Impact of Coronavirus Outbreak on NO2 Pollution Assessed Using TROPOMI and OMI Observations.

Spaceborne NO2 column observations from two high-resolution instruments, Tropospheric Monitoring Instrument (TROPOMI) on board Sentinel-5 Precursor and Ozone Monitoring Instrument (OMI) on Aura, reveal unprecedented NO2 decreases over China, South Korea, western Europe, and the United States as a result of public health measures enforced to contain the coronavirus disease outbreak (Covid-19) in January-April 2020. The average NO2 column drop over all Chinese cities amounts to -40% relative to the same period in 2019 and reaches up to a factor of ~2 at heavily hit cities, for example, Wuhan, Jinan, while the decreases in western Europe and the United States are also significant (-20% to -38%). In contrast with this, although Iran is also strongly affected by the disease, the observations do not show evidence of lower emissions, reflecting more limited health measures.

Influence of housing characteristics on bacterial and fungal communities in homes of asthmatic children.

Variations in home characteristics, such as moisture and occupancy, affect indoor microbial ecology as well as human exposure to microorganisms. Our objective was to determine how indoor bacterial and fungal community structure and diversity are associated with the broader home environment and its occupants. Next-generation DNA sequencing was used to describe fungal and bacterial communities in house dust sampled from 198 homes of asthmatic children in southern New England. Housing characteristics included number of people/children, level of urbanization, single/multifamily home, reported mold, reported water leaks, air conditioning (AC) use, and presence of pets. Both fungal and bacterial community structures were non-random and demonstrated species segregation (C-score, P < 0.00001). Increased microbial richness was associated with the presence of pets, water leaks, longer AC use, suburban (vs. urban) homes, and dust composition measures (P < 0.05). The most significant differences in community composition were observed for AC use and occupancy (people, children, and pets) characteristics. Occupant density measures were associated with beneficial bacterial taxa, including Lactobacillus johnsonii as measured by qPCR. A more complete knowledge of indoor microbial communities is useful for linking housing characteristics to human health outcomes. Microbial assemblies in house dust result, in part, from the building's physical and occupant characteristics.

Effectiveness of dinoprostone gel, misoprostol vaginal insert and dinoprostone vaginal insert for induction of labour in twin pregnancies.

OBJECTIVES: To compare the effectiveness and safety of Dinoprostone Gel (DG), Misoprostol Vaginal Insert (MVI) and Dinoprostone Vaginal Insert (DVI) for induction of labour (IOL) in twin pregnancies. STUDY DESIGN: Retrospective cohort study of twin pregnancies > 34 + 0 weeks gestation that underwent induction of labour (IOL) with DG, MVI or DVI between December 2016 and November 2019 in a Tertiary NHS hospital, North West England, UK. Delivery characteristics, maternal complications and neonatal outcomes were compared between the three groups. RESULTS: A total of 87 twin pregnancies were included for analysis. 27 women received DG, 34 received MVI and 26 DVI. The MVI cohort had a higher proportion of nulliparous women (55.9%) compared to the DG and DVI cohorts, 29.6% and 38.5% respectively. No other differences amongst demographic characteristics were considered clinically significant. DG demonstrated a significantly quicker time to delivery (minutes) compared to DVI (1021 ± 556 versus 1649 ± 852; P = 0.0026). Significantly fewer women required terbutaline for hyperstimulation/tachysystole in the DG group compared to MVI (0% vs 32%; RR 0.05; 95% CI 0.003-0.88). Both DG and MVI groups required significantly less oxytocin following artificial rupture of membranes compared to DVI (33% vs 65%; RR 0.51; 95% CI 0.28-0.93) and (29% vs 65%; RR 0.45; 95% CI 0.25-0.81). There were no significant differences in mode of delivery, maternal complications and neonatal outcomes. CONCLUSION: Our data suggests that for women with a twin pregnancy considering a planned labour that induction with DG, MVI and DVI appear to be equally safe and effective IOL methods. These results should be interpreted with caution due to the study being underpowered to detect significant adverse outcomes. In order to determine the optimal method of IOL in twins, direct randomised comparison is needed.

