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1.
Soc Sci Med ; 351: 116955, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38762996

RESUMO

The intersectional Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA) approach is gaining prominence in health sciences and beyond, as a robust quantitative method for identifying intersectional inequalities in a range of individual outcomes. However, it has so far not been applied to longitudinal data, despite the availability of such data, and growing recognition that intersectional social processes and determinants are not static, unchanging phenomena. Drawing on intersectionality and life course theories, we develop a longitudinal version of the intersectional MAIHDA approach, allowing the analysis not just of intersectional inequalities in static individual differences, but also of life course trajectories. We discuss the conceptualization of intersectional groups in this context: how they are changeable over the life course, appropriate treatment of generational differences, and relevance of the age-period-cohort identification problem. We illustrate the approach with a study of mental health using United Kingdom Household Longitudinal Study data (2009-2021). The results reveal important differences in trajectories between generations and intersectional strata, and show that trajectories are partly multiplicative but mostly additive in their intersectional inequalities. This article provides an important and much needed methodological contribution, enabling rigorous quantitative, longitudinal, intersectional analyses in social epidemiology and beyond.

2.
Soc Sci Med ; 350: 116898, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38705077

RESUMO

Intersectional Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA) has been welcomed as a new gold standard for quantitative evaluation of intersectional inequalities, and it is being rapidly adopted across the health and social sciences. In their commentary "What does the MAIHDA method explain?", Wilkes and Karimi (2024) raise methodological concerns with this approach, leading them to advocate for the continued use of conventional single-level linear regression models with fixed-effects interaction parameters for quantitative intersectional analysis. In this response, we systematically address these concerns, and ultimately find them to be unfounded, arising from a series of subtle but important misunderstandings of the MAIHDA approach and literature. Since readers new to MAIHDA may share confusion on these points, we take this opportunity to provide clarifications. Our response is organized around four important clarifications: (1) At what level are the additive main effect variables defined in intersectional MAIHDA models? (2) Do MAIHDA models have problems with collinearity? (3) Why does the Variance Partitioning Coefficient (VPC) tend to be small, and the Proportional Change in Variance (PCV) tend to be large in MAIHDA? and (4) What are the goals of MAIHDA analysis?


Assuntos
Análise Multinível , Humanos , Fatores Socioeconômicos , Disparidades nos Níveis de Saúde
3.
Artigo em Inglês | MEDLINE | ID: mdl-38710871

RESUMO

When David Kemp discovered "spontaneous ear noise" in 1978, it opened up a whole new perspective on how the cochlea works. The continuous tonal sound emerging from most healthy human ears, now called spontaneous otoacoustic emissions or SOAEs, was an unmistakable sign that our hearing organ must be considered an active detector, not just a passive microphone, just as Thomas Gold had speculated some 30 years earlier. Clearly, something is oscillating as a byproduct of that sensitive inbuilt detector, but what exactly is it? Here, we give a chronological account of efforts to model SOAEs as some form of oscillator, and at intervals, we illustrate key concepts with numerical simulations. We find that after many decades there is still no consensus, and the debate extends to whether the oscillator is local, confined to discrete local sources on the basilar membrane, or global, in which an assembly of micro-mechanical elements and basilar membrane sections, coupled by inner ear fluid, interact over a wide region. It is also undecided whether the cochlear oscillator is best described in terms of the well-known Van der Pol oscillator or the less familiar Duffing or Hopf oscillators. We find that irregularities play a key role in generating the emissions. This paper is not a systematic review of SOAEs and their properties but more a historical survey of the way in which various oscillator configurations have been applied to modelling human ears. The conclusion is that the difference between the local and global approaches is not clear-cut, and they are probably not mutually exclusive concepts. Nevertheless, when one sees how closely human SOAEs can be matched to certain arrangements of oscillators, Gold would no doubt say we are on the right track.

