Emerging role of sertindole in the management of schizophrenia

The atypical antipsychotic sertindole is a phenylindole-derived compound that has affinity for and functions as an antagonist at a number of receptor systems, including dopamine D2 receptors, 5-HT2A and 5-HT2C receptors, and α-1-noradrenergic receptors. Although previous data suggested that sertindole was well tolerated and had good efficacy against both positive and negative symptom clusters, reports of QT prolongation with sertindole prompted its voluntary removal from the market in 1998. After further safety analyses, it recently regained approval and was reintroduced to the European market for the treatment of schizophrenia, where its role in therapy among available atypicals remains unclear. This article evaluates the preclinical and clinical data regarding sertindole’s effectiveness and concludes that sertindole continues to demonstrate a number of strengths, including effective management of both positive and negative symptoms, well-tolerated side effects (including little or no sedation, weight gain, and extrapyramidal side effects), and a superior procognitive profile that is unique among atypical antipsychotics. However, minor concerns regarding its sexual side effects and the major consideration of QT prolongation suggest that additional comparative effectiveness studies are needed to determine the superiority of sertindole vs other atypical antipsychotics recently introduced

Application of the MEGNO technique to the dynamics of Jovian irregular satellites

We apply the MEGNO (Mean Exponential Growth of Nearby Orbits) technique to the dynamics of Jovian irregular satellites. We demonstrate the efficiency of applying the MEGNO indicator to generate a mapping of relevant phase-space regions occupied by observed jovian irregular satellites. The construction of MEGNO maps of the Jovian phase-space region within its Hill-sphere is addressed and the obtained results are compared with previous studies regarding the dynamical stability of irregular satellites. Since this is the first time the MEGNO technique is applied to study the dynamics of irregular satellites we provide a review of the MEGNO theory. We consider the elliptic restricted three-body problem in which Jupiter is orbited by a massless test satellite subject to solar gravitational perturbations. The equations of motion of the system are integrated numerically and the MEGNO indicator computed from the systems variational equations. An unprecedented large set of initial conditions are studied to generate the MEGNO maps. The chaotic nature of initial conditions are demonstrated by studying a quasi-periodic orbit and a chaotic orbit. As a result we establish the existence of several high-order mean-motion resonances detected for retrograde orbits along with other interesting dynamical features. The computed MEGNO maps allows to qualitatively differentiate between chaotic and quasi-periodic regions of the irregular satellite phase-space given only a relatively short integration time. By comparing with previous published results we can establish a correlation between chaotic regions and corresponding regions of orbital instability.Comment: 15 pages, 13 figures, 2 tables, submitted to MNRA

Fingerprinting the impacts of global change on tropical forests

Recent observations of widespread changes in mature tropical forests such as increasing tree growth, recruitment and mortality rates and increasing above-ground biomass suggest that 'global change' agents may be causing predictable changes in tropical forests. However, consensus over both the robustness of these changes and the environmental drivers that may be causing them is yet to emerge. This paper focuses on the second part of this debate. We review (i) the evidence that the physical, chemical and biological environment that tropical trees grow in has been altered over recent decades across large areas of the tropics, and (ii) the theoretical, experimental and observational evidence regarding the most likely effects of each of these changes on tropical forests. Ten potential widespread drivers of environmental change were identified: temperature, precipitation, solar radiation, climatic extremes (including El Niño Southern Oscillation events), atmospheric CO2 concentrations, nutrient deposition, O3/acid depositions, hunting, land-use change and increasing liana numbers. We note that each of these environmental changes is expected to leave a unique 'fingerprint' in tropical forests, as drivers directly force different processes, have different distributions in space and time and may affect some forests more than others (e.g. depending on soil fertility). Thus, in the third part of the paper we present testable a priori predictions of forest responses to assist ecologists in attributing particular changes in forests to particular causes across multiple datasets. Finally, we discuss how these drivers may change in the future and the possible consequences for tropical forests

Does stream water composition at sleepers river in vermont reflect dynamic changes in soils during recovery from acidification?

Stream water pH and composition are widely used to monitor ongoing recovery from the deposition of strong anthropogenic acids in many forested headwater catchments in the northeastern United States. However, stream water composition is a function of highly complex and coupled processes, flowpaths, and variations in soil and bedrock composition. Spatial heterogeneity is especially pronounced in headwater catchments with steep topography, potentially limiting stream water composition as an indicator of changes in critical zone (CZ) dynamics during system recovery. To investigate the link between catchment characteristics, landscape position, and stream water composition we used long-term data (1991–2015) from the Sleepers River Research Watershed (SRRW) in northeastern Vermont. We investigated trends with time in stream water and trends with time, depth, and landscape position (upslope, midslope, and riparian zone) in groundwater (GW) and soil solution. We further determined soil elemental composition and mineralogy on archived (1996) and modern (2017) soil samples to assess changes in composition with time. SRRW is inherently well-buffered by calcite in bedrock and till, but soils had become acidified and are now recovering from acidification. Although base cations, especially Ca, decrease progressively with time in GW, riparian soils have become more enriched in Ca, due to a mixture of lateral and vertical transfers. At the same time stream water Ca fluxes increased over the past two decades, likely due to the leaching of (transient) legacy Ca from riparian zones and increased water fluxes. The stream water response therefore reflects the dynamic changes in soil chemistry, flow routing and water inputs