Comparison of international guidelines on the management of twin pregnancy.

OBJECTIVES: To review current international clinical guidelines on the antenatal and intrapartum management of twin pregnancies, examining areas of consensus and conflict. METHODS: We conducted a database search using Medline, Pubmed, Scopus, Academic Search Complete, CINAHL and ERCI Guidelines website. Guidelines were screened for eligibility using our inclusion and exclusion criteria. Those deemed eligible were quality assessed using the AGREE II tool and relevant data was extracted. RESULTS: We identified 21 relevant guidelines from 16 countries including two international society guidelines. There was consensus in determination of chorionicity and amnionicity within the first trimester, fetal anomaly scan between 18 and 22 weeks and the recommended screening for twin-to-twin transfusion syndrome (TTTS). For those that provided intrapartum guidance, there was agreement in recommending caesarean section to deliver monochorionic monoamniotic (MCMA) twins, epidural anaesthesia for intrapartum analgesia and the use of cardiotocography (CTG) for intrapartum fetal monitoring. The main areas of conflict included cervical length screening, frequency of ultrasound surveillance, timing of delivery of dichorionic twin pregnancies and circumstances for recommending vaginal delivery. There was a lack of advice on intrapartum management. CONCLUSIONS: This review has highlighted the need for unified international guidance on the management of twin pregnancy. Comparisons of current guidance demonstrates a lack of confidence in the management of labour in twin pregnancies. Further evidence on intrapartum care of twin pregnancies is needed to inform practice guidelines and improve both short and long term maternal and fetal outcomes.

Impact of Transfused Citrate on Pathophysiology in Massive Transfusion.

This narrative review article seeks to highlight the effects of citrate on physiology during massive transfusion of the bleeding patient. DATA SOURCES: A limited library of curated articles was created using search terms including "citrate intoxication," "citrate massive transfusion," "citrate pharmacokinetics," "hypocalcemia of trauma," "citrate phosphate dextrose," and "hypocalcemia in massive transfusion." Review articles, as well as prospective and retrospective studies were selected based on their relevance for inclusion in this review. STUDY SELECTION: Given the limited number of relevant studies, studies were reviewed and included if they were written in English. This is not a systematic review nor a meta-analysis. DATA EXTRACTION AND SYNTHESIS: As this is not a meta-analysis, new statistical analyses were not performed. Relevant data were summarized in the body of the text. CONCLUSIONS: The physiologic effects of citrate independent of hypocalcemia are poorly understood. While a healthy individual can rapidly clear the citrate in a unit of blood (either through the citric acid cycle or direct excretion in urine), the physiology of hemorrhagic shock can lead to decreased clearance and prolonged circulation of citrate. The so-called "Diamond of Death" of bleeding-coagulopathy, acidemia, hypothermia, and hypocalcemia-has a dynamic interaction with citrate that can lead to a death spiral. Hypothermia and acidemia both decrease citrate clearance while circulating citrate decreases thrombin generation and platelet function, leading to ionized hypocalcemia, coagulopathy, and need for further transfusion resulting in a new citrate load. Whole blood transfusion typically requires lower volumes of transfused product than component therapy alone, resulting in a lower citrate burden. Efforts should be made to limit the amount of citrate infused into a patient in hemorrhagic shock while simultaneously addressing the induced hypocalcemia.

An environmental epigenetic study of ADRB2 5'-UTR methylation and childhood asthma severity.

