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Blood Advances Dec 2021β1-Tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet...
β1-Tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying 6 β1-tubulin variants, p.Cys12LeufsTer12, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size, and a minority had no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets but had a negligible effect on platelet activation, secretion, or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.
Topics: Blood Platelets; Humans; Megakaryocytes; Thrombocytopenia; Tubulin
PubMed: 34516618
DOI: 10.1182/bloodadvances.2020004057 -
Journal of Cerebral Blood Flow and... Oct 2023Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are...
Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width - RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p - [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers.
Topics: Humans; Middle Aged; Age Factors; Alzheimer Disease; Apolipoprotein E4; Cerebrovascular Circulation; Erythrocyte Indices; Heterozygote
PubMed: 37132287
DOI: 10.1177/0271678X231173587 -
Antioxidants (Basel, Switzerland) Jan 2023Viral infections activate the innate immune response and the secretion of inflammatory cytokines. They also alter oxidative stress markers, which potentially can have an...
Viral infections activate the innate immune response and the secretion of inflammatory cytokines. They also alter oxidative stress markers, which potentially can have an involvement in the pathogenesis of the disease. The aim of this research was to study the role of the oxidative stress process assessed through lactate dehydrogenase (LDH) on the severity of COVID-19 measured by oxygen saturation (SaO) and the putative interaction with inflammation. The investigation enrolled 1808 patients (mean age of 68 and 60% male) with COVID-19 from the HM Hospitals database. To explore interactions, a regression model and mediation analyses were performed. The patients with lower SaO presented lymphopenia and higher values of neutrophils-to-lymphocytes ratio and on the anisocytosis coefficient. The regression model showed an interaction between LDH and anisocytosis, suggesting that high levels of LDH (>544 U/L) and an anisocytosis coefficient higher than 10% can impact SaO in COVID-19 patients. Moreover, analysis revealed that LDH mediated 41% ( value = 0.001) of the effect of anisocytosis on SaO in this cohort. This investigation revealed that the oxidative stress marker LDH and the interaction with anisocytosis have an important role in the severity of COVID-19 infection and should be considered for the management and treatment of the oxidative phenomena concerning this within a precision medicine strategy.
PubMed: 36829793
DOI: 10.3390/antiox12020234 -
Frontiers in Pediatrics 2023Although SARS-CoV-2 infection can lead to severe COVID-19 in children, the role of biomarkers for assessing the risk of progression to severe disease is not well...
INTRODUCTION
Although SARS-CoV-2 infection can lead to severe COVID-19 in children, the role of biomarkers for assessing the risk of progression to severe disease is not well established in the pediatric population. Given the differences in monocyte signatures associated with worsening COVID-19 in adults, we aimed to determine whether monocyte anisocytosis early in the infectious course would correspond with increasing severity of COVID-19 in children.
METHODS
We performed a multicenter retrospective study of 215 children with SARS-CoV-2 infection, Multisystem Inflammatory Syndrome in Children (MIS-C), convalescent COVID-19, and healthy age-matched controls to determine whether monocyte anisocytosis, quantified by monocyte distribution width (MDW) on complete blood count, was associated with increasing severity of COVID-19. We performed exploratory analyses to identify other hematologic parameters in the inflammatory signature of pediatric SARS-CoV-2 infection and determine the most effective combination of markers for assessing COVID-19 severity in children.
RESULTS
Monocyte anisocytosis increases with COVID-19 severity and need for hospitalization. Although other inflammatory markers such as lymphocyte count, neutrophil/lymphocyte ratio, C-reactive protein, and cytokines correlate with disease severity, these parameters were not as sensitive as MDW for identifying severe disease in children. An MDW threshold of 23 offers a sensitive marker for severe pediatric COVID-19, with improved accuracy when assessed in combination with other hematologic parameters.
CONCLUSION
Monocyte anisocytosis corresponds with shifting hematologic profiles and inflammatory markers in children with COVID-19, and MDW serves as a clinically accessible biomarker for severe COVID-19 in children.
PubMed: 37425266
DOI: 10.3389/fped.2023.1177048 -
Frontiers in Veterinary Science 2023Red blood cell distribution width (RDW) and visual assessments of anisocytosis assess variability in erythrocyte size. Veterinary studies on the correlation between the...
