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1
Sampogna, Francesca, Marina Frontani, Giannandrea Baliva, Damiano Abeni, Giuseppe A. Lombardo, Alessandro Monopoli, Claudio Barbieri, et al. "Characteristics and Survival of 29 Patients with Sezary Syndrome." Blood 106, no. 11 (November 16, 2005): 5587. http://dx.doi.org/10.1182/blood.v106.11.5587.5587.
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Abstract We created a relational database of patients with cutaneous T-cell lymphoma (CTCL) to collect in a standardised fashion, anagraphic variables, clinical history, clinical, histological, haematological, and immunological information on CTCL patients hospitalised at IDI-IRCCS, Rome, Italy. At present, there are data on 424 patients, hospitalised from 1983 to July 2005. Active follow-up is performed yearly to ensure a standardised ascertainment of survival time. For deceased patients, the actual date of death (for all causes) is recorded, while surviving patients are censored at the date of last contact. The database includes 29 patients with Sezary syndrome (SS). Follow-up times ranged from 0 to 105 months. At first hospitalisation the median values of cells/mL were: white blood cells (WBC) 8750, neutrophils 4250, eosinophils 140, basophils 120, lymphocytes 2760, monocytes 500, CD3+ 2780, CD4+ 2431, CD8+ 192, CD19+ 96. Seventeen patients were deceased. We included in the Kaplan-Meier survival analysis only patients who were diagnosed before July 2004 (n=26). Median survival time from diagnosis was 52 months. No significant differences were observed in mortality for WBC (cutoff 9000 cells/uL), neutrophils (cutoff 4500 cells/uL), basophils (cutoff 200 cells/uL), lymphocytes (cutoff 3000 cells/uL), monocytes (cutoff 500 cells/uL), CD3+ (cutoff 2000 cells/uL), CD4+ (cutoff 2000 cells/uL), CD8+ (cutoff 200 cells/uL), CD19+ (cutoff 70 cells/uL). A lower survival was observed for patients with eosinophils <200 cells/uL (p=.08). Survival in patients with SS does not seem to be influenced by haemathologic parameters. However, patients with long-term survival (>90 months) are observed, and their characteristics should be further investigated. Survival analysis of 26 patients with Sézary syndrome, Rome, Italy, 1991–2004. Survival analysis of 26 patients with Sézary syndrome, Rome, Italy, 1991–2004.
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Ding, Haoxuan, Jianan Han, and Jie Feng. "PSII-38 Tolerable upper intake levels of iron damage the intestine and alter the intestinal flora in weaned piglets." Journal of Animal Science 98, Supplement_4 (November 3, 2020): 381. http://dx.doi.org/10.1093/jas/skaa278.670.
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Abstract Iron supplementation has been an intervention to improve iron storage and prevent iron deficiency anaemia in weaned piglets. NRC has set recommended nutrient intake (RNI) and tolerable upper intake levels (UL). The purpose of this study was to investigate the potential harm of UL iron to the gut and microbes of weaned piglets. Thirty 23-day old weaned piglets assigned to three dietary treatments: a basal diet supplemented with 100 (RNI), 300, or 3000 (UL) mg FeSO4/kg diet for 28 days. Piglets were then euthanized, and the gut and cecum microbes were collected. UL iron significantly reduced the height of the villi in the duodenum, ileum, and jejunum of weaned piglets, and showed duodenal mitochondrial swelling (P < 0.05). The addition of UL iron to the diet significantly reduced the expression of tight junction proteins Claudin-1, Occludin, and ZO-1 in weaned piglet duodenal mucosa (P < 0.05). The protein levels of DMT1 and Zip14 decreased (P < 0.05), and the protein levels of ferritin increased in the duodenal mucosa of UL iron fed weaned piglets (P < 0.05). Moreover, UL iron also increased the content of ROS and MDA and decreased the activity of SOD in the weaned piglet duodenal mucosa (P < 0.05). Additionally, UL iron significantly increased intestinal microbial diversity and species richness in weaned piglets. At the phylum level, UL iron supplementation was associated with a significant increase in Proteobacteria relative abundance, and significantly decreased the relative abundance of Firmicutes (P < 0.05). At the genus level, the relative abundance of Clostridiales, Faecalibacterium, and Prevotellaceae decreased significantly (P < 0.05), while the relative abundance of Desulfovibrio and Anaerovibrio increased significantly (P < 0.05). In conclusion, UL iron caused damage to the intestinal villi, damaged the intestinal barrier, reduced iron absorption, induced oxidative stress, led to histopathological changes, and modified the intestinal microbial structure in weaned piglets.
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Norsiah, Wahdah. "Perbedaan Kadar Hemoglobin Metode Sianmethemoglobin dengan dan Tanpa Sentrifugasi pada Sampel Leukositosis." Medical Laboratory Technology Journal 1, no. 2 (December 1, 2015): 72. http://dx.doi.org/10.31964/mltj.v1i2.19.
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Examination of hemoglobin levels influenced leukocytosis sianmethemoglobin method that causes increased absorbance measurements of hemoglobin levels increased significantly and the false blood sample that has been diluted with a solution Drabkins in centrifugation at 3000 rpm for 10 minutes and then the absorbance of the supernatant was measured with a photometer at λ 546 nm. This study aimed to analyze the differences in hemoglobin level examination siamethemoglobin method with and without centrifugation at sample leukocytosis. This type of research is observational research laboratory. The study design was cross-sectional study. Samples were taken from the remaining blood samples of patients who have been examined leukositnya number more than 20,000 / uL with Hematology Analyzer (CEL-DYN Ruby) February-April 2014, and were divided into 4 groups based on criteria that group 1. leukocyte count of 20,000 / uL-29 999 / mL, group II. 30,000 / uL-39 999 / uL, the group III. 40,000 / uL-49,999 / uL, the group IV. More than 50,000 / uL. The number of samples taken were 20 samples of each group, a total sample of 80 samples. The analysis showed no significant difference in hemoglobin levels siamethemoglobin method with and without centrifugation at sample leukocytosis with a value of p = 0.000 less than 0.05 α. Leukocytosis Turbidity affects the difference in hemoglobin levels with and without centrifugation, the higher the number the greater the difference in leukocyte levels of hemoglobin, hemoglobin level examination results of the study based on the criteria of the number of leukocytes obtained by the difference in hemoglobin levels with and without centrifugation in group I. 0.22 ± 0.07 g / dL, group II 0.40 ± 0.22 g / dL, a group III. 0.44 ± 0.14 g / dL, Group IV. 0.85 ± 0.41 g / dL. The level of hemoglobin in the sample sianmethemoglobin method leukocytosis with more than 20,000 / uL need a centrifuge so that appropriate hemoglobin levels over the patient's clinical condition.
