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1
Yang, Lan, Shiqi Huang, Zhirong Zhang, Zhenmi Liu y Ling Zhang. "Roles and Applications of Red Blood Cell-Derived Extracellular Vesicles in Health and Diseases". International Journal of Molecular Sciences 23, n.º 11 (25 de mayo de 2022): 5927. http://dx.doi.org/10.3390/ijms23115927.
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Red blood cell-derived extracellular vesicles (RBCEVs) are vesicles naturally produced by red blood cells and play multiple roles such as acting as cell-to-cell communication messengers in both normal physiological and diseased states. RBCEVs are highly promising delivery vehicles for therapeutic agents such as biomolecules and nucleic acids as they are easy to source, safe, and versatile. RBCEVs autonomously target the liver and pass the blood–brain barrier into the brain, which is highly valuable for the treatment of liver and brain diseases. RBCEVs can be modified by various functional units, including various functional molecules and nanoparticles, to improve their active targeting capabilities for tumors or other sites. Moreover, the RBCEV level is significantly shifted in many diseased states; hence, they can also serve as important biomarkers for disease diagnoses. It is clear that RBCEVs have considerable potential in multiple medical applications. In this review, we briefly introduce the biological roles of RBCEVs, presented interesting advances in RBCEV applications, and discuss several challenges that need to be addressed for their clinical translation.
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CHEN, YONG, JIYE CAI y JINGXIAN ZHAO. "DISEASED RED BLOOD CELLS STUDIED BY ATOMIC FORCE MICROSCOPY". International Journal of Nanoscience 01, n.º 05n06 (octubre de 2002): 683–88. http://dx.doi.org/10.1142/s0219581x02000899.
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In recent years, many mammalian cells, especially erythrocytes because of simpleness of their membrane surfaces, were widely studied by atomic force microscopy. In our study, diseased erythrocytes were taken from patients of lung cancer, myelodisplastic syndrome (MDS), and so on. We obtained many clear topographical images of numerous erythrocytes, single erythrocyte, and ultramicrostructure of erythrocyte membrane surfaces from normal persons and patients. By studying the red cells of lung cancer patients, we found that many erythrocytes of lung cancer patient have changed into echinocytes. One erythrocyte has 10–20 short projections, most of which, with a mean width of 589.0 nm and a length of 646.7 nm, are on the edge of cell. The projections in the center of echinocytes are lodged and embedded, but in conventional model of echinocytes, the projections in the center stretch outside cell membrane, so a novel model of erythrocytes was designed in our paper. After observation of microstructure of MDS patient's erythrocyte membrane surface, we found that many apertures with different diameters of tens to hundreds nanometers appeared on the surface of cell membrane. It can be concluded that AFM may be widely applied in clinic pathological inspection.
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Mattè, Alessandro, Enrica Federti, Elena Tibaldi, Maria Luisa Di Paolo, Giovanni Bisello, Mariarita Bertoldi, Andrea Carpentieri et al. "Tyrosine Phosphorylation Modulates Peroxiredoxin-2 Activity in Normal and Diseased Red Cells". Antioxidants 10, n.º 2 (1 de febrero de 2021): 206. http://dx.doi.org/10.3390/antiox10020206.
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Peroxiredoxin-2 (Prx2) is the third most abundant cytoplasmic protein in red blood cells. Prx2 belongs to a well-known family of antioxidants, the peroxiredoxins (Prxs), that are widely expressed in mammalian cells. Prx2 is a typical, homodimeric, 2-Cys Prx that uses two cysteine residues to accomplish the task of detoxifying a vast range of organic peroxides, H2O2, and peroxynitrite. Although progress has been made on functional characterization of Prx2, much still remains to be investigated on Prx2 post-translational changes. Here, we first show that Prx2 is Tyrosine (Tyr) phosphorylated by Syk in red cells exposed to oxidation induced by diamide. We identified Tyr-193 in both recombinant Prx2 and native Prx2 from red cells as a specific target of Syk. Bioinformatic analysis suggests that phosphorylation of Tyr-193 allows Prx2 conformational change that is more favorable for its peroxidase activity. Indeed, Syk-induced Tyr phosphorylation of Prx2 enhances in vitro Prx2 activity, but also contributes to Prx2 translocation to the membrane of red cells exposed to diamide. The biologic importance of Tyr-193 phospho-Prx2 is further supported by data on red cells from a mouse model of humanized sickle cell disease (SCD). SCD is globally distributed, hereditary red cell disorder, characterized by severe red cell oxidation due to the pathologic sickle hemoglobin. SCD red cells show Tyr-phosphorylated Prx2 bound to the membrane and increased Prx2 activity when compared to healthy erythrocytes. Collectively, our data highlight the novel link between redox related signaling and Prx2 function in normal and diseased red cells.
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Aoki, T. y T. Inoue. "Glycophorin in red blood cell membranes of healthy and diseased carp, Cyprinus carpio L." Journal of Fish Diseases 34, n.º 7 (18 de mayo de 2011): 573–76. http://dx.doi.org/10.1111/j.1365-2761.2011.01262.x.
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Li, He, Lu Lu, Xuejin Li, Pierre A. Buffet, Ming Dao, George E. Karniadakis y Subra Suresh. "Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders". Proceedings of the National Academy of Sciences 115, n.º 38 (6 de septiembre de 2018): 9574–79. http://dx.doi.org/10.1073/pnas.1806501115.
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In red blood cell (RBC) diseases, the spleen contributes to anemia by clearing the damaged RBCs, but its unique ability to mechanically challenge RBCs also poses the risk of inducing other pathogenic effects. We have analyzed RBCs in hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), two typical examples of blood disorders that result in membrane protein defects in RBCs. We use a two-component protein-scale RBC model to simulate the traversal of the interendothelial slit (IES) in the human spleen, a stringent biomechanical challenge on healthy and diseased RBCs that cannot be directly observed in vivo. In HS, our results confirm that the RBC loses surface due to weakened cohesion between the lipid bilayer and the cytoskeleton and reveal that surface loss may result from vesiculation of the RBC as it crosses IES. In HE, traversing IES induces sustained elongation of the RBC with impaired elasticity and fragmentation in severe disease. Our simulations thus suggest that in inherited RBC disorders, the spleen not only filters out pathological RBCs but also directly contributes to RBC alterations. These results provide a mechanistic rationale for different clinical outcomes documented following splenectomy in HS patients with spectrin-deficient and ankyrin-deficient RBCs and offer insights into the pathogenic role of human spleen in RBC diseases.
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Wilkes, Mark C., Aya Shibuya y Kathleen M. Sakamoto. "Signaling Pathways That Regulate Normal and Aberrant Red Blood Cell Development". Genes 12, n.º 10 (19 de octubre de 2021): 1646. http://dx.doi.org/10.3390/genes12101646.
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Blood cell development is regulated through intrinsic gene regulation and local factors including the microenvironment and cytokines. The differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature erythrocytes is dependent on these cytokines binding to and stimulating their cognate receptors and the signaling cascades they initiate. Many of these pathways include kinases that can diversify signals by phosphorylating multiple substrates and amplify signals by phosphorylating multiple copies of each substrate. Indeed, synthesis of many of these cytokines is regulated by a number of signaling pathways including phosphoinositide 3-kinase (PI3K)-, extracellular signal related kinases (ERK)-, and p38 kinase-dependent pathways. Therefore, kinases act both upstream and downstream of the erythropoiesis-regulating cytokines. While many of the cytokines are well characterized, the nuanced members of the network of kinases responsible for appropriate induction of, and response to, these cytokines remains poorly defined. Here, we will examine the kinase signaling cascades required for erythropoiesis and emphasize the importance, complexity, enormous amount remaining to be characterized, and therapeutic potential that will accompany our comprehensive understanding of the erythroid kinome in both healthy and diseased states.
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Nayani, Karthik, Arthur A. Evans, Saverio E. Spagnolie y Nicholas L. Abbott. "Dynamic and reversible shape response of red blood cells in synthetic liquid crystals". Proceedings of the National Academy of Sciences 117, n.º 42 (2 de octubre de 2020): 26083–90. http://dx.doi.org/10.1073/pnas.2007753117.
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Mammalian cells are soft, and correct functioning requires that cells undergo dynamic shape changes in vivo. Although a range of diseases are associated with stiffening of red blood cells (RBCs; e.g., sickle cell anemia or malaria), the mechanical properties and thus shape responses of cells to complex viscoelastic environments are poorly understood. We use vapor pressure measurements to identify aqueous liquid crystals (LCs) that are in osmotic equilibrium with RBCs and explore mechanical coupling between RBCs and LCs. When transferred from an isotropic aqueous phase into a LC, RBCs exhibit complex yet reversible shape transformations, from initially biconcave disks to elongated and folded geometries with noncircular cross-sections. Importantly, whereas the shapes of RBCs are similar in isotropic fluids, when strained by LC, a large variance in shape response is measured, thus unmasking cell-to-cell variation in mechanical properties. Numerical modeling of LC and cell mechanics reveals that RBC shape responses occur at constant cell membrane area but with membrane shear moduli that vary between cells from 2 to 16 × 10−6N/m. Temperature-dependent LC elasticity permits continuous tuning of RBC strains, and chemical cross-linking of RBCs, a model for diseased cells, leads to striking changes in shape responses of the RBCs. Overall, these results provide insight into the coupling of strain between soft mammalian cells and synthetic LCs, and hint at new methods for rapidly characterizing mechanical properties of single mammalian cells in a population and thus cell-to-cell variance.
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Li, He, Dimitrios Papageorgiou, Hung-Yu Chang, Lu Lu, Jun Yang y Yixiang Deng. "Synergistic Integration of Laboratory and Numerical Approaches in Studies of the Biomechanics of Diseased Red Blood Cells". Biosensors 8, n.º 3 (10 de agosto de 2018): 76. http://dx.doi.org/10.3390/bios8030076.
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In red blood cell (RBC) disorders, such as sickle cell disease, hereditary spherocytosis, and diabetes, alterations to the size and shape of RBCs due to either mutations of RBC proteins or changes to the extracellular environment, lead to compromised cell deformability, impaired cell stability, and increased propensity to aggregate. Numerous laboratory approaches have been implemented to elucidate the pathogenesis of RBC disorders. Concurrently, computational RBC models have been developed to simulate the dynamics of RBCs under physiological and pathological conditions. In this work, we review recent laboratory and computational studies of disordered RBCs. Distinguished from previous reviews, we emphasize how experimental techniques and computational modeling can be synergically integrated to improve the understanding of the pathophysiology of hematological disorders.
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Polák, J., M. Jokes y Marie Ulrychová. "Cell wall disintegration consistently found in tissues of reversion diseased red currant cv. Heinemann’s rote spätlesse". Biologia Plantarum 27, n.º 6 (noviembre de 1985): 462–64. http://dx.doi.org/10.1007/bf02894718.
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Prodanovic, Radisa, Ivan Vujanac, Danijela Kirovski, Vojin Ivetic, Bozidar Savic, Milenko Zutic, Branislav Kureljusic y Oliver Radanovic. "Paratuberculosis in breeding stock of red Holstein cows". Veterinarski glasnik 65, n.º 3-4 (2011): 179–90. http://dx.doi.org/10.2298/vetgl1104179p.
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This paper describes paratuberculosis in an isolated breeding herd of 25 high-yield dairy cows of the Red Holstein breed. The animals were examined clinically and then given the test for ldelayed type hypersensitivity and their blood serum was examined for the presence of specific antibodies against Mycobacterium avium subsp. paratuberculosis (Map). The clinical examination revealed that two cows exhibited symptoms of the disease that indicated an advanced stage of paratuberculosis. The following parameters were examined in the blood of the cows that showed clinical signs of the disease: leukocytes and erythrocytes count, concentrations of total proteins, albumin, iron, sodium, potassium, and activity of creatine kinase. The analysis of the red blood cell count revealed certain digressions that indicated the existence of hypochromic microcytic anaemia. The number of leukocytes was within the physiological values, but the neutrophil-lymphocyte ratio was disrupted and stood at almost 1:1. The results of the biochemical analyses of the blood serum of diseased cows indicated hypoproteinaemia, hypoalbuminaemia, hypoferremia, hyposodiumaemia, hypokalemia, and increased activities of creatine kinase enzymes. A suspect reaction on the site of application of avian tuberculin was determined in two animals. Animals with clinical signs of the disease reacted negative to the test of delayed type hypersensitivity. The presence of specific antibodies against the cause of paratuberculosis was proven in four animals (16%), including two animals with clinical signs of the disease and one that had a suspect reaction on the site of application of avian tuberculin. Furthermore, one animal that died exhibited macroscopic and microscopic changes regarding the intensity and distribution of lesions, the type of cellular infiltrate, and the number of present acidresistent bacteria, and the changes were characterized as diffuse changes of multibacillary type. The cause of bovine paratuberculosis was isolated from the altered organs.
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Kodippili, Gayani C., Jeff Spector, Caitlin Sullivan, Richard Labotka, Ken Ritchie y Philip S. Low. "Evaluation of the Spectrin Compartment Size in Normal and Diseased Red Blood Cells by Single Particle Tracking." Blood 110, n.º 11 (16 de noviembre de 2007): 143. http://dx.doi.org/10.1182/blood.v110.11.143.143.
