Pathophysiology Of Dysfunction Research Articles

Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.

Associations of ventriculomegaly and white matter hyperintensities with glymphatic dysfunction in idiopathic normal pressure hydrocephalus.

To investigate glymphatic function in idiopathic normal pressure hydrocephalus (iNPH) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and to explore the associations of ALPS index with ventriculomegaly and white matter hyperintensities (WMH). This study included 41 patients with iNPH and 40 age- and sex-matched normal controls (NCs). All participants underwent brain MRI. Based on DTI, we then calculated the ALPS index to obtain the water diffusivity along the perivascular space. Ventricular volume and WMH were also determined. Differences in the diffusivities and ALPS indexes between the iNPH and NC groups were investigated; associations of the DTI-ALPS index with ventriculomegaly and WMH were analysed. Patients with iNPH had a lower ALPS index than NCs (p < 0.001). The ALPS index was significantly correlated with the normalised ventricular volume (r = -0.446, p = 0.004), but not with total WMH volume (r = -0.246, p = 0.126). Further regression analyses indicated that the reduced ALPS index was associated with increased ventricular volume (β = -7.158, p = 0.016), but not with normalised WMH volume (β = -2.796, p = 0.161). The receiver operating characteristic analysis demonstrated the ALPS index's excellent diagnostic performance for iNPH (the optimal cut-off point = 1.322; sensitivity, 100.0%; specificity, 87.5%; AUC = 0.980). Patients with iNPH had a lower ALPS index, which may suggest impaired glymphatic function. This study demonstrated an association of DTI-ALPS index with ventriculomegaly, but not WMH in patients with iNPH. Question Glymphatic dysfunction is crucial in idiopathic normal pressure hydrocephalus (iNPH) development, yet its associations with neuroimaging features remains unclear. Findings Diffusion tensor image analysis along the perivascular space (DTI-ALPS) revealed a reduced ALPS index in idiopathic normal pressure hydrocephalus, negatively correlating with ventricular volume. Clinical relevance DTI-ALPS enables non-invasive assessment of glymphatic function and its relationship with neuroimaging characteristics in idiopathic normal pressure hydrocephalus, facilitating the investigation of glymphatic dysfunction in iNPH pathophysiology.

Regulatory Mechanisms and Therapeutic Implications of Lysosomal Dysfunction in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs) formed from hyperphosphorylated Tau, and widespread neuronal loss. The autophagy-lysosomal pathway plays a crucial role in maintaining cellular homeostasis by degrading and recycling of damaged organelles and aggregate amyloid proteins implicated in AD. Lysosomes are key effectors of autophagic process, responsible for the breakdown of a variety of damaged organelles and aggregate or dysfunctional proteins. This review examines the role of lysosomal dysfunction in AD pathophysiology, focusing on genetic factors, acidification abnormalities, and other contributing factors. We also explore the involvement of lysosomal dysfunction of microglia in AD pathology, and cover the role of lysosomal stress response (LSR) in cellular response to neuronal injury associated with AD. Furthermore, we discuss potential therapeutic strategies targeting lysosomal proteolysis pathway and addressing lysosomal dysfunction for AD treatment, including the pharmacologically activating lysosomal activity, regulating TFEB, and considering other emerging approaches.

Takotsubo syndrome during percutaneous coronary intervention: the role of myocardial ischaemia and microvascular dysfunction in pathophysiology

Takotsubo syndrome during percutaneous coronary intervention: the role of myocardial ischaemia and microvascular dysfunction in pathophysiology

Nomination of a novel plasma protein biomarker panel capable of classifying Alzheimer's disease dementia with high accuracy in an African American cohort.

African Americans (AA) are widely underrepresented in plasma biomarker studies for Alzheimer's disease (AD) and current diagnostic biomarker candidates do not reflect the heterogeneity of AD. Untargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in a cohort of AA clinically diagnosed as AD dementia (n=183) or cognitively unimpaired (CU, n=145). Machine learning approaches were implemented to identify the set of plasma proteins that yields the best classification accuracy. A plasma protein panel achieved an area under the curve (AUC) of 0.91 to classify AD dementia vs CU. The reproducibility of this finding was observed in the ANMerge plasma and AMP-AD Diversity brain datasets (AUC=0.83; AUC=0.94). This study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning approaches. Our findings also highlight the potential importance of the matrisome and cerebrovascular dysfunction in AD pathophysiology.