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Chacin Zambrano, Christian Andrei, Yessica Paola Quintero Avila, Leydy Gabriela Rodríguez González, and Johanna Alexandra Gómez Santos. "Evaluation of the in vitro growth of perolera pineapple (Ananas comosus) explants using organogenesis technique." Revista Colombiana de Investigaciones Agroindustriales 7, no. 2 (February 28, 2021): 32–39. http://dx.doi.org/10.23850/24220582.3271.
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From an economic standpoint, pineapple (Ananas comosus) is one of the most important fruits in Colombia. A decade ago, the Perolera variety was the most cropped cultivar of the Santander department, however, the variety has been displaced considerably due to the lack of technical extension services and theintroduction of new varieties. This research project was carried out with the intention to conserve the speciesthrough the development of in vitro pineapple explants using the organogenesis technique. Meristemsthat have been extracted from the crown of the Perolera pineapple variety were used for this purpose. Four disinfectant treatments were evaluated by looking at the different kinds of disinfectant exposure times.The treatment that gave the best results in terms of contaminant-free explants was the T2: Commercialdetergent + Tween 80 for 8 minutes, ethyl alcohol at 70% for 1 minute and sodium hypochlorite at 1,5% over10 minutes, with a contamination rate of 7% and 93% of the explants thriving. For the establishment phase,it was found that the medium MS MEP1 with 100% solid salts supplemented with 2000 ul/L BAP - 1000 ul/L ANA - 1000 ul/L AIA and 500 ul/L thiamine enabled 90 % of the pineapple explants to continue developing four weeks after planting. Similarly, the medium containing 3000 ul/L of BAP for the multiplication phase permitted an average proliferation of 4.62 shoots with 9.12 leaves per shoot and a length of 2.25 mm.
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Nguyen, Tuan Anh, Thi Mai Huong Pham, Thi Huong Dang, Thi Hanh Do, and Quang Tung Nguyen. "Study on Mechanical Properties and Fire Resistance of Epoxy Nanocomposite Reinforced with Environmentally Friendly Additive: Nanoclay I.30E." Journal of Chemistry 2020 (April 30, 2020): 1–13. http://dx.doi.org/10.1155/2020/3460645.
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The main purpose of this study is to complete the research process of dispersing nanoclay I.30E (montmorillonite) into epoxy Epikote 240 by mechanical method combined with energy-saving ultrasonic method. We investigate appropriate dispersion conditions such as stirring speed, mechanical stirring temperature, ultrasonic stirring time, and ultrasonic stirring capacity, which affect the mechanical properties and fire resistance of nanocomposite materials. The nanoclay contents studied were 1, 2, 3, and 4% by weight, and the methods used in this study are FE-SEM; XRD; and flame-retardant evaluation methods: LOI, UL 94HB. The mechanical properties were studied: tensile strength, flexural strength, compression strength, and impact resistance Izod. The dispersion method was recommended to stir mechanically at a speed of 3000 rpm at 80°C for 8 hours and then conduct ultrasonic vibrations for 6 hours at 65°C. The results showed that epoxy Epikote 240/nanoclay I.30E nanocomposite material had mechanical properties and improved fire retardancy with a small amount of nanoclay I.30E added (2% by weight): tensile strength of 63.5 MPa (increased by 13.59%), flexural strength of 116.80 MPa (increased by 34.63%), compressive strength of 179.67 MPa (increased by 15.11%), impact resistance Izod of 12.81 KJ/m2 (increased by 80.16%), oxygen limit of 23.7%, and combustion rate of 24.5 mm/min; according to UL 94HB, the combustion rate reached 22.59 mm/min.
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Takeshita, Masataka, Risen Hirai, Akira Tanimura, Miki Nakamura, Shotaro Hagiwara, and Akiyoshi Miwa. "Application of Hematopoietic Progenitor Cell Count: To Optimize Peripheral Blood Stem Cell Harvest." Blood 124, no. 21 (December 6, 2014): 5837. http://dx.doi.org/10.1182/blood.v124.21.5837.5837.
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Abstract background. High dose therapy and autogenic or allogeneic stem cell transplantation plays an important role in the treatment course of hematological malignancies. In some countries, major method of unrelated stem cell donation programs had shifted from bone marrow harvest (BM) to peripheral blood stem cell harvest (PBSCH). PBSCH is a heavy duty not only for donor or patient, also for medical staffs. In some cases, poor mobilization may cause poor collection of stem cells. Hemogram needs time for May-Giemsa stain, and CD34 count needs complicated technique and running cost. New simple tool to predict the count of mobilized stem cell is needed to optimize PBSCH. methods. Since 2009, we started measuring peripheral blood hematopoietic progenitor cell (HPC) with Sysmex XE-5000(R) blood cell counter. With IMI channel method, we could rapidly know the count of circulating stem cells. Daily HPC count and yielded CD 34 positive cell count were analyzed. results. 189 samples were collected from 122 donors/patients. Diagnosis of patients: malignant lymphoma (n=29), leukemia (3), multiple myeloma (74), amyloidosis (5), cryoglobulinemia (1). 10 healthy donors were also included. Age: 18-66, Sex: male 82/female 40. Mobilization regimen: G-CSF 57, chemo+G-CSF 74, G-CSF+plerixafor 1 HPC count (cells/ul) and collected CD34 positive cells (106cells/kg) had positive correlation. When HPC count was above 25/ul, collected CD34 positive cells were above 1x106/kg (positive predictive value: 80.9%). Number of PBSCH operation was 1.59 in average. We also show three cases in which HPC count was useful to make clinical decision of initiating PBSCH. discussion. HPC and CD34 had positive correlation, and HPC >25/ul seems to be appropriate cut-off to start PBSCH. With our former threshold of PBSCH (G-CSF day>4, WBC >3000/ul), 241 operations were to be planned. Including HPC count, we could reduce PBSCH operation to 204. Hematopoietic progenitor cell count is rapid and inexpensive method. Within 5 minutes, mobilized stem cells can be measured, and it may be also useful in outpatient-based harvest settings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Faso, L., E. Rappa, G. Vernon, and R. Witkus. "Site of hemocyanin synthesis in the terrestrial isopod, Armadillidiom vulgare." Proceedings, annual meeting, Electron Microscopy Society of America 47 (August 6, 1989): 970–71. http://dx.doi.org/10.1017/s0424820100156833.
