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The global prevalence of diabetes is steadily rising, with an estimated 537 million adults affected by diabetes in 2021, projected to reach 783 million by 2045. A severe consequence of diabetes is the development of painful diabetic neuropathy (PDN), afflicting approximately one in every three diabetic patients and significantly compromising their quality of life. Current pharmacotherapies for PDN provide inadequate pain relief for many patients, underscoring the need for novel treatments that are both safe and effective. The Sigma 1 Receptor (S1R) is a ligand-operated chaperone protein that resides at the mitochondria-associated membrane of the endoplasmic reticulum. The S1R has been shown to play crucial roles in regulating cellular processes implicated in pain modulation. This study explores the potential of PW507, a novel S1R antagonist, as a therapeutic candidate for PDN. PW507 exhibited promising in vitro and in vivo properties in terms of ADME, toxicity, pharmacokinetics, and safety. In preclinical rat models of Streptozotocin-induced diabetic neuropathy, PW507 demonstrated significant efficacy in alleviating mechanical allodynia and thermal hyperalgesia following both acute and chronic (2-week) administration, without inducing tolerance and visual evidence of toxicity. To the best of our knowledge, this is the first report to evaluate an S1R antagonist in STZ-induced diabetic rats following both acute and 2-week chronic administration, offering compelling preclinical evidence for the potential use of PW507 as a promising therapeutic option for PDN.
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We assessed the relative importance of environmental filtering and dispersal limitation in structuring foliage- and ground-dwelling arthropod communities in central North Carolina. We hypothesized that differences in both local environment and dispersal distance between sites would predict differences in community composition, but that dispersal distance would be more important for ground arthropods than for foliage arthropods. We used variance partitioning to quantify the relative explanatory power of differences in the local environment and dispersal distance between sampling plots. For foliage arthropods, the full set of predictors explained 37-39% of the variance in community dissimilarity, while the full set of predictors explained 42-56% of the variance for ground arthropods. Environmental predictors alone consistently explained more variance in community dissimilarity than geographic predictors alone for ground arthropods, but the variance explained by each predictor set alone varied for foliage arthropods depending on the metric of community dissimilarity. Examining communities of multiple arthropod groups across the same spatial gradient highlights the scale-dependence of these processes and illustrates how variation in the environment can alter the relative abundance of specialist and generalist taxa.
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Artrópodos , Artrópodos/fisiología , Animales , North Carolina , Biodiversidad , Ecosistema , CiudadesRESUMEN
The Chemical Assessment of Surfaces and Air (CASA) study aimed to understand how chemicals transform in the indoor environment using perturbations (e.g., cooking, cleaning) or additions of indoor and outdoor pollutants in a well-controlled test house. Chemical additions ranged from individual compounds (e.g., gaseous ammonia or ozone) to more complex mixtures (e.g., a wildfire smoke proxy and a commercial pesticide). Physical perturbations included varying temperature, ventilation rates, and relative humidity. The objectives for CASA included understanding (i) how outdoor air pollution impacts indoor air chemistry, (ii) how wildfire smoke transports and transforms indoors, (iii) how gases and particles interact with building surfaces, and (iv) how indoor environmental conditions impact indoor chemistry. Further, the combined measurements under unperturbed and experimental conditions enable investigation of mitigation strategies following outdoor and indoor air pollution events. A comprehensive suite of instruments measured different chemical components in the gas, particle, and surface phases throughout the study. We provide an overview of the test house, instrumentation, experimental design, and initial observations - including the role of humidity in controlling the air concentrations of many semi-volatile organic compounds, the potential for ozone to generate indoor nitrogen pentoxide (N2O5), the differences in microbial composition between the test house and other occupied buildings, and the complexity of deposited particles and gases on different indoor surfaces.
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Measurements of sphingolipid metabolism are most accurately performed by LC-MS. However, this technique is expensive, not widely accessible, and without the use of specific probes, it does not provide insight into metabolic flux through the pathway. Employing the fluorescent ceramide analogue NBD-C6-ceramide as a tracer in intact cells, we developed a comprehensive HPLC-based method that simultaneously measures the main nodes of ceramide metabolism in the Golgi. Hence, by quantifying the conversion of NBD-C6-ceramide to NBD-C6-sphingomyelin, NBD-C6-hexosylceramides, and NBD-C6-ceramide-1-phosphate (NBD-C1P), the activities of Golgi resident enzymes sphingomyelin synthase 1, glucosylceramide synthase, and ceramide kinase (CERK) could be measured simultaneously. Importantly, the detection of NBD-C1P allowed us to quantify CERK activity in cells, a usually difficult task. By applying this method, we evaluated the specificity of commonly used sphingolipid inhibitors and discovered that 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, which targets glucosylceramide synthase, and fenretinide (4HPR), an inhibitor for dihydroceramide desaturase, also suppress CERK activity. This study demonstrates the benefit of an expanded analysis of ceramide metabolism in the Golgi, and it provides a qualitative and easy-to-implement method.
