Aggressive angiomyxoma (AAM) is a rare tumor with a high risk of local recurrence. Scrotal AAM mimics common pediatric pathologies including hernia or hydrocele. We present 11-year-old boy who ...underwent macroscopically radical excision of right scrotal AAM. The patient has been already followed up for 29 months utilizing US every 6 months and MRI every 2 years. Residual scrotal mass has been visualized in MRI 3 months after surgery however no further growth was reported. Long term follow up with reliable local imaging is mandatory.
Summary
Esophageal atresia (EA) is a congenital defect of the esophagus involving the interruption of the esophagus with or without connection to the trachea (tracheoesophageal fistula TEF). EA/TEF ...may occur as an isolated anomaly, may be part of a complex of congenital defects (syndromic), or may develop within the context of a known syndrome or association. The molecular mechanisms underlying the development of EA are poorly understood. It is supposed that a combination of multigenic factors and epigenetic modification of genes play a role in its etiology.
The aim of our work was to assess the human gene expression microarray study in esophageal tissue samples. Total RNA was extracted from 26 lower pouches of esophageal tissue collected during thoracoscopic EA repair in neonates with the isolated (IEA) and the syndromic form (SEA).
We identified 787 downregulated and 841 upregulated transcripts between SEA and controls, and about 817 downregulated and 765 upregulated probes between IEA and controls. Fifty percent of these genes showed differential expression specific for either IEA or SEA. Functional pathway analysis revealed substantial enrichment for Wnt and Sonic hedgehog, as well as cytokine and chemokine signaling pathways. Moreover, we performed reverse transcription polymerase chain reaction study in a group of SHH and Wnt pathways genes with differential expression in microarray profiling to confirm the microarray expression results. We verified the altered expression in SFRP2 gene from the Wnt pathway as well as SHH, GLI1, GLI2, and GLI3 from the Sonic hedgehog pathway. The results suggest an important role of these pathways and genes for EA/TEF etiology.
Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory ...system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.
Parkinson’s disease (PD) is a progressive neurological disorder estimated to affect 7–10 million people worldwide. There is no treatment available that cures or slows the progression of PD. Elevated ...leucine-rich repeat kinase 2 (LRRK2) activity has been associated with genetic and sporadic forms of PD and, thus, reducing LRRK2 function is a promising therapeutic strategy. We have previously reported that an antisense oligonucleotide (ASO) that blocks splicing of LRRK2 exon 41, which encodes part of the kinase domain, reverses aberrant endoplasmic reticulum (ER) calcium levels and mitophagy defects in PD patient-derived cell lines harboring the LRRK2 G2019S mutation. In this study, we show that treating transgenic mice expressing human wild-type or G2019S LRRK2 with a single intracerebroventricular injection of ASO induces exon 41 skipping and results in a decrease in phosphorylation of the LRRK2 kinase substrate RAB10. Exon 41 skipping also reverses LRRK2 kinase-dependent changes in LC3B II/I ratios, a marker for the autophagic process. These results demonstrate the potential of LRRK2 exon 41 skipping as a possible therapeutic strategy to modulate pathogenic LRRK2 kinase activity associated with PD development.
Display omitted
Splice-switching antisense oligonucleotides (ASOs) targeting a Parkinson’s disease (PD)-associated LRRK2 variant were tested in human-derived fibroblasts and transgenic mice. One ASO dose in mice resulted in long-term LRRK2 targeting and decreased RAB10 phosphorylation and LC3B II/I ratios, suggesting LRRK2 functional changes, and promoting ASOs as a therapeutic strategy for PD.
Sandhoff disease (SD) is a lysosomal storage disease, caused by loss of β-hexosaminidase (HEX) activity resulting in the accumulation of ganglioside GM2. There are shared features between SD and ...Parkinson's disease (PD). α-synuclein (aSYN) inclusions, the diagnostic hallmark sign of PD, are frequently found in the brain in SD patients and HEX knockout mice, and HEX activity is reduced in the substantia nigra in PD. In this study, we biochemically demonstrate that HEX deficiency in mice causes formation of high-molecular weight (HMW) aSYN and ubiquitin in the brain. As expected from HEX enzymatic function requirements, overexpression in vivo of HEXA and B combined, but not either of the subunits expressed alone, increased HEX activity as evidenced by histochemical assays. Biochemically, such HEX gene expression resulted in increased conversion of GM2 to its breakdown product GM3. In a neurodegenerative model of overexpression of aSYN in rats, increasing HEX activity by AAV6 gene transfer in the substantia nigra reduced aSYN embedding in lipid compartments and rescued dopaminergic neurons from degeneration. Overall, these data are consistent with a paradigm shift where lipid abnormalities are central to or preceding protein changes typically associated with PD.
There is increasing evidence that cell elastic properties should change considerably in response to chemical agents affecting the physiological state of the endothelium. In this work, a novel assay ...for testing prospective endothelium-targeted agents in vitro is presented.
The proposed methodology is based on nanoindentation spectroscopy using an atomic force microscope tip, which allows for quantitative evaluation of cell stiffness. As an example, we chose a pyridine derivative, 1-methylnicotinamide chloride (MNA), known to have antithrombotic and anti-inflammatory properties, as reported in recent in vivo experiments.
First, we determined a concentration range of MNA in which physiological parameters of the endothelial cells in vitro are not affected. Then, cell dysfunction was induced by incubation with tumor necrosis factor-alpha (TNF-α) and the cellular response to MNA treatment after TNF-α incubation was studied. In parallel to the nanoindentation spectroscopy, the endothelium phenotype was characterized using a fluorescence spectroscopy with F-actin labeling, and biochemical methods, such as secretion measurements of both nitric oxide (NO), and prostacyclin (PGI2) regulatory agents.