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Abstract In a process termed “hop diffusion”, membrane proteins diffuse randomly within a cytoskeletally-enclosed compartment over short time scales, periodically hopping from one compartment to the next. Band 3 diffuses in the erythrocyte membrane bilayer in a manner that is thought to be restricted by the size and stability of the spectrin network. Although a fraction of band 3 may exhibit reduced mobility due to its association with spectrin (mediated by proteins such as ankyrin and adducin), another subpopulation of band 3 is thought to diffuse freely within the spectrin compartments, hopping from one corral to the next by transient opening of the barrier (presumably a spectrin tetramer) separating adjacent corrals. Based on this hypothesis, measurement of the compartment size and hopping frequency of a band 3 molecule in the erythrocyte membrane can provide information on the structure and stability of the spectrin network. We have combined single particle tracking (SPT) techniques with high-speed video microscopy to determine the average compartment size and diffusion coefficient of the mobile fraction of band 3 in both normal and diseased red blood cells (RBCs). Streptavidin-linked quantum dots (525nm emission) and 40 nm fluorescent beads were attached to band 3 via a DIDS-biotin-linker, and fluorescence microscopy coupled to a high speed camera was used to determine the position of band 3 with a time resolution of 8 ms (120 fps). Labeling specificity was demonstrated by blotting with streptavidin-horseradish peroxidase, and flow cytometry studies established the binding constant of DIDS-biotin for band 3 in the intact cell of ∼1-2*10−5 M. For diffusion studies, RBCs were incubated with 10−11 M conjugate in order to attach only one or two streptavidin-quantum dots per cell. SPT data were collected on both healthy and pathologic human RBCs, including HbSS (sickle cells), HbSC (sickle cell hemoglobin C), HbSBo (sickle cell zero-beta-thalasamia), HbSB+ (sickle cell beta-plus-thalasamia), HS (hereditary spherocytosis), and HPP (hereditary pyropoikilocytosis). Movement within the observed compartments was found to be random, with an average diagonal length for the mobile fraction in healthy cells of ∼100nm and a diffusion coefficient of ∼1–2*10−10cm2/s. HbSS cells, however, displayed a comparatively smaller compartment size (∼60–80nm) with a lower diffusion coefficient (0.1−1*10−10cm2/s). In contrast, HPP cells exhibited an average compartment size of ∼133nm with a diffusion coefficient of 6*10−10cm2/s. SPT data further suggest the presence of multiple populations of band 3, exhibiting both free diffusion and restricted mobilities with different characteristics. Details of band 3 diffusion in all of the aforementioned diseased and normal blood cells will be provided, and a model accounting for the multiple populations of band 3 will be presented.
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Chi, Jen-Tsan Ashley, Carolyn Sangokoya y Carlos M. de Castro. "MicroRNA Expression in Red Blood Cells from Patients with PNH." Blood 110, n.º 11 (16 de noviembre de 2007): 3675. http://dx.doi.org/10.1182/blood.v110.11.3675.3675.
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Abstract Although recent advances in microarray technology and analytic tools have led to an explosion of knowledge in many human diseases, the application of these tools to erythrocyte diseases has been limited by the long-held belief that mature erythrocytes lack most RNA expression. Recently, we have found that although mature erythrocytes lack most large-sized RNA, they possess abundant and diverse microRNAs (miRNAs), a class of small-sized RNAs with important regulatory functions [2]. While their functional role in mature erythrocytes remains to be investigated, these miRNAs are likely to play important regulatory roles during earlier stages of erythropoeisis. The discovery of these expressed miRNAs also allows us to use genomic tools and advanced bioinformatics to elucidate the biological role of miRNAs in the erythrocyte, particularly their contribution to phenotypic variations in erythrocyte disorders. As an initial step toward this aim, we obtained reticulocyte-free erythrocyte RNAs from seven HbAA individuals, sixteen HbSS individuals (homozygous sickle cell anemia) and six individuals with paroxysmal nocturnal hemoglobinuria (PNH). We analyzed these samples with microRNA microarrays and compared their gene expression of mature erythrocytes. The most prominent feature is the robust separation of HbAA and HbSS samples into two distinct groups with unsupervised analysis with hierarchical clustering. Interestingly, the new 7 PNH samples were split into two branches, one branch (four samples) was arranged together with normal individuals (thus termed “normal-like” group) while the other branch (three samples) was arranged with sickle cell individuals (thus termed “HbSS-like”). The four patients with the “normal-like” gene expression all exhibited a low level of hemolysis when compared with the other three patients with the “HbSS-like” gene expression. Three of the PNH patients with “normal-like” gene expression were receiving Eculizumab, a humanized antibody blocking complement C5 protein expected to reduce hemolysis and transfusion requirement in patients with PNH. The fourth patient, thought not receiving eculizumab treatment, has very mild hemolysis clinically. In contrast, the two PNH patients with “HbSS-like” gene expression pattern exhibit significant hemolysis. It also suggests that one important component of dysregulated gene expression seen in HbSS erythrocytes may reflect hemolysis, a clinical feature shared by all HbSS patients and a subset of PNH patients. Supervised analysis of erythrocyte gene expression with SAM also allowed the identification of 256 miRNAs associated with one of the three groups (HbAA, PNH or HbSS) of erythrocytes with a SAM analysis. The PNH-specific genes included miR-17 and miR-130a. The HbSS-specific genes included miR-223 and miR-451. And the normal-specific genes included miR-320 and let-7 family. These selected microRNAs may be valuable as diagnostic tools and reveal distinct pathophysiological processes in these diseases. Taken together, the genomic analysis of erythrocyte microRNA expression may provide relevant biomarkers and important insights into the diseased phenotypes of erythrocytes in human anemia disorders.
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Bachratá, Katarína, Katarína Buzáková, Michal Chovanec, Hynek Bachratý, Monika Smiešková y Alžbeta Bohiniková. "Classification of Red Blood Cell Rigidity from Sequence Data of Blood Flow Simulations Using Neural Networks". Symmetry 13, n.º 6 (26 de mayo de 2021): 938. http://dx.doi.org/10.3390/sym13060938.
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Numerical models for the flow of blood and other fluids can be used to design and optimize microfluidic devices computationally and thus to save time and resources needed for production, testing, and redesigning of the physical microfluidic devices. Like biological experiments, computer simulations have their limitations. Data from both the biological and the computational experiments can be processed by machine learning methods to obtain new insights which then can be used for the optimization of the microfluidic devices and also for diagnostic purposes. In this work, we propose a method for identifying red blood cells in flow by their stiffness based on their movement data processed by neural networks. We describe the performed classification experiments and evaluate their accuracy in various modifications of the neural network model. We outline other uses of the model for processing data from video recordings of blood flow. The proposed model and neural network methodology classify healthy and more rigid (diseased) red blood cells with the accuracy of about 99.5% depending on the selected dataset that represents the flow of a suspension of blood cells of various levels of stiffness.
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Bhat, Kishore G., Aradhana Chhatre, Vijay M. Kumbar, Manohar S. Kugaji y Sanjeevani Patil. "DETECTION AND QUANTITATION OF RED COMPLEX BACTERIA IN SUBGINGIVAL PLAQUE BY USING FLUORESCENT IN SITU HYBRIDIZATION (FISH)". International Journal of Research -GRANTHAALAYAH 5, n.º 11 (30 de noviembre de 2017): 279–89. http://dx.doi.org/10.29121/granthaalayah.v5.i11.2017.2354.
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Motivation/Background: Red complex bacteria are proven periodontal pathogens. In dentistry, there is a need to identify and quantitate the organisms from the diseased sites quickly and reliably. Since culture requires several days, molecular methods are being used frequently to detect these bacteria. Among them, Fluorescent in situ hybridization (FISH) is rapid, sensitive and quantitative. An attempt is made here to evaluate the applicability of this technique as a diagnostic tool in periodontology.
Method: Subgingival plaque was collected from participants, fixed with paraformaldehyde and subjected to FISH. Fluorescently labeled oligonucleotide probes were used for hybridization. After the procedure, the fluorescently stained bacteria were identified and counted from the smear and quantitated using a simple grading.
Results: There was a significant difference in the prevalence and numbers of red complex bacteria in healthy and diseased subjects. A strong linear relationship existed between P. gingivalis, T. forsythia and T. denticola.
Conclusions: The procedure used in the study is simple, rapid and can be easily adaptable. It also has a high sensitivity and has the ability to detect a single bacterial cell. The method can be directly applied to the clinical samples and can be used as a rapid diagnostic tool in periodontics.
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Lalefar, Nahal Rose y Ward Hagar. "A Comparison of Hematologic Parameters in Patients with Sickle Cell Disease Undergoing Red Cell Exchange Using Terumo BCT Spectra Optia and COBE Spectra Apheresis Systems". Blood 126, n.º 23 (3 de diciembre de 2015): 4743. http://dx.doi.org/10.1182/blood.v126.23.4743.4743.
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Abstract Introduction: Therapeutic red blood cell exchange (RBCX) is a process by which diseased red cells are replaced by healthy donor red blood cells. In patients with sickle cell disease, RBCX has been used to treat acute stroke, severe acute chest syndrome, multiorgan failure, priapism and splenic sequestration. It is also being used more commonly in the prevention of vaso-occlusive pain crises and for stroke prophylaxis for patients considered to be at high risk of stroke based on abnormal transcranial Doppler flow rates. In May 2014, we transitioned from the COBE Spectra apheresis system (Terumo BCT) to the next-generation Spectra Optia apheresis system (Terumo BCT) for all red cell exchange transfusions performed on our patients with sickle cell disease. A previous small study (n = 33 RBCX transfusions) compared the two instruments (Caridian BCT) and showed no difference between exchange volumes, processing time, pre and post-exchange hematocrit and HbS levels (Perseghin et al. Transfusion and Apheresis Science, 2013). However, other clinical parameters such as changes in white blood cell count and platelet counts were not examined. In order to determine if there were any differences in hematologic parameters between the 2 apheresis instruments, we measured the differences between pre and post-exchange HbS levels, white blood cell count (WBC), hematocrit (Hct), and platelet counts for all of our adult patients who underwent RBCX transfusions on both instruments. Methods: This was a single institution, retrospective chart review of all adult patients with sickle cell disease (HbSS n=17, HbS/β0 thalassemia n = 1, HbSC n =1) who underwent routine, monthly RBCX at Children's Hospital and Research Center Oakland between November 2013 and February 2015. Indications for RBCX included a risk of stroke or a history of stroke, acute chest syndrome, or renal failure. All patients received RBCX transfusions on the COBE Spectra prior to May 2014 and were then transitioned to Spectra Optia in May 2014. Pre and post-exchange transfusion HbS levels, WBC, Hct, and platelet counts were measured for each procedure. All exchange transfusions were non-emergent and well tolerated. Statistical analyses using the student's t test and rank sum test were performed with Stata 14.0 software (College Station, Texas). Results: A total of 19 adult patients (mean average age 25 years old) underwent 153 red blood cell exchange transfusions (Spectra Optia n =87, COBE Spectra n = 66). There was a small increase in mean hematocrit percentage for both instruments (28.33 + 4.3 % to 29 + 3.06 % and 28.16 + 4.29% to 29.2 + 3.04% on the Spectra Optia and COBE Spectra, respectively). All other post-RBCX parameters decreased. The mean changes are shown in Table I. The HbS percent decreased from a combined mean of 39.86 + 12.11 % to 20.26 + 8.43 % for both instruments. The WBC decreased from a combined mean of 12.72 + 3.13 x 1000/ mm3 to 8.67 + 2.15 x 1000/ mm3. The platelet count decreased from a combined mean of 368.82 + 125.75 x 1000/ mm3 to 191.01 + 62.78 x 1000/ mm3. The mean parameter values for each patient correlated with the mean changes for each instrument based on statistical analysis using both the student's t test and rank sum test. Conclusions: The starting hematologic values were similar between the two instruments. There was no statistical difference between the raw pre and post-RBCX HbS, Hct, WBC, or platelet values or the mean changes in these parameters between the COBE Spectra and Spectra Optia instruments. There was also no statistical difference in the mean changes between the pre and post RBCX hematologic parameters amongst the 19 patients. Both instruments allowed for effective reduction in HbS percentage with comparable decreases in WBC and platelet counts while maintaining adequate hematocrit values for all 19 adult patients with sickle cell disease. Table 1. Mean changes between Pre-RBCX and Post-RBCX. Instrument Change in % HbS Change in WBC x1000/mm3 Change in % Hct Change in platelet count x1000/mm3 Spectra Optia N 84 87 87 85 Mean -20.28 -4.01 0.67 -172.44 SD 7.02 2.55 2.86 76.98 COBE Spectra N 66 66 66 66 Mean -19.18 -4.12 1.09 -178.02 SD 7.89 2.26 2.57 81.02 p-value 0.37 0.78 0.34 0.67 There are 3 missing values for HbS and 2 missing values for platelet count for Spectra Optia. SD = standard deviation, WBC = white blood cell count, Hct = hematocrit Disclosures No relevant conflicts of interest to declare.
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Akada, Hajime, Saeko Hamada y Golam Mohi. "Erythroid Lineage-Restricted Expression of Jak2V617F Is Sufficient to Induce a Myeloproliferative Disease in Mice",. Blood 118, n.º 21 (18 de noviembre de 2011): 3861. http://dx.doi.org/10.1182/blood.v118.21.3861.3861.
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Abstract Abstract 3861 A somatic point mutation (V617F) in the JAK2 tyrosine kinase was found in most cases of Ph-negative myeloproliferative neoplasms (MPNs) including ∼95% patients with polycythemia vera (PV) and 50–60% patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). To investigate the contribution of JAK2V617F in MPNs, we generated a conditional Jak2V617F knock-in mouse (Akada et al., Blood 2010; 115: 3589–3597). Expression of Jak2V617F in all hematopoietic compartments including the hematopoietic stem cells (HSC) resulted in a PV-like disease associated with a marked expansion of erythroid progenitors in the bone marrow and spleen. Since Jak2 is essential for normal erythropoiesis and expression of Jak2V617F mutant enhances erythropoiesis, so we asked if erythroid progenitors are actual target cells for Jak2V617F mutation. To address this question, we have specifically expressed Jak2V617F in erythroid progenitors using the EpoR-Cre mice. Expression of heterozygous Jak2V617F in erythroid progenitors resulted in a polycythemia-like phenotype characterized by increase in hematocrit and hemoglobin, increased red blood cells, Epo-independent erythroid colonies, and splenomegaly. Erythroid lineage-specific expression of homozygous Jak2V617F resulted in significantly greater increase in hematocrit, hemoglobin, red blood cells, Epo-independent erythroid colonies, and splenomegaly compared to heterozygous Jak2V617F expression. These results suggest that erythroid lineage-restricted expression of Jak2V617F is sufficient to induce a polycythemia-like disease in a gene-dose dependent manner. However, transplantation of Jak2V617F-expressing erythroid progenitors (c-kithighTer119lowCD71high or c-kitlowTer119highCD71high) from the diseased mice into lethally irradiated recipients could not transfer the disease suggesting that Jak2V617F mutation does not confer self-renewal capacity to erythroid progenitors. We also observed that only Jak2V617F-expressing HSC has the unique capacity to serially transplant the myeloproliferative disease in mice. Taken together, our results suggest that HSCs are the disease-initiating cancer stem cells and erythroid progenitors are the target cells in Jak2V617F-evoked MPN. Disclosures: No relevant conflicts of interest to declare.