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Although hemocyanin, an oxygen binding protein, is found freely dissolved in the hemolymph of isopods its site of synthesis is still unknown.Circulating blood cel Is such as granular hemocytes have been implicated in hemocyanin synthesis in a number of arthropods including Astacus astacus and Homarus vulgaris. Circulating blood cells of Armadillidium vulgare were examined using a transmission electron microscope (TEM) for evidence of hemocyanin synthesis.For each experiment hemolymph was collected from twenty adult A. vulgare and fixed for 1 hour in 200 uL of 3.5% glutaraldehyde in 0.1M sodium cacodylate buffer pH 7.4 with 0.05% calcium chloride added. Hemolymph was then centrifuged at 3000 rpm in an IEC-DPR-6000 centrifuge for 15 minutes at 15 degrees centigrade. The supernatant was removed, and the resulting pellet was washed with three changes of sodium cacodylate buffer. Postfixation of the pellet was done in 1% osmium tetroxide for 1 hour.
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O'Brien, MM, M. Kiely, KE Harrington, PJ Robson, JJ Strain, and A. Flynn. "The North/South Ireland Food Consumption Survey: vitamin intakes in 18–64-year-old adults." Public Health Nutrition 4, no. 5a (October 2001): 1069–79. http://dx.doi.org/10.1079/phn2001188.
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AbstractObjectiveTo estimate vitamin intakes and assess the contribution of different food groups to vitamin intakes in adults aged 18–64 years in Ireland as estimated in the North/South Ireland Food Consumption Survey. Intakes are reported for retinol, carotene, total vitamin A, vitamin D, vitamin E, thiamin, riboflavin, pre-formed niacin, total niacin equivalents, vitamin B6, vitamin B12, folate, biotin, pantothenate and vitamin C. The adequacy of vitamin intakes in the population and the risk of occurrence of excessive vitamin intakes are also assessed.DesignFood consumption was estimated using a 7-day food diary for a representative sample (n = 1379; 662 men and 717 women) of 18–64-year-old adults in the Republic of Ireland and Northern Ireland selected randomly from the electoral register. Vitamin intakes were estimated using tables of food composition.ResultsIn general, the percentage of the population with vitamin intakes below the average requirement (AR) was low. Mean daily intake of total vitamin A was below the AR in 20.2% and 16.6% of men and women, respectively, and mean daily intake of riboflavin was below the AR in 12.5% and 20.6% of men and women, respectively. Mean daily folate intakes were below the AR for folate in 11.2% and 6.6% of women aged 18–35 years and 36–50 years, respectively. Only 2.2% of women aged 18–35 years and 52% of women aged 36–50 years achieved the recommended folate intake of 600 (μg day−1 for women of reproductive age for the prevention of neural tube defects. A high proportion of the population has a low dietary vitamin D intake and is largely dependent on sunlight exposure to maintain adequate vitamin D status. Except for pre-formed niacin, the 95th percentile intake of vitamins did not exceed the tolerable upper intake level (UL) for any group and was much less than the UL for most vitamins. Although 20.8% of men and 6.3% of women exceeded the UL for pre-formed niacin (which is 35 mg, based on nicotinic-acid-induced flushing), the large contribution of meat and fish to the intake of niacin (as nicotinamide) suggests that the risk of overexposure to nicotinic acid is much lower than this and is probably solely related to supplement use. A small proportion of men (4.0%) and women (1.2%) aged 51-64 years had retinol intakes that exceeded the UL (3000 μg) and while the 95th percentile intake of women in the 18–50 year age group was well below the UL, 1.5% of 18–35-year-old and 2.4% of 36–50-year-old women had mean daily retinol intakes above the UL. About 2.0% of women had intakes of vitamin B6 that exceeded the UL (25 mg). There were significant differences by age and sex in nutrient densities of vitamin intakes between men and women and between age groups, which may be explained by differences in consumption of particular food groups as well as different patterns of supplement use.ConclusionNutritional adequacy of the population for most vitamins was good. Folate intake in women of childbearing age is not meeting current recommendations for the prevention of neural tube defects. The public health significance of the relatively high proportion of men and women with inadequate intakes of vitamin A and riboflavin and with low dietary intakes of vitamin D is unclear and should be investigated further. With the possible exception of niacin (flushing) and vitamin B6 (neuropathy), there appears to be little risk of the occurrence of adverse effects due to excessive consumption of vitamins in this population, based on current dietary practices.
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Horstman, Larry Lawrence, Yeon-Soong Ahn, Jacob Esquenazi, Wenche Jy, Carlos J. Bidot, and Camile Ortega. "Elevated Cholinesterase Activity in Patients with TIA and Other Thrombotic Disorders." Blood 114, no. 22 (November 20, 2009): 2991. http://dx.doi.org/10.1182/blood.v114.22.2991.2991.