We found that MNA could reverse the dysfunction of the endothelium caused by inflammation, if applied in the proper time and to the concentration scheme established in our investigations. A surprisingly close correlation was found between effective Young's modulus of the cells and actin polymerization/depolymerization processes in the endothelium cortical cytoskeleton, as well as NO and PGI2 levels. These results allow us to construct the physiological model of sequential intracellular pathways activated in the endothelium by MNA.
IMPORTANCE: Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor ...disease progression in AD remains unclear. OBJECTIVE: To study the potential of longitudinal plasma p-tau181 measures for assessing neurodegeneration progression and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study included data from the Alzheimer’s Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2016. Follow-up blood sampling was performed for up to 8 years. Plasma p-tau181 measurements were performed in 2020. This was a multicentric observational study of 1113 participants, including cognitively unimpaired participants as well as patients with cognitive impairment (mild cognitive impairment and AD dementia). Participants were eligible for inclusion if they had available plasma p-tau181 and NfL measurements and at least 1 fluorine-18–labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan performed at the same study visit. Exclusion criteria included any significant neurologic disorder other than suspected AD; presence of infection, infarction, or multiple lacunes as detected by magnetic resonance imaging; and any significant systemic condition that could lead to difficulty complying with the protocol. EXPOSURES: Plasma p-tau181 and NfL measured with single-molecule array technology. MAIN OUTCOMES AND MEASURES: Longitudinal imaging markers of neurodegeneration (FDG PET and structural magnetic resonance imaging) and cognitive test scores (Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks). Data were analyzed from June 20 to August 15, 2020. RESULTS: Of the 1113 participants (mean SD age, 74.0 7.6 years; 600 men 53.9%; 992 non-Hispanic White participants 89.1%), a total of 378 individuals (34.0%) were cognitively unimpaired (CU) and 735 participants (66.0%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia. Longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r = –0.24, P < .001; CImp: r = 0.34, P < .001) and a prospective decrease in glucose metabolism (CU: r = –0.05, P = .48; CImp: r = –0.27, P < .001) and gray matter volume (CU: r = –0.19, P < .001; CImp: r = –0.31, P < .001) in highly AD-characteristic brain regions. These associations were restricted to amyloid-β–positive individuals. Both plasma p-tau181 and NfL were independently associated with cognition and neurodegeneration in brain regions typically affected in AD. However, NfL was also associated with neurodegeneration in brain regions exceeding this AD-typical spatial pattern in amyloid-β–negative participants. Mediation analyses found that approximately 25% to 45% of plasma p-tau181 outcomes on cognition measures were mediated by the neuroimaging-derived markers of neurodegeneration, suggesting links between plasma p-tau181 and cognition independent of these measures. CONCLUSIONS AND RELEVANCE: Study findings suggest that plasma p-tau181 was an accessible and scalable marker for predicting and monitoring neurodegeneration and cognitive decline and was, unlike plasma NfL, AD specific. The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials.
Abstract
Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by National Science Center grant SONATA BIS No. ...2016/22/E/NZ3/00405 (AGP) and the project for PhD students and Young Scientists FBBB N19/MNW/000005 (AK).
Background
Abdominal aortic aneurysm (AAA) is a permanent dilatation of the abdominal aorta, which bears a high risk of rupture and sudden death of the patient. The pathogenic mechanisms of AAA remain elusive and surgical intervention represents the only treatment option. The involvement of endothelial cells (ECs) in the formation of aneurysms is still a matter of debate.
Purpose
As AAA is an age-related cardiovascular disease, we aimed to investigate the role of age-related miRNA-34a in ECs in pathogenesis of AAA. The deficiency of this miRNA has been so far proved preventive in several cardiovascular disease settings; however, the detailed mechanisms of protection have not been elucidated and the impact on EC function has not been addressed.
Methods
In vitro experiments were performed on primary human aortic ECs with RNA interference-mediated depletion of miRNA-34a. Animal studies were done on tamoxifen-induced EC-specific knockout of miRNA-34a or Rainbow mice. For aneurysm studies, we used an angiotensin II (AngII)-based model. Aortas and ECs were characterised using intravital microscopy, atomic force microscopy, fluorescent stainings, EPR, blood pressure measurements and Doppler flowmetry.
Results
Deficiency of miRNA-34a in vivo led to age-dependent EC dysfunction, as evidenced by a decreased length and coverage of glycocalyx and reduced NO production, with a concomitant increase in arterial stiffness, leukocyte adhesion and prothrombotic phenotype. However, despite detrimental effects of miRNA-34a deficiency on EC function, it did not result in a higher aneurysm incidence in young mice in AngII model. Quite surprisingly, the formation of the aneurysm was abrogated in older miRNA-34aEC-KO animals. Changes in expression of AngII receptors, proinflammatory molecules or blood pressure could not account for these anti-AAA effects of miRNA deficiency. Instead, we found significantly enhanced proliferation of intimal ECs upon AngII in young and old miRNA-34aEC-KO mice. The results were further corroborated in vitro, where we demonstrated loss of endothelial markers, with a concomitant increase in proliferation and preserved angiogenic function of miRNA-34aEC-KO. Additionally, we used multicolour EC lineage tracing to address the significance of endothelial proliferation during aneurysm formation. In stable aneurysms, we observed a polyclonal expansion of ECs in the intimal layer and, particularly, in the aneurysmal area. Of note, we did not detect any EC proliferation in the ruptured AAA.
Conclusions
miRNA-34a deficiency impairs EC function and stimulate EC proliferation, the latter presumably determined protection against Ang-II AAA in older mice. Therefore, we postulate that EC proliferation plays a more significant role than the preservation of EC function in protection against AAA. The fine-tuning of ECs proliferation may have a therapeutical role in the treatment of aneurysms.
PDF
