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1.
Nat Chem ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38744915

RESUMO

Homobimetallic dimetallocenes exhibiting two identical metal atoms sandwiched between two η5 bonded cyclopentadienyl rings is a narrow class of compounds, with representative examples being dizincocene and diberyllocene. Here we report the synthesis and structural characterization of a heterobimetallic dimetallocene, accessible through heterocoupling of lithium and aluminylene fragments with pentaisopropylcyclopentadienyl ligands. The Al-Li bond features a high ionic character and profits from attractive dispersion interactions between the isopropyl groups of the cyclopentadienyl ligands. A key synthetic step is the isolation of a cyclopentadienylaluminylene monomer, which also enables the structural characterization of this species. In addition to their structural authentication by single-crystal X-ray diffraction analysis, both compounds were characterized by multinuclear NMR spectroscopy in solution and in the solid state. Furthermore, reactivity studies of the lithium-aluminium heterobimetallic dimetallocene with an N-heterocyclic carbene and different heteroallenes were performed and show that the Al-Li bond is easily cleaved.

2.
PLOS Glob Public Health ; 4(5): e0003177, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691565

RESUMO

Congenital anomalies in Sub-Sahara Africa (SSA) are understudied despite the significant pediatric health burden. This retrospective longitudinal hospital-based study evaluated the records of 326 inpatient children under the age of two years with congenital anomalies at Bugando Medical Centre, a tertiary referral hospital in northwestern Tanzania. Classical logistic regression was used in the analysis of congenital malformation of muscles, gastrointestinal malformation, oral facial clefts, neural tube defects, and skeletal malformations. A modified poisson regression was used to model risk factors for Central Nervous System (CNS) hydrocephalus and congenital heart disease (CHD). A majority (78.8%) of children included in the study were less than six months of age. Nearly half (48.8%) were diagnosed with CHD followed by CNS hydrocephalus (10.4%) and congenital malformation of muscles (8.9%). Babies whose mothers missed periconceptual folic acid supplementation had 83% higher risk of hydrocephalus (aPR = 1.83, 95% CI = 1.11-1.96) and 78% higher for CHD (aPR = 1.78, 95% CI = 1.31-1.94). Male children had 1.67 higher odds of muscular congenital malformations (aOR = 1.67, 95% CI = 1.23-1.89). Less than 37 gestational age had a 1.86 higher odds of muscular congenital malformations (aOR = 1.86, 95% CI = 1.53-3.66). Our study highlights the critical need for folic acid supplementation and establishes a need for a registry and the potential for mapping.

3.
ACS Org Inorg Au ; 4(2): 188-222, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38585514

RESUMO

The present review summarizes important aspects of the crystal chemistry of ytterbium-based intermetallic compounds along with a selection of their outstanding physical properties. These originate in many cases from the ytterbium valence. Different valence states are possible here, divalent (4f14), intermediate-valent, or trivalent (4f13) ytterbium, resulting in simple diamagnetic, Pauli or Curie-Weiss paramagnetic, or valence fluctuating behavior. Especially, some of the Yb3+ intermetallics have gained deep interest due to their Kondo or heavy Fermion ground states. We have summarized their property investigations using magnetic and transport measurements, specific heat data, NMR, ESR, and Mössbauer spectroscopy, elastic and inelastic neutron scattering, and XAS data as well as detailed thermoelectric measurements.