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Abstract Abstract 2991 Poster Board II-967 Background. The natural function of ACTH in blood is not well defined. However elevated plasma level was reported in patients with chronic inflammation, suggesting as one of inflammatory markers. Erythrocytes possess membrane-bound acetylcholinesterase (AChE) while plasma contains a less specific cholinesterase (ChE). We reported at a previous meeting [Blood 2008, 112(11) Abst #3849] that AChE activity of RBC-derived microparticles (RMP) is 6 times higher than those in PMP. In this study we measured plasma ACTH levels in several groups and encountered unexpectedly high plasma ChE activities in patients with TIA and other thrombosis. Methods. (i) Patient population. A series of n=108 consenting patients were recruited sequentially having various disorders For purpose of analysis, they were divided in 2 main groups: n=53 with thrombosis (TBS), F/M 27/26; and n=55 non-TBS, F/M 24/31. Thrombosis group consists of venous and arterial thrombosis including those with TIA. Non TBS group consists of anemias, thrombocytopenias including ITP, MDS. (ii) Assay was essentially by Ellman's method. In our system, milli-absorbance units/min (mA/min) x 0.065 = umols substrate cleaved/min. Values reported here are in unitsof mA/min per mL plasma. Normal controls (NC, n=14) had a cutoff of 3000 mA/min per mL plasma, = mean +2SD. (iii) Sample handling. Platelet-poor plasma (PPP) was prepared by centrifuging 10 min at 1800 xg, then frozen in aliquots. For assay, it was diluted 1:20 with saline, then 5 uL and 10 uL were used in 96-well microtiter plate. Results: (i) Significantly higher ChE activity was observed in thrombosis (TBS) patients compared to non-TBS. Mean value ±SD in TBS was 2928 ±773, and in Non-TBS was 1897 ±713 (units as above). This difference was significant, p<0.001. (ii) When analyzed elevated levels of ACTH above 2SD of normal controls (n=26) between 2 groups, the TBS group had elevated ChE (>3000) in 30% of patients, while the Non-TBS had elevated ChE in 7.8%. (iii) Further analysis among thrombosis group revealed that the subgroup with neurological TBS (TIA, minor strokes) had the most consistent elevations of ACTH; 10 of15 with TIA group (66%) had ChE activities >3000. Summary/ Discussion. Although ChE and AChE in blood has long been studied, to our knowledge, this is the first report to show a relation between plasma ChE and thrombosis. Its elevation is very pronounce in thrombosis of the CNS, manifesting as TIA. Further study is warranted to elucidate how ChE is related to AChE of the CNS and on red cells. Disclosures: No relevant conflicts of interest to declare.
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Bidot, Carlos J., Yeon-Soong Ahn, Jacob Esquenosi, Carlos Bidot, Camile Ortega, Larry Lawrence Horstman, Pamela B. Dudkiewicz, and Wenche Jy. "Plasma Cholinesterase Activity in ITP Patients with/without Thrombosis." Blood 114, no. 22 (November 20, 2009): 3997. http://dx.doi.org/10.1182/blood.v114.22.3997.3997.
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Abstract Abstract 3997 Poster Board III-933 Introduction In the process of immune mediated destruction, platelets may become activated and release procoagulant microparticles in ITP (Immune Thrombocytopenic Purpura). Although bleeding is common manifestation, some patients with ITP may suffer thrombotic complications, often presenting with TIA like syndromes. Brain MRI revealed findings consistent with ischemic small vessel disease in this subgroup (J Lab Clin Med 119: 334, 1992, Thromb Res 107:337, 2002). Recently acetylcoholinesterase (AChE) of RBC and/or non-specific plasma cholinesterase (ChE) was reported to be associated with the inflammation of blood vessels and may be a marker of some inflammatory states. In the present study we investigated plasma ChE activity in patients with ITP with or without thrombotic complication. Methods (i) Patients. We measured ChE activity in 49 patients with ITP. They were sub-grouped as having thrombosis (TBS), F/M (11/7), and non-thrombosis (Non-TBS), F/M (23/8). The TBS group included 9 with TIA like syndrome, 6 with CAD and 3 with venous thrombosis. (ii) Assay of ChE was essentially by Ellman's method. In our system, milli-absorbance units/min (mA/min) x 0.065 = umols substrate cleaved/min. Values reported here are in units of mA/min per mL plasma. Normal controls (NC, n=14) had a cutoff of 3000 mA/min per mL plasma (=mean +2SD). (iii) Sample handling. Platelet-poor plasma (PPP) was prepared by centrifuging 10 min at 1800 xg, then frozen in aliquots. For assay, it was diluted 1:20 with saline, then 5 uL and 10 uL were used in 96-well microtiter plate. Results (i) We observed higher level of ChE in the TBS group compared to Non-TBS in ITP. The TBS group (+/- SD) had mean value 2859 ±866, while the Non-TBS group had 2267 ±777 (units as above). This difference was significant, p<0.02. (ii) In TBS groups, we compared TIA subgroup with other TBS subgroup and observed that the n=9 patients with TIA had higher activity compared to the other TBS: 3250 vs 2466 mA/min per mL plasma. However, this difference did not reach significance in this small patient population. Further, 5/9 TIA patients (66%) had ChE activities >3000 (normal cutoff values) compared to only 2/9 (22%) of those with other TBS >3000. Conclusion (i) The ChE activity of ITP patients with TBS is significantly increased compared to Non-TBS in ITP patients. It has been suggested that Blood ChE/AChE may reflect some inflammatory, prothrombotic states. (ii) ITP patients with TIA exhibited higher ChE activity among TBS subgroups in ITP, suggesting that ChE activity may serve as a useful biomarker in TIA like syndrome associated with ITP. However, further study in a larger number of patients is needed to confirm these preliminary findings. Disclosures: No relevant conflicts of interest to declare.
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Chan, Frieda, Olivier Humbert, Troy Torgerson, Nicholas Hubbard, Patricia O'Donnell, Daniel R. Humphrys, Jennifer E. Adair, et al. "Rapid Expansion of Gene-Marked Lymphocytes in X-SCID Dogs after AMD3100+G-CSF-Based Hematopoietic Stem/Progenitor Cell Mobilization and Intravenous Injection of a Common γ-Chain Expressing Foamy Viral Vector." Blood 128, no. 22 (December 2, 2016): 1348. http://dx.doi.org/10.1182/blood.v128.22.1348.1348.
