RESUMEN
Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.
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Basófilos/patología , Neuronas/patología , Prurito/patología , Enfermedad Aguda , Alérgenos/inmunología , Animales , Enfermedad Crónica , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Histamina/metabolismo , Humanos , Inmunoglobulina E/inmunología , Inflamación/patología , Leucotrienos/metabolismo , Mastocitos/inmunología , Ratones Endogámicos C57BL , Fenotipo , Prurito/inmunología , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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Prurito/inmunología , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/metabolismo , Transducción de Señal , Enfermedades de la Piel/inmunología , Animales , Ganglios Espinales , Humanos , Interleucina-13/inmunología , Interleucina-4/inmunología , Janus Quinasa 1/metabolismo , Ratones , Ratones Endogámicos C57BL , Prurito/metabolismo , Enfermedades de la Piel/patologíaRESUMEN
BACKGROUND: BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy. METHODS: Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants. RESULTS: BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)-induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (P≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%; P=0.001) and in patients receiving ticagrelor alone (-28%; P=0.001), aspirin alone (-23%; P=0.018), or both in combination (-24%; P≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (P≤0.001 for all) and total thrombus area under high shear stress conditions (P≤0.01 for all). CONCLUSIONS: PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790.
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Enfermedad de la Arteria Coronaria , Trombosis , Humanos , Inhibidores de Agregación Plaquetaria/farmacología , Ticagrelor/uso terapéutico , Fibrinolíticos/uso terapéutico , Enfermedad de la Arteria Coronaria/metabolismo , Aspirina , Agregación Plaquetaria , Plaquetas/metabolismoRESUMEN
Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intravital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neutrophils. During the initial stages of inflammation, neutrophils traffic predominantly to subpleural vessels, where their aggregation is directed by chemoattractants produced by nonclassical monocytes that are spatially restricted in this vascular compartment. Subsequent neutrophilic disruption of capillaries resulting in vascular leakage is associated with impaired graft function. We found that TLR4 signaling in vascular endothelial cells and downstream NADPH oxidase 4 expression mediate the arrest of neutrophils, a step upstream of their extravasation. Neutrophil extracellular traps formed in injured lungs and their disruption with DNase prevented vascular leakage and ameliorated primary graft dysfunction. Thus, we have uncovered mechanisms that regulate the initial recruitment of neutrophils to injured lungs, which result in selective damage to subpleural pulmonary vessels and primary graft dysfunction. Our findings could lead to the development of new therapeutics that protect lungs from ischemia reperfusion injury.
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Endotelio Vascular/metabolismo , Pulmón/metabolismo , Necroptosis , Infiltración Neutrófila , Neutrófilos/metabolismo , Daño por Reperfusión/metabolismo , Animales , Endotelio Vascular/lesiones , Humanos , Pulmón/irrigación sanguínea , Ratones , Ratones Noqueados , Daño por Reperfusión/genética , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
Neuronal signals mediated by the biogenic amine serotonin (5-HT) underlie critical survival strategies across the animal kingdom. This investigation examined serotonin-like immunoreactive neurons in the cerebral ganglion of the panpulmonate snail Biomphalaria glabrata, a major intermediate host for the trematode parasite Schistosoma mansoni. Five neurons comprising the cerebral serotonergic F (CeSF) cluster of B. glabrata shared morphological characteristics with neurons that contribute to withdrawal behaviors in numerous heterobranch species. The largest member of this group, designated CeSF-1, projected an axon to the tentacle, a major site of threat detection. Intracellular recordings demonstrated repetitive activity and electrical coupling between the bilateral CeSF-1 cells. In semi-intact preparations, the CeSF-1 cells were not responsive to cutaneous stimuli but did respond to photic stimuli. A large FMRF-NH2-like immunoreactive neuron, termed C2, was also located on the dorsal surface of each cerebral hemiganglion near the origin of the tentacular nerve. C2 and CeSF-1 received coincident bouts of inhibitory synaptic input. Moreover, in the presence of 5-HT they both fired rhythmically and in phase. As the CeSF and C2 cells of Biomphalaria share fundamental properties with neurons that participate in withdrawal responses in Nudipleura and Euopisthobranchia, our observations support the proposal that features of this circuit are conserved in the Panpulmonata.NEW & NOTEWORTHY Neuronal signals mediated by the biogenic amine serotonin underlie critical survival strategies across the animal kingdom. This investigation identified a group of serotonergic cells in the panpulmonate snail Biomphalaria glabrata that appear to be homologous to neurons that mediate withdrawal responses in other gastropod taxa. It is proposed that an ancient withdrawal circuit has been highly conserved in three major gastropod lineages.
