bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of Cataracts among Idiopathic Thrombocytopenic Purpura (ITP) Patients in the UK General Practice Research Database (GPRD).
Authors: Feudjo-Tepie Maurille A. , Hall Susan A. , Logie John W. , Robinson Noah J. , Bennett Dimitri 
Published: October 2019

Abstract
ITP is a disease caused by inadequate platelet production as well as increased platelet destruction. Oral systemic steroids are recommended as first-line treatment. Prolonged use of oral steroids in other disease populations has been associated with an approximately two-fold increase in the risk of developing a cataract. This study aimed to quantify the underlying risk of cataracts among ITP patients compared with non-ITP patients. Using the GPRD, a retrospective matched cohort study was conducted in which each ITP patient newly diagnosed between 1992 and 2005 and age 18 years or older was matched to 5 non-ITP patients on gender, age, practice and duration of follow-up. ITP patients and cataract events were identified using specific Read/Oxmis disease codes and validated by a clinical epidemiologist. The exposure of interest was oral steroid use and the primary outcome was cataracts (recorded as cataracts or cataract surgery). Patients with a history of cataracts were not excluded from the study. Potential covariates of interest were diabetes, schizophrenia, glaucoma, splenectomy and hypertension. The risk of cataracts was quantified using incidence rates and 95% confidence intervals (CI) and, the difference between groups was estimated using a rate ratio and 95% CI. All analyses were further stratified by age and gender. Adjusted rate ratios were estimated using the Cox proportional hazard model. Seven hundred sixty ITP patients were identified, 745 (98%) of whom had 5 matched controls. The entire sample had a mean age of 56.4 years and 60.1% were female. Among ITP patients, users of oral steroids had a cataract incidence rate of 14.0 per 1000 person-years (PY) (95% CI: 8.7 – 21.4) and non steroid users 6.1 per 1000 PY (95% CI: 2.7 – 11.4). In the non-ITP population, these figures were 16.9 per 1000 PY (95% CI: 11.9 – 23.3) and 9.2 per 1000 PY (95% CI: 7.6 – 11.0), respectively. The incidence of cataracts was observed to increase with age. Adjusting for steroid use and other factors, the risk of cataracts was similar in the ITP and non-ITP populations (adjusted rate ratio 0.8, 95% CI: 0.5 – 1.2) whereas, oral steroid use was associated with an increased risk of cataracts in both ITP and non ITP populations (adjusted rate ratio 1.6, 95% CI: 1.2 – 2.2). There was no evidence of increased risk with either inhaled steroids, or intranasal steroids. As expected, our study shows that the use of oral steroids is associated with an increased risk of cataracts in both ITP and non-ITP populations. However, we found no evidence of a difference in the risk of cataracts between an ITP and a matched non-ITP population.
Microfluidic Tools To Probe the Spatial Dynamics of Coagulation.
Authors: Kastrup Christian J. , Runyon Matthew K. , Shen Feng , Ismagilov Rustem F. 
Published: October 2019

Abstract
To investigate the biophysical mechanisms that regulate the spatial dynamics of blood coagulation, we have developed a set of microfluidic tools that allow analysis and perturbation of blood coagulation on the micrometer scale with precise control of fluid flow, geometry, and surface chemistry. Physiological coagulation occurs in a localized manner; specifically, coagulation is believed to occur exclusively at regions of substantial vascular damage and does not spread throughout the entire vascular system. In vitro analysis and characterization of these spatial dynamics requires the ability to reproduce and perturb this system, an ability that is not provided by the mixed reactor systems commonly used for in vitro studies of blood coagulation. We developed microfluidic devices with micrometer-scale channels and methods to coat these channels with various phospholipids, including components of the blood coagulation network such as thrombomodulin and tissue factor, to reproduce in vitro the geometry and surface chemistry of blood vessels in vitro. In a microfluidic device with channels coated with phospholipids and thrombomodulin, we demonstrated that clots propagate in a wave-like fashion with a constant velocity in the absence of flow. We also showed that propagation of coagulation from an occluded channel to a channel with flowing blood plasma can be regulated by the geometry of the junction and the shear rate in the channel with flowing plasma. We also developed microfluidic tools to probe the spatial dynamics of initiation of clotting by patterning surfaces with tissue factor reconstituted into phospholipids bilayers. When human plasma or whole blood was exposed to these surfaces in a microfluidic device, clotting occurred only on patches of tissue factor larger than a threshold size. This threshold patch size is controlled by the rate of activation of clotting factors at the patch and the rate of transport of activated factors off the patch. These results suggest a mechanism for how tissue factor can circulate in blood without causing clotting, and how small regions of vascular damage can exist without causing clotting. These results also suggest new biophysical mechanisms that may control interactions between the coagulation cascade and bacterial surfaces.
Biochemical Comparison of VWF/FVIII Concentrates - Are There Differences in Product Characteristics and Purity?.
Authors: Schwartz B.A. , Pock K. , Stadler M. , Gruber G. , Kannicht C. , Romisch J. , Svae T.-E. 
Published: October 2019