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.

Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization. We describedthe clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling. ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways. This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity. ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.

Combination of Dasatinib and Quercetin alleviates heat stress-induced cognitive deficits in aged and young adult male mice

ObjectiveDasatinib and quercetin (D & Q) have demonstrated promise in improving aged-related pathophysiological dysfunctions in humans and mice. Herein we aimed to ascertain whether the heat stress (HS)-induced cognitive deficits in aged or even young adult male mice can be reduced by D & Q therapy. MethodsBefore the onset of HS, animals were pre-treated with D & Q or placebo for 3 consecutive days every 2 weeks over a 10-week period. Cognitive function, intestinal barrier permeability, and blood-brain barrier permeability were assessed. ResultsCompared to the non-HS young adult male mice, the HS young adult male mice or the aged male mice had significantly lesser extents of the exacerbated stress reactions, intestinal barrier disruption, endotoxemia, systemic inflammation and oxidative stress, blood-brain barrier disruption, hippocampal inflammation and oxidative stress, and cognitive deficits evaluated at 7 days post-HS. All the cognitive deficits and other syndromes that occurred in young adult HS mice or in aged HS mice were significantly attenuated by D & Q therapy (P < 0.01). Compared to the young adult HS mice, the aged HS mice had significantly (P < 0.01) higher severity of cognitive deficits and other related syndromes. ConclusionsFirst, our data show that aged male mice are more vulnerable to HS-induced cognitive deficits than those of the young adult male mice. Second, we demonstrate that a combination of D and Q therapy attenuates cognitive deficits in heat stressed aged or young adult male mice via broad normalization of the brain-gut-endotoxin axis function.

Mass Spectrometry-Based Proteomic Technology and Its Application to Study Skeletal Muscle Cell Biology.

Voluntary striated muscles are characterized by a highly complex and dynamic proteome that efficiently adapts to changed physiological demands or alters considerably during pathophysiological dysfunction. The skeletal muscle proteome has been extensively studied in relation to myogenesis, fiber type specification, muscle transitions, the effects of physical exercise, disuse atrophy, neuromuscular disorders, muscle co-morbidities and sarcopenia of old age. Since muscle tissue accounts for approximately 40% of body mass in humans, alterations in the skeletal muscle proteome have considerable influence on whole-body physiology. This review outlines the main bioanalytical avenues taken in the proteomic characterization of skeletal muscle tissues, including top-down proteomics focusing on the characterization of intact proteoforms and their post-translational modifications, bottom-up proteomics, which is a peptide-centric method concerned with the large-scale detection of proteins in complex mixtures, and subproteomics that examines the protein composition of distinct subcellular fractions. Mass spectrometric studies over the last two decades have decisively improved our general cell biological understanding of protein diversity and the heterogeneous composition of individual myofibers in skeletal muscles. This detailed proteomic knowledge can now be integrated with findings from other omics-type methodologies to establish a systems biological view of skeletal muscle function.

Perfluoroundecanoic acid induces DNA damage, reproductive and pathophysiological dysfunctions via oxidative stress in male Swiss mice