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Li, Ying, Yanping Lian, Lucy T. Zhang, Saad M. Aldousari, Hassan S. Hedia, Saeed A. Asiri y Wing Kam Liu. "Cell and nanoparticle transport in tumour microvasculature: the role of size, shape and surface functionality of nanoparticles". Interface Focus 6, n.º 1 (6 de febrero de 2016): 20150086. http://dx.doi.org/10.1098/rsfs.2015.0086.
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Through nanomedicine, game-changing methods are emerging to deliver drug molecules directly to diseased areas. One of the most promising of these is the targeted delivery of drugs and imaging agents via drug carrier-based platforms. Such drug delivery systems can now be synthesized from a wide range of different materials, made in a number of different shapes, and coated with an array of different organic molecules, including ligands. If optimized, these systems can enhance the efficacy and specificity of delivery compared with those of non-targeted systems. Emerging integrated multiscale experiments, models and simulations have opened the door for endless medical applications. Current bottlenecks in design of the drug-carrying particles are the lack of knowledge about the dispersion of these particles in the microvasculature and of their subsequent internalization by diseased cells (Bao et al . 2014 J. R. Soc. Interface 11 , 20140301 ( doi:10.1098/rsif.2014.0301 )). We describe multiscale modelling techniques that study how drug carriers disperse within the microvasculature. The immersed molecular finite-element method is adopted to simulate whole blood including blood plasma, red blood cells and nanoparticles. With a novel dissipative particle dynamics method, the beginning stages of receptor-driven endocytosis of nanoparticles can be understood in detail. Using this multiscale modelling method, we elucidate how the size, shape and surface functionality of nanoparticles will affect their dispersion in the microvasculature and subsequent internalization by targeted cells.
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Wooden, Jason M., Greg L. Finney, Michael J. MacCoss, Luanne L. Peters y Diana M. Gilligan. "Proteomic Analysis of RBC Ghosts from the Beta-Adducin and Protein 4.2 Knock-Out Mouse Models of Inherited Hemolytic Anemia." Blood 110, n.º 11 (16 de noviembre de 2007): 1728. http://dx.doi.org/10.1182/blood.v110.11.1728.1728.
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Abstract Inherited hemolytic anemia (spherocytosis or elliptocytosis) is one of the most common inherited diseases with an incidence of 1:2500 to 1:5000 in populations of Northern European descent. While it is known that mild to severe inherited hemolytic anemias can arise from defects in the red blood cell (RBC) membrane skeleton, fundamental questions remain unanswered surrounding the clinical variability and non-erythroid effects of known RBC membrane skeleton mutations. To identify proteins that may be involved in disease severity and secondary effects, we used shotgun proteomics to globally profile proteins in RBC ghosts (i.e., RBC membrane skeleton and associated proteins) from well-defined mouse models of inherited hemolytic anemia. A peptide level ‘bottom-up’ analysis was performed on RBCs from normal mice, beta-adducin knock-out mice (Add2-KO, compensated anemia), and protein 4.2 knock-out mice (4.2-KO, mild anemia). For each genotype, whole blood was taken from independent biological replicates and RBCs were purified using cellulose acetate chromatography. The isolated RBCs were lysed to generate RBC ghosts whose protein complements were digested with trypsin. For each biological replicate, five replicate runs utilizing 0.1 ug digested protein were performed via microcapillary liquid chromatography coupled with tandem mass spectrometry. Normal versus diseased comparisons were made using a protein profile found consistently across all independent samples for each genotype. In total, 435 unique proteins were identified for the normal mouse RBC ghost. In contrast, 731 and 848 unique proteins were identified for the Add2-KO and 4.2-KO mice RBC ghosts respectively. Previously identified membrane skeleton proteins were found for all three genotypes with the predicted absence of the knock-out proteins. In addition to well-known membrane proteins, a surprising number of proteins were found involved in processes such as protein repair, protein degradation, Ras oncogene biology, and glycolysis. For both knock-out mice, a large number of proteins involved in translation were identified most likely reflecting their elevated reticulocytosis status. Comparison of the normal and Add2-KO RBC profiles revealed 5 proteins present only in normal the RBC while 53 proteins were present only in the diseased RBC. Likewise, normal vs 4.2 KO comparison revealed 6 proteins present only in the normal RBC while 111 were only in the diseased RBC. Comparison between the two KO mice revealed 34 proteins present only in the Add2-KO and 88 proteins present only in the 4.2 KO. Some of the identified differences are proteins with unknown functions (example, SH3-binding domain glutamic acid-rich protein like). Other differences involve proteins associated with diverse processes such as protein folding (Bcl2-associated athanogene 2), protein modification (magnesium-dependent phosphatase-1), protein transport (RAB35), metabolism (N-acetylneuraminic acid phosphatase), signal transduction (Prohibitin 2), and apoptosis (Rho GTPase activating protein 1). We report that tandem mass spec analysis of disease model RBC ghosts have demonstrated differences in their proteomes and that these identified differences potentially represent candidate proteins involved in disease severity and secondary effects.
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Zhao, Huifen, Tamara I. Pestina, Md Nasimuzzaman, Perdeep Mehta, Phillip W. Hargrove y Derek A. Persons. "Amelioration of murine β-thalassemia through drug selection of hematopoietic stem cells transduced with a lentiviral vector encoding both γ-globin and the MGMT drug-resistance gene". Blood 113, n.º 23 (4 de junio de 2009): 5747–56. http://dx.doi.org/10.1182/blood-2008-10-186684.
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Abstract Correction of murine models of β-thalassemia has been achieved through high-level globin lentiviral vector gene transfer into mouse hematopoietic stem cells (HSCs). However, transduction of human HSCs is less robust and may be inadequate to achieve therapeutic levels of genetically modified erythroid cells. We therefore developed a double gene lentiviral vector encoding both human γ-globin under the transcriptional control of erythroid regulatory elements and methylguanine methyltransferase (MGMT), driven by a constitutive cellular promoter. MGMT expression provides cellular resistance to alkylator drugs, which can be administered to kill residual untransduced, diseased HSCs, whereas transduced cells are protected. Mice transplanted with β-thalassemic HSCs transduced with a γ-globin/MGMT vector initially had subtherapeutic levels of red cells expressing γ-globin. To enrich γ-globin–expressing cells, transplanted mice were treated with the alkylator agent 1,3-bis-chloroethyl-1-nitrosourea. This resulted in significant increases in the number of γ-globin–expressing red cells and the amount of fetal hemoglobin, leading to resolution of anemia. Selection of transduced HSCs was also obtained when cells were drug-treated before transplantation. Mice that received these cells demonstrated reconstitution with therapeutic levels of γ-globin–expressing cells. These data suggest that MGMT-based drug selection holds promise as a modality to improve gene therapy for β-thalassemia.
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Hennig, Till L., Harald Unterweger, Stefan Lyer, Christoph Alexiou y Iwona Cicha. "Magnetic Accumulation of SPIONs under Arterial Flow Conditions: Effect of Serum and Red Blood Cells". Molecules 24, n.º 14 (16 de julio de 2019): 2588. http://dx.doi.org/10.3390/molecules24142588.
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Magnetic drug targeting utilizes an external magnetic field to target superparamagnetic iron oxide nanoparticles (SPIONs) and their cargo to the diseased vasculature regions. In the arteries, the flow conditions affect the behavior of magnetic particles and the efficacy of their accumulation. In order to estimate the magnetic capture of SPIONs in more physiological-like settings, we previously established an ex vivo model based on human umbilical cord arteries. The artery model was employed in our present studies in order to analyze the effects of the blood components on the efficacy of magnetic targeting, utilizing 2 types of SPIONs with different physicochemical characteristics. In the presence of freshly isolated human plasma or whole blood, a strong increase in iron content measured by AES was observed for both particle types along the artery wall, in parallel with clotting activation due to endogenous thrombin generation in plasma. Subsequent studies therefore utilized SPION suspensions in serum and washed red blood cells (RBCs) at hematocrit 50%. Interestingly, in contrast to cell culture medium suspensions, magnetic accumulation of circulating SPION-3 under the external magnet was achieved in the presence of RBCs. Taken together, our data shows that the presence of blood components affects, but does not prevent, the magnetic accumulation of circulating SPIONs.
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Naser Zangana, Salam. "The evaluation of red cell distribution width in type 2 diabetic patients with acute ST- segment elevation myocardial infarction in Erbil city: a cross sectional study". Diyala Journal of Medicine 23, n.º 1 (15 de octubre de 2022): 60–71. http://dx.doi.org/10.26505/djm.v23i1.926.
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Background: The relationship of high red cell distribution width (RDW) with many hematological and angiographic characteristics in type 2 diabetic patients with acute ST-segment elevation myocardial infarction (STEMI) is still a matter of debate.
Objective: To evaluate the relationship of high RDW with multiple hematological and angiographic characteristics in type 2 diabetic patients with acute STEMI.
Patients and Methods: In this cross-sectional study, one hundred patients with acute STEMI who underwent coronary angiography were enrolled. The patients were divided into two groups according to the presence of type 2 diabetes mellitus (T2DM); group I, diabetic patients and group II, non-diabetic patients. Further division was made to group I patients based on how high or low RDW level was; subgroup A patients with high RDW level, and subgroup B patients with low RDW level. The groups were evaluated and compared regarding baseline demographic, laboratory and angiographic characteristics.
Results: The mean RDW was higher (P=0.04) in group I compared to group II. The mean values of white blood cell (WBC) , RDW, CK-MB, Troponin T high sensitive (hs) , and HbA1C levels were significantly higher in subgroup A compared to subgroup B (P=0.007, 0.003, 0.03 and < 0.001, respectively). Subgroup A patients have significantly more extension of coronary diseases than subgroup B (P=0.001). A positive correlation was detected between RDW and WBC, CK-MB, Troponin T hs, HbA1C as well as number of diseased vessels in diabetic patients (0.76, 0.4, 0.98 and 0.79, respectively).
Conclusion: Diabetic patients with acute STEMI had higher levels of RDW than non-diabetics and higher levels were positively correlated with inflammatory and poor outcome cardiovascular markers as well as multiple vessel diseases involvement. It was also correlated with poor glycemic control represented by high HbA1C.
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Naser Zangana, Salam. "The evaluation of red cell distribution width in type 2 diabetic patients with acute ST- segment elevation myocardial infarction in Erbil city: a cross sectional study". Diyala Journal of Medicine 23, n.º 1 (15 de octubre de 2022): 60–71. http://dx.doi.org/10.26505/djm.23016510508.
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Background: The relationship of high red cell distribution width (RDW) with many hematological and angiographic characteristics in type 2 diabetic patients with acute ST-segment elevation myocardial infarction (STEMI) is still a matter of debate. Objective: To evaluate the relationship of high RDW with multiple hematological and angiographic characteristics in type 2 diabetic patients with acute STEMI. Patients and Methods: In this cross-sectional study, one hundred patients with acute STEMI who underwent coronary angiography were enrolled. The patients were divided into two groups according to the presence of type 2 diabetes mellitus (T2DM); group I, diabetic patients and group II, non-diabetic patients. Further division was made to group I patients based on how high or low RDW level was; subgroup A patients with high RDW level, and subgroup B patients with low RDW level. The groups were evaluated and compared regarding baseline demographic, laboratory and angiographic characteristics. Results: The mean RDW was higher (P=0.04) in group I compared to group II. The mean values of white blood cell (WBC) , RDW, CK-MB, Troponin T high sensitive (hs) , and HbA1C levels were significantly higher in subgroup A compared to subgroup B (P=0.007, 0.003, 0.03 and < 0.001, respectively). Subgroup A patients have significantly more extension of coronary diseases than subgroup B (P=0.001). A positive correlation was detected between RDW and WBC, CK-MB, Troponin T hs, HbA1C as well as number of diseased vessels in diabetic patients (0.76, 0.4, 0.98 and 0.79, respectively). Conclusion: Diabetic patients with acute STEMI had higher levels of RDW than non-diabetics and higher levels were positively correlated with inflammatory and poor outcome cardiovascular markers as well as multiple vessel diseases involvement. It was also correlated with poor glycemic control represented by high HbA1C.
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Villa, Carlos Hipolito, Daniel Pan, Ian Johnston, Colin F. Greineder, Marion E. Reid, Douglas B. Cines, Mortimer Poncz, Don L. Siegel y Vladimir R. Muzykantov. "Coupling Therapeutics to Human Erythrocytes Demonstrates Target-Dependent Effects on Red Cell Physiology While Preserving Efficacy". Blood 128, n.º 22 (2 de diciembre de 2016): 701. http://dx.doi.org/10.1182/blood.v128.22.701.701.
