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1.
Environ Res Lett ; 19(8): 081002, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39007070

RESUMO

Households that burn biomass in inefficient open fires-a practice that results in $1.6 trillion in global damages from health impacts and climate-altering emissions yearly-are often unable to access cleaner alternatives, like gas, which is widely available but unaffordable, or electricity, which is unattainable for many due to insufficient supply and reliability of electricity services. Governments are often reluctant to make gas affordable. We argue that condemnation of all fossil fuel subsidies is short-sighted and does not adequately consider subsidizing gas for cooking as a potential strategy to improve public health and reduce greenhouse gas emissions.

2.
CHEST Crit Care ; 2(2)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38993934

RESUMO

Cardiogenic shock (CS) is a heterogenous syndrome broadly characterized by inadequate cardiac output leading to tissue hypoperfusion and multisystem organ dysfunction that carries an ongoing high mortality burden. The management of CS has advanced rapidly, especially with the incorporation of temporary mechanical circulatory support (tMCS) devices. A thorough understanding of how to approach a patient with CS and to select appropriate monitoring and treatment paradigms is essential in modern ICUs. Timely characterization of CS severity and hemodynamics is necessary to optimize outcomes, and this may be performed best by multidisciplinary shock-focused teams. In this article, we provide a review of CS aimed to inform both the cardiology-trained and non-cardiology-trained intensivist provider. We briefly describe the causes, pathophysiologic features, diagnosis, and severity staging of CS, focusing on gathering key information that is necessary for making management decisions. We go on to provide a more detailed review of CS management principles and practical applications, with a focus on tMCS. Medical management focuses on appropriate medication therapy to optimize perfusion-by enhancing contractility and minimizing afterload-and to facilitate decongestion. For more severe CS, or for patients with decompensating hemodynamic status despite medical therapy, initiation of the appropriate tMCS increasingly is common. We discuss the most common devices currently used for patients with CS-phenotyping patients as having left ventricular failure, right ventricular failure, or biventricular failure-and highlight key available data and particular points of consideration that inform tMCS device selection. Finally, we highlight core components of sedation and respiratory failure management for patients with CS.

3.
bioRxiv ; 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38979341

RESUMO

Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with manifestations spanning molecular, neuroanatomical, and behavioral changes. Astrocytes contribute to FXS pathogenesis and show hundreds of dysregulated genes and proteins; targeting upstream pathways mediating astrocyte changes in FXS could therefore be a point of intervention. To address this, we focused on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, and found this lessens audiogenic seizure severity in FXS mice. To ask how this occurs on a molecular level, we performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted proteins in FXS astrocytes, with these alterations no longer present when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses present in FXS auditory cortex. Thus, astrocytes contribute to FXS molecular and functional phenotypes, and targeting astrocytes can mitigate FXS symptoms.

4.
medRxiv ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38978662

RESUMO

Traumatic brain injury (TBI) is a risk factor for neurodegeneration and cognitive decline, yet the underlying pathophysiologic mechanisms are incompletely understood. This gap in knowledge is in part related to the lack of analytic methods to account for cortical lesions in prior neuroimaging studies. The objective of this study was to develop a lesion detection tool and apply it to an investigation of longitudinal changes in brain structure among individuals with chronic TBI. We identified 24 individuals with chronic moderate-to-severe TBI enrolled in the Late Effects of TBI (LETBI) study who had cortical lesions detected by T1-weighted MRI at two time points. Initial MRI scans were performed more than 1-year post-injury and follow-up scans were performed 3.1 (IQR=1.7) years later. We leveraged FreeSurfer parcellations of T1-weighted MRI volumes and a recently developed super-resolution technique, SynthSR, to identify cortical lesions in this longitudinal dataset. Trained raters received the data in a randomized order and manually corrected the automated lesion segmentation, yielding a final lesion mask for each scan at each timepoint. Lesion volume significantly increased between the two time points with a median volume change of 3.2 (IQR=5.9) mL (p<0.001), and the increases significantly exceeded the possible variance in lesion volume changes due to manual tracing errors (p < 0.001). Lesion volume significantly expanded longitudinally in 23 of 24 subjects, with all FDR corrected p-values ≤ 0.02. Inter-scan duration was not associated with the magnitude of lesion growth. We also demonstrated that the semi-automated tool showed a high level of accuracy compared to "ground truth" manual lesion segmentation. Semi-automated lesion segmentation is feasible in TBI studies and creates opportunities to elucidate mechanisms of post-traumatic neurodegeneration.