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Biomphalaria , Neuronas Serotoninérgicas , Serotonina , Animales , Biomphalaria/fisiología , Biomphalaria/parasitología , Serotonina/metabolismo , Neuronas Serotoninérgicas/fisiología , Ganglios de Invertebrados/fisiología , Ganglios de Invertebrados/citologíaRESUMEN
BACKGROUND: Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. METHODS: We utilized an established murine model of intranasal infection with VEEV and a repository of scRNAseq data from IFN-treated OSN to assess the cellular targets and IFN signaling responses after VEEV exposure. RESULTS: We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 h during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. CONCLUSIONS: Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures.
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Virus de la Encefalitis Equina Venezolana , Neuronas Receptoras Olfatorias , Humanos , Ratones , Animales , Virus de la Encefalitis Equina Venezolana/genética , Sistema Nervioso Central , Replicación ViralRESUMEN
Listeria monocytogenes (Lm) is a food-borne pathogen that causes severe bacterial gastroenteritis, with high rates of hospitalization and mortality. Lm is ubiquitous in soil, water and livestock, and can survive and proliferate at low temperatures. Following oral ingestion of contaminated food, Lm crosses the epithelium through intestinal goblet cells in a mechanism mediated by Lm InlA binding host E-cadherin. Importantly, human infections typically occur with Lm growing at or below room temperature, which is flagellated and motile. Even though many important human bacterial pathogens are flagellated, little is known regarding the effect of Lm motility on invasion and immune evasion. Here, we used complementary imaging and computer modeling approaches to test the hypothesis that bacterial motility helps Lm locate and engage target cells permissive for invasion. Imaging explanted mouse and human intestine, we showed that Lm grown at room temperature uses motility to scan the epithelial surface and preferentially attach to target cells. Furthermore, we integrated quantitative parameters from our imaging experiments to construct a versatile "layered" cellular Potts model (L-CPM) that simulates host-pathogen dynamics. Simulated data are consistent with the hypothesis that bacterial motility enhances invasion by allowing bacteria to search the epithelial surface for their preferred invasion targets. Indeed, our model consistently predicts that motile bacteria invade twice as efficiently over the first hour of infection. We also examined how bacterial motility affected interactions with host cellular immunity. In a mouse model of persistent infection, we found that neutrophils migrated to the apical surface of the epithelium 5 hours post infection and interacted with Lm. Yet in contrast to the view that neutrophils "hunt" for bacteria, we found that these interactions were driven by motility of Lm-which moved at least ~50x faster than neutrophils. Furthermore, our L-CPM predicts that motile bacteria maintain their invasion advantage even in the presence of host phagocytes, with the balance between invasion and phagocytosis governed almost entirely by bacterial motility. In conclusion, our simulations provide insight into host pathogen interaction dynamics at the intestinal epithelial barrier early during infection.
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Enfermedades Intestinales , Listeria monocytogenes , Listeria , Listeriosis , Ratones , Animales , Humanos , Proteínas Bacterianas/metabolismo , Intestinos/microbiologíaRESUMEN
BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.