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Abstract Delivery of bio-therapeutics by red blood cells (RBCs) can greatly enhance pharmacokinetics and pharmacodynamics of the appended or loaded agents, and may even potentiate induction of immunologic tolerance. Our group and others have successfully used fusion proteins, antibodies, and peptides to couple therapeutics to murine, but not human, RBCs. It is known that extracellular ligands have the potential to induce marked, epitope-dependent changes in red cell physiology, including changes in deformability, phosphatidyl-serine (PS) exposure, and reactive oxygen species (ROS) production, particularly for agents targeted to glycophorin A and Band 3, two highly-expressed membrane proteins. To produce clinically translatable strategies for human RBCs, it is critical to identify optimal red cell target epitopes, understand their effects on red cell physiology, and create humanized or human-like ligands to minimize immunogenicity. We constructed single chain antibodies (scFv) against antigenic determinants on Band 3 protein (Wrb) and RHCE protein (Rh17/Hr0) on human erythrocytes using phage display libraries prepared from immunized cynamolgous macaques (Macacafascicularis). Both these antigens are present on essentially 100% of the human population. Unfused scFvs were produced in E.coli while fusions of scFv with the extracellular domain of human thrombomodulin (TM-scFv) were produced in Drosophila S2 cells. Binding of recombinant proteins to human RBCs was measured by radioimmunoassay and flow cytometry. Generation of activated protein (APC) by RBCs loaded with TM-scFv fusions was measured by colorimetric assay. RBCs pre-incubated with varying concentrations of anti-Band3 and anti-RHCE fusions were assessed for osmotic resistance and mechanical integrity by exposure to hypo-osmolar medium and rotation in the presence of glass beads, respectively. PS exposure was measured by annexin V binding, and ROS generation was measured by dihydrorhodamine-associated fluorescence. Effects on RBC rheology were measured by flowing through microfluidic channels under controlled shear rates. Efficacy of TM-scFv fusions in diseased micro-vessels was assessed using a TNF-alpha stimulated, endothelialized microfluidic model. Single-chain antibody fragments and TM fusion proteins targeted to conserved epitopes on Band 3 protein and RHCE protein bound to human, but not murine or porcine, RBCs with high specificity and affinity (~50 nM), and in numbers consistent with the expected level of target expression (105 and 106 copies/RBC for RHCE and Band3, respectively). Coating RBCs with proteins targeted to Band 3 lessened RBC hypo-osmolar hemolysis (20% reduction) but increased hemolysis (2-fold) under mechanical stress, changes compatible with decreased red cell deformability. Proteins targeted to RHCE did not induce significant changes in hemolysis of RBCs under either osmotic or mechanical stress. Targeting neither Band 3 nor RHCE induced significant exposure of PS or production of ROS. Target-dependent effects on RBC rheology were observed under varying shear stresses in a microfluidic system. Fusion proteins of TM targeted to both epitopes demonstrated dose- and surface-copy-number-dependent generation of APC in the presence of PC and thrombin. Both TM-scFv fusion proteins were efficacious in a microfluidic model of disseminated intravascular coagulation using whole human blood by demonstrating near complete abrogation of fibrin generation in response to endothelial activation with TNF-alpha. In summary, we designed human RBC-specific non-human primate single chain antibody fragments capable of fusion to therapeutic cargoes. The TM-scFv fusions maintained therapeutic activity when bound to human RBCs and showed effective thromboprophylaxis in a whole-blood model of vasculitic injury. These antibodies and fusion proteins bound to erythroid-specific epitopes, and demonstrated target-dependent effects on several aspects of red cell physiology. The non-human primate origin of the antibodies should minimize their potential immunogenicity and the findings provide a platform to translate red cell targeted drug delivery into the clinical realm. Disclosures No relevant conflicts of interest to declare.
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Chmurska-Gąsowska, Maria, Bartosz Bojarski, Natalia Sowińska y Magdalena Strus. "Changes in Leukogram and Erythrogram Results in Bitches with Vaginitis". Animals 11, n.º 5 (14 de mayo de 2021): 1403. http://dx.doi.org/10.3390/ani11051403.
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Vaginitis in female dogs is a problem most veterinarians face in their practice. It manifests as localized inflammation, and its variable etiology and different severities often make diagnosis problematic. The study consisted of comparing blood smears taken from 16 animals: 8 healthy bitches and 8 bitches with confirmed vaginitis. We analyzed the percentage of different types of white blood cells (leukogram) and changes in the shape of red blood cells (erythrogram) in both groups. We observed changes in red blood cell morphology, i.e., a higher percentage of lacrimocytes and schistocytes in female dogs with vaginitis compared to their healthy counterparts. The observed hematological changes may illustrate the severity of inflammation. The analysis of erythrograms showed a significantly higher percentage of lacrimocytes and schistocytes in diseased bitches (1.58 ± 1.19% and 0.13 ± 0.12%) compared to healthy animals (0.58 ± 0.38 and 0.00 ± 0.00, respectively). The obtained results may indicate that the analysis of erythrograms throughout the course of vaginitis in bitches may constitute a diagnostic tool, as opposed to the analysis of leukograms, which is more sensitive when it comes to the systemic inflammatory response of the organism. It seems that simultaneous analysis of erythrograms and leukograms may facilitate the diagnostic process in clinical practice.
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K.C, Suma, Manasa H, Likhitha A y Nagamani T.S. "Isolation, Purification, and Characterization of Serratiopeptidase Enzyme from Serratia marcescens". International Journal of Innovative Science and Research Technology 5, n.º 7 (21 de julio de 2020): 156–61. http://dx.doi.org/10.38124/ijisrt20jul135.
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Serratiopeptidase is a proteolytic enzyme that is derived from a member of Enterobacteriaceae. Serratia marcescens is a gram-negative bacteria identified characteristically, which produces a red pigment called prodigiosin. Serratiopeptidase is a multifunctional proteolytic enzyme that dissolves non-living tissues such as fibrin, blood clots, inflammation in all forms without harming living tissues. In this study, the organism was isolated from the diseased silkworm's pupa by using Luria- Bertani (LB) agar media. The enzyme production can be enhanced by applying different physical and chemical parameters. Serratia marcescens was subjected to production such that in order to obtain the maximum level of cell-free supernatant Serratiopeptidase enzyme with all the optimized conditions. The enzyme was subjected to purification by four methods such as salt precipitation, dialysis, ion-exchange chromatography and gel filtration. When subjected to enzyme kinetics, Serratiopeptidase was active at temperature 350C, pH-9 with 8 minutes of the incubation period. The molecular weight of serratiopep
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Wilkes, Mark C., Aya Shibuya, Jacqueline D. Mercado, Anupama Narla, Bert Glader y Kathleen M. Sakamoto. "Nutritional Supplements, Ginseng and Leucine, Increase Erythropoiesis in Diamond Blackfan Anemia Models through Inhibition of Nemo-like Kinase". Blood 138, Supplement 1 (5 de noviembre de 2021): 1129. http://dx.doi.org/10.1182/blood-2021-153728.
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Abstract Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome that is typically associated with mutations in one of at least 20 ribosomal genes and is associated with anemia, congenital abnormalities, and cancer predisposition. The current treatment for DBA is associated with toxicities including iron overload from repeated transfusions, immune suppression from chronic corticosteroid therapy or consequences from stem cell transplantation. Developing new therapies for DBA remains a challenge, since it is a rare disease and the connection between faulty ribosomes and defects in erythropoiesis is still being explored. As such, repurposing existing, approved drugs is one approach to find new ways to treat this disease. We recently identified that Nemo-like Kinase (NLK) is hyper-activated and contributes to disease pathogenesis in the erythroid progenitors of patients with DBA, irrespective of the genetic mutation. NLK is an atypical member of the MAPK family of kinases. Due to a high degree of conservation, kinase inhibitors that specifically target NLK are not currently available, although several small molecules inhibit NLK as an off-target. We are actively pursuing a number of these compounds as potential therapies for DBA. In addition to known kinase inhibitors, we have examined the active components of widely available nutritional supplements. Although rigorous clinical evaluation is required, these supplements are well tolerated and offer an alternative or a complement to conventional drug therapy for DBA. Ginsenoside Rb1, an active component of ginseng, increases erythropoiesis in in vitro models of DBA (2.6-fold) at 50mM (p=0.048) with an EC 50 of 2.3mM. Importantly, ginsenoside Rb1 does not impact healthy erythropoiesis or other hematopoietic lineages and is nontoxic to normal cells. Our results demonstrate that ginsenoside Rb1 does not inhibit NLK kinase activity directly, but rather induces a microRNA (miR-208) that binds to NLK mRNA leading to degradation of transcript by 35.9% (p=0.007) before the protein can be translated. Another nutritional supplement that has been indicated to improve erythropoiesis (in DBA and non-diseased models) and is currently in clinical trials is the amino acid leucine. In DBA progenitors, 5mM leucine increases erythropoiesis from 8.8 to 16.3% of healthy controls. Leucine acts by stimulating the activity of mTORC1 but similar to erythropoiesis, mTORC1 activity is only stimulated from 26.4 to 57.2% of controls in DBA progenitors. Our results demonstrate that leucine does not impact NLK expression or activity directly. Aberrantly activated NLK phosphorylates and inhibits the activation of mTORC1 (target of leucine). The suppression of NLK by 50mM ginsenoside Rb1 restored mTORC1 activity to basal (94.7% of non-diseased control) but also restored leucine sensitivity (from 57.2 to 88.1% of non-diseased controls). Importantly, combining 5mM leucine and 50mM ginsenoside Rb1 increased erythropoiesis from 1.9-fold and 2.6-fold when used alone, to 8.9-fold (or 78.3% of healthy controls) together in our in vitro models of DBA (CI=0.31). Ginseng and leucine offer promising alternatives to steroids and other immunosuppressive drugs for DBA patients. The goal of these studies is to raise the hemoglobin in DBA patients to avoid the need for red cell transfusions. As nutritional supplements are widely available and well tolerated, this class of compounds provides alternatives to currently approved drugs to treat DBA. Disclosures Glader: Agios: Consultancy.
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Garibaldi, A., D. Bertetti y M. L. Gullino. "First Report of Powdery Mildew Caused by Erysiphe pulchra on Cornus florida in Italy". Plant Disease 93, n.º 3 (marzo de 2009): 320. http://dx.doi.org/10.1094/pdis-93-3-0320c.
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Cornus florida L. (Cornaceae), flowering dogwood, is a small deciduous tree whose showy inflorescences, clusters of bright red fruits and red and purple leaves in autumn, make it a much appreciated ornamental. During the summer of 2008, severe outbreaks of a previously unknown powdery mildew were observed in several gardens and nurseries in Piedmont (northern Italy). Young leaves were covered with dense, white mycelia and conidia, especially on the adaxial surface. As the disease progressed, infected leaves turned red. Conidia were hyaline, elliptical, borne singly, and measured 32 to 46 × 15 to 20 (average 38 × 17) μm. Conidiophores measured 68 to 77 × 8 to 9 (average 73 × 8) μm, with a cylindrical foot cell measuring 26 to 37 × 8 to 10 (average 31 × 9) μm, followed by two shorter cells. Fibrosin bodies were absent. No chasmothecia were observed. The ITS region (internal transcribed spacer) of rDNA was amplified using primers ITS4/ITS6 and sequenced. The 627-bp sequence (Accession No. EU FJ436989 in GenBank) has 99% identity with Erysiphe pulchra. As proof of pathogenicity, diseased leaves were pressed against leaves of three healthy 3-year-old plants. Three noninoculated plants served as controls. Inoculated and noninoculated plants were maintained outdoors at 13 to 21°C. After 15 days, typical powdery mildew colonies developed on inoculated plants. Noninoculated plants did not show symptoms. The pathogenicity test was carried out twice. To our knowledge, this is the first report of the presence of powdery mildew on C. florida caused by E. pulchra in Italy. Powdery mildew of dogwood, caused by Microsphaera (Erysiphe) pulchra, has been reported in the United States (3) and Japan (1). In Italy, a powdery mildew caused by an Oidium sp. has been reported on C. sanguinea (2). Herbarium specimens of this disease are available at AGROINNOVA Collection, University of Torino, Italy. References: (1) T. Kobayashi. Index of Fungi Inhabiting Woody Plants in Japan. Host, Distribution, and Literature. Zenkoku-Noson-Kyoikai Publishing Co., Ltd., Tokyo, 2007. (2) G. Sicoli et al. Inf. Agrario 56/48:84, 2000. (3) V. L. Smith. Plant Dis. 83:782, 1999.
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Gazda, Hanna, Agnieszka Grabowska, Lilia Long, Elzbieta Latawiec, Hal Schneider, Jeffrey Lipton, Adrianna Vlachos et al. "Ribosomal Protein S24 Gene Is Mutated in Diamond-Blackfan Anemia." Blood 108, n.º 11 (16 de noviembre de 2006): 181. http://dx.doi.org/10.1182/blood.v108.11.181.181.
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Abstract Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia with marked clinical heterogeneity, an increased risk of malignancy and mutations in ribosomal protein (RP) S19 in 25% of probands. To identify other gene(s) mutated in DBA and investigate their expression and function, we performed a genome-wide screen using a 10,000 single nucleotide polymorphism mapping set (Affymetrix) on a large family comprising 10 informative meioses. We found linkage of the DBA phenotype to regions on chromosome 8q, 10 and 6. The RP gene RPS24, is located in the linked region on chromosome 10; we sequenced exons, intron-exon boundaries and the promoter regions in this family, and found a nonsense mutation (316C>T) in exon 4 of RPS24 in five affected individuals, and a wild type sequence in five unaffected family members. This mutation causes the change of Gln106STOP and is predicted to result in formation of a truncated RPS24 protein. Subsequently, we sequenced DNA from 215 unrelated DBA probands, 30 with RPS19 mutations and 185 without. We found another nonsense mutation in exon 2 in a sporadic case, and a splice site deletion resulting in skipped exon 2 in another proband and in his father; over 200 control individuals did not have any of the above sequence changes, indicating that they are pathogenic mutations. To explore the normal role of RPS24 and consider how its dysfunction might result in DBA we performed real time RT-PCR (rt-PCR) and western blotting experiments on 20 normal human tissues and on lymphoblastoid cell lines from diseased and control individuals. Interestingly, rt-PCR of total human RPS24 and RPS19 mRNA revealed a tissue-specific variation in expression level. We found co-ordinate expression of both genes in the majority of studied tissues. Lymphoblastoid cell lines from both probands with nonsense mutations showed a reduced level of RPS24 mRNA, suggesting degradation of mutated transcripts due to nonsense mediated decay, while the RPS19 mRNA level in these patients was normal or elevated. Western blot experiments revealed a reduction of RPS24 protein in lymphoblastoid cell lines from all three mutated probands compared to control samples. Interestingly, co-ordinate expression of RPS24 and RPS19 protein was found in these patients as well as in other patients with RPS19 mutations or without any mutations, suggesting co-regulation of RP expression. To determine whether recruitment of mRNA to polysomes was impaired in DBA patients, we separated lymphoblast cell line lysates from nine diseased and four control individuals on sucrose gradients. We did not detect any significant difference in the RNA ratio of polysome-bound/free ribosomal subunits between diseased and control samples (p<0.3). It is likely that lymphoblasts, which are not defective in DBA, have sufficient ribosomes to mask an abnormality in translation. In summary, our results suggest that in addition to RPS24 and RPS19, which are mutated in ~ 27% of index cases, other DBA genes are also RP genes or genes involved in ribosome biogenesis or translation, and reinforce the notion that DBA is a ribosomal disease. This study opens new avenues for studying and understanding the pathogenesis of DBA.