BACKGROUND: Beta-2 adrenergic receptor (ADRB2) is the primary target of both short- and long-acting beta-agonist asthma medications. ADRB2 5'-UTR methylation changes in blood have the potential to act as a surrogate biomarker of responsiveness to beta-agonist treatment and childhood asthma severity. OBJECTIVE: To study the association between ADRB2 5'-UTR methylation, NO (2) exposure and childhood asthma severity. METHODS: We compared ADRB2 5'-UTR methylation levels in blood between 60 children with mild asthma and 122 children with severe asthma using methylation-specific PCR. We also investigated potential joint effects between NO (2) exposure and ADRB2 5'-UTR methylation. RESULTS: We found a significant association between intermediate (OR: 4.11, 95% CI: 1.58-10.73) and high levels (OR: 7.63, 95% CI: 3.02-19.26) of ADRB2 methylation and severe childhood asthma. In addition, we found a significant association between indoor exposure to NO (2) , an air pollutant and known asthmogen, and severe asthma among children exhibiting high ADRB2 methylation (OR: 4.59, 95% CI: 1.03-20.55) but no association among children exhibiting low levels of ADRB2 methylation (OR: 0.35, 95% CI: 0.01-14.13). CONCLUSIONS AND CLINICAL RELEVANCE: These findings support the potential use of ADRB2 5'-UTR methylation as a biomarker of both asthma severity and risk for NO (2) -associated asthma exacerbations in children, and present the first evidence of an epigenetic link between an important environmental exposure and childhood asthma severity.

Comparison of the Respiratory Resistomes and Microbiota in Children Receiving Short versus Standard Course Treatment for Community-Acquired Pneumonia.

Pediatric community-acquired pneumonia (CAP) is often treated with 10 days of antibiotics. Shorter treatment strategies may be effective and lead to less resistance. The impact of duration of treatment on the respiratory microbiome is unknown. Data are from children (n = 171), ages 6 to 71 months, enrolled in the SCOUT-CAP trial (NCT02891915). Children with CAP were randomized to a short (5 days) versus standard (10 days) beta-lactam treatment strategy. Throat swabs were collected at enrollment and the end of the study and used for shotgun metagenomic sequencing. The number of beta-lactam and multidrug efflux resistance genes per prokaryotic cell (RGPC) was significantly lower in children receiving the short compared to standard treatment strategy at the end of the study (Wilcoxon rank sum test, P < 0.05 for each). Wilcoxon effect sizes were small for beta-lactam (r: 0.15; 95% confidence interval [CI], 0.01 to 0.29) and medium for multidrug efflux RGPC (r: 0.23; 95% CI, 0.09 to 0.37). Analyses comparing the resistome at the beginning and end of the trial indicated that in contrast to the standard strategy group, the resistome significantly differed in children receiving the short course strategy. Relative abundances of commensals such as Neisseria subflava were higher in children receiving the standard strategy, and Prevotella species and Veillonella parvula were higher in children receiving the short course strategy. We conclude that children receiving 5 days of beta-lactam therapy for CAP had a significantly lower abundance of antibiotic resistance determinants than those receiving standard 10-day treatment. These data provide an additional rationale for reductions in antibiotic use when feasible. IMPORTANCE Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance. We examined relationships between the duration of antibiotic treatment and its impact on resistance genes and bacteria in the respiratory microbiome using data from a randomized controlled trial of beta-lactam therapy for pediatric pneumonia. The randomized design provides reliable evidence of the effectiveness of interventions and minimizes the potential for confounding. Children receiving 5 days of therapy for pneumonia had a lower prevalence of two different types of resistance genes than did those receiving the 10-day treatment. Our data also suggest that children receiving longer durations of therapy have a greater abundance of antibiotic resistance genes for a longer period of time than do children receiving shorter durations of therapy. These data provide an additional rationale for reductions in antibiotic use.

Corresponding affections: emotional exchange among siblings in the Nassau family.

This article examines the nature of emotional exchange among the siblings who were the children of William the Silent, leader of the nascent Dutch Republic. Using evidence from extensive familial correspondence, it asks how the language of emotions could constitute forms of power within the family, by analyzing how actions and expressions of emotion were presented, discussed, and interpreted in epistolary form, to whom, and with what intention and impact. The article studies social, geographic, linguistic, and other distinctions between siblings in their use of affective discourses in correspondence and argues that attention to affective language can help to elucidate the agentive force of emotions in both reflecting and informing notions of power within the family.

Ubiquitin system-dependent regulation of growth hormone receptor signal transduction.