5.
SSM Popul Health ; 26: 101664, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38690117

RESUMO

Intersectional multilevel analysis of individual heterogeneity and discriminatory accuracy (I-MAIHDA) is an innovative approach for investigating inequalities, including intersectional inequalities in health, disease, psychosocial, socioeconomic, and other outcomes. I-MAIHDA and related MAIHDA approaches have conceptual and methodological advantages over conventional single-level regression analysis. By enabling the study of inequalities produced by numerous interlocking systems of marginalization and oppression, and by addressing many of the limitations of studying interactions in conventional analyses, intersectional MAIHDA provides a valuable analytical tool in social epidemiology, health psychology, precision medicine and public health, environmental justice, and beyond. The approach allows for estimation of average differences between intersectional strata (stratum inequalities), in-depth exploration of interaction effects, as well as decomposition of the total individual variation (heterogeneity) in individual outcomes within and between strata. Specific advice for conducting and interpreting MAIHDA models has been scattered across a burgeoning literature. We consolidate this knowledge into an accessible conceptual and applied tutorial for studying both continuous and binary individual outcomes. We emphasize I-MAIHDA in our illustration, however this tutorial is also informative for understanding related approaches, such as multicategorical MAIHDA, which has been proposed for use in clinical research and beyond. The tutorial will support readers who wish to perform their own analyses and those interested in expanding their understanding of the approach. To demonstrate the methodology, we provide step-by-step analytical advice and present an illustrative health application using simulated data. We provide the data and syntax to replicate all our analyses.

6.
Brain Behav Immun ; 119: 494-506, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38657842

RESUMO

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks in 32 male rats subjected to a 35 % ethanol liquid diet or a control liquid diet (n = 8 per group). The study evaluated PCSK9 expression, LDL receptor (LDLR) expression, oxidative stress, and neuroinflammatory markers in brain tissues. Chronic ethanol exposure increased PCSK9 expression in the brain, while alirocumab treatment significantly upregulated neuronal LDLR and reduced oxidative stress in neurons and brain vasculature (3-NT, p22phox). Alirocumab also mitigated ethanol-induced microglia recruitment in the cortex and hippocampus (Iba1). Additionally, alirocumab decreased the expression of pro-inflammatory cytokines and chemokines (TNF, CCL2, CXCL3) in whole brain tissue and attenuated the upregulation of adhesion molecules in brain vasculature (ICAM1, VCAM1, eSelectin). This study presents novel evidence that alirocumab diminishes oxidative stress and modifies neuroimmune interactions in the brain elicited by chronic ethanol exposure. Further investigation is needed to elucidate the mechanisms by which PCSK9 signaling influences the brain in the context of chronic ethanol exposure.

7.
Microbiology (Reading) ; 170(3)2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38488830

RESUMO

Sialic acid (Sia) transporters are critical to the capacity of host-associated bacteria to utilise Sia for growth and/or cell surface modification. While N-acetyl-neuraminic acid (Neu5Ac)-specific transporters have been studied extensively, little is known on transporters dedicated to anhydro-Sia forms such as 2,7-anhydro-Neu5Ac (2,7-AN) or 2,3-dehydro-2-deoxy-Neu5Ac (Neu5Ac2en). Here, we used a Sia-transport-null strain of Escherichia coli to investigate the function of members of anhydro-Sia transporter families previously identified by computational studies. First, we showed that the transporter NanG, from the Glycoside-Pentoside-Hexuronide:cation symporter family, is a specific 2,7-AN transporter, and identified by mutagenesis a crucial functional residue within the putative substrate-binding site. We then demonstrated that NanX transporters, of the Major Facilitator Superfamily, also only transport 2,7-AN and not Neu5Ac2en nor Neu5Ac. Finally, we provided evidence that SiaX transporters, of the Sodium-Solute Symporter superfamily, are promiscuous Neu5Ac/Neu5Ac2en transporters able to acquire either substrate equally well. The characterisation of anhydro-Sia transporters expands our current understanding of prokaryotic Sia metabolism within host-associated microbial communities.


Assuntos
Ácido N-Acetilneuramínico , Ácido N-Acetilneuramínico/análogos & derivados , Transportadores de Ânions Orgânicos , Simportadores , Ácido N-Acetilneuramínico/química , Simportadores/genética , Simportadores/metabolismo , Bactérias/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo
9.
Cell Mol Gastroenterol Hepatol ; 17(1): 29-40, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37703945