4.
Inorg Chem ; 63(18): 8180-8193, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38652050

RESUMO

Laves phases exhibit a plethora of different structures and a multitude of physical properties. Investigations in the ternary system Hf-V-Al led to the discovery of numerous members of the solid solution Hf(V1-xAlx)2, which adopt the hexagonal MgZn2 type (C14) for medium to high amounts of Al (x = 0.2-1) and the cubic MgCu2 type (C15) for small Al amounts (x = 0.05-0.1). While all members exhibit Pauli-paramagnetic behavior due to the absence of localized magnetic moments, the V-rich cubic member Hf(V0.95Al0.05)2 additionally exhibits a superconducting state below TC = 7.6(1) K. All synthesized compounds were characterized by powder X-ray diffraction, and selected samples were furthermore investigated by 27Al solid-state magic-angle spinning (MAS) NMR. HfAl2 exhibits two Al resonances, one rather sharp and one significantly broadened signal, in line with the crystal structure and respective coordination environments. The members of the solid solution exhibit extremely broadened resonances due to the mixing of V and Al on the same crystallographic sites. For nominal Hf(V0.125Al0.875)2, however, two distinct sharp NMR signals were observed. This contrasts with the description of a solid solution. Therefore, single-crystal X-ray studies were conducted, showing that Hf(V0.125Al0.875)2 really is an ordered compound with the sum formula Hf4VAl7 (P3̅m1), which exhibits an, thus far, unknown superstructure of MgZn2.

5.
J Psychoactive Drugs ; : 1-10, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341606

RESUMO

Interest in psychedelics and their possible therapeutic potential has been growing. Metaphysical belief theory asserts that these benefits stem from the adoption of comforting supernatural beliefs following a mystical experience. By contrast, predictive self-binding theory suggests that the beneficial outcomes of psychedelics are primarily driven by psychological insights. The present study tests these competing models of psychedelic benefits. We conducted a quantitative content analysis on unsolicited self-reports of psychedelic users available on Erowid.org, to examine the potential relations between psychological insight, ego dissolution, therapeutic intent, altered metaphysical belief, and enduring health outcomes. We randomly selected, coded, and analyzed two hundred forty psychedelic experience reports from the website. Path analysis using structural equation modeling showed that psychological insight, not metaphysical beliefs, uniquely predicted beneficial outcomes. Moreover, beneficial outcomes' positive relation to ego dissolution and therapeutic intent was fully mediated by psychological insight. These findings support the predictive self-binding model over the metaphysical belief model.

6.
PLOS Glob Public Health ; 4(2): e0002923, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38416749

RESUMO

Often with minimal formal training and protections, informal welders face significant occupational health and safety (OSH) risks. This cross-sectional study of 219 adult informal welders at 70 informal welding sites in Mwanza City, Tanzania aimed to: 1) capture knowledge and awareness of occupational risks and safety precautions, training, and self-reported work-related injuries and illness and 2) observe worker use of personal protective equipment and site safety. We hypothesized that knowledge, awareness, and site inspections would improve use of PPE and that improved safety and site inspections would reduce self-reported injuries and illness. A generalized linear model (GLM) was used to model all relationships. Robust standard error estimation was used to avoid overestimation of parameters. Having a post-secondary education (aß = 1.01, 95% CI: 0.962, 1.061; p = 0. 0679), having training in OSH (aß = 0.927, 95% CI: 0.872, 0.984, p = 0.014), increased knowledge of occupational risks (aß = 1.305, 95% CI: 1.143, 1.491; p<0.001), and knowledge of safety measures (aß = 1.112, 95% CI: 0.881, 1.404; p = 0.372) increased PPE use by 1%, 7.3%, 30.5%, and 11.2% respectively. Workers who used PPE were less likely to experience fire explosions (AOR = 0.149, 95% CI: 0.029, 0.751; p = 0.02), radiation exposure (AOR = 0.097, 95% CI: 0.016, 0.579, p = 0.01) or electric shocks (AOR = 0.012; 95% CI: 0.001, 0.11, p<0.001). Having increased knowledge of safety practices also decreased the odds of fire explosions (AOR = 0.075, 95% CI: 0.018, 0.314; p<0.001). Those with higher knowledge of occupational risk (aß = 1.57, 95% CI: 1.404, 1.756; p<0.001) and safety measures (aß = 1.628, 95% CI: 1.34, 1.978; p<0.001) were more likely to have more positive attitudes towards safety practices. Our findings suggest that comprehensive targeted interventions including increased knowledge of occupational risks, safety practices, and occupational health law through training, along with enforcement and inspection by government officials, would benefit the environmental and occupational health for informal welders.