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Cannabis , Trastornos por Estrés Postraumático , Trastornos Relacionados con Sustancias , Humanos , Femenino , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/diagnóstico , Depresión/diagnóstico , Trastornos Relacionados con Sustancias/complicaciones , PsicopatologíaRESUMEN
Traumatic stress is associated with both accelerated epigenetic age and increased risk for dementia. Accelerated epigenetic age might link symptoms of traumatic stress to dementia-associated biomarkers, such as amyloid-beta (Aß) proteins, neurofilament light (NFL), and inflammatory molecules. We tested this hypothesis using longitudinal data obtained from 214 trauma-exposed military veterans (85 % male, mean age at baseline: 53 years, 75 % White) who were assessed twice over the course of an average of 5.6 years. Cross-lagged panel mediation models evaluated measures of lifetime posttraumatic stress disorder and internalizing and externalizing comorbidity (assessed at Time 1; T1) in association with T1 epigenetic age (per the GrimAge algorithm) and T1 plasma markers of neuropathology along with bidirectional temporal paths between T1 and T2 epigenetic age and the plasma markers. Results revealed that a measure of externalizing comorbidity was associated with accelerated epigenetic age (ß = 0.30, p <.01), which in turn, was associated with subsequent increases in Aß-40 (ß = 0.20, p <.001), Aß-42 (ß = 0.18, p <.001), and interleukin-6 (ß = 0.18, p <.01). T1 advanced epigenetic age and the T1 neuropathology biomarkers NFL and glial fibrillary acidic protein predicted worse performance on T2 neurocognitive tasks assessing working memory, executive/attentional control, and/or verbal memory (ps = 0.03 to 0.009). Results suggest that advanced GrimAge is predictive of subsequent increases in neuropathology and inflammatory biomarkers as well as worse cognitive function, highlighting the clinical significance of this biomarker with respect to cognitive aging and brain health over time. The finding that advanced GrimAge mediated the association between psychiatric comorbidity and future neuropathology is important for understanding potential pathways to neurodegeneration and early identification of those at greatest risk.
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Envejecimiento Cognitivo , Disfunción Cognitiva , Demencia , Masculino , Humanos , Persona de Mediana Edad , Femenino , Estudios Longitudinales , Péptidos beta-Amiloides , Biomarcadores , EnvejecimientoRESUMEN
While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.
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Enfermedad de Alzheimer , Negro o Afroamericano , Personal Militar , Anciano , Humanos , Persona de Mediana Edad , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/genética , Negro o Afroamericano/genética , Negro o Afroamericano/estadística & datos numéricos , Bases de Datos Genéticas/estadística & datos numéricos , Demencia/epidemiología , Demencia/etnología , Demencia/genética , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Personal Militar/estadística & datos numéricos , Polimorfismo Genético , Estados Unidos/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms.
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Miedo , Trastornos por Estrés Postraumático , Humanos , Estudios Longitudinales , Miedo/fisiología , Amígdala del Cerebelo , Giro del Cíngulo/patología , Imagen por Resonancia Magnética , Corteza Prefrontal/patologíaRESUMEN
Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.
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RATIONALE: Although ubiquitous in explosives and ammunition, few trace methods for detection of heavy metal-containing primary explosives from forensic samples are currently in practice. METHODS: Extracts of cotton swabs or direct sampling of items were cleaned up using solid-phase extraction to remove heavy metal contaminants (i.e., lead) while retaining the organic styphnate component. The styphnate was chromatographically separated using hydrophilic interaction chromatography (HILIC) and detected via high-resolution tandem mass spectrometry (MS/MS) using a sensitive, targeted approach in five minutes or less. RESULTS: A mass spectrometric method for the detection of styphnate, including limit of detection (LOD), sample stability, and interferences was developed. We present a validated method for the extraction, separation, and detection of styphnate from lead(II) styphnate with an estimated LOD of 257 ppt (pg/mL). CONCLUSIONS: We detail an improved LOD relative to previous reports for trace detection of styphnate and, for the first time to our knowledge, the post-blast analysis of styphnate.
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Exposure to particles from air pollution has been associated with kidney disease; however, the underlying biological mechanisms are incompletely understood. Inhaled particles can gain access to the circulation and, depending on their size, pass into urine, raising the possibility that particles may also sequester in the kidney and directly alter renal function. This study optimised an inductively coupled plasma mass spectrometry (ICP-MS) method to investigate the size dependency of particle accumulation in the kidneys of mice following pulmonary instillation (0.8 mg in total over 4 weeks) to gold nanoparticles (2, 3-4, 7-8, 14 or 40 nm or saline control). Due to the smallest particle sizes being below the limit of detection in single particle mode, ICP-MS was operated in total quantification mode. Gold was detected in all matrices of interest (blood, urine and kidney) from animals treated with all sizes of gold nanoparticles, at orders of magnitude higher than the methodological limit of detection in biological matrices (0.013 ng/mL). A size-dependent effect was observed, with smaller particles leading to greater levels of accumulation in tissues. This study highlights the value of a robust and reliable method by ICP-MS to detect extremely low levels of gold in biological samples for indirect particle tracing. The finding that nano-sized particles translocate from the lung to the kidney may provide a biological explanation for the associations between air pollution and kidney disease.