RESUMO

BACKGROUND & AIMS: Observational studies have linked lipid-lowering drug targets pro-protein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) with adverse liver outcomes; however, liver disease incidence varies across diverse populations, and the long-term hepatic impact of these lipid-lowering drugs among non-white Europeans remains largely unknown. METHODS: We use single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR loci from genome-wide association study data of low-density lipoprotein cholesterol in 4 populations (East Asian [EAS], South Asian [SAS], African [AFR], and European [EUR]) to perform drug-target Mendelian randomization investigating relationships between PCSK9 and HMGCR inhibition and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin. RESULTS: Analyses of PCSK9 instruments, including functional variants R46L and E670G, failed to find evidence for relationships of low-density lipoprotein cholesterol lowering via PCSK9 variants and adverse effects on ALT, AST, GGT, or ALP among the cohorts. PCSK9 inhibition was associated with increased direct bilirubin levels in EUR (ß = 0.089; P value = 5.69 × 10-6) and, nominally, in AFR (ß = 0.181; P value = .044). HMGCR inhibition was associated with reduced AST in SAS (ß = -0.705; P value = .005) and, nominally, reduced AST in EAS (ß = -0.096; P value = .03), reduced ALP in EUR (ß = -2.078; P value = .014), and increased direct bilirubin in EUR (ß = 0.071; P value = .032). Sensitivity analyses using genetic instruments derived from circulating PCSK9 protein levels, tissue-specific PCSK9 expression, and HMGCR expression were in alignment, strengthening causal inference. CONCLUSIONS: We did not find ALT, AST, GGT, or ALP associated with genetically proxied PCSK9 and HMGCR inhibition across ancestries. We identified possible relationships in several ancestries between PCSK9 and increased direct and total bilirubin and between HMGCR and reduced AST. These findings support long-term safety profiles and low hepatotoxic risk of PCSK9 and HMGCR inhibition in diverse populations.


Assuntos
Pró-Proteína Convertase 9 , Subtilisina , Humanos , Pró-Proteína Convertase 9/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Fígado , Bilirrubina , Lipoproteínas LDL , Colesterol , Lipídeos , Hidroximetilglutaril-CoA Redutases/genética
10.
Nat Commun ; 14(1): 6614, 2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37857603

RESUMO

Shallow magmatic reservoirs that produce measurable volcanic surface deformation are often considered as discrete independent systems. However, petrological analyses of erupted products suggest that these may be the shallowest expression of extensive, heterogeneous magmatic systems that we show may be interconnected. We analyse time series of satellite-radar-measured displacements at Western Galápagos volcanoes from 2017 to 2022 and revisit historical displacements. We demonstrate that these volcanoes consistently experience correlated displacements during periods of heightened magma supply to the shallow crust. We rule out changes in static stress, shallow hydraulic connections, and data processing and analysis artefacts. We propose that episodic surges of magma into interconnected magmatic systems affect neighbouring volcanoes, simultaneously causing correlations in volcanic uplift and subsidence. While expected to occur globally, such processes are uniquely observable at the dense cluster of Western Galápagos volcanoes, thanks to the high rate of surface displacements and the wealth of geodetic measurements.

11.
Lancet Reg Health West Pac ; 41: 100912, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37780636

RESUMO

Background: In response to increasing overweight and obesity, the Philippine government introduced a tax on sweetened beverages (SBs) in 2018. Evidence suggests that the beverage industry influenced the final tax design, making it more favourable for industry than the initially proposed bill. This study aimed to compare the relative health and economic benefits of the proposed SB tax with the implemented SB tax. Methods: Philippine dietary consumption data were combined with price elasticity data from Mexico and data from Australia adapted to the Philippine context to estimate reductions in SB purchases and changes in body mass index (BMI) following the implementation of the tax. A multi-state, multiple-cohort Markov model was used to estimate the change in health-adjusted life years (HALYs) due to reduction in the epidemiology of obesity-related diseases, healthcare cost savings and government taxation revenue, resulting from both the proposed and implemented tax policies, over the lifetime of the 2018 Philippine population. Findings: The proposed and implemented taxes were modelled to be dominant (cost-saving and improving health). Intervention costs were modelled to be PHP305.2 million (M) (approximately US$6M). Compared to the proposed tax, the implemented tax was modelled to result in a 43.0% smaller reduction in targeted beverage intake (51.1 ml/person/day vs. 89.7 ml/person/day), a 43.5% smaller reduction in BMI (0.35 kg/m2 vs. 0.62 kg/m2), 39.7% fewer HALYs gained (2,503,118 vs. 4,149,030), 39.9% fewer healthcare cost savings (PHP16.4 billion (B) vs. PHP27.3B), and 27.7% less government taxation revenue (PHP426.3B vs. PHP589.4B). Interpretation: While the implemented tax in the Philippines will benefit population health, it is likely to yield less benefit than the proposed tax. The influence of the food and beverage industry on policy processes has the potential to lessen the benefits of population NCD prevention policies. Funding: OH was supported to conduct this research by an Australian Government Research Training Program Stipend Scholarship. The funding body had no role in data collection and analysis, or manuscript preparation.

12.
bioRxiv ; 2023 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-37786726

RESUMO

The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify 3 clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 & ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons.