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Abstract In both humans and canines, X-linked severe combined immunodeficiency disease (XSCID) is caused by mutations in the interleukin-2 receptor gamma chain gene (IL2RG) which results in a lack of response to common gamma-chain (gammaC) dependent cytokines and abnormal development of T and B lymphocytes, and natural killer (NK) cells. Death from infections usually occurs before 1 year of age unless allogeneic hematopoietic cell transplantation (HCT) is performed. While HCT is successful if an HLA-matched sibling donor is available, transplants from mismatched and unrelated donors are associated with greater morbidity and overall survival can be as low as 50%. To circumvent these complications, several clinical trials are testing the possibility of utilizing blood and marrow stem cells from the patient for ex vivo gene therapy to treat X-SCID. Although these trials show promising results, they require expensive GMP cell manufacturing that are not accessible to many patients, and may also necessitate low level of conditioning to improve engraftment of gene-corrected cells. With these limitations in mind, we have explored in vivo gene therapy as a treatment for X-SCID. We previously showed that foamy virus vectors (FVs), exhibit a potentially more favorable integration profile compared to lenti- and gamma-retroviral vectors. In vivo delivery of a gammaC-FV in dogs resulted in immune reconstitution with gene-corrected T cells in dogs but the treated animals still developed infections and had low levels of immunoglobulin levels. We hypothesized that an increased transduction of hematopoietic stem/progenitor cells in vivo might result in more rapid and sustained immune reconstitution. Thus, in the current study, we used cG-CSF and AMD3100 to mobilize hematopoietic stem/progenitor cells into the peripheral blood prior to in vivo injection with a FV expressing the gammaC gene driven by a PGK promoter (PGK-gammaC-FV). We mobilized two X-SCID dogs at ~3 weeks of age with 5ug/kg of cG-CSF bi-daily from day -4 to -1 prior to FV injection, and with 4mg/kg of AMD3100 on the morning of the injection with 4x10e8 IU of PGK-gammaC-FV. Our mobilization protocol resulted in a 10-fold increase in CD34+ cells in the peripheral blood of mobilized X-SCID dogs as compared to a unmobilized normal littermate control (Figure 1 A). Lymphocyte recovery and gene marking in the mobilized animals was significantly improved as compared to animals that were previously injected with similar doses of either PGK-gammaC-FV or EF1a-gammaC-FV but without mobilization. As illustrated in Figure 1B-C, lymphocyte counts expanded to ~3000 cells/uL with ~75% gene marking in the mobilized animals treated with PGK-gammC-FV within 30 days, as compared to <1500 cells/uL with <5% gene marking in unmobilized dogs treated with EF1a-gammaC-FV and to <1000 cells/uL with <50% gene marking in unmobilized dogs treated with PGK-gammaC-FV at all time points post-therapy. The expansion of CD3+ T-cells at 6 weeks post injection for the mobilized dogs was about 2700 cells/uL, as compared to <380 cells/uL in the PGK-gammaC-FV and <210 cells/uL in the EF1a-gammaC-FV unmobilized dogs. Notably, in human clinical trials, CD3 T cell counts were <250 cells/uL following transplantation with autologous CD34+ cells modified with EF1a-gammaC-SIN gamma-retrovirus (Hacein-Bey-Abina, NEJM, 2014). In conclusion, mobilization with cG-CSF and AMD3100 prior to in vivo injection of PGK-gammaC-FV substantially improved the lymphocyte expansion and immune reconstitution in X-SCID dogs and resulted in a higher level of gene marking in myeloid cells (about 1%) at one-month post injection than seen in our previous studies in unmobilized dogs. These results suggest remarkable potential for an accessible and portable approach for treatment of human X-SCID clinical trials using combination of hematopoietic stem/progenitor cells mobilization and in vivo foamy viral vector delivery. Disclosures Adair: Rocket Pharmaceuticals: Consultancy, Equity Ownership. Scharenberg:bluebird bio: Consultancy, Equity Ownership, Research Funding; Alpine Immune Sciences: Consultancy. Kiem:Rocket Pharmaceuticals: Consultancy, Equity Ownership, Research Funding.
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Przybył-Sadowska, Elżbieta. "Biblioteka Wiedzy Religijnej w Warszawie (1919-1939)." Z Badań nad Książką i Księgozbiorami Historycznymi 10 (December 11, 2019): 211–28. http://dx.doi.org/10.33077/uw.25448730.zbkh.2016.121.
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Biblioteka Wiedzy Religijnej, założona przez Irenę Tyszkiewicz w 1919 r. w jej domu przy ul. Litewskiej 6 w Warszawie, była instytucją całkowicie prywatną, bo finansowaną przez założycielkę, a jednocześnie – publiczną w swoim społecznym wymiarze, gdyż pozycje gromadzone w książnicy były wypożyczane bezpłatnie każdemu, kto przedstawił jakiekolwiek poręczenie. Choć głównym celem założenia Biblioteki, jak wskazuje jej pełna nazwa, było szerzenie wiedzy religijnej w duchu katolickim, pomyślano także o specjalnym dziale dla dzieci i młodzieży oraz o dziale książki popularnej, gdzie gromadzono literaturę piękną i poezję. Jednak główny trzon zbiorów stanowiła literatura religijna zarówno polska, jak i obcojęzyczna, co dobrze odzwierciedlają dane liczbowe: zbiory Biblioteki Wiedzy Religijnej w 1939 r. liczyły ponad 17 000 woluminów, działu dziecięcego – ponad 3000 książek, a działu literatury popularnej – zaledwie kilkaset tomów. Liczba czytelników korzystających z biblioteki jest trudna do ustalenia. Według I. Tyszkiewiczowej założonych było 4000 kart czytelniczych, lecz pod wieloma z nich kryły się całe rodziny, a nawet instytucje, np. zgromadzenia zakonne. Choć Biblioteka uległa całkowitemu zniszczeniu (została spalona wraz z miastem po upadku powstania warszawskiego w 1944 r.), zachowane dokumenty archiwalne pozwalają na częściowe zapoznanie się z informacjami o jej zbiorach i funkcjonowaniu.
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Wang, Michael, Kay Delasalle, Sergio Giralt, and Raymond Alexanian. "Rapid Control of Previously Untreated Multiple Myeloma with Bortezomib-Lenalidomide-Dexamethasone (BLD)." Blood 110, no. 11 (November 16, 2007): 3611. http://dx.doi.org/10.1182/blood.v110.11.3611.3611.