5.
Microbiol Spectr ; : e0431123, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38980026

RESUMO

Electrofulguration (EF) of areas of chronic cystitis in women with antibiotic-recalcitrant recurrent urinary tract infections (RUTIs) can result in improvement of their urinary tract infections (UTIs). We compared urine culture (UC) findings in patients before and after EF, as well as how they vary with cystitis stage at the time of EF, to evaluate for persistent species. After obtaining institutional review board approval, we retrospectively reviewed a prospectively maintained database of EF patients for those with positive UC findings in the 3-6 months preceding EF. Patient pre-EF UC was then compared with first positive UC after EF prompted by a new symptomatic UTI episode, with the hypothesis that the same species will be identified before and after EF. Exclusion criteria included UC from outside institution, neurogenic bladder, and need for catheterization. Ninety-nine women with pre- or post-EF UC-recorded organisms met the study criteria. The median age was 65 years (interquartile range 64-74), with a median time to first positive culture following fulguration of 9.7 months. For 26 patients with positive cultures both pre- and post-EF, the same organism was present in both cultures in 73% of the patients, with predominantly Escherichia coli. EF was effective at reducing the rate of UTIs in this population. For women undergoing EF for antibiotic-recalcitrant RUTIs and associated chronic cystitis lesions, 73% of those with a UC obtained at the time of a first symptomatic recurrent UTI episode post-EF expressed the same organism as before EF. Further study is needed to better understand the evolution of the microbiome post-EF.IMPORTANCEAmong women who experience a recurrent urinary tract infection after a fulguration procedure on areas of chronic cystitis in their bladder, there are no data available on whether the bacterial species found in urine cultures are the same or different from those present before fulguration. By removing the inflamed surface layer of cystitis during fulguration, it is possible that the procedure unmasks deep-seated bacteria. The bacterial kingdom in the bladder wall of these chronically infected women may be different from what is expressed sporadically in urine cultures. Confirming prior studies, we found that fulguration in women with antibiotic-recalcitrant recurrent urinary tract infections and cystitis lesions was effective at reducing the rate of urinary tract infections. At the time of a first symptomatic recurrent UTI episode post-fulguration, 73% expressed the same organism in urine culture as before fulguration. Further study is needed to better understand the evolution of the microbiome post-EF. This article evaluates persistent infections after electrofulguration of areas with chronic cystitis in post-menopausal women with antibiotic-recalcitrant recurrent urinary tract infections. Pre-fulguration urine cultures were compared with the first positive urine culture prompted by a new symptomatic UTI episode after electrofulguration, with the hypothesis that the same species will be identified before and after the fulguration procedure. Electrofulguration was effective at reducing the rate of UTIs in this population. However, 73% of those with a urine culture obtained at the time of a first symptomatic recurrent UTI episode post-electrofulguration expressed the same organism (predominantly Escherichia coli) as before the fulguration procedure. Further study is needed to better understand the evolution of the microbiome after electrofulguration.

6.
Diagnostics (Basel) ; 14(12)2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38928667

RESUMO

Osteochondral lesions of the talus are common injuries that are most often the result of trauma. The natural progression of osteochondral lesions is not well understood. It is still unclear which lesions eventually lead to joint degeneration and osteoarthritic changes and if the treatment method affects the progression. The existing literature surrounding this topic is sparse, with inconsistent findings. The presented images are taken from a 72-year-old man with bilateral osteochondral lesions of the talus. To our knowledge, this is the first published series of images illustrating the natural progression of a patient with bilateral osteochondral lesions of the talus over a 12-year time period.

7.
Obesity (Silver Spring) ; 32(7): 1362-1372, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38831482

RESUMO

OBJECTIVE: The main objective of this study is to better understand the effects of diet-induced weight loss on brain connectivity in response to changes in glucose levels in individuals with obesity. METHODS: A total of 25 individuals with obesity, among whom 9 had a diagnosis of type 2 diabetes, underwent functional magnetic resonance imaging (fMRI) scans before and after an 8-week low-calorie diet. We used a two-step hypereuglycemia clamp approach to mimic the changes in glucose levels observed in the postprandial period in combination with task-mediated fMRI intrinsic connectivity distribution (ICD) analysis. RESULTS: After the diet, participants lost an average of 3.3% body weight. Diet-induced weight loss led to a decrease in leptin levels, an increase in hunger and food intake, and greater brain connectivity in the parahippocampus, right hippocampus, and temporal cortex (limbic-temporal network). Group differences (with vs. without type 2 diabetes) were noted in several brain networks. Connectivity in the limbic-temporal and frontal-parietal brain clusters inversely correlated with hunger. CONCLUSIONS: A short-term low-calorie diet led to a multifaceted body response in patients with obesity, with an increase in connectivity in the limbic-temporal network (emotion and memory) and hormone and eating behavior changes that may be important for recovering the weight lost.