13.
J Sci Med Sport ; 26(8): 410-414, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37541867

RESUMO

OBJECTIVES: The aims were to (1) prospectively observe the incidence of bone marrow oedema in asymptomatic adult male domestic professional cricketers during a season and evaluate its relationship to the development of lumbar bone stress injury and (2) further understand the practicalities of implementing a Magnetic Resonance Imaging-based screening program to prevent lumbar bone stress injury in New Zealand cricket. DESIGN: Prospective observational cohort. METHODS: Adult male pace bowlers received 6-weekly pre-planned Magnetic Resonance Imaging scans over a single season to determine the presence and intensity of bone marrow oedema in the posterior vertebral arches of the lumbar spine. The participants bowling volume and back pain levels were monitored prospectively. RESULTS: 22 participants (mean age 25.3 years (range 20-32 years)) completed all 4 scans. Ten participants had a prior history of lumbar bone stress injury. Ten participants (45 %, 95 % confidence interval 24-68 %) had bone marrow oedema evident on at least one scan, with 9 (41 %) participants recording a bone marrow oedema intensity ≥ 2 and 5 (23 %) participants demonstrated an intensity ≥ 3. During the study one participant was diagnosed with a lumbar bone stress reaction. No participants developed a lumbar bone stress fracture. CONCLUSIONS: Due to the lower incidence of lumbar bone stress injuries in adult bowlers coupled with uncertainty over appropriate threshold values for bone marrow oedema intensity, implementation of a resource intense screening program aimed at identifying adult domestic cricketers at risk of developing a lumbar bone stress injury is not currently supported.


Assuntos
Traumatismos em Atletas , Lesões nas Costas , Críquete , Fraturas da Coluna Vertebral , Humanos , Masculino , Adulto , Adulto Jovem , Traumatismos em Atletas/diagnóstico por imagem , Traumatismos em Atletas/epidemiologia , Traumatismos em Atletas/etiologia , Projetos Piloto , Medula Óssea , Nova Zelândia/epidemiologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/lesões , Imageamento por Ressonância Magnética/efeitos adversos , Edema/diagnóstico por imagem
14.
Nat Aging ; 3(8): 1020-1035, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37550455

RESUMO

The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor ('mvAge'). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1. Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge (P value = 8.41 × 10-5). Similarly, genetically proxied thiazolidinediones (P value = 3.50 × 10-10), proprotein convertase subtilisin/kexin 9 inhibition (P value = 1.62 × 10-6), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.


Assuntos
Estudo de Associação Genômica Ampla , Envelhecimento Saudável , Fenótipo , Longevidade
15.
Elife ; 122023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37490401

RESUMO

Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here, we investigate the role of interneurons that continue to express NPY (NPY-INs) in the adult mouse spinal cord. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen-evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY-IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.


Assuntos
Neuralgia , Neuropeptídeo Y , Camundongos , Animais , Neuropeptídeo Y/genética , Corno Dorsal da Medula Espinal/patologia , Prurido/patologia , Interneurônios/fisiologia , Medula Espinal/fisiologia
16.
Medicina (Kaunas) ; 59(7)2023 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-37511999

RESUMO

Background and Objectives: This narrative review of the literature explores the effect of body temperature on hearing. In particular, its focus is on extended high frequency (EHF) hearing-the range beyond the standard audiometric limit of 8 kHz. Such high frequencies are the first to be affected by noise-induced hearing loss, and so monitoring them can provide an early warning sign of incipient damage. Materials and Methods: This review builds on a personal literature database of 216 references covering the general topic of EHF hearing; the procedure was to then identify papers related to whole-body or cochlear cooling. A starting point was the paper by Munjal et al. who in 2013 reported changes of up to 15-30 dB in the EHF thresholds of subjects who had undergone cardiopulmonary bypass (CBP) surgery, which typically involves mild to moderate hypothermia-cooling of the blood-to reduce cellular oxygen demand and minimise tissue damage. Results: Reviewing the surrounding literature, we find that although CBP surgery by itself can impair hearing thresholds, lower body and cochlear temperatures in general provide neuroprotective effects. A connection between hearing loss and CBP surgery has been periodically documented, but the mechanism behind it has yet to be conclusively identified. Conclusions: The observations reviewed here tend to confirm the otoprotective effects of cooling. We consider that the high sensitivity of EHF thresholds to temperature is a major factor that has not been sufficiently recognised, although it has important implications for otological research and practice. Two important inferences are that, first, monitoring EHF thresholds might have considerable value in audiology, and, second, that lowering temperature of the cochlea during cochlear implantation might provide substantially better hearing preservation, as some researchers have already suggested.