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Abstract Introduction: Both bortezomib (B) and lenalidomide (L) are effective against relapsed/refractory and newly-diagnosed multiple myeloma (MM). The 3-drug combination of bortezomib-thalidomide-dexamethasone had induced remission in 87% of patients with untreated myeloma, significantly higher than the frequency of 66% observed with thalidomide dexamethasone. Patients and Method: We conducted a retrospective review of a pilot study in 17 previously-untreated patients with MM who were treated with bortezomib-lenalidomide dexamethasone between 4/06–4/07. Median age was 60 (35–71), median B2M was 3.7 mg/L (1.8–11.7) and median Hgb was 11 g/dl (6–14.7). Serum creatinine was greater than 2 mg/dl in one patient (6%). Bortezomib was given at 1.3 mg/m2 intravenously on days 1,4, 8 and 11; lenalidomide was at 25 mg orally daily for 21 days; and dexamethasone was at 20 mg/m2 daily orally for 4 days beginning on days 1, 9 and 17. Each cycle was 28 days. After the first cycle, a second cycle was given to 10 patients so that the median cycles of therapy was 2. As prophylaxis for deep vein thrombosis, all patients received warfarin with a targeted INR range between 2–3. All patients received daily orally vancyclovir to prevent herpes zoster. Results: Applying the Blade criteria of response (PR: greater than 50% reduction of serum myeloma protein and/or greater than 90% reduction of Bence Jones protein), remission of disease was observed in 14/17 patients (82%), including 2 patients (12%) with CR based on negative immunofixations and 12 patients (70%) with PR. All but one patient achieved remission after 1 cycle of treatment. Three patients were resistant to bortezomib-lenalidomide-dexamethasone after 2 cycles. One patient had deep vein thrombosis with pulmonary emboli. One patient had short-term grade 3 neuropathy. One patient had grade 3 thrombocytopenia and one patient had nonneutropenic pneumonia. Median nadir neutrophil count was 3000/ul (range 1400–5400/ul), and median nadir platelet count was 174 k/ul (range 38–270 k/ul). After a median 3.6 months (range 3.3–5.5), intensive therapy supported by autologous blood stem cells was given to 11 patients. Three of the 11 patients in PR after induction with bortezomib-lenalidomide-dexamethasone were converted to CR with intensification. Consequently, the CR rate after intensification 29%. Intensification is planned for the 3 patients with primary resistant MM. Discussion: Overall response and CR rates were similar to those observed previously among similar patients treated with bortezomib-thalidomide-dexamethasone. All reported primary treatment programs based on bortezomib-dexamethasone have induced high response rates of 82–92%, regardless of whether melphalan, lenalidomide, or thalidomide were included. Conclusions: One or two cycles of bortezomib-lenalidomide-dexamethasone were associated with rapid onset of response in patients with newly-diagnosed multiple myeloma. Toxicity was infrequent due to short exposure to bortezomib-lenalidomide-dexamethasone. There was early access to intensive therapy supported by autologous stem cells. Reduced exposure to drugs given as primary treatment should help preserve disease sensitivity to later treatment upon relapse.
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Yue, Li, Chaoke Bu, Zhirui Ma, Chunfu Li, Wenjun Wang, and Jun Zhou. "Dual Anticoagulant Facilitied Peripheral Blood Stem Cell Harvest from Childhood Donors with Low Weight and Low MCV." Blood 134, Supplement_1 (November 13, 2019): 5639. http://dx.doi.org/10.1182/blood-2019-129585.
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Background:Low weight children can sometimes be selected as donor in HSCT. Donor with thalassemia minor has low MCV, which affects peripheral blood stem cell (PBSC) harvest. It is worthwhile to explore a harvest program for donors with low body weight and low MCV. Objective:The aim of this study is to find out an appropriate program of PBSC collection in children with low body weight and low MCV. Methods:10 children, with median age of 2 (1-6) years, average weight of 13.4 (9.5- 20) kg and average MVC value of 63fl (54-78)) were hospitalized in our center from October 2018 to July 2019 for stem cell mobilization. Donor weight were less than recipients in 7 cases. 5 donors have 5 kg less than recipient, 3 have 10 kg less and 1 has 18 kg less, respectively. They received G-CSF of 5 mg/kg/d twice a day for 5 days before harvest. 500 ml ACD-A solution and 3000 IU heparin were mixed and given by the ratio of 1 ml mixed anticoagulant versus 24 ml whole blood. Blood-flow was 25-40 ml/min. Results:More 20/ul CD34+ cells were harvested in 9 cases (90%), and 19.2/ul in 1 case (10%). Median nucleated cells were13.2(6.7-22.4)x108/kg in donor weightand 9.8 (8.3-13.9) x108/kg in recipient weight. The median CD34+ cells were 5 (1.9-10.2) x106/kg in donor weight and 3.4 (1.4-9.7) x106/kg in recipient weight. The coagulation function was normal in reexamination. PBSC were harvested only once in all donors. Average circulating volume was 2.48 (1.14-5.79) total body volume, average harvesting time was 2.75 (2-6) hours, and average PBSC volume was 89 (63-160) ml. Donor peripheral blood calcium and potassium ion concentration showed no obvious abnormality. Conclusion:Combination of citrate and heparin can be well used to collect PBSC in donors with low body weight and low MCV. All children were well tolerance to the program, which was safe and effective for large volume collection of PBSC. Disclosures No relevant conflicts of interest to declare.
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Woldegebreal, Demewoz, Reina Engle-Stone, Bess Caswell, Hanqi Luo, Kevin Dodd, Charles Arnold, Modou Jobarteh, Marjorie Haskell, and Amanda Palmer. "Simulated Impact of Vitamin A Fortified Sugar on Dietary Adequacy and Association of Usual Sugar Intake With Plasma and Breast Milk Retinol Among Lactating Women in Rural Zambia." Current Developments in Nutrition 5, Supplement_2 (June 2021): 1104. http://dx.doi.org/10.1093/cdn/nzab053_097.