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Xu, F., S. X. Wang, Y. Liu, Y. W. Ma, D. P. Zhang y S. Zhao. "First Report of Sporobolomyces symmetricus Induced Red Spot Disease of Pleurotus eryngii in China". Plant Disease 98, n.º 5 (mayo de 2014): 693. http://dx.doi.org/10.1094/pdis-09-13-0928-pdn.
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Pleurotus eryngii is cultivated on a large scale in China and other Asian countries due to its exceptional flavor and its popularity in cuisine. In January of 2009, red spot disease on cultivated P. eryngii was observed in several workshops of mushroom producing factories located at Fangshan District, Beijing, China. Symptoms of this disease began as orange red spots 2 to 4 cm in diam. on the surface of stipes near pilei. The spots did not arise from wounding, and growth of the affected mushrooms halted. Commercial losses for these factories were estimated at 10 to 15%. Samples of diseased tissue were plated on potato dextrose agar (PDA), and dominant colonies were selected for characterization. After 3 days in YM broth (Difco) at 25°C, yeast cells developed that were ellipsoid, botuliform, 4.8 to 7.2 × 2.4 to 3.6 μm, and sediment-formed. After incubation for 1 month on YM agar at 25°C, streak cultures were nacarat, cheese-like, glistening and had a smooth surface and complete margin. On Dalmau plate cultures on cornmeal agar (Difco), no pseudohyphae were formed. The internal transcribed spacer (ITS) and D1/D2 domain of the 26S rRNA were sequenced (GenBank Accession Nos. KF314801 and KF314803). A neighbor-joining (NJ) tree for the D1/D2 domain showed that the yeast belonged to the Urediniomycetes with the highest similarity (99.6%) to Sporobolomyces symmetricus CBS 9727T. BLAST results for the ITS sequence showed that it was 100% identical to S. symmetricus CBS 9727T. Furthermore, the metabolic profile of the fungal strain also closely resembled the database profile of S. symmetricus CBS 9727T with the exception of two phenotypic characteristics (positive assimilation of D-Galactose and D-Xylose). The DNA G+C content of the strain was measured by HPLC and was found to be 55.40 mol%. The whole-cell fatty acid methyl ester major composition determined using the cells harvested from cultures grown on PDA for 3 days at 25°C was as follows: 1.23% C16:1 w7c/16:1 w6c, 21.87% C16:0, 29.40% C18:0 antei/C18:2 w6, 9c, 40.41% C18:1 w9c, 3.36% C18:1 w7c, 1.93% C18:0. After comparing the morphological, phenotypic, and molecular analyses with the type strain of S. symmetricus CBS 9727T, the strain isolated in the present study was identified as S. symmetricus (2). Pathogenicity tests for the isolate were carried out with yeast suspensions (~1 × 106 CFU/ml) grown for 72 h in PDB (Difco) cultures. Mycelia of P. eryngii were cultivated for 35 days in a plastic bottle to serve as a host source. The prepared yeast cell suspensions were directly inoculated on the surface of the young fruiting body. After 5 to 7 days, red spot symptoms identical to those described above developed on the stipes and pilei and development of the mushrooms was inhibited. Fruiting bodies in negative control bottles inoculated with PDB did not develop symptoms. Koch's postulates were thus fulfilled by re-isolating S. symmetricus that was identical to the inoculated strain from lesions on the inoculated fruiting bodies. Sporobolomyces spp. are closely phylogenetically related to the genus Rhodotorula. Pathogenic potential of Rhodotorula species has been increasingly recognized in recent years (1). To our knowledge, this is the first report of S. symmetricus-induced red spot disease of P. eryngii in China. Information on this pathogen will be useful in the development of management practices for this emerging disease in the near future. References: (1) M. A. Pfaller and D. J. Diekema. J. Clin. Microbiol. 42:4419, 2004. (2) Q. M. Wang and F. Y. Bai. FEMS Yeast Res. 4:579, 2004.
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Krömer, G., K. Schauenstein, H. Dietrich, R. Fässler y G. Wick. "Mechanisms of T cell hyperreactivity in obese strain (OS) chickens with spontaneous autoimmune thyroiditis: lack in nonspecific suppression is due to a primary adherent cell defect." Journal of Immunology 138, n.º 7 (1 de abril de 1987): 2104–9. http://dx.doi.org/10.4049/jimmunol.138.7.2104.
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Abstract The disturbed homeostasis of the immune system in Obese strain (OS) chickens with spontaneous autoimmune thyroiditis consists in a general T cell hyperreactivity (concanavalin A hyperresponsiveness, interleukin 2 (IL 2) hypersecretion), particularly expressed by those lymphocytes which infiltrate the diseased thyroid gland. This abnormality has been attributed to a defective regulation of both IL 2 production and IL 2 function by low m.w. factors, which are present in serum and splenocyte culture supernatants of normal chickens, but deficient in the OS. In the present study we identified the cellular origin of IL 2 antagonistic activity as a nonlymphoid, adherent cell. Suppressor factor production in vitro was confined to the plastic adherent fraction of spleen cells and preincubation of splenocytes with nylon wool, silica particles, or carbonyl iron significantly reduced the nonspecific suppressive activity of the culture supernatant. Kinetic studies revealed the defect in nonspecific suppression to entail prolonged IL 2 production by concanavalin A-activated OS spleen cells. In vivo treatment of normal White Leghorn chickens with silica led to a decrease in suppressive serum activity down to the OS level, whereas neither neonatal thymectomy nor bursectomy had any effect. The defective suppressor factor production in autoimmune chickens appeared to be due to a functional, but not numeric defect of macrophages as revealed by phenol red staining. The possibility that this aberration in adherent cell function might be a secondary phenomenon to the recently described reduced corticosterone tonus in OS chickens was excluded by in vivo substitution with exogenous glucocorticoids which did not normalize the suppressor defect in serum or in conditioned medium. Finally, we present evidence that T lymphoblasts from OS animals are less susceptible to IL 2 antagonistic regulation than normal cells, which possibly further contributes to the T cell hyperfunction of this autoimmune strain.
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Madrigal-Matute, Julio, Roxana Martinez-Pinna, Priscila Ramos-Mozo, Luis Blanco-Colio, Juan Moreno, Carlos Tarin, Elena Burillo et al. "Erythrocytes, leukocytes and platelets as a source of oxidative stress in chronic vascular diseases: Detoxifying mechanisms and potential therapeutic options". Thrombosis and Haemostasis 108, n.º 09 (2012): 435–42. http://dx.doi.org/10.1160/th12-04-0248.
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SummaryOxidative stress is involved in the chronic pathological vascular remodelling of both abdominal aortic aneurysm and occlusive atherosclerosis. Red blood cells (RBCs), leukocytes and platelets present in both, aneurysmal intraluminal thrombus and intraplaque haemorraghes, could be involved in the redox imbalance inside diseased arterial tissues. RBCs haemolysis may release the pro-oxidant haemoglobin (Hb), which transfers heme to tissue and low-density lipoproteins. Heme-iron potentiates molecular, cell and tissue toxicity mediated by leukocytes and other sources of reactive oxygen species (ROS). Polymorphonuclear neutrophils release myeloperoxidase and, along with activated platelets, produce superoxide mediated by NADPH oxidase, causing oxidative damage. In response to this pro-oxidant milieu, several anti-oxidant molecules of plasma or cell origin can prevent ROS production. Free Hb binds to haptoglobin (Hp) and once Hp-Hb complex is endocytosed by CD163, liberated heme is converted into less toxic compounds by heme oxygenase-1. Iron homeostasis is mainly regulated by transferrin, which transports ferric ions to other cells. Transferrin-bound iron is internalised via endocytosis mediated by transferrin receptor. Once inside the cell, iron is mainly stored by ferritin. Other non hemo-iron related antioxidant enzymes (e.g. superoxide dismutase, catalase, thioredoxin and peroxiredoxin) are also involved in redox modulation in vascular remodelling. Oxidative stress is a main determinant of chronic pathological remodelling of the arterial wall, partially linked to the presence of RBCs, leukocytes, platelets and oxidised fibrin within tissue and to the imbalance between pro-/anti-oxidant molecules. Understanding the complex mechanisms underlying redox imbalance could help to define novel potential targets to decrease atherothrombotic risk.
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Kumar, Priyatham. "Deep Vein Thrombosis and Pulmonary Embolism in Sickle Cell Disease". Biomedical Research and Clinical Reviews 1, n.º 5 (4 de diciembre de 2020): 01–04. http://dx.doi.org/10.31579/2692-9406/024.
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Sickle Cell Disease (SCD) is considered a group of genetic red blood cell (RBC) disorders. Healthy red blood cells (RBC) are round in shape and migrates throughout the body to carry oxygen in the small blood vessels. In SCD, the RBC turns into hard and sticky, and the shape is similar to a C-Shaped tool called "SICKLE." Because of the early death of the sickle cells, a constant shortage of red blood cells arises. Because of the typical shape of the sickle cells, their movement in the blood vessel is not as smooth as normal RBC and get stuck and clog the blood flow leading to anemia. The changes in shape make the cells more easily destroyed, causing anemia. Defective hemoglobin is the primary cause of SCD.
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Wooden, Jason M., Greg Finney, Michael MacCoss y Diana M. Gilligan. "Comprehensive Analysis of Murine and Human RBC Ghost Proteomes." Blood 108, n.º 11 (16 de noviembre de 2006): 1569. http://dx.doi.org/10.1182/blood.v108.11.1569.1569.
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Abstract Inherited hemolytic anemia (spherocytosis or elliptocytosis) is one of the most common inherited diseases with an incidence of 1:2500 to 1:5000 in populations of Northern European descent. Mild to severe inherited hemolytic anemias can arise from defects in the red blood cell (RBC) membrane skeleton. Genetic knock-out of various components of this apparatus has led to the creation of mouse models which have contributed significantly to our understanding of these disorders in humans. However, the mouse and human RBC protein complements have not been comprehensively compared. Using newly developed proteomic methodology, we conducted a peptide level ‘bottom-up’ analysis of the normal mouse and human RBC ghost (i.e., RBC membrane skeleton and associated proteins). RBCs were purified using cellulose acetate chromatography from whole blood taken from three genetically identical mice and two hematologically normal yet genetically diverse humans. The isolated RBCs were lysed to generate RBC ghosts whose protein complements were digested with trypsin and analyzed by shotgun proteomics using microcapillary liquid chromatography coupled with tandem mass spectrometry. In total, 400 and 491 unique proteins were identified in human samples A and B respectively while 469 proteins were found in common across the three mouse samples. All previously identified membrane skeleton proteins were found in the human and mouse samples. Likewise, well-known RBC membrane proteins were represented. Of interest, a surprising number of proteins were found associated with the RBC ghost involved in processes such as protein repair (15–20), protein degradation (30–43), oxidative stress response (4–6), Ras oncogene biology (28–30), and glycolysis (3–6). Collectively, the two human samples represented 544 unique proteins. These results affirm the usefulness of inherited anemia mouse models given the observed conservation of membrane skeleton components and the inherent challenges with doing normal versus diseased RBC analysis in humans due to genetic variation.
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Anagnostopoulos, Athanasios, Lia A. Moulopoulos, Maria Roussou, Efstathios Kastritis, Dimitra Gika, George Bozas, Aikaterini Stefanoudaki et al. "Prognostic Significance of Magnetic Resonance Imaging (MRI) of Bone Marrow (BM) in Patients with Multiple Myeloma (MM) Undergoing Treatment with High-Dose Melphalan (HDM) and Autologous Stem Cell Transplantation (ASCT)." Blood 108, n.º 11 (16 de noviembre de 2006): 3095. http://dx.doi.org/10.1182/blood.v108.11.3095.3095.