Abstract
Introduction: Product characteristics and purity are important in assessing the safety and efficacy of VWF/FVIII products. Purity has been defined as the specific activity of the active ingredients in relation to the total protein in the products. This is important because it indicates the content of co-purified plasma proteins in the product. An extensive biochemical comparison of several VWF/FVIII concentrates licensed for the treatment of Haemophilia A and/or von Willebrand disease (VWD), including the novel new generation VWF/FVIII concentrate (Wilate), was performed to compare their properties.
Methods: Different batches of a number of commercially available VWF and VWF/FVIII products were analysed using state-of-the-art VWF and FVIII assays including VWF multimer analysis with examination of the multimeric triplet structure. The total protein as well as any accompanying plasma proteins, which may co-harvested in the final concentrate, were also quantified.
Results: All concentrates generally contained the specified VWF and FVIII amounts and activities. The VWF and FVIII specific activities and overall purity was highest for Wilate®, while all other concentrates contained considerable amounts of albumin used as a stabilizer as well as other residual plasma proteins that where found in varied concentration specific for the concentrate. The VWF:RCo/FVIII:C ratios varied greatly. The new generation product (Wilate®) was the only product tested that has high purity and showed a physiological 1:1 ratio. As compared to some of the other products, Wilate’s, native multimeric triplet structure was preserved.
Conclusion: There was a great variation in properties and purity of the concentrates tested. The new generation VWF/FVIII concentrate (Wilate®), showed a high purity and physiological VWF/FVIII ratio that should reduce the load of non-essential proteins given to the patient during treatment. Even though there are some differences in the content of the highest VWF multimers in this concentrate, the role of this in the in vivo physiological process of clot formation has not been established. The altered triplet structure seen in some of the older generation products may be the result of proteolysis in the manufacturing process. The clinical consequence of this has also not been established. The physiologic ratio of VWF and FVIII as well as their optimal PK profile, may ease the difficulties of dosing and monitoring in these patients.
Higher Incidence of Venous Thromboembolism Is Associated with Initial Cycles of Chemotherapy in Lymphoma Patients: Creatinine and Hemoglobin as Key Risk Factors.
Authors: Zhou Xiao , Huen Auris , Teegala Shyam , Ji Yuan , Fayad Luis , Hagemeister F.B. , Vadhan-Raj Saroj 
Published: October 2019

Abstract
Background: While Lymphoma patients are at increased risk of venous thromboembolism (VTE), the timing of VTE occurrence in reference to chemotherapy (CT) and risk factors are not well defined.
Methods: Medical records of all newly referred lymphoma patients (1046) to MD Anderson Cancer Center (MDACC) in 2003 were retrospectively reviewed over a follow-up period of two years for demographics, tumor histology, laboratory values, CT regimens, incidence of VTE, risk factors and management of VTE.
Results: Four hundred and twenty-two (422) out of 1046 patients received at least one cycle of CT at MDACC (total CT cycles 2126). The median age of the patients was 57 years (range, 17 to 87). Fifty eight % of pts were male and 62% were newly diagnosed. Seventy-three patients (17.3%) out of 422 had 80 new episodes of VTE; 58 deep vein thromboses (DVT) only, 17 pulmonary embolisms (PE) only, and 5 were combined DVT and PE. Only less than 5% (20/422) of pts received thromboprophylaxis during treatment for lymphoma. Interestingly, 68% (54/80) of episodes occurred by cycle 3 of CT suggesting that VTE episodes occurred primarily in patients with highest disease burden or during initiation of CT. Since the incidence was highest during the initial cycles of CT, we analyzed risk factors for the first regimen of CT. By multivariate logistic regression analysis, gender (female vs. male, OR=3.6, 95%CI 1.707 to 7.61, p=0.0008), high hemoglobin (OR=1.29, 95%CI 1.059 to 1.561, p =0.011), high serum creatinine (OR=3.36, 95%CI 1.372 to 8.228, p=0.0080), doxorubicin (DOX) and/or methotrexate (MTX)-based CT regimen (OR=2.948, 95%CI 1.352 to 6.429, p=0.0066) were found to be important risk factors for new VTE. Specifically, the estimated risk for lymphoma patients with baseline hemoglobin 12 gm/dL receiving DOX and/or MTX based CT with renal insufficiency (creatinine 2.0mg/dL) is 50% in females and 21% in males.
Conclusions: Lymphoma patients are at higher risk for VTE in the initial cycles of CT (cycles 1–3). Patients with high hemoglobin, elevated creatinine, female gender, and those receiving DOX and/or MTX based CT regimens are at higher risk for VTE than others. These clinically relevant findings suggest that a thromboprophylaxis strategy is needed in the patients presenting with these risk factors, particularly, in the initial cycles of chemotherapy.
A Novel Marker for Blood Platelet Storage Lesion: Newly Synthesized Rap1 in Integrin Signaling.
Authors: Schubert Peter , Thon Jonathan N. , Walsh Geraldine M. , Serrano Katherine , Moore Edwin D. , Kast Juergen , Devine Dana V. 
Published: October 2019