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Abstract Objectives Zambia introduced mandatory sugar fortification with vitamin A (VA) in 1998; however, regulatory monitoring and evaluation have been limited. We studied the contribution of VA-fortified sugar intake to dietary adequacy, and examined associations between usual sugar and VA intakes with plasma and breast milk retinol concentrations in lactating women in rural Zambia. Methods We conducted three 24-h dietary recalls among each of 255 lactating women enrolled in a randomized trial, at the time of baseline venous blood and breast milk collection. We measured retinol in biospecimens using high-performance liquid chromatography. We simulated VA intake under various sugar fortification scenarios: 3.1 and 8.8 mg/kg (measured median fortification levels of VA in sugar from previous studies), 10 mg/kg (minimum legal requirement) and 15 mg/kg (minimum legal requirement at factory level). Usual intake distributions, prevalence of inadequate VA intake (< Estimated Average Requirement of 900 μg RAE/d) and prevalence of retinol intake above the tolerable upper intake level (UL, >3000 μg/d) for each scenario were estimated using the National Cancer Institute (NCI) method. We applied the NCI's “bivariate model” as a regression calibration tool to examine associations of usual intake of sugar and dietary VA with plasma and breast milk retinol concentrations. Results In the absence of sugar fortification, the prevalence of VA inadequacy was predicted to be 83% (SE: 6). Fortification of sugar with VA at 3.1 mg/kg, 8.8 mg/kg, 10 mg/kg and 15 mg/kg would reduce the prevalence of VA inadequacy by 7 (SE:6), 24 (SE:14), 30 (SE:15) and 47 (SE:18) percentage points, respectively, without increasing the risk of retinol intake above the UL. Usual sugar intake and usual VA intake were not associated with plasma retinol or breastmilk retinol concentrations. Conclusions The sugar fortification program has the potential to reduce dietary VA inadequacy, but the impact is likely to be limited if actual fortification levels are lower than mandated levels. Even if target fortification levels are achieved (10 mg/kg), sugar fortification alone is unlikely to eliminate dietary VA inadequacy among lactating women in rural Zambia. Funding Sources HarvestPlus and the Sight and Life Global Nutrition Research Institute at Johns Hopkins University.
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Panch, Sandhya R., Yu Ying Yau, Courtney Fitzhugh, Matthew M. Hsieh, John F. Tisdale, Charles D. Bolan, and Susan F. Leitman. "Hematopoietic Progenitor Cell Mobilization In Response To G-CSF Is More Robust In Healthy African American Compared To Caucasian Donors." Blood 122, no. 21 (November 15, 2013): 696. http://dx.doi.org/10.1182/blood.v122.21.696.696.
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Abstract Hematopoietic progenitor cells (HPCs) collected by apheresis of G-CSF-stimulated donors have surpassed bone marrow as the predominant graft source for hematopoietic stem cell transplantation in adults. Among healthy allogeneic donors, demographic characteristics (age, sex, and BMI) and baseline hematologic parameters have been shown to affect HPC mobilization, leading to significant variability in peak levels of CD34 cell egress into the blood and in quantity of CD34 cells harvested by apheresis. Racial differences in G-CSF-mediated HPC mobilization are less well characterized. Benign physiologic neutropenia is common among healthy African Americans (AAs), and may be due to decreased stem cell reserve, fewer G-CSF receptors, or Duffy (null) blood group antigen-mediated decrease in leukocyte trafficking into the circulation. However, preliminary studies have shown relatively robust CD34+ cell mobilization among non-Caucasians given G-CSF (Vasu et al., Blood 2006). We retrospectively analyzed 1,096 consecutive healthy allogeneic related and unrelated first-time donors who self-characterized their race as AA or Caucasian. They underwent G-CSF (filgrastim, Neupogen, Amgen) stimulated HPC collection by leukapheresis from April 1999 to May 2013. G-CSF dose ranged from 10-16 mcg/kg, given daily for 5 days. An unstimulated leukapheresis procedure for lymphocyte collection was performed in the 7 days preceding G-CSF in 336 subjects. Apheresis procedures were performed on the CS-3000 Plus or COBE Spectra device. Baseline lab data included CBC, serologic blood group antigen typing, and Hb electrophoresis in AA donors. CD34+ cell counts were performed on peripheral blood immediately pre-apheresis (2 hours after the 5th dose of G-CSF) and on the apheresis product. Values are given as mean ± SD. All AA (n=215) and Caucasian donors (n=881) with complete data sets were included. Sex ratio was similar among the groups (45 vs 52% male; p=0.09). AAs were younger (39 vs 43 yrs, p=0.001) and had greater weight (86 vs 81 kg, p=0.001) and BMI (30 vs 27; p<0.0001) than Caucasians. G-CSF dose/kg was similar in the 2 groups, but total daily dose of G-CSF was greater in AAs than Caucasians (920 vs 850 mcg, p<0.0001). After adjusting for age, sex, height, weight, and total daily G-CSF dose, peak CD34+ cell mobilization immediately pre-apheresis was higher among AAs than Caucasians (123 ± 87 vs 75 ± 47 cells/uL; p<0.0001) (Figure). When laboratory parameters such as baseline WBC, MNC, and platelet counts were included in the stepwise regression model, AA race remained a significant predictor of higher peak CD34 cell counts. At higher G-CSF doses (16 mcg/kg/d), the difference in mobilization responses between the 2 groups was less apparent (peak CD34 counts 123 vs 93 cells/uL, AA (n=33) vs Caucasian (n=73), p=0.07) than at lower doses (10 mcg/kg/d), where peak CD34 counts were 123 vs 74 cells/uL, AA (n=182) vs Caucasian (n=808), p<0.0001. AAs had lower baseline ANC (3.4 vs 4.0 x 103 cells/uL, p<0.001) than Caucasians, but demonstrated significantly higher peak WBC and MNC counts after G-CSF. In AA donors with known HbS status, presence of sickle cell trait had no effect on CD34 mobilization (peak CD34 counts 123 ± 91 vs 107 ± 72 cells/uL, HbAS (n=41) vs HbAA (n=84), p=0.34). Similarly, in AA donors with known Duffy phenotype, Duffy expression did not affect CD34 mobilization (peak CD34 counts 114 ± 81 vs 134 ± 85 cells/uL, Fya-b- (n=49) vs Fya+ &/Fyb+ (n=20), p=0.4). Lymph-apheresis prior to starting G-CSF was associated with significantly improved CD34+ cell mobilization; however the effect did not differ by race. CD34 apheresis yield was also greater in AAs than Caucasians (51 ± 35 vs 32 ± 21 x 106 cells per liter processed, p <0.0001), consistent with higher pre-apheresis counts. African Americans demonstrated significantly more robust CD34 mobilization responses to G-CSF than Caucasians. The effect was independent of age, BMI, HbS and other variables, and occurred despite physiologically lower neutrophil counts among AAs. A ceiling effect in response to increased doses of G-CSF (>10 mcg/kg) was seen in AAs but not in Caucasians, suggesting that dose titration based on race might be used to optimize HPC yields. Further evaluation of race-associated genetic polymorphisms in relation to G-CSF pharmacokinetics may help improve G-CSF dosing strategies. Disclosures: No relevant conflicts of interest to declare.