7.
PLOS Glob Public Health ; 4(2): e0002958, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38394051

RESUMO

Neither artisanal and small-scale gold mining (ASGM) or geophagy practices have received substantial attention related to blood lead levels despite the well documented deleterious effects of lead. This cross-sectional analytical study aimed to document the risk of lead exposure from geophagy and mining-related occupational activities for pregnant women. The study recruited 1056 pregnant women (883 in an ASGM area and 173 in a non-ASGM area) between April 2015 -April 2017. Generalized Linear Model with an identity link function was used to model the association between blood lead levels (BLLs) and geophagy practices and involvement in gold mining. The prevalence of geophagy was 36.2% (95% CI: 33.6, 39.4%) and 6.3% engaged in mining as a primary occupation. Practicing geophagy increased BLLs by 22% (ß = 1.22, 95% CI: 1.116, 1.309, p<0.0001). Living in a gold mining area increased BLLs by 33.4% (ß = 1.334, 95% CI: 1.2, 1.483, p<0.0001). Having mining as a primary occupation increased BLLs by 1.3% ß = 1.013, 95% CI: 0.872, 1.176, p = 0.869) even though the association was not statistically significant. Socioeconomic wealth quantile (ß = 1.037, 95% CI: 1.021, 1.054, p<0.001) increased blood lead levels by 3.7%. Developing a comprehensive inventory capturing sources of community-level lead exposure is essential. Further, increasing public health campaigns and education are crucial to limit geophagy practices and to minimize work in gold mining activities during pregnancy.

8.
PLOS Glob Public Health ; 4(2): e0002951, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38421969

RESUMO

Solid waste has been a major problem particularly in Sub-Saharan Africa countries as it has been increasing in several years. One of the methods employed in solid waste management is street sweeping which is done by street sweepers. Street sweepers are being predisposed to respiratory and non-respiratory infection like eye infection, skin infection and musculoskeletal disorders. This analytical cross-sectional study enrolled a total of 233 street sweepers to assess perceived occupational health risks, particulate matters (i.e., PM2.5, PM5 and PM10 measured in (mg/m3)) dust and noise exposure levels in decibel units-dB(A), and utilization of protective personnel equipment among street sweepers in Mwanza city, Northern Tanzania. Modified poison regression was used to determine the association between exposures variables (i.e., sociodemographic, and socioeconomic factors) and outcomes ((i.e., noise dose level and particulate matters))). More than half (50.2%) of the participants were aged between 46-80 years. Their Median age was 46(IQR: 28-59) years. Large percent (63.1%) of the participants reported that their working environment have high health risks. The Median concentrations of the noise dose and particulates matters were 85.4 (IQR = 76.4-92.3) for noise dose, 13426 (IQR = 9637-17632) for PM2.5, 5522 (IQR = 2453-7679) for PM5, and 2310(IQR = 1263-3201). The Median concentrations of the noise dose and particulates matters were 85.4 (IQR = 76.4-92.3) for noise dose in decibel units dB(A); 13426 (IQR = 9637-17632) for PM2.5; 5522 (IQR = 2453-7679) for PM5; and 2310(IQR = 1263-3201) for PM10. Individual Street sweepers in Mwanza city are highly exposed to noise dose and fine particulate matters at levels above the reference values for human of 85dB(A) and 5mg/m3 respectively, making it a public health issue that requires holistic public health measures.

9.
SLAS Discov ; 29(1): 34-39, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37573009

RESUMO

Hepatic metabolic stability is a crucial determinant of oral bioavailability and plasma concentrations of a compound, and its measurement is important in early drug discovery. Preliminary metabolic stability estimations are commonly performed in liver microsomal fractions. At the National Center for Advancing Translational Sciences, a single-point assay in rat liver microsomes (RLM) is employed for initial stability assessment (Tier I) and a multi-point detailed stability assay is employed as a Tier II assay for promising compounds. Although the in vitro and in vivo metabolic stability of compounds typically exhibit good correlation, conflicting results may arise in certain cases. While investigating one such instance, we serendipitously found vendor-related RLM differences in metabolic stability and metabolite formation, which had implications for in vitro and in vivo correlations. In this study, we highlight the importance of considering vendor differences in hepatic metabolic stability data and discuss strategies to avoid these pitfalls.