Perfluoroundecanoic acid (PFUnA) is an eleven carbon-chain compound that belongs to the perfluoroalkyl carboxylic acid family. It has been detected in the human blood, effluents, and surface/ground waters, but its toxic effects to the DNA and reproductive system remain unclear. This study was aimed at exploring the toxicity of PFUnA on the hepatic DNA, organ-system and reproductive system in orally treated male Swiss mice. In this present study, administration of PFUnA for 28 days with five doses (0.1, 0.3, 05, 0.7 and 1.0 mg kg-1 b.w./d) in male Swiss mice induced significant hepatic DNA damage which was observed using the alkaline comet assay and equally altered hematological and clinical biochemical parameters. In addition to testicular atrophy, sperm count and sperm motility significantly decreased while sperm abnormalities increased after 35 days exposure. Serum LH and FSH levels were remarkably increased while serum testosterone levels were strikingly reduced. Histopathology revealed the liver, kidney, and testis as potential targets of PFUnA toxicity. Increased activities of superoxide dismutase (SOD) and catalase (CAT), as well as levels of glutathione-s-transferase (GST) and reduced glutathione (GSH), with consistent reduction of glutathione peroxidase (GPx) and reduced glutathione (GSH) in the liver and testis induced oxidative stress. In conclusion, PFUnA exhibited both genotoxicity and reproductive toxicity via oxidative stress induction.

Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets.

Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.

CGMP signaling: a potential therapeutic target for neurodegeneration in glaucoma?

cGMP signaling: a potential therapeutic target for neurodegeneration in glaucoma?

Upregulation of HMGB1 promotes vascular dysfunction in the soft palate of patients with obstructive sleep apnea via the TLR4/NF-κB/VEGF pathway.

Obstructive sleep apnea (OSA) is characterized by the collapse of the soft palate in the upper airway, resulting in chronic intermittent hypoxia during sleep. Therefore, an understanding of the molecular mechanisms underlying pathophysiological dysfunction of the soft palate in OSA is necessary for the development of new therapeutic strategies. In the present study, we observed that high mobility group protein box 1 (HMGB1) was released by a large infiltration of macrophages in the soft palate of OSA patients. The toll-like receptor 4/nuclear factor kappa B pathway was observed to be activated by the release of HMGB1, and this was accompanied by an increased expression of pro-inflammatory factors, including tumor necrosis factor-α and interleukin-6. Importantly, increased expression of toll-like receptor 4 was observed in endothelial cells, contributing to upregulation of the angiogenesis-related factors vascular endothelial-derived growth factor and matrix metalloproteinase 9. Moreover, we confirmed the effect of the HMGB1-mediated toll-like receptor 4/nuclear factor kappa B pathway on cell proliferation and angiogenesis in an in vitro cell model of human umbilical vein endothelial cells. We conclude that HMGB1 may be a potential therapeutic target for preventing angiogenesis and pathology in OSA.

Spontaneous brain activity abnormalities in migraine: A meta-analysis of functional neuroimaging.

Neuroimaging studies have demonstrated that migraine is accompanied by spontaneous brain activity alterations in specific regions. However, these findings are inconsistent, thus hindering our understanding of the potential neuropathology. Hence, we performed a quantitative whole-brain meta-analysis of relevant resting-state functional imaging studies to identify brain regions consistently involved in migraine. A systematic search of studies that investigated the differences in spontaneous brain activity patterns between migraineurs and healthy controls up to April 2022 was conducted. We then performed a whole-brain voxel-wise meta-analysis using the anisotropic effect size version of seed-based d mapping software. Complementary analyses including jackknife sensitivity analysis, heterogeneity test, publication bias test, subgroup analysis, and meta-regression analysis were conducted as well. In total, 24 studies that reported 31 datasets were finally eligible for our meta-analysis, including 748 patients and 690 controls. In contrast to healthy controls, migraineurs demonstrated consistent and robust decreased spontaneous brain activity in the angular gyrus, visual cortex, and cerebellum, while increased activity in the caudate, thalamus, pons,and prefrontal cortex. Results were robust and highly replicable in the following jackknife sensitivity analysis and subgroup analysis. Meta-regression analyses revealed that a higher visual analog scale score in the patient sample was associated with increased spontaneous brain activity in the left thalamus. These findings provided not only a comprehensive overview of spontaneous brain activity patterns impairments, but also useful insights into the pathophysiology of dysfunction in migraine.

2D Short-Time Fourier Transform for local morphological analysis of meibomian gland images.