Abstract
Platelet transfusion is a standard live-saving medical procedure for patients with platelet-deficient diseases like leukemia. Platelets have a limited shelf-life of 5–7 days for transfusion purposes. This is in part due to a storage-related deterioration typified by altered morphology features and platelet metabolism as well as increased platelet activation. While the manifestations of the platelet storage lesion (PSL) are well known, the precise biochemical pathways involved in the initiation or exacerbation of this process have yet to be identified. Recently, we analyzed protein changes in the platelet proteome at day 1 and day 7 of storage by using a comprehensive proteomic approach. Out of 503 proteins, twelve were identified as significantly and consistently changing in relative concentration across all proteomic probes, including glycoprotein (GP) IIb/IIIa, Rap1 and talin, which showed an increase in their concentration paralleled with an increase in surface expression of GPIIb/IIIa. Synthesis of Rap1 in stored platelets could be demonstrated after incubation with the translational inhibitor rapamycin at a final concentration of 10 nM for twelve hours and subsequent activation with thrombin. Flow cytometry revealed that storage lead to a moderate level of platelet activation (10.5 ± 1.4% at day1 and 28.8 ± 1.3% at day 7 of storage) compared to ADP-treated controls (73.7 ± 1.2%) monitored by CD62P surface expression, in a rapamycin-independent manner. Microscopic analyses revealed similar re-localization patterns for GPIIIa, Rap1 and talin comparing changes during platelet storage and agonist induced activation. A significant correlation (p=0.007) between Rap1 activation and CD62P surface expression was seen. This observation is in strong agreement with a model for platelet GP IIb/IIIa activation [Han et al., Current Biology, 16, 1796–1806, 2007] also suggesting a calcium-dependent initiation of signal transduction. To analyze this hypothesis in more detail, treatment of platelets sampled at days 1, 4 and 7 of storage with 1 mM EDTA for 2 hours resulted in decreased Rap1 activation, in reduced surface expression of CD41 (GPIIb) and CD61 (GPIIIa) as well as in a lower level of platelet activation compared to untreated controls, respectively. This study unravels one aspect of the PSL, showing involvement of integrin signaling and identifying Rap1 as a novel marker for PSL. Therefore, this pathway offers potential targets for intervention which might lead to a reduction in platelet activation during storage, and may enable platelets to be stored for longer periods of time. From a transfusion point of view, however, extending the shelf-life of platelet units will ultimately need to be balanced with maintaining the quality of transfused platelets, their functionality, and efficacy in the patient.
Preparation of Platelet Membrane Microparticles with High Pressure Homogenization Method.
Authors: Li Cui-ping , OuYang Jian , Huang Cheng-yin , Shi Guang-yao , Pei Xiao-ping 
Published: October 2019