Assuntos
Descoberta de Drogas , Fígado , Ratos , Animais , Fígado/metabolismo , Descoberta de Drogas/métodos , Microssomos Hepáticos/metabolismo , Disponibilidade Biológica , Avaliação Pré-Clínica de Medicamentos/métodos
10.
SLAS Technol ; 29(1): 100116, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37923083

RESUMO

Transepithelial electrical resistance (TEER) is a widely used technique for quantifying the permeability of epithelial and endothelial cell layers. However, traditional methods of measuring TEER are limited to single timepoint measurements and can subject cells to an altered environment during the measurement. Here, we assessed the validity of TEER measurements by the ECIS TEER96 device, which is designed to take continuous TEER measurements of a cell culture system in a standard laboratory incubator. We found that the instrument accurately measures TEER across TEER values ranging from 10 to 2050 Ω*cm2 and is more accurate than the manual epithelial voltohmmeter electrode at high TEER values. Furthermore, the high-resolution measurements provided by the device allowed for a unique insight into the mechanisms and kinetics of cells in vitro. To demonstrate the continuous measurement capability of the device, we tracked the formation of an MDCKI cell monolayer until TEER plateaued. Furthermore, we treated Caco-2 monolayers with different concentrations of DMSO and the antimicrobial and surfactant compound benzethonium chloride to measure disruptions to barrier integrity. Treatment of both compounds resulted in concentration-dependent loss of barrier integrity. Our results suggest that the ECIS TEER96 device is a reliable and convenient option for measuring TEER in cell cultures and can provide valuable insights into the behavior of cells in vitro. This technology will be especially useful for increasing throughput of drug permeability assays, inflammation studies, and gaining better understanding of disease states in a cell culture system.


Assuntos
Técnicas de Cultura de Células , Células Endoteliais , Humanos , Células CACO-2 , Impedância Elétrica
11.
BMC Pregnancy Childbirth ; 23(1): 854, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38087268

RESUMO

BACKGROUND: Artisanal and small-scale gold mining (ASGM) areas potentially pose increased exposure to arsenic and mercury through community contamination, occupations at gold mines, and/or geophagy when soil is locally sourced. This study examined the effects of geophagy, a deliberate soil eating practice, along with community and occupational exposures in ASGM areas on urinary arsenic and blood mercury levels among pregnant women in the Mining and Health Longitudinal Cohort in northwestern Tanzania. METHODS: Data on maternal arsenic and mercury levels were captured for 1056 pregnant women using an unprovoked morning urine samples and dried blood spots respectively. We used a step-wise generalized linear regression model to retain the most relevant covariates for the model. A generalized linear regression model with identity link function was used to predict the effect of geophagy practices on arsenic and mercury levels separately. The model was adjusted using sociodemographic correlates, including maternal age, education level, whether respondents lived in mining or non-mining area, years of residence, marital status, maternal occupation, individual partner's education, and occupational, and socioeconomic status. RESULTS: In the adjusted regression model, eating soil during pregnancy increased arsenic concentration by almost 23% (ß = 1.229, 95% CI: 1.094, 1.38, p < 0.001) and living in mining areas had a 21.2% (ß = 1.212; 95% CI: 1.039,1.414, p = 0.014) increased risk. Geophagy significantly increased mercury levels by 13.3% (ß = 1.133, 95% CI: 1.022, 1.257, p = 0.018). Living in areas with ASGM activities was associated with a 142% (ß = 2.422, 95% CI: 2.111, 2.776, p < 0.0001) increase in blood mercury. CONCLUSION: Geophagy practices increased urinary arsenic and blood mercury levels in pregnant women, which was especially true for arsenic when living in areas with ASGM activities. Working in mining = increased risk for blood mercury levels. Community-based environmental health policies should address reductions in occupational and community exposures, along with strategic geophagy reduction interventions.