Assuntos
Encéfalo , Restrição Calórica , Diabetes Mellitus Tipo 2 , Fome , Imageamento por Ressonância Magnética , Obesidade , Redução de Peso , Humanos , Obesidade/fisiopatologia , Obesidade/dietoterapia , Masculino , Feminino , Redução de Peso/fisiologia , Adulto , Pessoa de Meia-Idade , Fome/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Leptina/sangue , Glicemia/metabolismo , Ingestão de Alimentos/fisiologia
8.
Perm J ; : 1-8, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38916447

RESUMO

BACKGROUND: Patients with limited English proficiency that are hospitalized without regular access to professional medical interpreters have a longer length of stay (LOS). 1 The authors studied the difference in LOS between English-speaking patients and patients with limited English proficiency in New Hampshire's only academic trauma medical center. The authors also examined race, ethnicity, and distance of residence from hospital. METHODS: Retrospective data were queried from EPIC, the electronic medical record system used by the authors. Queried data focused on inpatient hospitalizations between January 1, 2019, and December 31, 2021. Patient primary language was grouped into English, Spanish, and other non-English language. RESULTS: Spanish-speaking patients live on average 39.6 miles farther from a hospital than English-speaking patients and have a 0.34 lower case mix index. After English, Spanish is the second-most frequently spoken language. Regression analyses found language to be a significant factor in LOS, LOS variance, and case mix index. DISCUSSION: A 2.34-day longer LOS for Spanish-speaking patients demonstrates an important health care disparity warranting further attention.

9.
Am J Ind Med ; 67(8): 679-695, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38853462

RESUMO

Previously published analyses of suicide case investigations suggest that work or working conditions contribute to 10%-13% of suicide deaths. Yet, the way in which work may increase suicide risk is an underdeveloped area of epidemiologic research. In this Commentary, we propose a definition of work-related suicide from an occupational health and safety perspective, and review the case investigation-based and epidemiologic evidence on work-related causes of suicide. We identified six broad categories of potential work-related causes of suicide, which are: (1) workplace chemical, physical, and psychosocial exposures; (2) exposure to trauma on the job; (3) access to means of suicide through work; (4) exposure to high-stigma work environments; (5) exposure to normative environments promoting extreme orientation to work; and (6) adverse experiences arising from work-related injury or illness. We summarise current evidence in a schema of potential work-related causes that can also be applied in workplace risk assessment and suicide case investigations. There are numerous implications of these findings for policy and practice. Various principle- and evidence-based workplace intervention strategies for suicide prevention exist, some of which have been shown to improve suicide-prevention literacy, reduce stigma, enhance helping behaviours, and in some instances maybe even reduce suicide rates. Prevailing practice in workplace suicide prevention, however, overly emphasises individual- and illness-directed interventions, with little attention directed to addressing the working conditions that may increase suicide risk. We conclude that a stronger emphasis on improving working conditions will be required for workplace suicide prevention to reach its full preventive potential.


Assuntos
Suicídio , Local de Trabalho , Humanos , Local de Trabalho/psicologia , Suicídio/estatística & dados numéricos , Suicídio/psicologia , Saúde Ocupacional , Prevenção do Suicídio , Fatores de Risco , Exposição Ocupacional/efeitos adversos , Estigma Social , Medição de Risco
10.
Commun Med (Lond) ; 4(1): 107, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844576