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Abstract Purpose: We have previously reported that diffuse pattern of bone marrow involvement as determined by MRI imaging of the spine, in newly diagnosed patients with MM is associated with features of advanced disease and with shorter survival compared to patients with normal, focal or variegated pattern of BM involvment. Purpose of the study was to determine the prognostic value of spinal bone MRI in the outcome of MM patients undergoing treatment with HDM and ASCT. Materials and methods: Between October 1995 and June 2006, 63 MM patients for whom a MRI of the spine before first line therapy was available, received treatment with HDM (200mg/m2 iv) and ASCT, in our Department. Four patterns of BM involvement in MRI were identified: normal pattern which required no evidence of abnormal signal, focal pattern, which consists of localized areas of abnormal marrow (on T1-weighted images, focal lesions are darker than yellow marrow and slightly darker or isointense to red marrow; on T2-weighted images they are brighter than both red and yellow marrow), diffuse pattern of abnormal marrow, where the normal bone marrow is completely replaced by the abnormal process and the intervertebral discs appear brighter or are isointense to the diseased marrow, and variegated pattern, which consists of innumerable small foci of disease on a background of intact marrow. MRI pattern of BM involvement and multiple clinical and laboratory parameters were evaluated for their possible correlation with progression free survival (PFS) after HDM. Results: Patients’ median age was 55years (range: 23 to 74 years), 60% of patients had ISS 2 or 3 before initial treatment, 54% of patients were transplanted during remission and 46% of patients had active myeloma at the time of HDM (primary refractory: 34%, resistant relapse: 12%). Nine patients (14%) had a normal MRI pattern, 33 (53%) had focal, 4 (6%) variegated and 17 (27%) diffuse MRI pattern of BM involvement. The median PFS for all patients was 20 months. Significant adverse prognostic factors for PFS included elevated creatinine and LDH serum levels, and ISS stage 3 at diagnosis. Furthermore the pattern of BM involvement by MRI correlated strongly with PFS: median PFS of 72 months for normal pattern, 20 months for focal pattern, 16 months for variegated and 9 months for diffuse pattern (p=0.016). Patients with both ISS stage 3 and diffuse MRI pattern had a median PFS of only 6 months. Conclusion: MRI of the spine before treatment provides prognostic information for the outcome of MM patients with myeloma after HDM and ASCT. Diffuse marrow replacement on MRI of the spine identifies patients with advanced MM who have a poor prognosis even after intensive therapy. Such patients are candidates for innovative treatments.
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Aly, Mahmoud, Mohamed Nayel, Akram Salama, Emad Ghazy y Ibrahim Elshahawy. "Cardiac troponin I as a cardiac biomarker has prognostic and predictive value for poor survival in Egyptian buffalo calves with foot-and-mouth disease". May-2020 13, n.º 5 (2020): 890–95. http://dx.doi.org/10.14202/vetworld.2020.890-895.
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Background and Aim: Foot-and-mouth disease (FMD) causes huge economic losses in Egypt due to reductions in the production of red meat, milk, and milk by-products and can also lead to myocarditis in young animals. The aim of our study was to evaluate cardiac biomarkers, in particular cardiac troponin I (cTnI), and to reveal the relations of cardiac biomarkers with poor survival in FMD-infected Egyptian buffalo calves. Materials and Methods: Forty-two Egyptian buffalo calves were included in this study. The calves were divided into 12 apparently healthy control calves and 30 calves clinically diagnosed with FMD during a disease outbreak in Menofia and Behera Governorates, Egypt. The diseased calves were divided, according to age, into 13 calves <3 months old and 17 calves between 3 and 6 months old. The animals were examined clinically and subjected to analysis of cardiac biomarkers. Results: Biochemical analysis revealed significant elevations of cardiac biomarkers, especially creatine kinase myocardial band (CK-MB), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), cardiac troponin T (cTnT), and cardiac troponin I (cTnI) in FMD-infected calves in comparison with control calves. There was a significant association between cTnI and poor survival in infected calves. Conclusion: Cardiac biomarkers could be used as a rapid method for diagnosis of myocarditis induced by FMD in Egyptian buffalo calves. In addition, cTnI is a very sensitive and accurate tool for determining myocardial cell damage in the earlier stages of the disease and a good predictor of poor survival in calves.
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Güçlü, Aydın, Turgut Tursem Tokmak, Hacı Kaymaz, Kültigin Türkmen, Hande Şenol, Nail Özhan y Yusuf Dursun. "The Relationship of Red-Cell Distribution Width and Carotid Intima Media in Chronic Kidney Disease". Turkish Nephrology Dialysis Transplantation 25, n.º 2 (12 de mayo de 2016): 187–91. http://dx.doi.org/10.5262/tndt.2016.1002.11.
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Bauer, Natali, Julia Nakagawa, Cathrin Dunker, Klaus Failing y Andreas Moritz. "Evaluation of the automated hematology analyzer Sysmex XT-2000iV™ compared to the ADVIA® 2120 for its use in dogs, cats, and horses". Journal of Veterinary Diagnostic Investigation 23, n.º 6 (noviembre de 2011): 1168–80. http://dx.doi.org/10.1177/1040638711425572.
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The automated laser-based hematology analyzer Sysmex XT-2000 iV™ providing a complete blood cell count (CBC) and 5-part differential has been introduced in large veterinary laboratories. The aim of the current study was to determine precision, linearity, and accuracy of the Sysmex analyzer. Reference method for the accuracy study was the laser-based hematology analyzer ADVIA® 2120. For evaluation of accuracy, consecutive fresh blood samples from healthy and diseased cats ( n = 216), dogs ( n = 314), and horses ( n = 174) were included. A low intra-assay coefficient of variation (CV) of approximately 1% was seen for the CBC except platelet count (PLT). An intra-assay CV ranging between 2% and 5.5% was evident for the differential count except for feline and equine monocytes (7.7%) and horse eosinophils (15.7%). Linearity was excellent for white blood cell count (WBC), hematocrit value, red blood cell count (RBC), and PLT. For all evaluated species, agreement was excellent for WBC and RBC, with Spearman rank correlation coefficients (rs) ranging from >0.99 to 0.98. Hematocrit value correlated excellently in cats and dogs, whereas for horses, a good correlation was evident. A good correlation between both analyzers was seen in feline and equine PLT (rs = 0.89 and 0.92, respectively), whereas correlation was excellent for dogs (rs = 0.93). Biases were close to 0 except for mean corpuscular hemoglobin concentration (4.11 to −7.25 mmol/l) and canine PLT (57 × 109/l). Overall, the performance of the Sysmex analyzer was excellent and compared favorably with the ADVIA analyzer.
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Baranidharan, G. R., P. Ramesh, M. Chandrasekar, D. Sumathi, B. G. Thilagar, K. Jeyaraja y M. G. Jayathangaraj. "Efficacy of Darbepoetin alfa in anemic dogs with Chronic Kidney Disease – a review of 21 cases". International Journal of Hematology and Blood Disorders 4, n.º 1 (21 de marzo de 2019): 1–3. http://dx.doi.org/10.15226/ijhbd/4/1/00134.
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Anemia due to Chronic Kidney Disease (CKD) represents a major portion of hemodynamic imbalance in dogs. Although the pathogenesis of the anemia in CKD is multifactorial, decreased production of erythropoietin by the diseased kidneys has been proven and the severity of anemia correlates positively with serum creatinine concentrations in affected dogs. Therapeutic whole and Packed Red Blood Cell transfusion has always been a main stay in practice. However, the unavailability of appropriate dog donors, blood typing modalities and occurrence of post transfusion reactions are the common hurdles encountered. Alternatively, Darbepoetin alfa, a hyperglycosylated synthetic recombinant erythropoietin which is commonly used in human patients with CKD induced anemia is used in recent canine practice. Unlike human transfusion medicine, not much of study has been documented in dogs in India. However anecdotally, darbepoetin is perceived to less likely form antibodies compared to erythropoietin. A study comprising of 21 dogs referred to Madras Veterinary College Teaching Hospital (MVCTH) with CKD (stage II, III & IV were 7, 9 & 5 respectively) of multifactorial etiology during the period of January to December 2017 was done. Injectable Darbepoetin was administered @0.5μg/kg subcutaneously once in a week for three weeks along with supplementation of Iron to achieve a medium hematocrit of 30%. Efficacy of Darbepoetin was evaluated by measuring pre and post therapeutic clinico pathological studies. Darbepoetin proved effective in increasing PCV, anemic crisis potentially in 66.7% of dogs. Hypertension, vomiting, melena, inappetance were common findings in affected dogs and coexistence of normocytic, normochromic progressive anemia which responds to Darbepoetin alfa therapy. Though expensive than Erythropoietin, Darbepoetin @0.5μg/kg s/c proved safe and effective in improving packed cell volume in CKD dogs as an alternative to packed RBC or whole blood transfusion. Further immunological, toxicological and clinical studies on Darbepoetin therapy is warranted in a large population in dogs. Keywords: Ckd; Azotemia; Anemia; Darbepoetin
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Hsieh, Chia-Shan, Chia-Ti Tsai, Yau-Hung Chen, Sheng-Nan Chang, Juey-Jen Hwang, Eric Chuang y I.-Hui Wu. "Global Expression Profiling Identifies a Novel Hyaluronan Synthases 2 Gene in the Pathogenesis of Lower Extremity Varicose Veins". Journal of Clinical Medicine 7, n.º 12 (11 de diciembre de 2018): 537. http://dx.doi.org/10.3390/jcm7120537.
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Lower extremities varicose veins (VV) are among the most easily recognized venous abnormalities. The genetic mechanism of VV is largely unknown. In this study, we sought to explore the global expressional change of VV and identify novel genes that might play a role in VV. We used next-generation ribonucleic acid (RNA) sequence (RNA seq) technology to study the global messenger RNA expressional change in the venous samples of five diseased and five control patients. We identified several differentially expressed genes, which were further confirmed by conventional reverse transcription polymerase chain reaction (RT-PCR). Using these significant genes we performed in silico pathway analyses and found distinct transcriptional networks, such as angiogenesis, cell adhesion, vascular injury, and carbohydrate metabolisms that might be involved in the mechanism of VV. Among these significant genes, we also found hyaluronan synthases 2 gene (HAS2) played a pivotal role and governed all these pathways. We further confirmed that HAS2 expression was decreased in the venous samples of patients with VV. Finally, we used a zebrafish model with fluorescence emitting vasculature and red blood cells to see the morphological changes of the venous system and blood flow. We found that HAS2 knockdown in zebrafish resulted in dilated venous structural with static venous flow. HAS2 may modulate the transcriptional networks of angiogenesis, cell adhesion, vascular injury, and carbohydrate metabolisms in venous tissues and downregulation of HAS2 may underlie the mechanism of VV.
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Garibaldi, A., D. Bertetti y M. L. Gullino. "First Report of Powdery Mildew (Oidium sp.) on Akebia quinata in Italy". Plant Disease 88, n.º 6 (junio de 2004): 682. http://dx.doi.org/10.1094/pdis.2004.88.6.682d.
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Akebia quinata Decne., an ornamental species belonging to the family Lardizabalaceae, is used as a climbing species in gardens to cover walls as well as supports and is very much appreciated because of its dark red flowers. During the summer of 2003, severe outbreaks of a previously unknown powdery mildew were observed on established plantings in several gardens near Biella (northern Italy). The upper surfaces of leaves were covered with white mycelium, and the corresponding abaxial surface of infected leaves were chlorotic. Young, green stems also affected showed extended chlorosis. As the disease progressed, infected leaves turned yellow and died. Foot cell was cylindric and appressorium lobed. Conidia formed singly were hyaline, ellipsoid, and measured 26.4 to 45.6 × 10.6 to 15.6 μm (average 35.1 × 12.7 μm). Fibrosin bodies were not present. The pathogen was identified as Oidium sp. subgenus Pseudoidium (1) partially because cleistothecia were not observed. Conidial measurements are close to those reported for Microsphaera akebiae Sawada. Pathogenicity was confirmed by gently pressing diseased leaves onto leaves of healthy A. quinata plants. Three plants of A. quinata were used as replicates. Noninoculated plants served as controls. Plants were maintained between 20 and 30°C in a garden located 5 km from where the disease was originally found. After 10 days, typical symptoms of powdery mildew developed on inoculated plants. Noninoculated plants did not show symptoms. To our knowledge, this is the first report of the presence of powdery mildew on A. quinata in Italy. The disease is currently restricted to the area of Biella. The presence of M. akebiae was recently reported in the Netherlands (2). Specimens of this disease are available at the DIVAPRA Collection at the University of Torino. References: (1) U. Braun and S. Takamatsu. Schlechtendalia, 4:1, 2000. (2) M. Scholler and W. Gams. Nova Hedwigia, 67:101, 1998.
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Arranz, Lorena, Abel Sánchez-Aguilera, Joan Isern, Daniel Martín-Pérez, Alexandar Tzankov, Juerg Schwaller, Radek C. Skoda y Simón Méndez-Ferrer. "Sympathetic Neuropathy Of The Hematopoietic Stem Cell Niche Is Essential For Myeloproliferative Neoplasms". Blood 122, n.º 21 (15 de noviembre de 2013): 268. http://dx.doi.org/10.1182/blood.v122.21.268.268.