Meibography is becoming an integral part of dry eye diagnosis. Being objective and repeatable this imaging technique is used to guide treatment decisions and determine the disease status. Especially desirable is the possibility of automatic (or semi-automatic) analysis of a meibomian image for quantification of a particular gland's feature. Recent reports suggest that in addition to the measure of gland atrophy (quantified by the well-established "drop-out area" parameter), the gland's morphological changes may carry equally clinically useful information. Here we demonstrate the novel image analysis method providing detailed information on local deformation of meibomian gland pattern. The developed approach extracts from every Meibomian image a set of six morphometric color-coded maps, each visualizing spatial behavior of different morphometric parameter. A more detailed analysis of those maps was used to perform automatic classification of Meibomian glands images. The method for isolating individual morphometric components from the original meibomian image can be helpful in the diagnostic process. It may help clinicians to see in which part of the eyelid the disturbance is taking place and also to quantify it with a numerical value providing essential insight into Meibomian gland dysfunction pathophysiology.

Transient stress-related hyperviscosity and endothelial dysfunction in Takotsubo syndrome: a time course study.

Takotsubo syndrome (TTS) is an acute and usually reversible heart failure syndrome, frequently associated with emotional or physical stress. Its pathophysiology remains largely unclear, although several mechanisms related to catecholaminergic storm have been proposed. In this study we analyzed during the acute phase of TTS and at follow-up both hemorheological parameters and biomarkers of endothelial damage, whose time course has never been fully explored. In 50 TTS women, we analyzed several hemorheological parameters [whole blood viscosity (WBV) at 0.512s-1 and at 94.5s-1, plasma viscosity (PLV), erythrocyte deformability and aggregation index] as well as biomarkers of endothelial dysfunction [von Willebrand Factor (vWF), Plasminogen activator inhibitor-1 and factor VIII levels] during the acute phase and after a median 6months follow-up. These variables were also assessed in 50 age-matched healthy women. Respect to follow-up, in the acute phase of TTS we observed higher values of white blood cell count, fibrinogen, WBV at low and high shear rates, PLV, erythrocyte aggregation index and lower values of erythrocyte elongation index. Moreover, all biomarkers of endothelial dysfunction resulted significantly higher in the acute phase. During follow-up WBV at 94.5s-1, erythrocyte elongation index and vWF resulted significantly altered with respect to controls. The results of this study confirm the role of hyperviscosity and endothelial dysfunction in TTS pathophysiology. Moreover, they suggest the persistence of alterations of erythrocyte deformability and endothelial dysfunction even beyond the acute phase that could be the target of therapeutic strategies also during follow-up.

Transcriptome Architecture of Osteoblastic Cells Infected With Staphylococcus aureus Reveals Strong Inflammatory Responses and Signatures of Metabolic and Epigenetic Dysregulation.

Staphylococcus aureus is an opportunistic pathogen that causes a range of devastating diseases including chronic osteomyelitis, which partially relies on the internalization and persistence of S. aureus in osteoblasts. The identification of the mechanisms of the osteoblast response to intracellular S. aureus is thus crucial to improve the knowledge of this infectious pathology. Since the signal from specifically infected bacteria-bearing cells is diluted and the results are confounded by bystander effects of uninfected cells, we developed a novel model of long-term infection. Using a flow cytometric approach we isolated only S. aureus-bearing cells from mixed populations that allows to identify signals specific to intracellular infection. Here we present an in-depth analysis of the effect of long-term S. aureus infection on the transcriptional program of human osteoblast-like cells. After RNA-seq and KEGG and Reactome pathway enrichment analysis, the remodeled transcriptomic profile of infected cells revealed exacerbated immune and inflammatory responses, as well as metabolic dysregulations that likely influence the intracellular life of bacteria. Numerous genes encoding epigenetic regulators were downregulated. The later included genes coding for components of chromatin-repressive complexes (e.g., NuRD, BAHD1 and PRC1) and epifactors involved in DNA methylation. Sets of genes encoding proteins of cell adhesion or neurotransmission were also deregulated. Our results suggest that intracellular S. aureus infection has a long-term impact on the genome and epigenome of host cells, which may exert patho-physiological dysfunctions additionally to the defense response during the infection process. Overall, these results not only improve our conceptual understanding of biological processes involved in the long-term S. aureus infections of osteoblast-like cells, but also provide an atlas of deregulated host genes and biological pathways and identify novel markers and potential candidates for prophylactic and therapeutic approaches.