Red blood cell distribution width (RDW) and visual assessments of anisocytosis assess variability in erythrocyte size. Veterinary studies on the correlation between the two methods and on observer agreement are scarce. The objectives were to assess the correlation of the grading of anisocytosis by means of conventional microscopy of canine blood smears to RDW, and to assess intra- and inter-observer variation in assessing the degree of anisocytosis. The study included 100 canine blood samples on which blood smear examination and RDW measurement were performed. RDW was measured on the Advia 2120i analyzer. The degree of anisocytosis was based on a human grading scheme assessing the ratio between the size of the representative largest red blood cell and that of the representative smallest red blood cell (1+ if <2x, 2+ if 2-3x, 3+ if 3-4x, and 4+ if >4x). Three observers participated and assessed the blood smears by conventional microscopy twice, 3 weeks apart by each observer. The correlation was assessed for each observer on each occasion using Kendahl-tau-b analysis. Intra-observer agreement was assessed using quadratically weighted kappa. Inter-observer agreement was assessed using free-marginal multi-rater kappa. Anisocytosis graded on blood smears correlated significantly with RDW values as assessed by Kendahl-tau-b ranging between 0.37 and 0.51 ( < 0.0001). Intra-observer agreement ranged from weak to moderate with resulting kappa-coefficients being 0.58, 0.68, and 0.75, respectively. Inter-observer agreement was weak (Kappa-values 0.44). The weak to moderate observer agreement in the visual assessment of anisocytosis indicates that the more precise and more repeatable RDW measurement should be used for clinical decision-making.
PubMed: 37808118
DOI: 10.3389/fvets.2023.1258857 -
Journal of Comparative Pathology Apr 2023A 12-year-old male neutered Australian Shepherd Dog was presented to Charlotte Animal Referral & Emergency with a history of a thoracic mass. On physical examination,...
A 12-year-old male neutered Australian Shepherd Dog was presented to Charlotte Animal Referral & Emergency with a history of a thoracic mass. On physical examination, physiological parameters were within the normal ranges, and a complete haemogram and serum biochemistry profile were unremarkable except for mild thrombocytopenia. A computed tomography scan revealed a 21 × 15 × 12.7 cm thoracic mass encompassing the cranial mediastinum and extending to the right caudal thorax. The mass was surgically removed and histopathological evaluation revealed that it comprised remnants of the thymus and a neoplasm composed of large blood-filled vascular spaces lined by a single layer of endothelial cells with mild anisocytosis and anisokaryosis. The neoplastic cells had diffuse strong immunolabeling for endothelial cell marker CD31. Multifocally, there were large cystic degenerated areas of thymic tissue lined by plump cytokeratin AE1/AE3-positive epithelial cells. Based on these findings, a diagnosis of thymic cavernous haemangioma (CH) was made. Thymic CH is rare in animals, with the only reported case in a cross bred cow. To our knowledge, this is the first case of a thymic CH in a dog.
Topics: Male; Female; Cattle; Dogs; Animals; Endothelial Cells; Australia; Hemangioma, Cavernous; Dog Diseases; Tomography, X-Ray Computed; Cattle Diseases
PubMed: 36931010
DOI: 10.1016/j.jcpa.2023.02.001 -
Kardiologia Polska May 2020Previous studies have shown that red blood cell distribution width (RDW) is an independent predictor of poor prognosis in type 2 diabetes (T2D) and atherosclerotic...
Relationship among the leptin-to-adiponectin ratio, systemic inflammation, and anisocytosis in well-controlled type 2 diabetic patients with atherosclerotic cardiovascular disease.
BACKGROUND
Previous studies have shown that red blood cell distribution width (RDW) is an independent predictor of poor prognosis in type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). The mechanisms underlying increased anisocytosis in patients with T2D and confirmed ASCVD remain poorly understood.
AIMS
We sought to evaluate the relationship among the leptin-to-adiponectin ratio, systemic low -grade inflammation, and RDW in optimally treated patients with T2D and established ASCVD.
METHODS
A total of 68 patients, aged 47 to 85 years (mean [SD], 65.3 [6.8] years) and including 21 women (30.9%), were enrolled and grouped according to median RDW into those with RDW <13.5% (n = 33) and those with RDW ≥13.5% (n = 35).
RESULTS
Patients with RDW ≥13.5% had a significantly higher median (interquartile range [IQR]) serum leptin-to-adiponectin ratio (1.7 [0.49-2.3] ng/μg vs 0.66 [0.31-1.25] ng/μg; P = 0.04) and median (IQR) tumor necrosis factor α levels (1.58 [1.42-1.97] pg/ml vs 1.39 [1.18-1.57] pg/ml; P = 0.02). There were no significant differences in the concentrations of other inflammatory markers. The leptin-to-adiponectin ratio (r = 0.25; P = 0.04) and levels of tumor necrosis factor α (r = 0.32; P = 0.01) and soluble intercellular adhesion molecule 1 (r = 0.31; P = 0.01) were positively correlated with RDW, which was confirmed by univariate linear regression analysis. A multivariable regression model, which included demographic, clinical, and laboratory data, showed that white blood cell count (β = 0.25; 95% CI, 0.05-0.45; P = 0.01), soluble intercellular adhesion molecule 1 levels (β = 0.21; 95% CI, 0.02-0.41; P = 0.03), and mean corpuscular hemoglobin concentration (MCHC), (β = -0.48; 95% CI, 0.67 to -0.28; P < 0.001) were independent predictors of RDW in our patients.
CONCLUSIONS
In well-controlled patients with T2D and ASCVD, the RDW values are associated with leptin-to-adiponectin imbalance and selected inflammatory markers.