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Contaminación del Aire , Enfermedades Renales , Nanopartículas del Metal , Nanopartículas , Ratones , Animales , Oro/química , Nanopartículas del Metal/química , Tamaño de la Partícula , Espectrometría de MasasRESUMEN
BACKGROUND: While the cognitive hallmark of typical Alzheimer's disease (AD) is impaired memory consolidation, increasing evidence suggests that the frontal lobes and associated executive functions are also impacted. OBJECTIVE: We examined two neurobehavioral executive function tasks and associations with cortical thickness in patients diagnosed with mild cognitive impairment (MCI), suspected AD dementia, and a healthy control group. METHODS: First, we compared group performances on a go/no-go (GNG) task and on Luria's Fist-Edge-Palm (FEP) motor sequencing task. We then examined correlations between neurobehavioral task performance and the thickness of frontal cortical regions, AD signature regions, broader unbiased brain regions, and white matter hyperintensities (WMH). RESULTS: Participants with MCI performed worse than healthy controls, but better than participants with suspected AD dementia on both tasks. Both GNG and FEP (to a slightly greater extent) tasks showed diffuse associations with most AD signature regions and multiple additional regions within the temporal, parietal, and occipital cortices. Similarly, both tasks showed significant associations with all other cognitive tasks examined. Of the frontal regions examined, only the middle frontal gyrus and pars opercularis were associated with performance on these tasks. Interactions between the precuneus and transtemporal gyri were most predictive of GNG task performance, while the interaction between superior temporal and lingual gyri was most predictive of FEP task performance. CONCLUSION: This study replicates difficulties with both GNG and FEP tasks in participants with MCI and AD dementia. Both tasks showed widespread associations with the cortical thickness of various brain structures rather than localizing to frontal regions, consistent with the diffuse nature of AD.
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Although recent studies have shown good results of anterior cruciate ligament primary repair at 2-year follow-up, one must be careful in adopting this technique. Historically, the classic study from West Point showed repair fails at 5 years. Perhaps future results will be improved with scaffolds, augmentation, or biologics. Only time will tell. For now, what's the (West) Point?
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Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Humanos , Ligamento Cruzado Anterior/cirugía , Lesiones del Ligamento Cruzado Anterior/cirugía , Estudios de Seguimiento , Reconstrucción del Ligamento Cruzado Anterior/métodosRESUMEN
Technical complications are a leading cause of graft failure following anterior cruciate ligament reconstructions. Complications can occur during any phase of the procedure, from graft harvesting to tunnel preparation to graft fixation. Predicting potential causes of technical difficulty and developing strategies to avoid potential pitfalls can limit the number of intraoperative complications. If adverse events do occur intraoperatively, prompt recognition and treatment can lead to favorable outcomes. It is important to discuss strategies to understand potential complications and develop tactics to avoid and correct adverse events that can occur during anterior cruciate ligament reconstruction.