Carotid intima-media thickness and flow-mediated dilation do not predict acute in-hospital outcomes in patients hospitalized with COVID-19.

Studies have suggested a potential role of endothelial dysfunction and atherosclerosis in the pathophysiology of COVID-19. Herein, we tested whether brachial flow-mediated dilation (FMD) and carotid intima-media thickness (cIMT) measured upon hospital admission are associated with acute in-hospital outcomes in patients hospitalized with COVID-19. A total of 211 patients hospitalized with COVID-19 were submitted to assessments of FMD and mean and maximum cIMT (cIMTmean and cIMTmax) within the first 72 h of hospital admission. Study primary outcome was a composite of intensive care unit admission, mechanical ventilation, or death during the hospitalization. These outcomes were also considered independently. Thrombotic events were included as a secondary outcome. Odds ratios (ORs) and confidence intervals (CIs) were calculated using unadjusted and adjusted multivariable logistic regression models. Eighty-eight (42%) participants demonstrated at least one of the composite outcomes. cIMTmean and cIMTmax were predictors of mortality and thrombotic events in the univariate analysis (cIMTmean and mortality: unadjusted OR 12.71 [95% CI 1.71–94.48]; P = 0.014; cIMTmean and thrombotic events: unadjusted OR 11.94 [95% CI 1.64–86.79]; P = 0.015; cIMTmax and mortality: unadjusted OR 8.47 [95% CI 1.41–51.05]; P = 0.021; cIMTmax and thrombotic events: unadjusted OR 12.19 [95% CI 2.03–73.09]; P = 0.007). However, these associations were no longer present after adjustment for potential confounders (P > 0.05). In addition, FMD% was not associated with any outcome. In conclusion, cIMT and FMD are not independent predictors of clinical outcomes in patients hospitalized with COVID-19. These results suggest that subclinical atherosclerosis and endothelial dysfunction may not be the main drivers of COVID-19 complications in patients hospitalized with COVID-19.NEW & NOTEWORTHY Studies have suggested a role of endothelial dysfunction and atherosclerosis in COVID-19 pathophysiology. In this prospective cohort study, we assessed the prognostic value of carotid intima-media thickness (IMT) and flow-mediated dilation (FMD) in patients with COVID-19. Carotid IMT and FMD were not independent predictors of major outcomes. These results suggest that other risk factors may be the main drivers of clinical outcomes in patients with COVID-19.

Association of choroidal blood flow with autonomic dysfunction in patients with normal tension glaucoma

There is increasing evidence that autonomic dysfunction is an important factor in the progression of glaucoma. Mechanism of the association between autonomic dysfunction and progression of glaucoma is poorly understood. Since blood circulation is basically regulated by the autonomic nervous system, autonomic dysfunction may contribute to unstable or fluctuating blood pressure. Therefore, It is hypothesized that autonomic dysfunction may contribute to impaired ocular blood flow and lead to glaucoma progression. However, no clinical study yet has evaluated the relationship between ocular blood flow and autonomic nervous function. We enrolled 152 open angle glaucoma patient. Ocular blood flow was assessed by measuring vessel density (VD) using optical coherence tomography angiography, and autonomic nervous function was evaluated with heart-rate variability (HRV) parameters. The low frequency/high frequency (LF/HF) ratio, which is one of the HRV parameters, quantified the degree of sympathovagal balance. This indicator could represent autonomic dysfunction. Higher LF/HF ratio was associated with reduction of the deep parapapillary VD (R = − 0.243, P = 0.003). Linear regression analysis showed a significant negative association between parapapillary choroidal VD and LF/HF ratio (β = − 0.249; 95% confidential interval = − 1.193 to − 0.249; P = 0.002) in multivariate analysis. We demonstarted the association between impaired ocular blood flow (parapapillary choroidal vessel density) and autonomic dysfunction (LF/HF ratio). This study could help understand the role of the autonomic dysfunction in pathophysiology of glaucoma progression.