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Despite declines in transportation emissions, urban North America and Europe still face unhealthy air pollution levels. This has challenged conventional understanding of the sources of their volatile organic compound (VOC) precursors. Using airborne flux measurements to map emissions of a wide range of VOCs, we demonstrate that biogenic terpenoid emissions contribute ~60% of emitted VOC OH reactivity, ozone, and secondary organic aerosol formation potential in summertime Los Angeles and that this contribution strongly increases with temperature. This implies that control of nitrogen oxides is key to reducing ozone formation in Los Angeles. We also show some anthropogenic VOC emissions increase with temperature, which is an effect not represented in current inventories. Air pollution mitigation efforts must consider that climate warming will strongly change emission amounts and composition.
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Technical and clinical developments have raised challenging questions about the concept and practice of brain death, culminating in recent calls for revision of the Uniform Determination of Death Act (UDDA), which established a whole brain standard for neurologic death. Proposed changes range from abandoning the concept of brain death altogether to suggesting that current clinical practice simply should be codified as the legal standard for determining death by neurologic criteria (even while acknowledging that significant functions of the whole brain might persist). We propose a middle ground, clarifying why whole brain death is a conceptually sound standard for declaring death, and offering procedural suggestions for increasing certainty that this standard has been met. Our approach recognizes that whole brain death is a functional, not merely anatomic, determination, and incorporates an understanding of the difficulties inherent in making empirical judgments in medicine. We conclude that whole brain death is the most defensible standard for determining neurologic death-philosophically, biologically, and socially-and ought to be maintained.
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Muerte Encefálica , Encéfalo , Humanos , Muerte Encefálica/diagnósticoRESUMEN
Because humans spend about one-third of their time asleep in their bedrooms and are themselves emission sources of volatile organic compounds (VOCs), it is important to specifically characterize the composition of the bedroom air that they experience during sleep. This work uses real-time indoor and outdoor measurements of volatile organic compounds (VOCs) to examine concentration enhancements in bedroom air during sleep and to calculate VOC emission rates associated with sleeping occupants. Gaseous VOCs were measured with proton-transfer reaction time-of-flight mass spectrometry during a multiweek residential monitoring campaign under normal occupancy conditions. Results indicate high emissions of nearly 100 VOCs and other species in the bedroom during sleeping periods as compared to the levels in other rooms of the same residence. Air change rates for the bedroom and, correspondingly, emission rates of sleeping-associated VOCs were determined for two bounding conditions: (1) air exchange between the bedroom and outdoors only and (2) air exchange between the bedroom and other indoor spaces only (as represented by measurements in the kitchen). VOCs from skin oil oxidation and personal care products were present, revealing that many emission pathways can be important occupant-associated emission factors affecting bedroom air composition in addition to direct emissions from building materials and furnishings.
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Contaminación del Aire Interior , Sueño , Compuestos Orgánicos Volátiles , Compuestos Orgánicos Volátiles/análisis , Contaminación del Aire Interior/análisis , Humanos , Monitoreo del Ambiente , Vivienda , Contaminantes Atmosféricos/análisisRESUMEN
BACKGROUND: Having a haematological condition can adversely affect the quality of life (QoL) of family members/partners of patients. It is important to measure this often ignored burden in order to implement appropriate supportive interventions. OBJECTIVE: To measure current impact of haematological conditions on the QoL of family members/partners of patients, using the Family Reported Outcome Measure-16 (FROM-16). METHODS: A cross-sectional study, recruited online through patient support groups, involved UK family members/partners of people with haematological conditions completing the FROM-16. RESULTS: 183 family members/partners (mean age = 60.5 years, SD = 13.2; females = 62.8%) of patients (mean age = 64.1, SD = 12.8; females = 46.4%) with 12 haematological conditions completed the FROM-16. The FROM-16 mean total score was 14.0 (SD = 7.2), meaning 'a moderate effect on QoL'. The mean FROM-16 scores of family members of people with multiple myeloma (mean = 15.8, SD = 6.3, n = 99) and other haematological malignancies (mean = 13.9, SD = 7.8, n = 29) were higher than of people with pernicious anaemia (mean = 10.7, SD = 7.5, n = 47) and other non-malignant conditions (mean = 11, SD = 7.4, n = 56, p < .01). Over one third (36.1%, n = 183) of family members experienced a 'very large effect' (FROM-16 score>16) on their quality of life. CONCLUSIONS: Haematological conditions, in particular those of malignant type, impact the QoL of family members/partners of patients. Healthcare professionals can now, using FROM-16, identify those most affected and should consider how to provide appropriate holistic support within routine practice.