Phytochemical constituents, antioxidant activity, and toxicity assessment of the aerial part extracts from the infraspecific taxa of Matthiola fruticulosa (Brassicaceae) endemic to Sicily

In a project designed to investigate the specific and infraspecific taxa of Matthiola endemic to Sicily (Italy) as new potential sources of bioactive compounds in this work, the infraspecific taxa of Matthiola fruticulosa were studied, namely, subsp. fruticulosa and subsp. coronopifolia. HPLC-PDA/ESI-MS and SPME-GC/MS analyses of hydroalcoholic extracts obtained from the aerial parts of the two subspecies led to the detection of 51 phenolics and 61 volatile components, highlighting a quite different qualitative-quantitative profile. The antioxidant properties of the extracts were explored through in vitro methods: 1,1-diphenyl-2-picrylhydrazyl (DPPH), reducing power and Fe2+ chelating activity assays. The results of the antioxidant tests showed that the extracts possess a different antioxidant ability: Particularly, the extract of M. fruticulosa subsp. fruticulosa exhibited higher radical scavenging activity than that of subsp. coronopifolia (IC50 = 1.25 ± 0.02 mg/mL and 2.86 ± 0.05 mg/mL), which in turn displayed better chelating properties (IC50 = 1.49 ± 0.01 mg/mL and 0.63 ± 0.01 mg/mL). Lastly, Artemia salina lethality bioassay was performed for toxicity assessment. The results of the bioassay showed lack of toxicity against brine shrimp larvae for both extracts. The data presented indicate the infraspecific taxa of M. fruticulosa as new and safe sources of antioxidant compounds

Killing Hypoxic Cell Populations in a 3D Tumor Model with EtNBS-PDT

An outstanding problem in cancer therapy is the battle against treatment-resistant disease. This is especially true for ovarian cancer, where the majority of patients eventually succumb to treatment-resistant metastatic carcinomatosis. Limited perfusion and diffusion, acidosis, and hypoxia play major roles in the development of resistance to the majority of front-line therapeutic regimens. To overcome these limitations and eliminate otherwise spared cancer cells, we utilized the cationic photosensitizer EtNBS to treat hypoxic regions deep inside in vitro 3D models of metastatic ovarian cancer. Unlike standard regimens that fail to penetrate beyond ∼150 µm, EtNBS was found to not only penetrate throughout the entirety of large (>200 µm) avascular nodules, but also concentrate into the nodules' acidic and hypoxic cores. Photodynamic therapy with EtNBS was observed to be highly effective against these hypoxic regions even at low therapeutic doses, and was capable of destroying both normoxic and hypoxic regions at higher treatment levels. Imaging studies utilizing multiphoton and confocal microscopies, as well as time-lapse optical coherence tomography (TL-OCT), revealed an inside-out pattern of cell death, with apoptosis being the primary mechanism of cell killing. Critically, EtNBS-based photodynamic therapy was found to be effective against the model tumor nodules even under severe hypoxia. The inherent ability of EtNBS photodynamic therapy to impart cytotoxicity across a wide range of tumoral oxygenation levels indicates its potential to eliminate treatment-resistant cell populations

Oropharyngeal Microbiome Profiled at Admission is Predictive of the Need for Respiratory Support Among COVID-19 Patients [preprint]