The growth hormone (GH) receptor is a key regulator of cellular metabolism. Unlike most growth factor receptors, its downregulation is not initiated by its ligand. Like many growth factor receptors, specific molecular mechanisms guarantee that a receptor can signal only once in its lifetime. Three features render the GH receptor unique: (a) an active ubiquitination system is required for both uptake (endocytosis) and degradation in the lysosomes; (b) uptake of the receptor is a continuous process, independent of both GH binding and Jak2 signal transduction; (c) only the cell surface expression of dimerised GH receptors is controlled by the ubiquitin system. This system enables two independent regulatory mechanisms for the endocrinology of the GH/GHR axis: the pulsatile secretion of GH by the pituitary and the GH sensitivity of individual cells of the body by the effects of the ubiquitin system on GH receptor availability.

Comparison of the effects of two 'sleep' peptides, delta sleep-inducing peptide and arginine-vasotocin, on single neurons in the rat and rabbit brain stem.

The effects of delta sleep-inducing peptide and arginine-vasotocin were assessed on single neurons in the nucleus reticularis gigantocellularis of the brain stem in rats and rabbits. Both peptides showed predominantly excitatory actions in both species when applied by microiontophoresis. A small proportion of cells was inhibited by delta sleep-inducing peptide in the rat. Responses to delta sleep-inducing peptide were short-lasting, dose-dependent and showed no significant desensitization to repeated applications. Responses to arginine-vasotocin were of very long time course and showed profound desensitization. No statistically significant correlation was seen between cells responsive to delta sleep-inducing peptide and those responsive to arginine-vasotocin. We conclude that both 'sleep' peptides have similar actions on central neurons and that they are active in both rats and rabbits. However, no evidence was found to suggest a common mechanism of action for both substances.

The effects of chlormethiazole on single unit activity in rat brain; interactions with inhibitory and excitatory neurotransmitters.

Extracellular recordings were made of single unit activity in the brainstem of urethane anaesthetized rats. Drugs were applied by microiontophoresis from multibarrelled micropipettes or administered intraperitoneally. Chlormethiazole (CMZ) caused a decrease in spontaneous firing rate when applied with high currents (greater than 40 nA). When applied with lower currents CMZ did not cause changes in firing rate, but enhanced the inhibitory effects of gamma-aminobutyric acid (GABA), muscimol and glycine in a dose-dependent manner. The inhibitory actions of acetylcholine were not affected. Excitatory responses to glutamate and acetylcholine were unaffected by applications of CMZ which caused potentiation of GABA, muscimol and glycine. When applied at higher currents CMZ caused a decrease in the response to glutamate. Intraperitoneal administration of CMZ (50-600 mumol kg-1) also enhanced responses to microiontophoretically applied GABA, muscimol and glycine. These results are compared with those reported for other anticonvulsant drugs and possible mechanisms of action of CMZ are discussed.

Convulsive thresholds in mice during the recovery phase from anaesthesia induced by propofol, thiopentone, methohexitone and etomidate.

1. Convulsive thresholds were measured with intravenous pentylenetetrazol in mice during the recovery phase after intravenous anaesthetic doses of propofol (10 and 20 mg kg-1), thiopentone (30 mg kg-1), methohexitone (10 mg kg-1), and etomidate 3 mg kg-1). 2. The convulsive threshold rose after each agent, indicating an anticonvulsant action for all the drugs tested; this declined to control values with initial half times of: 1.56 min (propofol 10 mg kg-1); 1.03 min (propofol 20 mg kg-1): 1.02 min (methohexitone); 3.35 min (etomidate); 13.7 min (thiopentone). 3. At no time during the recovery phase of any agent did the convulsive threshold fall below control values, which might indicate an epileptogenic effect of the drug. 4. The threshold was depressed below control values by intravenous administration of Ro 15-4513, a partial inverse agonist at the benzodiazepine receptor, thus indicating the ability of this pentylenetetrazol test to demonstrate a proconvulsant effect. 5. We conclude that the abnormal movements or convulsions associated with recovery from anaesthesia with short-acting intravenous anaesthetics may not be the result of an intrinsic proconvulsant action of the drugs.

Inhibition of Ca(2+)-sensitive K+ currents in NG 108-15 cells by substance P and related tachykinins.