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Anemia Perniciosa , Familia , Mieloma Múltiple , Calidad de Vida , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/epidemiología , Mieloma Múltiple/psicología , Masculino , Estudios Transversales , Femenino , Persona de Mediana Edad , Familia/psicología , Anciano , Anemia Perniciosa/diagnóstico , Anemia Perniciosa/epidemiología , Anemia Perniciosa/etiología , Costo de Enfermedad , Encuestas y Cuestionarios , Adulto , Enfermedades Hematológicas/epidemiología , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/etiología , Enfermedades Hematológicas/psicologíaRESUMEN
Indoor sources of air pollution worsen indoor and outdoor air quality. Thus, identifying and reducing indoor pollutant sources would decrease both indoor and outdoor air pollution, benefit public health, and help address the climate crisis. As outdoor sources come under regulatory control, unregulated indoor sources become a rising percentage of the problem. This American Thoracic Society workshop was convened in 2022 to evaluate this increasing proportion of indoor contributions to outdoor air quality. The workshop was conducted by physicians and scientists, including atmospheric and aerosol scientists, environmental engineers, toxicologists, epidemiologists, regulatory policy experts, and pediatric and adult pulmonologists. Presentations and discussion sessions were centered on 1) the generation and migration of pollutants from indoors to outdoors, 2) the sources and circumstances representing the greatest threat, and 3) effective remedies to reduce the health burden of indoor sources of air pollution. The scope of the workshop was residential and commercial sources of indoor air pollution in the United States. Topics included wood burning, natural gas, cooking, evaporative volatile organic compounds, source apportionment, and regulatory policy. The workshop concluded that indoor sources of air pollution are significant contributors to outdoor air quality and that source control and filtration are the most effective measures to reduce indoor contributions to outdoor air. Interventions should prioritize environmental justice: Households of lower socioeconomic status have higher concentrations of indoor air pollutants from both indoor and outdoor sources. We identify research priorities, potential health benefits, and mitigation actions to consider (e.g., switching from natural gas to electric stoves and transitioning to scent-free consumer products). The workshop committee emphasizes the benefits of combustion-free homes and businesses and recommends economic, legislative, and education strategies aimed at achieving this goal.
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Contaminantes Atmosféricos , Contaminación del Aire Interior , Contaminación del Aire , Humanos , Niño , Estados Unidos , Contaminación del Aire Interior/efectos adversos , Contaminación del Aire Interior/prevención & control , Contaminación del Aire Interior/análisis , Gas Natural , Monitoreo del Ambiente , Contaminación del Aire/efectos adversos , Contaminación del Aire/prevención & control , Contaminación del Aire/análisis , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Material Particulado/análisisRESUMEN
The chemical composition of incense-generated organic aerosol in residential indoor air has received limited attention in Western literature. In this study, we conducted incense burning experiments in a single-family California residence during vacancy. We report the chemical composition of organic fine particulate matter (PM2.5), associated emission factors (EFs), and gas-particle phase partitioning for indoor semivolatile organic compounds (SVOCs). Speciated organic PM2.5 measurements were made using two-dimensional gas chromatography coupled with high-resolution time-of-flight mass spectrometry (GC×GC-HR-ToF-MS) and semivolatile thermal desorption aerosol gas chromatography (SV-TAG). Organic PM2.5 EFs ranged from 7 to 31 mg g-1 for burned incense and were largely comprised of polar and oxygenated species, with high abundance of biomass-burning tracers such as levoglucosan. Differences in PM2.5 EFs and chemical profiles were observed in relation to the type of incense burned. Nine indoor SVOCs considered to originate from sources other than incense combustion were enhanced during incense events. Time-resolved concentrations of these SVOCs correlated well with PM2.5 mass (R2 > 0.75), suggesting that low-volatility SVOCs such as bis(2-ethylhexyl)phthalate and butyl benzyl phthalate partitioned to incense-generated PM2.5. Both direct emissions and enhanced partitioning of low-volatility indoor SVOCs to incense-generated PM2.5 can influence inhalation exposures during and after indoor incense use.