RESUMO

BACKGROUND: A clear understanding of public perceptions of the social determinants of health remains lacking. This paper aimed to describe the relationship between income and urbanicity levels and public views of the determinants of health in eight middle-and high-income countries that varied across multiple characteristics. METHODS: We conducted a cross-sectional online survey in Brazil, China, Germany, Egypt, India, Indonesia, Nigeria, and the United States. Respondents were asked to select what they considered to be most important for health out of a list of ten determinants. We stratified the results by income and urbanicity levels and tested significance of differences between groups using two-tailed χ2 tests. Multivariable logistic regression models tested associations between demographic factors and the likelihood of respondents selecting the genetics, healthcare, income and wealth, or social support determinants. RESULTS: Here we show 8753 respondents across eight countries. Rankings of determinants are similar across income groups, except for two determinants. Respondents in the highest income group rank genetics in higher proportions (32.4%, 95%CI: 29.0%,35.8%) compared to other income groups. Conversely, those in lowest income group rank social support more frequently (27.9%, 95%CI: 25.3%,30.7%) than other income groups. Those living in urban settings rank healthcare in higher proportions (61.2%, 95%CI: 59.0%,63.4%) compared to non-urban respondents; meanwhile, higher proportions (26.6%, 95%CI: 24.9%,28.3%) of non-urban respondents rank social support as important for health compared to urban respondents. CONCLUSION: Demographic factors play a role in shaping public views of what affects health. Advancing public understanding about determinants of health requires tailoring public health messaging to account for socioeconomic position within a population.


Various factors determine our health, such as our environment, education, and genetics. Here, we explore how people from different income and urban backgrounds view the factors that affect health. We surveyed participants from Brazil, China, Germany, Egypt, India, Indonesia, Nigeria, and the United States. Respondents selected the most important factors for health from a list of ten choices. Overall, people's views on these factors were comparable across income groups, with exceptions. Those with higher incomes tended to emphasize the importance of genetics more, while lower-income individuals valued social support. People in urban areas prioritized healthcare, while those in non-urban areas valued social support. These findings suggest that factors such as income and where people live influence their views about health determinants. These factors should be considered in public health messaging and strategies to promote health amongst different groups.

11.
Transplant Cell Ther ; 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38897861

RESUMO

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV1) threshold, focus on obstructive defects defined by FEV1/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.

13.
Nat Commun ; 15(1): 5037, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866743

RESUMO

This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA (n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)-1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.


Assuntos
Anemia , Transcriptoma , Humanos , Anemia/genética , Anemia/sangue , Pré-Escolar , Lactente , Feminino , Malária/sangue , Malária/genética , Quênia , Masculino , Perfilação da Expressão Gênica , Imunidade Inata/genética , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/sangue
14.
bioRxiv ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38895245

RESUMO

Mutations in Prkra gene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkra lear-5J exhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of the Prkra lear-5J mutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygous Prkra lear-5J mice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation.

15.
JCI Insight ; 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38935435

RESUMO

Endoplasmic reticulum (ER) stress and proinsulin misfolding are heralded as contributing factors to ß-cell dysfunction in Type 2 diabetes (T2D), yet how ER function becomes compromised is not well understood. Recent data identifies altered ER redox homeostasis as a critical mechanism that contributes to insulin granule loss in diabetes. Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation. In this report, we identified glucose metabolism as a critical determinant in the redox homeostasis of the ER. Using multiple ß-cell models, we showed that loss of mitochondrial function or inhibition of cellular metabolism elicited ER hyperoxidation and delayed ER proinsulin export. Our data further demonstrated that ß-cell ER redox homeostasis was supported by the metabolic supply of reductive redox donors. We showed that limiting NADPH and thioredoxin flux delayed ER proinsulin export, whereas Txnip suppression restored ER redox and proinsulin trafficking. Taken together, we propose that ß-cell ER redox homeostasis is buffered by cellular redox donor cycles, which are maintained through active glucose metabolism.

16.
Neuroophthalmology ; 48(4): 272-278, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38933752

RESUMO

See-saw nystagmus (SSN) is a rare form of nystagmus characterised by alternating elevation with incyclotorsion of one eye and concomitant depression with excyclotorsion of the other eye, often due to abnormalities involving the midbrain and parasellar region. Herein, we highlight a rare case of pendular SSN, which demonstrated complete resolution following resection of a pituitary macroadenoma. A patient in their 40s was identified to have SSN and was diagnosed with a pituitary macroadenoma. They underwent an endoscopic endonasal transsellar approach for resection of the pituitary adenoma. Their nystagmus resolved immediately after surgery. From a review of the literature, resolution and/or significant improvement in SSN occurred in 74% of cases following treatment, with 100%, 86% and 50% following treatment for medication-induced, neurological infarcts, and mass-effect aetiologies of SSN, respectively. SSN is a rare entity with a wide array of aetiologies. Identification of the causative aetiology and appropriate treatment can lead to significant improvement or resolution of the nystagmus in most cases.