Assuntos
Arsênio , Mercúrio , Humanos , Feminino , Gravidez , Arsênio/análise , Ouro , Tanzânia , Pica , Mercúrio/análise , Vitaminas , Mineração , Solo
12.
Afr J Disabil ; 12: 1270, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38059153

RESUMO

Background: Persons with disabilities generally face greater challenges in accessing healthcare and interventions compared with the general population. Malaria is one of the diseases that can seriously affect individuals with disabilities, as it requires early diagnosis and prompt treatment. Objective: This study explores the extent to which locally available malaria services and interventions are inclusive of persons with disabilities and identifies associated access barriers. Method: A qualitative case study focusing on social, cultural and health system factors associated with the inclusion of persons with disabilities in malaria services was conducted in Kigoma Region, western Tanzania. Thematic analysis of emerging themes identified barriers affecting access to locally available malaria services and interventions. Results: Inclusion of persons with disabilities in planning, implementation and reporting of health issues in different malaria programmes was reported to be limited. Persons with disabilities were unable to access malaria services because of different barriers such as the distance of the service provision sites, communication and information issues and a lack of financial resources. Conclusion: Persons with disabilities are widely excluded from malaria care provision across the entire health services paradigm, impacting access and utilisation to this vulnerable population. Barriers to malaria service access among persons with disabilities were physical, attitudinal, financial and informational. Contribution: The findings of this study identify that malaria intervention stakeholders need to take a holistic approach and fully involve individuals with disabilities at all levels and scope of malaria service planning and provision.

13.
Front Cardiovasc Med ; 10: 1251817, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38155990

RESUMO

Introduction: Hypertension (HTN) among adolescents is common in high-income countries, and leads to increased premature cardiovascular diseases (CVD). In sub-Saharan Africa (SSA), the prevalence of HTN among adolescents, associated risk factors and CVD complications are not well-described. Such data is needed for planning public health programs to prevent premature CVD in SSA. Methods: We systematically searched 5 databases (MEDLINE, Embase, Google Scholar, Web of Science, and African Index Medicus) from their establishment to December 2021. Key search terms were: adolescent, arterial hypertension, and names of the 48 countries in SSA. We used Covidence® to manage the search results. The review was registered in the Open Science Framework (OSF) https://osf.io/p5sbt/. Results: We identified 4,008 articles out of which we screened 3,088 abstracts, and reviewed 583 full-text articles. We finally included 92 articles that were published between 1968 to December 2021. The majority were cross-sectional studies (80%) and conducted in school settings (78%). The risk of bias was low for 59 studies (64.1%), moderate for 29 studies (31.5%), and high for 4 studies (4.3%). Overall, the prevalence of HTN varied widely from 0.18% to 34.0% with a median (IQR) of 5.5% (3.1%, 11.1%). It was relatively higher in studies using automated blood pressure (BP) devices, and in studies defining HTN using thresholds based on percentile BP distribution for one's height, age, and sex. In addition, the prevalence of HTN was significantly higher in studies from Southern Africa region of SSA and positively correlated with the year of publication. Across studies, traditional risk factors such as age, sex, body mass index, and physical inactivity, were commonly found to be associated with HTN. In contrast, non-traditional risk factors related to poverty and tropical diseases were rarely assessed. Only three studies investigated the CVD complications related to HTN in the study population. Conclusion: The prevalence of HTN among adolescents in SSA is high indicating that this is a major health problem. Data on non-traditional risk factors and complications are scarce. Longitudinal studies are needed to clearly define the rates, causes, and complications of HTN. Systematic Review Registration: https://osf.io/p5sbt/, identifier (10.17605/OSF.IO/P5SBT).