Topics: Adiponectin; Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Erythrocyte Indices; Female; Humans; Inflammation; Leptin; Male; Middle Aged
PubMed: 32210218
DOI: 10.33963/KP.15257 -
Veterinary Clinical Pathology Jun 2022An 8-year-old mixed breed male dog was presented with a mass on the rostral mandibular gingiva that quickly emerged 2-3 weeks prior to presentation. The mass was firm,...
An 8-year-old mixed breed male dog was presented with a mass on the rostral mandibular gingiva that quickly emerged 2-3 weeks prior to presentation. The mass was firm, smooth, well-circumscribed, and approximately 2 × 1 × 0.5 cm in size rostral to the left mandibular canine tooth (304). Clinical examination and radiographs were unremarkable. Cytology revealed two distinct cell populations, consisting of numerous uniform-appearing epithelial cell clusters and low numbers of individual spindle cells. Epithelial cells had mild anisocytosis and anisokaryosis, round nuclei with finely stippled chromatin, no prominent nucleoli, high N:C ratios, and low amounts of pale basophilic cytoplasm. Slender spindle cells observed had oval nuclei with no prominent nucleoli and wispy cytoplasm. On histopathologic examination, the lamina propria of the gingiva was dissected by numerous irregular and anastomosing trabeculae and islands of neoplastic epithelial cells. Neoplastic cells were focally in connection with the hyperplastic overlying epithelium. The trabeculae were surrounded and embedded by cell-rich fibrous stroma. Peripheral to the islands and trabeculae, cells were arranged in palisades, and the nuclei had an antibasilar location. The epithelial cells had prominent intercellular bridges, low amounts of cytoplasm, and one round to oval nucleus. Anisocytosis and anisokaryosis were mild to moderate, and six mitoses/10 HPF were present. Tumor cells reached the deep sample margins. Histopathologic evaluation was consistent with acanthomatous ameloblastoma. This locally aggressive neoplasm causes alveolar bone lysis and often extends beyond alveolar bone margins. Acanthomatous ameloblastoma is an important differential for rostral mandibular gingival masses containing numerous uniform epithelial cell clusters with rare slender spindle cells.
Topics: Ameloblastoma; Animals; Dog Diseases; Dogs; Male
PubMed: 35178757
DOI: 10.1111/vcp.13080 -
Kardiologia Polska 2022
The relationship between anisocytosis, quantitative and qualitative characteristics of coronary atherosclerosis, and major adverse cardiac events in patients with coronary artery disease: Rationale and study design.
Topics: Coronary Angiography; Coronary Artery Disease; Humans; Myocardial Infarction; Risk Factors
PubMed: 35475462
DOI: 10.33963/KP.a2022.0111 -
Veterinary Clinical Pathology Sep 2023Nasal tumors account for less than 10% of all feline neoplasms, with lymphoma, followed by adenocarcinoma, and squamous cell carcinoma, the most commonly reported. Nasal... (Review)
Review
Nasal tumors account for less than 10% of all feline neoplasms, with lymphoma, followed by adenocarcinoma, and squamous cell carcinoma, the most commonly reported. Nasal neuroectodermal tumors, including olfactory neuroblastoma (ONB), are scarcely described, and their tumorigenesis is largely unknown. Here we report the cytological, histological, and immunohistochemical features of a feline ONB. We also provide a pathological review of nasal neuroendocrine neoplasms in cats. A 7-year-old Burmese cat was evaluated for sneezing, occasional epistaxis, and upper respiratory noise for 8 months. Computed tomography (CT) imaging revealed a 7 × 5 × 3 mm irregular mass effacing and expanding the nasal cavity, which extended to the nasopharynx. Cytologically, neoplastic cells were round to polygonal and had a round nucleus with finely stippled chromatin, a single small nucleolus, and abundant pale blue cytoplasm, which contained abundant fine pale pink granules. They exhibited mild cellular atypia, anisocytosis, and mild to occasionally moderate anisokaryosis. Rhinoscopic biopsies revealed a densely cellular, malignant neuroepithelial neoplasm. Cells were arranged in densely packed trabeculae and formed Homer Wright and Flexner-Wintersteiner-like rosettes, with rare mitotic figures and scant supportive fibrovascular stroma. Immunohistochemically, neoplastic cells were positive for vimentin, cytokeratin AE1/AE3, COX-2, and beta-tubulin and negative for S-100, chromogranin A, CD117, and epithelial membrane antigen (EMA). An ONB was diagnosed based on histological and immunohistochemical findings. Interestingly, and similar to nasal carcinomas, neoplastic cells diffusely neo-expressed COX-2. To the authors' knowledge, there is no previous evidence of COX-2 in feline ONB. Histopathology and immunohistochemistry are required for a definitive diagnosis of ONB.
Topics: Cats; Animals; Esthesioneuroblastoma, Olfactory; Cyclooxygenase 2; Nose Neoplasms; Nasal Cavity; Carcinoma; Cat Diseases
PubMed: 37468966
DOI: 10.1111/vcp.13255