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Abstract Myeloproliferative neoplasms (MPNs) are originated by mutations in a hematopoietic stem cell (HSC), frequently in the Janus kinase 2 (JAK2) gene. Different outcomes of this common event and limited efficacy of JAK2 inhibitors suggest the contribution of other factors. Additional HSC mutations and HSC-niche interaction might influence MPN progression, characterized by sequential expansion of HSCs, blood cells and megakaryocytes. Ensuing bone marrow (BM) fibrosis and osteosclerosis, which are contributed by osteoblastic lineage cells in a BCR/ABL CML model (Schepers et al Cell Stem Cell 2013), impede normal hematopoiesis. We have previously shown that BM nestin+ mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibers regulate HSCs (Méndez-Ferrer et al Nature 2008 & 2010). Here we demonstrate that damage to this regulatory network is required for MPN manifestation. Nestin+ MSCs and NESTIN mRNA expression were rapidly reduced in the BM of MPN patients and mice expressing the human JAK2-V617F mutation. This reduction was not due to nestin+ MSC differentiation into fibroblasts or osteoblasts, as shown by 25-week lineage-tracing studies using Nes-CreERT2;RCE-loxP mice, but instead caused by early MSC apoptosis. In turn, nestin+ cell reduction stimulated MPN progression; selective nestin+ cell depletion using Nes-CreERT2;iDTA mice increased peripheral white and red blood cells, megakaryocytic invasion of spleen germinal centers and BM osteosclerosis. Our recent results indicate that the neural crest contributes during development to BM MSCs with specialized HSC niche function and that postnatal murine BM Nestin-GFP+ cells do not only contain MSCs but also Schwann cell precursor-like cells (Isern et al, ISSCR Annual Meeting 2013). BM Nestin-GFP+ cells from MPN mice showed reduced expression of HSC maintenance and mesenchymal genes, and increased expression of genes related to axon guidance and Schwann cell differentiation. Principal component analyses of independent biological samples further showed that control BM nestin+ cells clustered together with MSCs, whereas MPN BM nestin+ cells resembled Schwann cell precursors. These data suggested alterations to the neural component of the BM HSC niche in MPN. Indeed, BM sympathetic nerve fibers and Schwann cells, closely associated but different from Nestin-GFP+ cells, were rapidly reduced in the BM of diseased animals. Symptomatic MPN mice were treated with selective β3-adrenergic agonists to compensate for the loss of sympathetic stimulation of nestin+ MSCs. Treatment with BRL37344 or the recently FDA approved drug Mirabegron prevented MPN-associated neutrophilia and thrombocytosis, while it did not affect peripheral blood counts of wild-type mice. While vehicle-injected animals showed severe BM fibrosis, long-term BRL37344 treatment led to virtual absence of focal reticulin deposits or excessive fibroblasts. To further confirm the contribution of BM neural damage to MPN pathogenesis, diseased mice were treated with a neuroprotective agent. Sympathetic nerve-ensheathing Schwann cells were strongly reduced in the BM of vehicle-injected animals but preserved in 4-methylcatechol-treated mice. Like in BRL37344-treated animals, this was associated with prevention of very early MPN events, including neutrophilia and BM overproduction of the pro-inflammatory cytokine interleukin-1β. Since MPN is originated by a mutant HSC, we reasoned that sympathetic neuropathy might contribute to MPN pathogenesis through early disruption of the HSC niche. The chemokine Cxcl12 regulates HSC migration and proliferation. At early MPN stage, HSC expansion and mobilization correlated with decreased BM Cxcl12 expression and protein levels. Concomitantly, BM nestin+ MSC number and their Cxcl12 expression were significantly reduced. BRL37344 treatment completely restored the number of BM nestin+ cells and improved Cxcl12 BM levels. Treatment with 4-methylcatechol or BRL37344 prevented the early expansion of mutant hematopoietic progenitors, whereas long-term BRL37344 treatment efficiently reduced mutant hematopoietic progenitor numbers in BM and peripheral blood. These results demonstrate that damage of the niche, induced by the mutated HSCs, critically contributes to JAK2-V617F+ MPN pathogenesis. They also unravel HSC niche-forming MSCs and their neural regulation as promising novel therapeutic targets in MPN. Disclosures: Arranz: Centro Nacional de Investigaciones Cardiovasculares (CNIC): National patent application number 201330677 entitled “Neuroprotective/neurocompensatory therapy for the treatment of myeloproliferative diseases”, with priority date May 10, 2013, National patent application number 201330677 entitled “Neuroprotective/neurocompensatory therapy for the treatment of myeloproliferative diseases”, with priority date May 10, 2013 Patents & Royalties. Off Label Use: Beta-3-adrenergic agonists (e.g. FDA-approved Mirabegron) and neuroprotective drugs for the treatment of myeloprolifeative diseases. Isern:Centro Nacional de Investigaciones Cardiovasculares (CNIC): National patent application number 201330677 entitled “Neuroprotective/neurocompensatory therapy for the treatment of myeloproliferative diseases”, with priority date May 10, 2013, National patent application number 201330677 entitled “Neuroprotective/neurocompensatory therapy for the treatment of myeloproliferative diseases”, with priority date May 10, 2013 Patents & Royalties. Méndez-Ferrer:Centro Nacional de Investigaciones Cardiovasculares (CNIC): National patent application number 201330677 entitled “Neuroprotective/neurocompensatory therapy for the treatment of myeloproliferative diseases”, with priority date May 10, 2013, National patent application number 201330677 entitled “Neuroprotective/neurocompensatory therapy for the treatment of myeloproliferative diseases”, with priority date May 10, 2013 Patents & Royalties.
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Yamate, J., H. Yoshida, Y. Tsukamoto, M. Ide, M. Kuwamura, F. Ohashi, T. Miyamoto, T. Kotani, S. Sakuma y M. Takeya. "Distribution of Cells Immunopositive for AM-3K, a Novel Monoclonal Antibody Recognizing Human Macrophages, in Normal and Diseased Tissues of Dogs, Cats, Horses, Cattle, Pigs, and Rabbits". Veterinary Pathology 37, n.º 2 (marzo de 2000): 168–76. http://dx.doi.org/10.1354/vp.37-2-168.
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The monoclonal antibody AM-3K, which was developed using human pulmonary macrophages as the immunogen, immunocytochemically labels most human macrophages except for blood monocytes and dendritic cell populations. AM-3K also shows cross-reactivity in some animal species. To evaluate the usefulness of AM-3K, the present study investigated the detailed distribution of AM-3K–immunopositive macrophages in normal and diseased tissues of dogs, cats, horses, cattle, pigs, and rabbits. Zamboni's solution-fixed, paraffinembedded sections were the most available for the immunocytochemistry with AM-3K. In all animal species examined, AM-3K labeled most macrophages in splenic red pulp, lymph node sinuses and thymus, and tissue macrophages in the interstitium of various organs and sites such as the kidneys, lungs, heart, pancreas, intestines, and skin. Alveolar macrophages and perivascular microglial cells were also immunoreactive for AM-3K. Interestingly, Kupffer cells of dogs, cats, and horses were labeled for AM-3K, but those of cattle, pigs, and rabbits were not. Furthermore, in tumor tissues and inflammatory lesions such as liver fibrosis and encephalomalacia that were obtained from dogs, infiltrating macrophages were stained with AM-3K, but not all infiltrating macrophages reacted to AM-3K. In addition, only 30–50% of pulmonary and peritoneal macrophages obtained from cats and dogs were reactive for AM-3K. AM-3K did not react with blood monocytes, dendritic cell populations, and osteoclasts. These observations indicate that AM-3K specifically labels most exudate and tissue macrophages in the animal species examined. However, the expression of antigens recognized by AM-3K on macrophages may be dependent on differential maturation stages or different functions evoked by some conditions. AM-3K immunoreaction products were seen on the cytoplasmic membrane of macrophages by immunoelectron microscopy. AM-3K would be useful for detection of macrophage populations in the animal species examined here.
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Johansen, Max E., Carlos Bidot, Martha Q. Gonzalez, Mirian Yaniz, Lawrence Horstman, Wenche Jy y Yeon S. Ahn. "Influence of Cell-Derived Microparticles on Thromboelastography." Blood 116, n.º 21 (19 de noviembre de 2010): 3698. http://dx.doi.org/10.1182/blood.v116.21.3698.3698.
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Abstract Abstract 3698 Background. Thromboelastography (TEG) is a method of analyzing coagulation commonly used to assess pre- and perioperative bleeding risk. We have been interested in the role of cell-derived microparticles (MP) in coagulation and in this study, examined correlations between TEG parameters and MP levels as described in Methods. Methods. Patients: Whole citrated blood from a total of 43 patients was examined by TEG (Haemoscope TEG 5000), within 5 hours of drawing. The study subjects consisted of 12 ITP, 5 TTP, 26 thrombocytopenia (TP) of various causes and 21 healthy controls. TEG: Parameters analyzed were maximum amplitude (MA), clot strength (G), lag time (R), time to formation of clot of amplitude 20 mm (k), rate of growth (a), coagulation index (CI). MP Assay: MP from platelets (PMP) were defined flow cytometrically by CD31+/CD41+; from red cells (RMP) by glycophorin A (CD235); from endothelia (EMP) by CD62E; and from leukocytes (LMP) by CD45. In addition, we employed generic markers, lectin FITC-Ulex europaeus (Ulex) as a measure of “total MP”; and annexin V+ (AnV+) MP, a marker of procoagulant phospholipids. Platelet counts were obtained from CBC at the clinical laboratory. Results. We assessed correlations between each TEG parameter, and each MP parameter, as well as platelet counts. Only those which were significant (p<0.05) are reported below. (1) RMP levels correlated positively and strongly with lag time, R (r=0.737, p<0.0001). LMP levels correlated positively with k (r=0.553, p=0.0001) moderately. Interestingly, we found moderate but consistent positive correlation between PMP levels and MA, G, and CI. These values were r=0.314, r=0.317, and r=0.346, respectively, and p<0.05 in each case. (2) Normal control values had an average G of 7.86 ±1.70 Kd/cm2 (mean ±SD), in contrast to ITP, TTP, and TP patients which had average G's of 8.62 ±3.96, 10.34 ±1.97, and 5.96 ±3.98 Kd/cm2, respectively. However, no statistically significant differences of means between patient groups and controls were found for any parameter in these small populations. (3) Platelet count was found to have a moderate correlation with G in TP patients (r=0.427, p<0.05) and with k (r= -0.459, p=0.018), but neither variable (G, k) correlated with platelet counts in ITP or TTP, possibly owing to the smaller populations in those groups. (4) Examining all patients combined for correlation between platelet count and G, we found r=0.633 (p<0.0001), confirming previous studies suggesting a relation between platelet count and G in both healthy and diseased patients. High platelet count was reasonably well correlated to high PMP (r=0.506, p<0.001). This may indicate that platelet activation as well as platelet count influences TEG, as it has been shown that PMP levels are a proxy of platelet activation. Conclusions: We conclude that MP contributes significantly to multiple variables in TEG profiles of patients with ITP, TTP, and TP, some positively, some negatively; and that there is wide variability in MP levels among these diseases. Platelets clearly also modulate TEG parameters, although the interplay between platelets and MP in forming a stable clot bears further research. PMP have the largest array of effects, positively correlating with MA, G, and CI, and negatively correlating with R+k, while having no significant effect on the other parameters. The data suggest that nearly all the MP affect the TEG parameters significantly. The most commonly affected parameter was MA, which is correlated to EMP, LMP, PMP, and Ulex. G and CI were also frequently affected by various MPs. This study is limited by the small patient population, various medications, and varying degree of severity of diseases. Disclosures: No relevant conflicts of interest to declare.
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Ospina-Prieto, Stephanie, Bruno K. L. Duarte, Jessica O. F. Guanaes, Fernando F. Costa y Margareth C. Ozelo. "Endothelial Colony-Forming Cells (ECFC) As an Autologous Model for Studying Endothelial Pathophysiology in Sickle Cell Anemia and Myeloproliferative Neoplasms". Blood 132, Supplement 1 (29 de noviembre de 2018): 74. http://dx.doi.org/10.1182/blood-2018-99-117218.
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Abstract Background: Endothelial colony-forming cells (ECFC) are an important source of autologous endothelial cells to study its implication in the pathophysiology of diseases with risk of vaso-occlusive events. Currently, our research group began to elucidate the ECFC mechanisms that contribute to the complex clinical vascular manifestations in two diseases, sickle cell anemia (SCA) and myeloproliferative neoplasms (MPN). Aims: In this study, we analyzed functional in vitro assays of endothelial cells. The adhesion to red blood cell (RBC), migration and angiogenesis process of ECFC isolated from patients with SCA and MPN, as well as from healthy individuals (CTR) were evaluated in seeking an expanded understanding of the biology of the endothelial cell and its role in vascular events. Methods: ECFC were obtained through the isolation and culture of human peripheral blood mononuclear cells. ECFC were isolated from 8 patients with SCA under regular transfusion, 6 patients with MPN and 10 CTR. Human umbilical vein endothelial cells (HUVEC) were used as additional controls. Flow cytometry of ECFC indicated that all cells were highly positive for endothelial cell markers CD31, CD144, CD146 and KDR with no indication of CD45 (leukocyte antigens), CD133 (endothelial progenitor cell marker) and CD34 (hematopoietic progenitor cell marker). RBCs from healthy individuals were obtained after centrifugation of whole blood. Cellular adhesion was evaluated after incubation of ECFCs with RBCs in the presence or absence of inflammatory stimulus (TNF-α). Endothelial adhesion molecules were analyzed by flow cytometry (ICAM-1, VCAM-1, E and P-selectin). ECFC migration was assessed using a scratch-wound healing assay and wound regression was analyzed by time-lapse videos. Angiogenesis capacity was evaluated through three-dimensional ECFC cultures in Matrigel. Network parameters (segments, junctions and meshes) were characterized during 24h after seeding. All experiments were performed in triplicate. Results: In total, 48 ECFC colonies were established, 10 from SCA, 25 MPN and 13 CTR. We observed a higher percentage of adhered RBCs to ECFCs isolated from patients with SCA (14.0%) and MPN (23.4%) without TNF-ɑ stimulus, when compared to ECFC from CTR, (8.4%, p< 0.04 and p< 0.001, respectively), and HUVEC (9.4%, p< 0.05 and p< 0.02, respectively). No differences were detected in the expression of adhesion molecules in ECFC. Mean wound regression rates at 14h were 79.9% for SCA, 84.4% for MPN, and 88.8% for CTR. The high variability among colonies in each group could explain why this difference was not statistically significant. Finally, HUVECs had a shorter time for wound closure, with complete wound regression at 10h. The angiogenesis analysis at 15h ECFC from SCA and MPN had, respectively, 20% and 50% less network parameters than CTR. Then beyond 15h post-seeding, the network parameters regressed until reaching a plateau. At 24h the segments began to disappear progressively, leading to a marked reduction in 40h. Unlike ECFC, HUVEC presented a high network formation. Conclusions: Our findings reveal distinct functional properties and behavior between the ECFCs from two diseases with vascular manifestations, SCA and MPN. ECFC do provide access to patient vascular endothelium and enable us to validate the use of these cells as investigative models. In contrast, HUVECs showed a unique behavior, which differed from both diseased and controls ECFCs. This highlights the differences between autologous in vitro and established cell lines as experimental models for vascular diseases. This raises the question of which is the most representative model of human endothelial pathophysiology in vascular diseases. Disclosures Ozelo: BioMarin: Honoraria, Speakers Bureau; Grifols: Honoraria; Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Honoraria, Research Funding.