17.
Ann Jt ; 9: 17, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38690074

RESUMO

Background: Arthroscopic-assisted treatment of ankle fractures has proven useful in the adult population, but little evidence exists for the utilization of arthroscopic-assisted ankle fracture fixation in the pediatric population. The purpose of this systematic review is to examine the management of pediatric ankle fractures using arthroscopy. Methods: A systematic review was performed using PubMed, Web of Science, CINAHL, and MEDLINE from database inception to February 22nd, 2023. Inclusion criteria for this systematic review was pediatric population less than age 18, arthroscopic surgery management, and ankle fracture. Results: A total of 19 articles (n=30 patients) out of 176 articles met final inclusion criteria with all articles consisting of case reports or case series. The average patient age was 13.8±1.6 years. Sixteen of the patients (53%) had arthroscopic surgery along with an adjunct surgery as indicated, whereas 14 patients (47%) had arthroscopic surgery with or without percutaneous fixation. A high majority of patients demonstrated full range-of-motion and large improvements in function. Conclusions: Arthroscopy is used with percutaneous fixation or in adjunct to open approaches for pediatric ankle fracture management with good results. More research is needed to determine the utility of arthroscopy in the management of pediatric ankle fractures.

18.
Aging Cell ; : e14172, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38747044

RESUMO

Slowing and/or reversing brain ageing may alleviate cognitive impairments. Previous studies have found that exercise may mitigate cognitive decline, but the mechanisms underlying this remain largely unclear. Here we provide unbiased analyses of single-cell RNA sequencing data, showing the impacts of exercise and ageing on specific cell types in the mouse hippocampus. We demonstrate that exercise has a profound and selective effect on aged microglia, reverting their gene expression signature to that of young microglia. Pharmacologic depletion of microglia further demonstrated that these cells are required for the stimulatory effects of exercise on hippocampal neurogenesis but not cognition. Strikingly, allowing 18-month-old mice access to a running wheel did by and large also prevent and/or revert T cell presence in the ageing hippocampus. Taken together, our data highlight the profound impact of exercise in rejuvenating aged microglia, associated pro-neurogenic effects and on peripheral immune cell presence in the ageing female mouse brain.

19.
eNeuro ; 11(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38777611

RESUMO

Homeostatic plasticity stabilizes firing rates of neurons, but the pressure to restore low activity rates can significantly alter synaptic and cellular properties. Most previous studies of homeostatic readjustment to complete activity silencing in rodent forebrain have examined changes after 2 d of deprivation, but it is known that longer periods of deprivation can produce adverse effects. To better understand the mechanisms underlying these effects and to address how presynaptic as well as postsynaptic compartments change during homeostatic plasticity, we subjected mouse cortical slice cultures to a more severe 5 d deprivation paradigm. We developed and validated a computational framework to measure the number and morphology of presynaptic and postsynaptic compartments from super-resolution light microscopy images of dense cortical tissue. Using these tools, combined with electrophysiological miniature excitatory postsynaptic current measurements, and synaptic imaging at the electron microscopy level, we assessed the functional and morphological results of prolonged deprivation. Excitatory synapses were strengthened both presynaptically and postsynaptically. Surprisingly, we also observed a decrement in the density of excitatory synapses, both as measured from colocalized staining of pre- and postsynaptic proteins in tissue and from the number of dendritic spines. Overall, our results suggest that cortical networks deprived of activity progressively move toward a smaller population of stronger synapses.


Assuntos
Potenciais Pós-Sinápticos Excitadores , Neocórtex , Plasticidade Neuronal , Sinapses , Animais , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Neocórtex/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Camundongos Endogâmicos C57BL , Privação Sensorial/fisiologia , Masculino , Camundongos , Feminino , Espinhas Dendríticas/fisiologia
20.
Sci Transl Med ; 16(745): eadj4303, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38691619

RESUMO

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.


Assuntos
Tronco Encefálico , Estado de Consciência , Imageamento por Ressonância Magnética , Vigília , Humanos , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/fisiologia , Vigília/fisiologia , Estado de Consciência/fisiologia , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Conectoma , Vias Neurais/fisiologia , Masculino , Feminino , Imagem de Difusão por Ressonância Magnética , Adulto , Nível de Alerta/fisiologia
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