14.
Front Pharmacol ; 14: 1291246, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38108064

RESUMO

Efficiently circumventing the blood-brain barrier (BBB) poses a major hurdle in the development of drugs that target the central nervous system. Although there are several methods to determine BBB permeability of small molecules, the Parallel Artificial Membrane Permeability Assay (PAMPA) is one of the most common assays in drug discovery due to its robust and high-throughput nature. Drug discovery is a long and costly venture, thus, any advances to streamline this process are beneficial. In this study, ∼2,000 compounds from over 60 NCATS projects were screened in the PAMPA-BBB assay to develop a quantitative structure-activity relationship model to predict BBB permeability of small molecules. After analyzing both state-of-the-art and latest machine learning methods, we found that random forest based on RDKit descriptors as additional features provided the best training balanced accuracy (0.70 ± 0.015) and a message-passing variant of graph convolutional neural network that uses RDKit descriptors provided the highest balanced accuracy (0.72) on a prospective validation set. Finally, we correlated in vitro PAMPA-BBB data with in vivo brain permeation data in rodents to observe a categorical correlation of 77%, suggesting that models developed using data from PAMPA-BBB can forecast in vivo brain permeability. Given that majority of prior research has relied on in vitro or in vivo data for assessing BBB permeability, our model, developed using the largest PAMPA-BBB dataset to date, offers an orthogonal means to estimate BBB permeability of small molecules. We deposited a subset of our data into PubChem bioassay database (AID: 1845228) and deployed the best performing model on the NCATS Open Data ADME portal (https://opendata.ncats.nih.gov/adme/). These initiatives were undertaken with the aim of providing valuable resources for the drug discovery community.

15.
PLOS Glob Public Health ; 3(10): e0002079, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37851636

RESUMO

Iron and folic acid (IFA) supplementation to reduce anemia is key for improving substantial lost disability adjusted life years (DALYs) for adolescent girls. This study assessed the impact of weekly IFA supplementation (WIFAS) on cognitive ability among adolescent girls in the Simiyu Region in northernwestern Tanzania. This cross-sectional comparative evaluation study of 770 adolescent girls (396 -WIFAS supplemented; 374 -not supplemented) evaluated the association between WIFAS and cognitive ability through a face-to-face survey and cognitive ability assessment using standardized tests (Span-forward Test, Span-backward Test and Maze Test). Using a modified Poisson regression, we controlled for the geographic setting (urban vs rural), availability of potable water and feeding programs in schools, age and school level of adolescent girls, parental status, main parental economic activities, and the number of teachers. Participants were between the ages of 11 and 19 years, with more than half (57%) between 12-15 years of age. Those with WIFAS had higher cognitive ability (Span-forward scores, χ2 = 46.34% p <0.001; Span-forward, χ2 = 46.34% p <0.001; and Global Composite Cognitive Performance (GCCP), χ2 = 32.52% p<0.001). Among the IFA supplemented adolescent girls, secondary school level had a significantly higher score with respect to Span-backward (aPR = 1.43, 95% CI = 1.06-1.62); Span-forward ability (aPR = 1.26, 95% CI = 1.04-1.53) and Maze Test ability (aPR = 1.12, 95% CI = 1.01-1.25) as compared to their counterpart in primary school level. Individual adolescent girls with WIFAS and living with both parents performed much better on the Span-backward Test (aPR = 1.22, 95% CI = 1.07-1.68) as compared to those living with relatives and/or orphans. The presence of potable water program among the WIFAS schools resulted in a higher Span-backward ability (aPR = 1.34, 95% CI = 1.03-1.89); and GCCP (aPR = 1.27, 95% CI = 1.03-1.75). Adolescent girls from WIFAS schools with feeding program had higher Span-forward (aPR = 1.38, 95% CI = 1.03-1.63) ability as well as a higher Maze Test (aPR = 1.15, 95% CI = 1.07-1.26) score. The present study provides compelling evidence that WIFAS is positively associated with higher cognitive ability among adolescent girls. Nevertheless, IFA interventions are still rare in communities across Tanzania.

16.
Biomed Pharmacother ; 168: 115178, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37890204

RESUMO

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that affects lysosome-related organelles, often leading to fatal pulmonary fibrosis (PF). The search for a treatment for HPS pulmonary fibrosis (HPSPF) is ongoing. S-MRI-1867, a dual cannabinoid receptor 1 (CB1R)/inducible nitric oxide synthase (iNOS) inhibitor, has shown great promise for the treatment of several fibrotic diseases, including HPSPF. In this study, we investigated the in vitro ADME characteristics of S-MRI-1867, as well as its pharmacokinetic (PK) properties in mice, rats, dogs, and monkeys. S-MRI-1867 showed low aqueous solubility (< 1 µg/mL), high plasma protein binding (>99%), and moderate to high metabolic stability. In its preclinical PK studies, S-MRI-1867 exhibited moderate to low plasma clearance (CLp) and high steady-state volume of distribution (Vdss) across all species. Despite the low solubility and P-gp efflux, S-MRI-1867 showed great permeability and metabolic stability leading to a moderate bioavailability (21-60%) across mouse, rat, dog, and monkey. Since the R form of MRI-1867 is CB1R-inactive, we investigated the potential conversion of S-MRI-1867 to R-MRI-1867 in mice and found that the chiral conversion was negligible. Furthermore, we developed and validated a PBPK model that adequately fits the PK profiles of S-MRI-1867 in mice, rats, dogs, and monkeys using various dosing regimens. We employed this PBPK model to simulate the human PK profiles of S-MRI-1867, enabling us to inform human dose selection and support the advancement of this promising drug candidate in the treatment of HPSPF.