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Contaminantes Atmosféricos , Contaminación del Aire Interior , Compuestos Orgánicos Volátiles , Contaminantes Atmosféricos/análisis , Contaminación del Aire Interior/análisis , Material Particulado/análisis , Compuestos Orgánicos Volátiles/análisis , California , Aerosoles/análisisRESUMEN
BACKGROUND: The FROM-16 is a generic family quality of life (QoL) instrument that measures the QoL impact of patients' disease on their family members/partners. The study aimed to assess the responsiveness of FROM-16 to change and determine Minimal Important Change (MIC). METHODS: Responsiveness and MIC for FROM-16 were assessed prospectively with patients and their family members recruited from outpatient departments of the University Hospital Wales and University Hospital Llandough, Cardiff, United Kingdom. Patients completed the EQ-5D-3L and a global severity question (GSQ) online at baseline and at 3-month follow-up. Family members completed FROM-16 at baseline and a Global Rating of Change (GRC) in addition to FROM-16 at follow-up. Responsiveness was assessed using the distribution-based (effect size-ES, standardized response mean -SRM) and anchor-based (area under the receiver operating characteristics curve ROC-AUC) approaches and by testing hypotheses on expected correlation strength between FROM-16 change score and patient assessment tools (GSQ and EQ-5D). Cohen's criteria were used for assessing ES. The AUC ≥ 0.7 was considered a good measure of responsiveness. MIC was calculated using anchor-based (ROC analysis and adjusted predictive modelling) and distribution methods based on standard deviation (SD) and standard error of the measurement (SEM). RESULTS: Eighty-three patients with 15 different health conditions and their relatives completed baseline and follow-up questionnaires and were included in the responsiveness analysis. The mean FROM-16 change over 3 months = 1.43 (SD = 4.98). The mean patient EQ-5D change over 3 months = -0.059 (SD = 0.14). The responsiveness analysis showed that the FROM-16 was responsive to change (ES = 0.2, SRM = 0.3; p < 0.01). The ES and SRM of FROM-16 change score ranged from small (ES = 0.2; SRM = 0.3) for the distribution-based method to large (ES = 0.8, SRM = 0.85) for anchor-based methods. The AUC value was above 0.7, indicating good responsiveness. There was a significant positive correlation between the FROM-16 change scores and the patient's disease severity change scores (p < 0.001). The MIC analysis was based on data from 100 family members of 100 patients. The MIC value of 4 was suggested for FROM-16. CONCLUSIONS: The results of this study confirm the longitudinal validity of FROM-16 which refers to the degree to which an instrument is able to measure change in the construct to be measured. The results yield a MIC value of 4 for FROM-16. These psychometric attributes of the FROM-16 instrument are useful in both clinical research as well as clinical practice.
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Medición de Resultados Informados por el Paciente , Calidad de Vida , Humanos , Encuestas y Cuestionarios , Reino Unido , GalesRESUMEN
The capacity to leverage high resolution mass spectrometry (HRMS) with transient isotope labeling experiments is an untapped opportunity to derive insights on context-specific metabolism, that is difficult to assess quantitatively. Tools are needed to comprehensively mine isotopologue information in an automated, high-throughput way without errors. We describe a tool, Stable Isotope-assisted Metabolomics for Pathway Elucidation (SIMPEL), to simplify analysis and interpretation of isotope-enriched HRMS datasets. The efficacy of SIMPEL is demonstrated through examples of central carbon and lipid metabolism. In the first description, a dual-isotope labeling experiment is paired with SIMPEL and isotopically nonstationary metabolic flux analysis (INST-MFA) to resolve fluxes in central metabolism that would be otherwise challenging to quantify. In the second example, SIMPEL was paired with HRMS-based lipidomics data to describe lipid metabolism based on a single labeling experiment. Available as an R package, SIMPEL extends metabolomics analyses to include isotopologue signatures necessary to quantify metabolic flux.
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Carbono , Metabolómica , Isótopos de Carbono/química , Espectrometría de Masas/métodos , Metabolómica/métodosRESUMEN
(1) Background: Intracortical microelectrodes (IMEs) are an important part of interfacing with the central nervous system (CNS) and recording neural signals. However, recording electrodes have shown a characteristic steady decline in recording performance owing to chronic neuroinflammation. The topography of implanted devices has been explored to mimic the nanoscale three-dimensional architecture of the extracellular matrix. Our previous work used histology to study the implant sites of non-recording probes and showed that a nanoscale topography at the probe surface mitigated the neuroinflammatory response compared to probes with smooth surfaces. Here, we hypothesized that the improvement in the neuroinflammatory response for probes with nanoscale surface topography would extend to improved recording performance. (2) Methods: A novel design modification was implemented on planar silicon-based neural probes by etching nanopatterned grooves (with a 500 nm pitch) into the probe shank. To assess the hypothesis, two groups of rats were implanted with either nanopatterned (n = 6) or smooth control (n = 6) probes, and their recording performance was evaluated over 4 weeks. Postmortem gene expression analysis was performed to compare the neuroinflammatory response from the two groups. (3) Results: Nanopatterned probes demonstrated an increased impedance and noise floor compared to controls. However, the recording performances of the nanopatterned and smooth probes were similar, with active electrode yields for control probes and nanopatterned probes being approximately 50% and 45%, respectively, by 4 weeks post-implantation. Gene expression analysis showed one gene, Sirt1, differentially expressed out of 152 in the panel. (4) Conclusions: this study provides a foundation for investigating novel nanoscale topographies on neural probes.