Assuntos
Implante Coclear , Surdez , Perda Auditiva , Humanos , Audição , Cóclea/cirurgia
17.
Sci Rep ; 13(1): 11561, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37464016

RESUMO

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.


Assuntos
Nociceptores , Medula Espinal , Animais , Camundongos , Calbindina 2 , Células do Corno Posterior , Medula Espinal/fisiologia , Sinapses
18.
bioRxiv ; 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37333120

RESUMO

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.

19.
Neurosci Biobehav Rev ; 149: 105155, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37019248

RESUMO

The gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and its protein product have been widely studied for their role in cholesterol and lipid metabolism. PCSK9 increases the rate of metabolic degradation of low-density lipoprotein receptors, preventing the diffusion of low-density lipoprotein (LDL) from plasma into cells and contributes to high lipoprotein-bound cholesterol levels in the plasma. While most research has focused on the regulation and disease relevance of PCSK9 to the cardiovascular system and lipid metabolism, there is a growing body of evidence that PCSK9 plays a crucial role in pathogenic processes in other organ systems, including the central nervous system. PCSK9's impact on the brain is not yet fully understood, though several recent studies have sought to illuminate its impact on various neurodegenerative and psychiatric disorders, as well as its connection with ischemic stroke. Cerebral PCSK9 expression is low but is highly upregulated during disease states. Among others, PCSK9 is known to play a role in neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, Alzheimer's Disease, Alcohol Use Disorder, and stroke. The PCSK9 gene contains several polymorphisms, including both gain-of-function and loss-of-function mutations which profoundly impact normal PCSK9 signaling and cholesterol metabolism. Gain-of-function mutations lead to persistent hypercholesterolemia and poor health outcomes, while loss-of-function mutations generally lead to hypocholesterolemia and may serve as a protective factor against diseases of the liver, cardiovascular system, and central nervous system. Recent genomic studies have sought to identify the end-organ effects of such mutations and continue to identify evidence of a much broader role for PCSK9 in extrahepatic organ systems. Despite this, there remain large gaps in our understanding of PCSK9, its regulation, and its effects on disease risk outside the liver. This review, which incorporates data from a wide range of scientific disciplines and experimental paradigms, is intended to describe PCSK9's role in the central nervous system as it relates to cerebral disease and neuropsychiatric disorders, and to examine the clinical potential of PCSK9 inhibitors and genetic variation in the PCSK9 gene on disease outcomes, including neurological and neuropsychiatric disease.


Assuntos
Lipoproteínas LDL , Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Lipoproteínas LDL/metabolismo , Encéfalo/metabolismo , Subtilisinas/metabolismo
20.
J Equine Vet Sci ; 126: 104492, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37072071

RESUMO

Acquisition of magnetic resonance images of the equine limb is still sometimes conducted under general anaesthesia. Despite low-field systems allow the use of standard anaesthetic equipment, possible interferences of the extensive electronic componentry of advanced anaesthetic machines on image quality is unknown. This prospective, blinded, cadaver study investigated the effects of seven standardised conditions (Tafonius positioned as in clinical cases, Tafonius on the boundaries of the controlled area, anaesthetic monitoring only, Mallard anaesthetic machine, Bird ventilator, complete electronic silence in the room (negative control), source of electronic interference [positive control]) on image quality through the acquisition of 78 sequences using a 0.31T equine MRI scanner. Images were graded with a 4-point scoring system, where 1 denoted absence of artefacts and 4 major artefacts requiring repetition in a clinical setting. A lack of STIR fat suppression was commonly reported (16/26). Ordinal logistic regression showed no statistically significant differences in image quality between the negative control and either the non-Tafonius or the Tafonius groups (P = 0.535 and P = 0.881, respectively), and with the use of Tafonius compared to the other anaesthetic machines (P = 0.578). The only statistically significant differences in scores were observed between the positive control and the non-Tafonius (P = 0.006) and the Tafonius groups (P = 0.017). Our findings suggest that anaesthetic machines and monitoring do not appear to affect MRI scan quality and support the use of Tafonius during acquisition of images with a 0.31T MRI system in a clinical context.


Assuntos
Anestesia , Anestésicos , Doenças dos Cavalos , Cavalos , Animais , Artefatos , Estudos Prospectivos , Imageamento por Ressonância Magnética/veterinária , Cadáver , Anestesia/veterinária
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