized methane ice particles at ~0.2 bar to explain the enhanced reflection at longer methane-absorbing wavelengths. We suggest that methane condensing onto the haze particles at the base of the 1-2-bar aerosol layer forms ice/haze particles that grow very quickly to large size and immediately 'snow out' (as predicted by Carlson et al. 1988), re-evaporating at deeper levels to release their core haze particles to act as condensation nuclei for H2S ice formation. In addition, we find that the spectral characteristics of 'dark spots', such as the Voyager-2/ISS Great Dark Spot and the HST/WFC3 NDS-2018, are well modelled by a darkening or possibly clearing of the deep aerosol layer only.Comment: 58 pages, 23 figures, 4 table

Hazy Blue Worlds:A Holistic Aerosol Model for Uranus and Neptune, Including Dark Spots

We present a reanalysis (using the Minnaert limb-darkening approximation) of visible/near-infrared (0.3 - 2.5 micron) observations of Uranus and Neptune made by several instruments. We find a common model of the vertical aerosol distribution that is consistent with the observed reflectivity spectra of both planets, consisting of: 1) a deep aerosol layer with a base pressure > 5-7 bar, assumed to be composed of a mixture of H2S ice and photochemical haze; 2) a layer of photochemical haze/ice, coincident with a layer of high static stability at the methane condensation level at 1-2 bar; and 3) an extended layer of photochemical haze, likely mostly of the same composition as the 1-2-bar layer, extending from this level up through to the stratosphere, where the photochemical haze particles are thought to be produced. For Neptune, we find that we also need to add a thin layer of micron-sized methane ice particles at ~0.2 bar to explain the enhanced reflection at longer methane-absorbing wavelengths. We suggest that methane condensing onto the haze particles at the base of the 1-2-bar aerosol layer forms ice/haze particles that grow very quickly to large size and immediately 'snow out' (as predicted by Carlson et al. 1988), re-evaporating at deeper levels to release their core haze particles to act as condensation nuclei for H2S ice formation. In addition, we find that the spectral characteristics of 'dark spots', such as the Voyager-2/ISS Great Dark Spot and the HST/WFC3 NDS-2018, are well modelled by a darkening or possibly clearing of the deep aerosol layer only.Comment: 58 pages, 23 figures, 4 table

An accurate test for homogeneity of odds ratios based on Cochran's Q-statistic

Background: A frequently used statistic for testing homogeneity in a meta-analysis of K independent studies is Cochran's Q. For a standard test of homogeneity the Q statistic is referred to a chi-square distribution with K - 1 degrees of freedom. For the situation in which the effects of the studies are logarithms of odds ratios, the chi-square distribution is much too conservative for moderate size studies, although it may be asymptotically correct as the individual studies become large. Methods: Using a mixture of theoretical results and simulations, we provide formulas to estimate the shape and scale parameters of a gamma distribution to t the distribution of Q. Results: Simulation studies show that the gamma distribution is a good approximation to the distribution for Q. Conclusions: : Use of the gamma distribution instead of the chi-square distribution for Q should eliminate inaccurate inferences in assessing homogeneity in a meta-analysis. (A computer program for implementing this test is provided.) This hypothesis test is competitive with the Breslow-Day test both in accuracy of level and in power