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Kodippili, Gayani C., Jeff Spector, Caitlin Sullivan, Frans A. Kuypers, Richard Labotka, Patrick G. Gallagher, Ken Ritchie y Philip S. Low. "Imaging of the diffusion of single band 3 molecules on normal and mutant erythrocytes". Blood 113, n.º 24 (11 de junio de 2009): 6237–45. http://dx.doi.org/10.1182/blood-2009-02-205450.
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Abstract Membrane-spanning proteins may interact with a variety of other integral and peripheral membrane proteins via a diversity of protein-protein interactions. Not surprisingly, defects or mutations in any one of these interacting components can impact the physical and biological properties on the entire complex. Here we use quantum dots to image the diffusion of individual band 3 molecules in the plasma membranes of intact human erythrocytes from healthy volunteers and patients with defects in one of their membrane components, leading to well-known red cell pathologies (hereditary spherocytosis, hereditary elliptocytosis, hereditary hydrocytosis, Southeast Asian ovalocytosis, and hereditary pyropoikilocytosis). After characterizing the motile properties of the major subpopulations of band 3 in intact normal erythrocytes, we demonstrate that the properties of these subpopulations of band 3 change significantly in diseased cells, as evidenced by changes in the microscopic and macroscopic diffusion coefficients of band 3 and in the compartment sizes in which the different band 3 populations can diffuse. Because the above membrane abnormalities largely arise from defects in other membrane components (eg, spectrin, ankyrin), these data suggest that single particle tracking of band 3 might constitute a useful tool for characterizing the general structural integrity of the human erythrocyte membrane.
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Weinthal, Joel, Melanie Praught y Heather Brown. "Analysis of Umbilical Cord Blood Stem Cell Therapy for Regenerative Medicine Applications". Blood 112, n.º 11 (16 de noviembre de 2008): 4660. http://dx.doi.org/10.1182/blood.v112.11.4660.4660.
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Abstract Over the past 20 years umbilical cord blood (UCB) has become valuable source of hematopoietic stem cells for use in transplantation to treat malignancies, blood disorders and genetic diseases. Cord blood stem cells have shown promising results in animal regenerative medicine studies for the repair of damaged or diseased tissues outside of the hematopoietic lineage. Family UCB banks provide collection and storage services for families to store their child’s UCB for clinical use. This study compared the release of UCB units from one family bank (Cord Blood Registry, CBR) for regenerative medicine versus traditional transplantation since the release of its first UCB unit for regenerative medicine in 2005. UCB was collected from the placenta of consenting mothers and transported to the processing facility from all 50 states and over 80 countries. The UCB was separated into a mononuclear cell fraction from the red blood cells and other non-engrafting cells. The processed UCB is stored in vapor-phase liquid nitrogen at −195° C until requested for use. To date, 230,000 units have been stored. Prior to release, viability and percent CD34+ (or CFU) content were assessed by the treating institution. Through July 2008, a total of 82 UCB units were released for clinical use, 47 of these units (57%) have been used for traditional transplantation and 35 (43%) have been used for regenerative medicine. From January 2005 through July 2008, 47 UCB units were released, 12 (26%) were used in traditional transplantation and 35 (74%) were used in regenerative medicine applications. Over this period the bank experienced a mean of 338% percent growth per year in the release of UCB units for regenerative medicine. The indications for regenerative medicine autologous infusions were cerebral palsy (24 units), brain injury (4 units), type 1 diabetes (6 units), and a rare immune disorder (1 unit). All patients in the regenerative medicine category did not receive any myeloablative chemotherapy or radiation. Released UCB units were stored a mean of 37 months prior to use, the mean CD34+ percent of TNC was 0.53% and mean viability was 95.9%. These data indicate that regenerative medicine applications utilizing autologous cord blood stem cells represent a significant and growing percentage of all treatments facilitated by a family cord blood bank. Regenerative medicine treatments for cerebral palsy and type 1 diabetes have the potential to impact many lives given that 10,000 cases of cerebral palsy and 13,000 cases of type 1 diabetes are diagnosed each year which compares to 2,500 cases of childhood leukemia and 650 cases of neuroblastoma, two common indications for pediatric transplantation. Further analysis is needed to assess the clinical outcomes which will provide background for larger clinical trials in the future.
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Reddy, R. Vamshidhar, Dimple Arora, P. Krishna Rao, Sagar Arjun Mapare, Venkat Ratna Nag y K. Gowtham. "An Investigation of Blood Hemogram and Estimation of Serum Iron and Protein Levels in Aggressive Periodontitis Patients: A Clinic Biochemical Study". Journal of Contemporary Dental Practice 14, n.º 5 (2013): 852–57. http://dx.doi.org/10.5005/jp-journals-10024-1415.
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ABSTRACT Aim The aim of this study is to investigate the blood hemogram and estimation of serum iron and proteins level in aggressive periodontitis patients. Materials and methods A total of 85 patients were selected and divided into two groups, 45 patients are with aggressive periodontitis and 40 patients are healthy. Periodontal parameters such as gingival inflammation oral hygiene index, Russell's periodontal index and radiograph were taken. Total 10 ml blood was collected and sent for estimation of blood hemogram protein estimation and serum electrophoresis. Results There was statistical significant difference observed in relation to gingival inflammation oral hygiene hemoglobin and total iron binding capacity level between both the groups. Conclusion It has been concluded that periodontitis does not induce anemia like state, as the hematological and biochemical parameters were almost equally affected in periodontally healthy and periodontally diseased individuals, but some parameters showed statistical significant difference between the both groups. Clinical significance In the present study, the clinical periodontal parameters, red blood cell parameters and serum iron and ferritin levels were compared among control and test groups. It was found that the values of gingival inflammation, oral hygiene and periodontal index, hemoglobulin level and total iron binding protein were statistically significant between the groups. However, the values of erythrocyte count, white blood cell count, serum iron and serum proteins, serum electrophoresis did not show any significant correlation. How to cite this article Rao PK, Reddy RV, Mapare SA, Nag VR, Gowtham K, Arora D. An Investigation of Blood Hemogram and Estimation of Serum Iron and Protein Levels in Aggressive Periodontitis Patients: A Clinic Biochemical Study. J Contemp Dent Pract 2013;14(5):852-857.
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Waltzek, Thomas B., Brian A. Stacy, Robert J. Ossiboff, Nicole I. Stacy, William A. Fraser, Annie Yan, Shipra Mohan et al. "A novel group of negative-sense RNA viruses associated with epizootics in managed and free-ranging freshwater turtles in Florida, USA". PLOS Pathogens 18, n.º 3 (11 de marzo de 2022): e1010258. http://dx.doi.org/10.1371/journal.ppat.1010258.
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Few aquatic animal negative-sense RNA viruses have been characterized, and their role in disease is poorly understood. Here, we describe a virus isolated from diseased freshwater turtles from a Florida farm in 2007 and from an ongoing epizootic among free-ranging populations of Florida softshell turtles (Apalone ferox), Florida red-bellied cooters (Pseudemys nelsoni), and peninsula cooters (Pseudemys peninsularis). Affected turtles presented with similar neurological signs, oral and genital ulceration, and secondary microbial infections. Microscopic lesions were most severe in the softshell turtles and included heterophilic/histiocytic meningoencephalitis, multi-organ vasculitis, and cytologic observation of leukocytic intracytoplasmic inclusions. The virus was isolated using Terrapene heart (TH-1) cells. Ultrastructurally, viral particles were round to pleomorphic and acquired an envelope with prominent surface projections by budding from the cell membrane. Viral genomes were sequenced from cDNA libraries of two nearly identical isolates and determined to be bi-segmented, with an ambisense coding arrangement. The larger segment encodes a predicted RNA-directed RNA polymerase (RdRP) and a putative zinc-binding matrix protein. The smaller segment encodes a putative nucleoprotein and an envelope glycoprotein precursor (GPC). Thus, the genome organization of this turtle virus resembles that of arenaviruses. Phylogenetic analysis shows that the RdRP of the turtle virus is highly diverged from the RdRPs of all known negative-sense RNA viruses and forms a deep branch within the phylum Negarnaviricota, that is not affiliated with any known group of viruses, even at the class level. In contrast, the GPC protein of the turtle virus is confidently affiliated with homologs from a distinct group of fish hantaviruses. Thus, the turtle virus is expected to become the founder of a new taxon of negative-sense RNA viruses, at least with a family rank, but likely, an order or even a class. These viruses probably evolved either by reassortment or by intrasegment recombination between a virus from a distinct branch of negarnaviruses distant from all known groups and a hanta-like aquatic virus. We suggest the provisional name Tosoviridae for the putative new family, with Turtle fraservirus 1 (TFV1) as the type species within the genus Fraservirus. A conventional RT-PCR assay, targeting the TFV1 RdRP, confirmed the presence of viral RNA in multiple tissues and exudates from diseased turtles. The systemic nature of the TFV1 infection was further supported by labeling of cells within lesions using in situ hybridization targeting the RNA of the TFV1 RdRP.
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Kaur, Amandeep, Katherine M. Hannan, Samina Nazir, Kylee H. Maclachlan, Gretchen Poortinga, Si Ming Man, Simon Harrison, Ross D. Hannan y Elizabeth E. Gardiner. "The Ribosomal Biogenesis Inhibitor CX-5461 Is an Anti-Cancer Therapeutic That Increases Platelet Count in Mice and in Humans". Blood 134, Supplement_1 (13 de noviembre de 2019): 2360. http://dx.doi.org/10.1182/blood-2019-121713.
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Background: The ribosomal biogenesis inhibitor CX-5461 is a first-in-class selective inhibitor of ribosomal RNA gene transcription with single-agent antitumor activity against advanced hematologic cancers and synergistic activity when combined with front-line and emerging agents (Devlin et al. 2015, Sornkom et al. 2018, Maclachlan et al. 2018). It has predictable pharmacokinetics and a safety profile allowing prolonged dosing (Khot et al, Cancer Discov 2019). Unexpectedly, CX-5461 treatment increases platelet count by ~50% in tumour diseased mice; an effect that was maintained for up to 6 months of treatment. Aims: We investigated mechanisms that may contribute to increased platelet counts following CX-5461 treatment in a liver carcinoma mouse model or disease-free mice and evaluated blood test data from patients with haematological malignancies treated with CX-5461. Methods: We evaluated blood cell numbers in blood from vehicle- or CX-5461 treated mice with liver carcinoma, and blood cell numbers, bone marrow megakaryocytes, platelet receptors, immature platelets, platelet function, thrombopoietin (TPO) and inflammatory cytokine levels in disease-free C57BL/6 KaLwRij mice treated with 35 mg/kg CX-5461 or vehicle (n=15). Human platelet receptors and function were assessed in CX-5461-treated platelet-rich plasma by flow cytometry, platelet spreading assays and light transmission aggregometry. We evaluated temporal platelet count, and the platelet activation marker soluble glycoprotein (GP) VI in patient plasma samples who had received a single dose of 25-250 mg/m2 CX-5461 (n=16) with 1-way ANOVA. Results: In a model of liver carcinoma, mice with disease displayed significantly elevated (2.3-fold) platelet counts after 3 months treatment with biweekly injections of 35 mg/kg CX-5461 compared with vehicle-treated diseased mice (p = 0.0013). Disease-free mice treated for 7 or 14 days (3 or 6 x 35 mg/kg doses) with CX-5461 showed ~60% increase in platelet count; in comparison white and red cells were mildly suppressed. The CX-5461-mediated platelet increase at d7 (p<0.0005) was reversible within 1 week. At d14 (p<0.01, 1.7-fold increase in platelet count) a significant increase in megakaryocytes (p<0.05) and immature platelets (p<0.01) was observed. CX-5461 treatment had no effect on plasma TPO, platelet lifespan or platelet GPVI or GPIbα levels. Integrin αIIb was significantly elevated. Inflammatory cytokines interleukin (IL)-6 (p<0.05) and TNFα (p<0.01) increased at d7 in plasma. After pre-treatment for 30 min with CX-5461 ex vivo, human platelet function (aggregation and platelet spreading on collagen and fibrinogen) and receptor levels were normal. In 8/16 patients receiving CX-5461, increases of up to 34% in platelet counts were measured at day 15 of CX-5461 treatment, with no change in sGPVI. Conclusions: CX-5461 treatment of mice for two weeks increased platelet counts, megakaryocyte number and immature platelet fraction by an unknown mechanism however IL-6 has been reported by others to enhance megakaryopoeisis. Brief CX-5461 treatment in a group of patients with advanced haematological malignancy resulted in small increases in platelet count with retained platelet activation and treatment ex-vivo demonstrated platelet function to be unaffected. Future work will explore the link between CX-5461 treatment and megakaryopoiesis and thrombopoiesis, including the potential for CX-5461 to ameliorate drug-induced thrombocytopenia. Disclosures Harrison: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hannan:Pimera: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Laamari, Kaoutar. "Red Plaque of the Breast: Think Of Paget Disease". Journal of Clinical Research and Reports 2, n.º 1 (13 de enero de 2020): 01. http://dx.doi.org/10.31579/2690-1919/010.
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Paget's disease was first described by Sir Paget in 1874 as an eczema-like lesion of the nipple linked to an underlying cancer. This is a rare entity that affects only 1 to 4% of breast cancers. It mainly affects menopausal women with an average age of 62.6 years. No clinical or epidemiological factors are recognized as predisposing to the development of this disease. Clinically, Paget's mammary disease manifests itself as a scaly, thickened, sometimes pigmented, patchy plaque with irregular edges. This lesion can be limited to the nipple or extended to the areola and even to the surrounding skin. In the case of an eczematous lesion, the main differential diagnosis of Paget's disease is nipple eczema. But unilaterality, scalability and lack of response to corticosteroid therapy help to correct the diagnosis. Other differential diagnoses, such as psoriasis, superficial basal cell carcinoma and melanoma, may also be discussed and only histology will confirm the diagnosis. Mastectomy has long been considered the appropriate treatment because of its frequent association with multifocal or multicenter breast cancer. Currently, the majority of teams adopt conservative treatment.