Abstract
Objective To investigate the preparation technique of infusible platelet membrane microparticles (IPMs), and evaluate hemostatic function and effect of IPMs on pathological thrombogenicity after transfused into model of rabbit thrombocytopenia.
Methods Whole bloods collected in the street were used to prepare platelet concentrates(PCs),white cells were removed by white cell filter, and red cells by centrifugation at 1000rpm in for 10min. After that, platelets were washed twice with 0.9% NaCl solution by repeated resuspension and centrifugation, and adjusted concentration to 2×109/ml with 0.9% NaCl. The washed platelets were disrupted by repeated freezing (at −80°) and thawing (at 25°) three times, and were heated at 60° for twenty hours to inactivate any viral contaminants. Finally, the heat 2 treated platelets were crushed by high pressure homogenizer to form IPMs. In this study, particle analyser was applied to mean diameter and the particle size distribution of IPMs, APCT to test the procoagulation activity of IPMs in vitro. Hemostatic function and effect of IPMs onpathological thrombogenicity were observed after IPMs were transfused into thrombocytopenia rabbitmodels.
Results mean diameter of IPMs was from 200 to 300 nm. The procoagulation activity of 50Lg/ml of IPMs was equal to 250×109/L of fresh platelets. Rabbit ear bleeding time and APCT significantly shortened from two hours to twelve hours after transfusion of 2mg IPMs per Kg into thrombocytopenia rabbit models, but other indexes such as PT, APTT, Fg, and TT changed less.
Conclusions IPMs possess good hemostatic function and less effect on pathological thrombogenicity. It is a kind of promising biologic hemostatic reagent.
High Frequency of HPA-1B in Leukemia Patients.
Authors: Novaretti Marcia C.Z. , Bonifacio Silvia L. , Ruiz Azulamara S. , Fontes Lia V.Q. , Dorlhiac-Llacer Pedro E. , Chamone Dalton A.F. 
Published: October 2019

Abstract
Background: The HPA-1 alloantigen is a biallelic co-dominant system on human platelets carried on glycoprotein IIIa. Alloimmunization against the HPA-1 has clinical relevance in multiple transfused patients, in neonates with alloimmune thrombocytopenia and in platelet refractoriness. Accurate HPA genotyping is important to facilitate the provision of HPA-matched blood components for these patients. The purpose of this study was to determine the HPA-1 gene frequencies in apheresis blood donors and in leukemia patients.
Methods: Genomic DNA was extracted from 149 peripheral blood samples of apheresis regular donors and from 84 leukemia patients with chronic myeloid leukemia (CML=56), acute myeloid leukemia (AML=13), chronic lymphoid leukemia (CLL=6) and acute lymphoid leukemia (ALL=9) using a commercial DNA extraction kit (QIAamp DNA, QIAGEN, Germany). Sequence specific PCR (SSP-PCR) was performed amplifying the HPA-1a/HPA-1b gene using a pair of primer for each allele under the following conditions: the PCR was carried out in a final volume of 20μL, containing 0.2μg of genomic DNA, 0.2mM of each dNTP, 5% of glycerol, 1.5 units of platinum Taq polymerase (Invitrogen, U.S.A) in the buffer supplied, 5.0mM MgCl2 and 10.0 pmoles of each primer. Fragments of 196 bp derived from HPA-1a/1a mutation were separated for 90 minutes at 102V using 0.5μg.mL-1 ethidium bromide-stained 2.0% agarose gels and visualized in a UV light apparatus (Eagle Eye II, EUA).
Results: Table 1 shows the results of HPA1a/b genotyping and gene frequencies in apheresis regular donors and in leukemia patients. HPA-1b/HPA-1b genotype frequency in patients with AML was higher when compared to apheresis blood donors.
Conclusion: In our study, high prevalence of HPA-1b in homozygous in AML patients was detected. This data can be useful to evaluate the alloimmunization against platelet specific antigens in acute myeloid leukemia patients.
Table 1 Leukemia type Number of samples tested HPA-1 Genotype Frequency (%) Gene Frequency a/a a/b b/b HPA-1a HPA-1b CML 56 85.71 12.50 1.78 0.920 0.080 AML 13 76.92 15.38 7.69 0.846 0.154 CLL 06 50.00 50.00 0 0.750 0.250 ALL 09 88.88 11.11 0 0.944 0.055 Apheresis donors 149 73.82 22.82 3.36 0.852 0.147
Severe Refractory Autoimmune Hemolytic Anemia with Both Warm and Cold Autoantibodies: Complete Response with Rituximab.
Authors: Gupta Shilpi , Varma Seema , Szerszen Anita , Nakhl Fadi , Gottesman Aaron , Forte Frank J. , Dhar Meekoo 
Published: October 2019

