We describe the case of a 62‐year‐old female presenting with new onset progressive dyspnea on exertion and a new diagnosis of aortic stenosis. Transesophageal echocardiography showed fusion of the ...aortic valve leaflets suspicious for bicuspid aortic valve with dilated ascending aorta. Surgical replacement of the valve revealed a unicuspid aortic valve with one true commissure at the level of the left and noncoronary cusps. The case is supported by clinical, echocardiographic and angiographic imaging and discussion of current imaging modalities used in diagnosis of aortic valve pathology.
Mini‐
We describe a case of a 62‐year old female with newly diagnosed severe aortic stenosis and is found to have a unicuspid aortic valve. Transesophageal echocardiography suggested a bicuspid aortic valve, however surgical valve replacement revealed the valve to be unicuspid. This case report provides discussion of epidemiology of unicuspid aortic valves as well as current imaging modalities used for diagnosis of aortic valve pathology.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with diverse oncogenic drivers, the relative contributions of which remain obscure. Enforced expression of select oncogenes is ...sufficient to generate T-ALL in mice, however, mouse models are limited in their value for understanding human disease. We recently developed the first “synthetic” model of human T-ALL by lentiviral transduction of normal human CD34+ cord blood progenitors with a combination of four known T-ALL oncogenes: NOTCH1, LMO2, TAL1, and BMI1 (NLTB). These cells expand robustly in culture and produce aggressive, serially transplantable T-ALL in immunodeficient mice. Additionally, we found that LTB alone fails to perform in vitro or in vivo, highlighting an essential role of NOTCH1. To determine the minimal complement of oncogenes required to generate de novo human T-ALL, we executed a “leave-one-out” and “leave-two-out” strategy. We scored the following oncogene combinations in vitro and in vivo: NLB, NLT, NTB, NL, NT, and NB. We found that the various oncogene combinations yielded a spectrum of aberrant phenotypes affecting cell differentiation and proliferation, and a subset produced aggressive leukemias in mice. We also performed RNA-seq on non-leukemogenic and preleukemic cell populations, and fully transformed leukemic cells to define gene expression programs necessary for cellular transformation. Our approach allows us to attribute specific gene programs and cellular phenotypes to each oncogene individually and in combination. Our synthetic approach is flexible, reproducible, and experimentally tractable, allowing functional testing of individual genetic variants and can also serve as a customizable platform for testing of targeted therapeutics.
During T-APC interactions in vivo, interfering with CD40-CD154 interactions leads to reduced T cell priming, defects in effector function, and, in some cases, T cell tolerance. As shown here, ...however, presentation of conventional peptide Ags by CD40-deficient spleen APC in vitro leads to normal CD4+ T cell proliferative responses. By contrast, responses to the same peptides presented by purified B cells were markedly reduced in the absence of CD40. Thus, the requirement for CD40-CD154 interactions appears to be strongly influenced by the type of APC involved. Analysis of responses to endogenous superantigens, which are known to be strongly dependent on B cells for presentation, indicated that CD4+ responses to strong Ags are less dependent on CD40 than are responses to weak Ags. Similar findings applied to negative selection in the thymus. Thus, deletion of potentially autoreactive cells depended on CD40 expression when B APC were involved, and this requirement was most pronounced when negative selection was directed to weak Ags.
Giant cell myocarditis (GCM), a rapidly progressive inflammation of the myocardium, is associated with fulminant heart failure, refractory ventricular arrhythmias, and conduction system ...abnormalities. Few case reports have noted orbital myositis as the initial clinical presentation. Our case demonstrates a unique presentation of GCM with only ocular symptoms, which unlike prior studies, rapidly progressed to heart failure, tachyarrhythmias, and conduction disease. Our case necessitated quick recognition and treatment with mechanical support making this the first known case of GCM with successful placement of biventricular assist devices and ultimately with heart transplantation.
Objective
Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late‐onset Alzheimer's disease, with the ε4 allele increasing risk in a dose‐dependent fashion. In addition to ...ApoE4 playing a crucial role in amyloid‐β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau‐mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau‐mediated neurodegeneration.
Methods
Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age.
Results
Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO‐treated mice.
Interpretation
We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952–966
Bone is capable of adapting during life in response to stress. Therefore, variation in locomotor and manipulative behaviours across extant hominoids may be reflected in differences in trabecular bone ...structure. The hand is a promising region for trabecular analysis, as it is the direct contact between the individual and the environment and joint positions at peak loading vary amongst extant hominoids. Building upon traditional volume of interest-based analyses, we apply a whole-epiphysis analytical approach using high-resolution microtomographic scans of the hominoid third metacarpal to investigate whether trabecular structure reflects differences in hand posture and loading in knuckle-walking (Gorilla, Pan), suspensory (Pongo, Hylobates and Symphalangus) and manipulative (Homo) taxa. Additionally, a comparative phylogenetic method was used to analyse rates of evolutionary changes in trabecular parameters. Results demonstrate that trabecular bone volume distribution and regions of greatest stiffness (i.e., Young's modulus) correspond with predicted loading of the hand in each behavioural category. In suspensory and manipulative taxa, regions of high bone volume and greatest stiffness are concentrated on the palmar or distopalmar regions of the metacarpal head, whereas knuckle-walking taxa show greater bone volume and stiffness throughout the head, and particularly in the dorsal region; patterns that correspond with the highest predicted joint reaction forces. Trabecular structure in knuckle-walking taxa is characterised by high bone volume fraction and a high degree of anisotropy in contrast to the suspensory brachiators. Humans, in which the hand is used primarily for manipulation, have a low bone volume fraction and a variable degree of anisotropy. Finally, when trabecular parameters are mapped onto a molecular-based phylogeny, we show that the rates of change in trabecular structure vary across the hominoid clade. Our results support a link between inferred behaviour and trabecular structure in extant hominoids that can be informative for reconstructing behaviour in fossil primates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce ...Aβ pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aβ pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in Aβ plaque size and a reduction in plaque-associated neuritic dystrophy with no change in overall plaque load. These results suggest that lowering apoE levels prior to plaque deposition can strongly affect the initiation of Aβ pathology while lowering apoE after Aβ seeding modulates plaque size and toxicity.
•ApoE has little effect on Aβ accumulation after the initial seeding stage•Decreasing apoE once fibrils have formed leads to an increase in plaque size•ApoE4 reduction decreases neuritic dystrophy, independent of Aβ plaque load•ApoE-targeted therapies aiming to reduce Aβ plaques should focus on prevention
Huynh et al. demonstrated that apoE3 and apoE4 are critical factors in promoting amyloidosis during the early stages of Aβ plaque formation but not during the exponential growth phase. Importantly, reduction of apoE4 decreases neuritic dystrophy independent of Aβ pathology.
De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized ...by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery. The intractable epilepsy that is associated with HME can be relieved by the surgical treatment hemispherectomy, allowing sampling of diseased tissue. Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. A recurrent PIK3CA c.1633G>A mutation was found in four separate cases. Identified mutations were present in 8-40% of sequenced alleles in various brain regions and were associated with increased neuronal S6 protein phosphorylation in the brains of affected individuals, indicating aberrant activation of mammalian target of rapamycin (mTOR) signaling. Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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