Assuntos
Síndrome de Hermanski-Pudlak , Fibrose Pulmonar , Humanos , Ratos , Camundongos , Animais , Cães , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/tratamento farmacológico , Síndrome de Hermanski-Pudlak/tratamento farmacológico , Projetos de Pesquisa
17.
Heliyon ; 9(10): e20489, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37810841

RESUMO

This paper examined the vulnerability of travelers to kidnapping, abduction and armed robbery attacks and in some extreme cases, death along Nigeria's highways. Insecurity on the nation's highways became a contemporary criminological discourse following the emergence of new strands of criminality like militancy, terrorism, kidnapping, herdsmen-farmers violence, communal conflicts and banditry. Nigerian highways have become the major operational hotspots for criminals who harass, terrorize, and traumatize travelers at will. With the ever-rising insecurity on Nigerian highways, the military and paramilitary offensives deployed by the Federal Government have not yielded the desired results culminating in the description of government's inertia as a form of state slumber. Data for this study were sourced from a content analysis of reported violent highway crimes by credible mainstream Nigerian newspapers, spanning a period of one year, from July 2020 to July 2021. Adopting the Social Disorganization Theory, the study indicated that the worrisome nature of insecurity on Nigeria's highways resulting in the high rate of abduction and murder of people of diverse military, professional, socioeconomic and political backgrounds has engendered a sense of helplessness, trauma and vulnerability among Nigerian road travelers. The paper recommends the de-centralization of Nigeria Police Force structure to create State Police that will encourage and electrify effective and better people oriented patrolling and management of insecurities on the Nigerian highways.

18.
Int J Cardiol Cardiovasc Risk Prev ; 18: 200197, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37521244

RESUMO

Background: In patients with established heart failure (HF) low total cholesterol levels associate with worse prognosis. Evidence concerning the impact of Low-density lipoprotein cholesterol (LDL-c) in HF is scarce. We aimed to evaluate the prognostic impact of LDL-c in patients with HF, both with and without diabetes mellitus (DM). Methods: We retrospectively analyzed outpatients with chronic HF with systolic dysfunction followed in our HF clinic from January/2012 to May/2018. LDL-c was calculated using the Friedewald's formula. Patients without a complete lipid profile were excluded. The endpoint under analysis was all-cause mortality. Patients were followed until January/2021. A Cox-regression analysis was used to study the prognostic impact of LDL-c. The LDL-c cut-off used was 100 mg/dL (mean value). Analysis was stratified according to the coexistence of DM. Multivariate models were built adjusting for age, sex, coronary artery disease, atherosclerotic non-coronary artery disease, arterial hypertension, smoking status, statin use, severity of systolic dysfunction, creatinine clearance and evidence-based therapy. Results: We studied 522 chronic HF patients, mean age was 70 years, 66.5% males. Severe systolic dysfunction was present in 42.7%, 30.5% had coronary heart disease, 60.5% had arterial hypertension, 41.6% had DM. A total of 92.0% were treated with beta blocker, 87.5% with an ACEi/ARB and 29.1% with a MRA. During a median follow-up of 53 (interquartile range 33-73) months, 235 (45%) patients died. Patients with LDL-c ≤100 mg/dL presented increased multivariate-adjusted risk of all-cause mortality: HR = 1.58 (95% CI: 1.08-2.30), p = 0.02. When patients were stratified according to DM, LDL-c ≤100 mg/dL was independently associated with increased death risk - HR = 1.55 (95% CI:1.05-2.30), p = 0.03 in patients without DM; in patients with DM no association was detected - multivariate-adjusted HR = 1.18 (95% CI: 0.77-1.80), p = 0.44. Conclusion: Non-DM HF patients with LDL-c>100 mg/dL have a 35% reduction in the mortality risk when compared with those with lower values. The "cholesterol paradox" in HF also applies to LDL-c in non-DM patients.