Abstract
Mixed warm and cold autoimmune hemolytic anemia (AIHA) runs a chronic course with severe, intermittent exacerbations. Therapeutic options for treatment of hemolysis associated with mixed AIHA are limited. There have been only two reported cases of effective use of rituximab in the treatment of mixed AIHA. We report a case of severe mixed AIHA that did not respond to steroids and responded to one cycle of rituximab. A 62-year-old male presented with dyspnea, jaundice and splenomegaly. Blood work revealed severe anemia (hemoglobin 4.9 g/dl) with biochemical evidence of hemolysis. Exposure to cold led to worsening of hemolysis and hemoglobinuria. Direct antiglobulin test was positive for IgG and complement (C3d); and cold agglutinins were detected. Bone marrow revealed erythroid hyperplasia. Positron emission tomography scan showed no sites of pathologic uptake. There was no other evidence of a lymphoid or myeloid disorder. Initial therapy consisted of avoidance of cold, intravenous methylprednisolone and a trial of plasmapheresis; however, there was no clinically significant response and the patient continued to be transfusion dependent. He was then started on intravenous rituximab 375 mg/m2/week. After two treatments, hemoglobin stabilized and transfusion requirement diminished.
Figure Figure
Rituximab, continued for a total of four weeks, led to complete resolution of hemolytic anemia and associated symptoms. At his last visit, about 8 months after initial rituximab treatment patient continues to be in complete remission. This is the first reported case of mixed type AIHA not responding to steroid therapy with complete response to only one cycle of rituximab. Previous two reports of rituximab use in mixed AIHA have described initial brief response to steroids and the use of rituximab at the time of relapse. In both the cases, response to one cycle of rituximab was short-lived requiring a second cycle of rituximab. Our case demonstrates that severe hemolysis associated with mixed AIHA can be unresponsive to steroid therapy and a single cycle of rituximab may lead to prompt and durable complete remission. Rituximab is an effective treatment for mixed AIHA, especially when immediate response is desired, and merits further evaluation in this setting.
Effect of Dioxin (TCDD) on Gene Transcription of Human CD34+ Hematopoietic Cells.
Authors: Fracchiolla Nicola S. , Servida Federica , Bertazzi Pier A. , Corradini Paolo , Colombi Antonio , Todoerti Katia , Agnelli Luca , Neri Antonino , Deliliers Giorgio Lambertenghi 
Published: October 2019

Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) binds to aryl hydrocarbon receptor (AhR), a member of the erb-A family, allowing, after DNA binding, gene expression regulation. TCDD has a large number of biological effects, as skin and cardiovascular disease, diabetes and cancer. An increase in myeloid leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, was observed after 15 years in the population exposed to TCDD after the 1976 accident in Seveso, Italy. In the present study, we analyzed the in vitro effect of TCDD exposure on human CD34+ progenitor cells from G-CSF stimulated leukapheresis of 4 normal donors. Gene expression modulation induced by TCDD was analysed on highly purified (>96%) CD34+ cells, after exposure to 10 nM of TCDD for 12 hrs. Gene expression profiles have been generated by high-density oligonucleotide arrays (Affymetrix GeneChip U133A) and subsequently analyzed with a supervised approach (DNA-Chip Analyzer, dChip 2006). The differential expression of 257 transcripts (150 up regulated and 106 down-regulated) distinguished the 4 TCDD treated from the 4 untreated control samples. Interestingly, a number of the differentially expressed genes were involved in skin and cardiovascular diseases, diabetes, and different cancers, all of which have been associated with TCDD exposure. Among skin diseases, defects in laminin beta 3, ALOX12B and keratin 2a, all downregulated in TCDD exposed CD34+ cells, are associated with development of epidermolysis bullosa, erythroderma ichthyosiform, and Siemens ichthyosis bullosa, respectively. As far as diabetes and cardiovascular disease pathogenesis are concerned, defects of SLC2A4 gene, dowregulated by TCDD, is associated with the development of non insulin dependent diabetes, while epoxide hydrolase 2 and EGR2 are associated with cardiovascular disease. Among cancer related genes, ARHGAP26 and ABL2 are associated with juvenile myelomonocytic leukemia and acute myeloid leukemia with eosinophilia, respectively. Nevertheless, the expression of numerous other genes potentially involved in hemopoiesis/leukemogenesis, was modulated by TCDD exposure. Among these examples are c-kit ligand, LIF receptor, pre B lymphocyte gene 1, piwi-like 2, FLT3 ligand, chemokine ligands 14 and 15, and cdk2, that were all up regulated, while MLL4, wnt inhibitory factor 1, chemokine ligand 7, and lymphoid blast crisis oncogene, were down regulated. In conclusion, the gene expression pattern induced by TCDD exposure on the CD34+ normal progenitor cells is consistent with the spectrum of TCDD induced toxicities/diseases. In particular, it provides the basis for a possible role of TCDD in the neoplastic transformation of hemopoietic stem cells and support the epidemiologic data of increased hematologic cancer risk in the population exposed accidentally to the substance.