The clinical course of infection due to respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), the causative agent of Coronavirus Disease 2019 (COVID-19) is thought to be influenced by the community of organisms that colonizes the upper respiratory tract, the oropharyngeal microbiome. In this study, we examined the oropharyngeal microbiome of suspected COVID-19 patients presenting to the Emergency Department and an inpatient COVID-19 unit with symptoms of acute COVID-19. Of 115 enrolled patients, 74 were confirmed COVID-19+ and 50 had symptom duration of 14 days or less; 38 acute COVID-19+ patients (76%) went on to require respiratory support. Although no microbiome features were found to be significantly different between COVID-19+ and COVID-19-patients, when we conducted random forest classification modeling (RFC) to predict the need of respiratory support for the COVID-19+ patients our analysis identified a subset of organisms and metabolic pathways whose relative abundance, when combined with clinical factors (such as age and Body Mass Index), was highly predictive of the need for respiratory support (F1 score 0.857). Microbiome Multivariable Association with Linear Models (MaAsLin2) analysis was then applied to the features identified as predicative of the need for respiratory support by the RFC. This analysis revealed reduced abundance of Prevotella salivae and metabolic pathways associated with lipopolysaccharide and mycolic acid biosynthesis to be the strongest predictors of patients requiring respiratory support. These findings suggest that composition of the oropharyngeal microbiome in COVID-19 may play a role in determining who will suffer from severe disease manifestations. Importance: The microbial community that colonizes the upper airway, the oropharyngeal microbiome, has the potential to affect how patients respond to respiratory viruses such as SARS-CoV2, the causative agent of COVID-19. In this study, we investigated the oropharyngeal microbiome of COVID-19 patients using high throughput DNA sequencing performed on oral swabs. We combined patient characteristics available at intake such as medical comorbidities and age, with measured abundance of bacterial species and metabolic pathways and then trained a machine learning model to determine what features are predicative of patients needing respiratory support in the form of supplemental oxygen or mechanical ventilation. We found that decreased abundance of some bacterial species and increased abundance of pathways associated bacterial products biosynthesis was highly predictive of needing respiratory support. This suggests that the oropharyngeal microbiome affects disease course in COVID-19 and could be targeted for diagnostic purposes to determine who may need oxygen, or therapeutic purposes such as probiotics to prevent severe COVID-19 disease manifestations

Variability in ultra cool dwarfs: evidence for the evolution of surface features

We present photometric light curves for a sample of 21 ultra cool M and L dwarfs in the field and in the young open clusters sigma Orionis and the Pleiades. Evidence for variability with RMS amplitudes (in the I band) of 0.01 to 0.055 magnitudes on timescales of 0.4 to 100 hours is discovered in half of these objects. Power spectral analysis using the CLEAN algorithm was performed to search for evidence of periodic variability. Some objects show strong periodicities at around a few hours, which could be due to rotational modulation of the light curve by surface features. However, several objects do not have any significant periodicities to explain their variability. The vsini values of a similar population of objects makes it very likely that our time sampling was sensitive to the expected range of rotation periods, and simulations show that we would have detected these if they were caused by long-lived surface features. We argue that this absence of periodicity is due to the evolution of the brightness, and presumably also the physical size, of surface features on timescales of a few to a few tens of hours. This is supported in the case of 2M1145 for which two light curves have been obtained one year apart and show no common periodicity. The surface features could plausibly be photospheric dust clouds or magnetically-induced spots. The recently observed decline in chromospheric activity for late type M and L dwarfs hints towards the former explanation for at least our later-type objects. Furthermore, our sample suggests that variability to be more common in objects later than M9, indicating that the variability may be related to dust formation. One light curve shows a brief, but significant, dip, which could be a short-lived feature or possibly an eclipse by a companion. (abridged)Comment: Accepted to Astronomy & Astrophysic

Knowledge and exposure to complementary and alternative medicine in paediatric doctors: a questionnaire survey

<p>Abstract</p> <p>Background</p> <p>Complementary and alternative medicines are increasingly used by the general population. A survey was conducted to ascertain the knowledge of Complementary and Alternative Medicines (CAMs) amongst paediatric physicians, and whether seniority increases the likelihood of its use being considered in consultations, or of families discussing it.</p> <p>Methods</p> <p>Anonymous survey of general paediatric doctors in a large inner-city district general hospital (DGH) and tertiary children's centre (TC) using a questionnaire. Statistical analysis was calculated using Minitab.</p> <p>Results</p> <p>43/49 (88%) questionnaires were returned correctly. 13 (30%, CI 17 – 46%) doctors had personally used CAMs. 24 (56%, CI 40 – 71%) of their families had used CAMs. 13 (30%, CI 17 – 46%) had received formal CAMs education. 21 (49%, CI 40 – 71%) could name a total of 5 types of CAMs. Consultants were significantly more likely to ask about CAM use than middle-grades and juniors (p < 0.05, CI 48 – 93%, 35 – 90%, 8 – 33% respectively) and have had a clinical encounter where they felt it was significant. 32 (74%, CI 59 – 86%) of the clinicians had been asked about CAMs. 33 (77%, CI 61 – 88%) of doctors had successful CAM use reported to them, and 20 (47%, CI 31 – 62%) had failure of CAMs reported to them.</p> <p>Conclusion</p> <p>CAM use is relatively common in paediatric doctors and their families. They have received little formal CAMs education. Consultants were more likely than juniors to ask about CAM use and have had a clinical encounter where it played a significant part. Around half of all doctors irrespective of grade have been asked about CAMs in a clinical encounter.</p