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Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Humanos , Ligamento Cruzado Anterior/cirugía , Reconstrucción del Ligamento Cruzado Anterior/efectos adversos , Complicaciones Intraoperatorias/etiología , Complicaciones Intraoperatorias/prevención & control , Complicaciones Intraoperatorias/cirugía , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/cirugía , Tendones/trasplante , Lesiones del Ligamento Cruzado Anterior/cirugíaRESUMEN
BACKGROUND: The supraspinatus (SS) is formed by a larger anterior bipennate muscle with a cord-like tendon and a posterior unipennate muscle with a strap-like tendon. There is a tendinous connection between the 2 SS subunits. Yet, the relative mechanical contribution of the SS cord and SS strap musculotendinous units to load transmission and subsequent shoulder abduction force is unknown. We hypothesized that a simulated SS cord vs. an SS strap tear would generate less shoulder abduction force and, further, an intact SS cord would offset the expected abduction loss from an SS strap tear, but the inverse would not be true. MATERIALS AND METHODS: Twenty fresh-frozen cadaveric specimens were tested in a shoulder simulator with physiological load vectors applied to the upper and lower subscapularis, SS cord, SS strap, infraspinatus, and teres minor. The roles of the SS cord and SS strap muscles were delineated by varying their loads, while keeping constant loads on other muscles. The randomized testing trials included a native condition and 4 test cases that simulated tears by dropping the load and force transfer via the SS cord-to-SS strap connection by adding the load. Testing was completed at both 0° and 30° of abduction. During each test, shoulder abduction force, rotator cuff strains, and humeral translation were measured. RESULTS: Simulated isolated SS cord and SS strap tears led to a significantly lower shoulder abduction force (P < .001). A simulated cord tear at 0° and 30° reduced the abduction force by 53% and 38%, respectively. A simulated strap tear at 0° and 30° dropped the abduction force by 27% and 23%, respectively. The decline in the abduction force was larger for the SS cord tear vs. SS strap tear (P ≤ .001). An SS cord tear with full-load transfer to the strap was able to recover to native values at both 0° and 30° (P ≥ .288). Likewise, an SS strap tear with full-load transfer to the SS cord showed a similar recovery to native values at both 0° and 30° (P ≥ .155). During full-load transfer, the tendon strain followed the loading pattern. An SS cord tear or SS strap tear did not cause a change in humeral translation (P ≥ .303). DISCUSSION: The mechanical findings support the efficacy of nonoperative treatment of small (<10 mm) SS tears,11 because an intact SS strap tendon can effectively offset the abduction loss of a torn SS cord tear and vice versa.
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Laceraciones , Lesiones del Manguito de los Rotadores , Articulación del Hombro , Humanos , Manguito de los Rotadores/cirugía , Hombro/cirugía , Articulación del Hombro/cirugía , Fenómenos Biomecánicos , Tendones , Rotura , Rango del Movimiento Articular/fisiología , CadáverRESUMEN
Chronic pain is a debilitating condition for many military Veterans and is associated with posttraumatic stress disorder (PTSD). This study examined the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) in 144 Veterans (88.2% male, mean age = 57.95 years) recruited from a VA outpatient pain clinic and associations with self-reported pain severity, pain-related interference in daily activities, prescription opioid use, and objective metrics of physical performance on tasks impacted by pain (walking, stair climbing, grip strength, indexed by a single latent variable). Among the cohort with valid responses on the MMPI-2-RF (n = 117) and probable PTSD, mean Somatic Complaints (RC1) and Ideas of Persecution (RC6) scores were clinically elevated. All MMPI-2-RF scales were more strongly correlated with self-reported pain interference than severity. Regressions revealed associations between self-rated pain interference (but not pain or PTSD severity) and physical performance scores (ß = .36, p = .001). MMPI-2-RF overreporting Validity and Higher-Order scales contributed incremental variance in predicting physical performance, including Infrequent Psychopathology Responses (ß = .33, p = .002). PTSD severity was associated with prescription opioid use when accounting for the effects of over-reported somatic and cognitive symptoms (odds ratio 1.05, p ≤ .025). Results highlight the role of symptom overreporting and perceptions of functional impairment to observable behaviors among individuals with chronic pain.
Asunto(s)
Dolor Crónico , Veteranos , Humanos , Masculino , Persona de Mediana Edad , Femenino , MMPI , Veteranos/psicología , Dolor Crónico/psicología , Clínicas de Dolor , Analgésicos Opioides/uso terapéutico , Simulación de Enfermedad/diagnóstico , Simulación de Enfermedad/psicología , Reproducibilidad de los ResultadosRESUMEN
Hippocampal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat-sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma (N=116, 76 Female), we found that PTSD symptoms at 2-weeks were associated with decreased hippocampal responses to threat as assessed with functional magnetic resonance imaging (fMRI). Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of Fear Potentiated Startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function, due to increases in fear-potentiated arousal.Significance StatementAlterations in hippocampal function linked to threat-related arousal are reliably associated with post-traumatic stress disorder (PTSD); however, how these alterations relate to the sequelae of trauma-related symptoms is unknown. Prior models based on non-trauma samples suggest that arousal may impact hippocampal neurophysiology leading to maladaptive behavior. Here we show that decreased hippocampal threat sensitivity interacts with fear-potentiated startle to predict PTSD symptoms. Specifically, individuals with high fear-potentiated startle and low, transient hippocampal threat sensitivity showed the greatest PTSD symptomology. These findings bridge literatures of threat-related arousal and hippocampal function to better understand PTSD risk.