1. The whole-cell patch-clamp technique was used to investigate the actions of substance P and other agonists at neurokinin (NK) receptors on voltage-gated K+ and Ca+ channel currents in undifferentiated mouse neuroblastoma x rat glioma NG 108-15 cells. 2. Both substance P (0.3-30 microM) and the NK1 receptor selective agonist GR73632 (10 nM-10 microM) caused concentration-dependent inhibition of K+ currents. GR64349 and senktide (agonists at NK2 and NK3 receptors respectively) also inhibited K+ currents, but only at concentrations which were several orders of magnitude greater than GR73632, suggesting that current inhibition was mediated via NK1 receptors. 3. Substance P and GR73632 were without effect on residual K+ currents recorded in the presence of extracellular Co2+ (4 mM) to abolish the Ca(2+)-sensitive component (IKca) of the K+ current. Ca2+ channel currents, recorded with either Ba2+ or Ca2+ as charge carrier, were unaffected by NK1, NK2 and NK3 receptor ligands. 4. Iontophoretic application of GR73632 produced a current-dependent reduction of K+ currents. In the presence of the non-peptide NK1 antagonists, CP-99,994 and RP67580, and the peptide antagonist, GR82334, the current-response relationship was reversibly shifted to the right. This indicates that the response is mediated by NK1 receptors. 5. Our results indicate that activation of NK1 receptors leads to the selective inhibition of IKca in undifferentiated NG 108-15 cells.

The relationship between the agonist-induced activation and desensitization of the human tachykinin NK2 receptor expressed in Xenopus oocytes.

1. Repeated applications of neurokinin A (NKA) to oocytes injected with 25 ng wild-type hNK2 receptor cRNA caused complete attenuation of second and subsequent NKA-induced responses while analogous experiments using repeated applications of GR64349 and [Nle10]NKA(4-10) resulted in no such desensitization. This behaviour has been previously attributed to the ability of the different ligands to stabilize different active conformations of the receptor that have differing susceptibilities to receptor kinases (Nemeth & Chollet. 1995). 2. However, for Xenopus oocytes injected (into the nucleus) with 10 ng wild-type hNK2 receptor cDNA, a single 100 nM concentration of any of the three ligands resulted in complete desensitization to further concentrations. 3. On the other hand, none of the ligands caused any desensitization in oocytes injected with 0.25 ng wild-type hNK2 receptor cRNA. even at concentrations up to 10 microM. 4. The two N-terminally truncated analogues of neurokinin A have a lower efficacy than NKA and it is likely that it is this property which causes the observed differences in desensitization, rather than the formation of alternative active states of the receptor. 5. The peak calcium-dependent chloride current is not a reliable measure of maximal receptor stimulation and efficacy is better measured in this system by studying agonist-induced desensitization. 6. The specific adenylyl cyclase inhibitor SQ22536 can enhance NKA and GR64349-mediated desensitization which suggests that agonist-induced desensitization involves the inhibition of adenylyl cyclase and the subsequent down-regulation of the cyclic AMP-dependent protein kinase, possibly by cross-talk to a second signalling pathway.

Opioid receptor independent inhibition of Ca2+ and K+ currents in NG108-15 cells by the kappa opioid receptor agonist U50488H.

The whole-cell patch clamp technique was used to investigate the actions of the opioid agonist U50488H on Ca2+ and K+ currents in differentiated NG108-15 cells. U50488H (5-50 microM) caused a concentration-dependent, reversible inhibition of high voltage-activated Ca2+ currents which persisted in the presence of nifedipine (2 microM), indicating a blockade of N-type Ca2+ channels. The actions of U50488H were also observed in the presence of 30 microM naloxone, which fully abolished current inhibition caused by a selective delta opioid receptor agonist. U50488H also inhibited Ca(2+)-insensitive, voltage-gated K+ currents in NG108-15 cells in the presence of naloxone. Our results indicate that U50488H can inhibit neuronal ionic channels via a mechanism which does not involve activation of kappa opioid receptors.

Electrophysiological properties of substantia gelatinosa neurones in a novel adult spinal slice preparation.