Metallome deregulation and health-related impacts due to long-term exposure to recent volcanic ash deposits: New chemical and isotopic insights

Volcanic ash exposure can lead to significant health risks. Damage to the respiratory and pulmonary systems are the most evident toxic side effects although the causes of these symptoms remain unclear. Conversely, the effects on other organs remain largely under-explored, limiting our understanding of the long-term volcanic ash-related risk at the whole-body scale. The metallome i.e. metal concentrations and isotopic compositions within the body, is suspected to be affected by volcanic ash exposure, having thus the potential for capturing some specificities of ash toxicity. However, the means by and extent to which the metallome is affected at the entire body scale and how the consequent chemical and isotopic deregulations correlate with pathophysiological dysfunctions are currently poorly understood. Here, we adopt a transdisciplinary approach combining high precision chemical analyses (major and trace element concentrations) and CuZn isotope measurements in seven organs and two biological fluids of isogenic mice (C57BL/6) exposed to eruption products from La Soufrière de Guadeloupe (Eastern Carribean), in tandem with biological parameters including physiological and morphological data. Based on principal component analysis, we show that after one month of exposure to volcanic ash deposits, the mice metallome; originally organ-specific and isotopically-typified, is highly disrupted as shown for example by heavy metal accumulation in testis (e.g., Fe, Zn) and Cu, Zn isotopic divergence in liver, intestine and blood. These metallomic variations are correlated with early testicular defects and might reflect the warning signs of premature (entero)hepatic impairments that may seriously affect fertility and favor the emergence of liver diseases after prolonged exposure. Monitoring the temporal evolution of the Cu and Zn isotope compositions seems to be a promising technique to identify the main biological processes and vital functions that are vulnerable to environmental volcanogenic pollutants although this will require further validation on human subjects.

Eyes on amyloidosis: microvascular retinal dysfunction in cardiac amyloidosis

AimsCardiac involvement in systemic amyloidosis is a marker of particularly poor prognosis. Cardiac amyloidosis (CA) is characterized by extracellular amyloid deposits inducing heart failure and symptoms of cardiac microvascular disease. While amyloid deposition is most common in the myocardium but also seen in pericardium and endocardium, atria, and vasculature, the role of (micro‐)vascular dysfunction in CA pathophysiology remains still elusive. Because vascular function is associated with cardiovascular risk and severity of heart failure and represents a potential therapeutic target in CA, the present study investigated retinal vascular function, flow‐mediated dilatation (FMD), and pulse‐wave analysis and velocity (PWA/PWV) in patients with CA.Methods and resultsFlicker‐induced arterial dilatation (FIDa) was measured using dynamic retinal vessel analysis additionally to FMD and PWA/PWV. Thirty‐three patients with CA [age 67 years [interquartile range, IQR, 62, 74], 14 with amyloid light‐chain (AL) and 19 with transthyretin (ATTR) amyloidosis] were prospectively included in this cross‐sectional, observational study and 70 healthy individuals (age 53 years [IQR 39, 67]) served as control. Potential confounders were balanced using entropy balancing propensity score analysis [inverse probability weighting (IPW)]. FIDa was reduced in CA patients (1.52 ± 1.73% vs. 3.09 ± 1.96%, P < 0.001, after IPW). While PWV was increased (8.74 ± 2.34 m/s vs. 7.49 ± 1.65 m/s, P = 0.018, after IPW), no difference in FMD was observed. FIDa was significantly associated with prognostic biomarkers of CA [estimated glomerular filtration rate (r = 0.33; P < 0.001), log‐scaled troponin T (r = −0.49; P < 0.001), and N‐terminal pro‐B‐type natriuretic peptide (r = −0.51; P < 0.001)].ConclusionsRetinal vascular function is impaired, associated with cardiac and renal biomarkers of CA severity, and may represent a potential therapeutic target in patients with amyloidosis.