19.
Inorg Chem ; 62(24): 9602-9617, 2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-37267603

RESUMO

During attempts to synthesize Sc4AuAl in the cubic Gd4RhIn-type structure, the solid solution Sc2Au0.5Al0.5 in the PbCl2-type structure formed instead. Subsequently, the solid solution Sc2Au1-xAlx was investigated with respect to its existence range along with the structure types formed for different compositions with x = 0, 0.25, 0.5, 0.75, and 1. According to X-ray powder diffraction studies, Sc2Al and nominal Sc2Au0.25Al0.75 crystallized in the hexagonal Ni2In-type structure (P63/mmc), while Sc2Au0.5Al0.5, Sc2Au0.75Al0.25, and Sc2Au were found to crystallize in the orthorhombic PbCl2-type structure (Pnma). The crystal structures of Sc2Au and Sc2Au0.59(1)Al0.41(1) were refined from single-crystal data (Sc2Au: a = 648.0(1), b = 467.2(1), c = 835.2(2) pm, wR2 = 0.0382, 535 F2 values, 25 variables; Sc2Au0.59(1)Al0.41(1): a = 632.48(5), b = 472.16(3), c = 848.67(6) pm, wR2 = 0.0484, 540 F2 values, 21 variables). Contamination with air during the synthesis of Sc2Au led to the discovery of a compound adopting the cubic W4Co2C-type structure (stuffed cubic Ti2Ni type). Using Sc2O3 as a defined oxygen source led to samples with high amounts of Sc4Au2O1-x. All intermetallic compounds exhibited Pauli paramagnetic behavior in the investigated temperature range of 2.1 to 300 K, and no superconductivity was observed at low temperatures and low fields. Sc2Au and Sc2Al were investigated by 27Al and 45Sc solid-state NMR investigations. For Sc2Al, one signal was found in the 27Al NMR spectra in line with the crystal structure; however, an extremely negative resonance shift of δ = -673 ppm was observed. In both compounds, two Sc resonances were observed, in line with the proposed crystal structure. Finally, it was observed that the stability of Sc2Au in air is limited. This was investigated via thermal analysis and (temperature-dependent) powder X-ray diffraction. DFT calculations helped in assessing charge analysis, electronic properties, and chemical bonding.

20.
Front Neuroendocrinol ; 70: 101069, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37149229

RESUMO

Hypothalamic melanin-concentrating hormone (MCH) neurons participate in many fundamental neuroendocrine processes. While some of their effects can be attributed to MCH itself, others appear to depend on co-released neurotransmitters. Historically, the subject of fast neurotransmitter co-release from MCH neurons has been contentious, with data to support MCH neurons releasing GABA, glutamate, both, and neither. Rather than assuming a position in that debate, this review considers the evidence for all sides and presents an alternative explanation: neurochemical identity, including classical neurotransmitter content, is subject to change. With an emphasis on the variability of experimental details, we posit that MCH neurons may release GABA and/or glutamate at different points according to environmental and contextual factors. Through the lens of the MCH system, we offer evidence that the field of neuroendocrinology would benefit from a more nuanced and dynamic interpretation of neurotransmitter identity.


Assuntos
Hormônios Hipotalâmicos , Hormônios Hipotalâmicos/metabolismo , Hormônios Hipotalâmicos/farmacologia , Hormônios Hipofisários/farmacologia , Hormônios Hipofisários/fisiologia , Neurônios/metabolismo , Melaninas/farmacologia , Melaninas/fisiologia , Hipotálamo/metabolismo , Ácido Glutâmico/farmacologia , Ácido Glutâmico/fisiologia , Neurotransmissores , Ácido gama-Aminobutírico
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