A novel longitudinal spinal cord slice prepared from adult rats aged 3-6 weeks is described. This preparation differs from conventional slices in that it retains multiple dorsal roots, each more than 10 mm in length, and presents a sagittal section through the laminae of the dorsal and ventral horns. The substantia gelatinosa can be visually distinguished from the other laminae of the dorsal horn, thus making the preparation particularly suited for the study of neurones located in this region. Extracellular recordings were made from 142 substantia gelatinosa cells, most of which responded to electrical stimulation of a dorsal root. Using measurements of latency it was possible to estimate conduction velocities for afferent input fibres. The effects of iontophoretically applied excitatory amino acids and of tachykinin peptides on spontaneous and afferent-evoked firing are briefly described. The preparation has applications in the investigation of mechanisms of primary afferent transmission within the dorsal horn and of transmission of afferent input between successive spinal segments.

Neurokinin actions on substantia gelatinosa neurones in an adult longitudinal spinal cord preparation.

We have used an adult longitudinal spinal cord preparation to study the effects of a range of selective neurokinin analogues on single neurones located exclusively within the substantia gelatinosa. Since the preparation retained attached dorsal roots it was possible synaptically to activate the substantia gelatinosa neurones by electrical stimulation of their afferent fibres, thus providing a means of studying directly the role of neurokinins in mechanisms of primary afferent transmission. The actions of three agonists selective for the three NK receptor subtypes (NK1, GR73632; NK2, GR64349; NK3, senktide), and a highly selective antagonist at NK1 receptors (GR82334) were investigated. Experiments were performed on a total of 274 substantia gelatinosa neurones, estimates of conduction velocity for evoked responses suggested that the majority of these neurones were innervated by unmyelinated afferents. A large proportion responded to iontophoretically applied neurokinin agonists. The majority responded to NK1, fewer responded to NK2; some, although not all, of the neurones tested responded to both NK1 and NK2 agonists. In most cases the responses were excitatory, although inhibitory effects were observed in some neurones. None of the neurones tested responded to NK3 agonist. Excitatory and inhibitory actions could be demonstrated following abolition of synaptic transmission by removal of calcium, suggesting direct mechanisms for both effects. The antagonist alone failed to modify either spontaneous firing or firing in response to afferent stimulation in any of the neurones studied, even though the doses used were shown to be effective in selectively antagonising responses to the NK1 agonist, suggesting that neither relied on the endogenous release of neurokinins.

Development of tolerance to the anticonvulsant effects of clobazam.

The anticonvulsant properties of the 1,5-benzodiazepine clobazam were studied in mice during and after chronic treatment at two different dose levels. Pentylenetetrazol given by slow intravenous infusion was used as the convulsant stimulus. Tolerance to the anticonvulsant effects was observed; this was rapid in onset and could be overcome by increasing the dose of clobazam.

Benzodiazepine cross-tolerance in mice extends to sodium valproate.

Slow intravenous infusion of pentylenetetrazol was used to measure the convulsive threshold in mice. The anticonvulsant effects of clobazam, clonazepam, diazepam, lorazepam, sodium phenobarbitone and sodium valproate were assessed in naive animals and compared with the effects of the same compounds in animals which had been pretreated (twice daily for 3 days) with one of the benzodiazepines or sodium valproate. Cross-tolerance was observed between all the benzodiazepines but not between benzodiazepines and sodium phenobarbitone. Animals pretreated with the benzodiazepines were cross-tolerant to valproate, but the converse was not true; nor did sodium valproate induce tolerance to itself.

Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?

The development of anticonvulsant tolerance with three benzodiazepines was assessed in mice using a slow intravenous infusion of pentylenetetrazol as the convulsive stimulus. Chlordiazepoxide (12.5 mg/kg b.d.) and midazolam (0.75 mg/kg b.d.) induced a slowly evolving tolerance over 15 days whereas nitrazepam (0.6 mg/kg b.d.) induced a very marked rapid tolerance which developed no further during 6 days treatment. Tolerance appeared to be incomplete with all three benzodiazepines. Possible explanations for the differences in tolerance profile are discussed and an alternative basis for the classification of benzodiazepines is suggested.