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Shin, Myung-Geun, Hyeoung-Joon Kim, Hye-Ran Kim, Hee-Nam Kim, Il-Kwon Lee, Hoon Kook, Duck Cho, Jong-Hee Shin, Soon-Pal Suh, and Dong-Wook Ryang. "Biological Significance and Profile of Length Heteroplasmy in the Hypervariable Segments of the Human Mitochondrial DNA Control Regions from Blood Cells." Blood 104, no. 11 (November 16, 2004): 3815. http://dx.doi.org/10.1182/blood.v104.11.3815.3815.
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Abstract A high incidence of mitochondrial DNA (mtDNA) variations was observed in both hypervariable region (HV) 1 and HV2; most mtDNA sequence variations were localized at poly C tract at nucleotides (nt) 303-315 (CCCCCCCTCCCCC, 7CT5C) in the HV2. Another poly C tract variant in HV1 at nt 16184-6193 have been suggested to be related with diabetes, dilated cardiomyopathy and some cancers. Poly C tract in HV2 is part of the conserved sequence block II located in 92-bp from the heavy strand replication origin. It is not yet clear whether poly C variants at nt 303–315 would lead to alterations in mtDNA replication. We hypothesized that some severe alterations in poly C tracts may lead to impairment of mtDNA replication. Here we present the profile of length heteroplasmy in HV from blood cells and its biological significance. A total of 57 maternally unrelated healthy donors were included and heparinized bloods were obtained from five age groups including 12 cord bloods. We amplified and sequenced the 1,121-bp control region including HV1 and HV2. In an attempt to investigate mtDNA length heteroplasmy, we carried out a qualitative and quantitative profiling length heteroplasmy using size-based PCR product separation by capillary electrophoresis (ABI 3100 Genetic Analyzer and ABI Prism Genotyper version 3.1). Length heteroplasmy was further confirmed by cloning and sequencing. Quantitative analysis of mtDNA molecules was performed using the QuantiTect SYBR Green PCR kit (Qiagen) and Rotor-Gene 3000 (Corbett Research) and standard plot was obtained from cloned cytochrome b gene. The mtDNA control region sequences showed 57 different haplotypes resulting from 77 polymorphic positions. Common polymorphisms were 73A>G (98%), 263A>G (91%), 16223C>T (47%), 16189T>C (35%), 150C>T (25%) and 152T>C (18%). The patterns of length heteroplasmy in the HV2 region were classified into 6 types. In the HV1 region, length heteroplasmy showed 8 variant peak patterns. The distribution of length heteroplasmy in poly C tracts at nt 303 – 315 was mtDNA mixture of 7CT6C+8CT6C (53%), 8CT6C+9CT6C (26%), 8CT6C+9CT6C+10CT6C (11%), 9CT6C+10CT6C +11CT6C (5%), 9CT6C+10CT6C (3%) and 7CT6C+6CT6C (2%). The distribution of length heteroplasmy pattern in poly C tract at nt 16184 – 16193 was 5CT4C+5CT3C (60%), 9C+10C+11C+12C (21%), 9C+10C+11C (5%), 3CT6C+3CT5C (3%), 9C+10C+11C+12C+13C (3%), 3CT4C+3CT3C (3%), 10C+11C+12C (2%), and 8C+9C+10C+11C+12C (2%). Interestingly, this study revealed that all healthy subjects showed length heteroplasmy in the HV1 and HV2 regions in contrast to previous studies. Length heteroplasmy in poly C 303–315 showed two groups of two peaks (n = 48) and more than three peaks (n = 9). MtDNA content from group with three peaks in poly C 303–315 (61,983,373 molecules/ul ± 33,219,871, mean±SD) was markedly lower than those with two peaks (133,777,955 molecules/ul ± 87,209,377). In conclusion, significantly higher rate of length heteroplasmy was observed in HV1 and HV2 from healthy donors and the presence of more than three mtDNA types in poly C at nt 303 – 315 might be associated with impairment of mtDNA replication.
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Advani, Anjali S., Holly Gundacker, Nolyn Nyatanga, Paul Elson, Peter J. Rosen, Jennifer Bates, Mikkael A. Sekeres, et al. "Response to High Dose Cytarabine (HIDAC) As First Salvage for Relapsed Acute Lymphocytic Leukemia in Patients Receiving HIDAC As Initial Therapy." Blood 118, no. 21 (November 18, 2011): 2594. http://dx.doi.org/10.1182/blood.v118.21.2594.2594.
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Abstract Abstract 2594 The treatment of adult acute lymphocytic leukemia (ALL) is challenging. Traditional induction regimens have incorporated vincristine, anthracycline, asparaginase, and steroids that result in high rates of complete remission (CR). However, less than half of pts in CR will be cured. To improve results, high dose cytarabine (HIDAC) has been increasingly incorporated into post-remission therapy. Since HIDAC is often used to treat relapsed ALL, we hypothesized that the prior use of HIDAC would reduce the CR rate when it is applied to pts at the time of their first relapse. Methods: Consecutive pts with ALL in first relapse treated with HIDAC-containing regimens either at the Cleveland Clinic (CC) between the years 1993–2010 or at any institution participating in SWOG trial S9030 (HIDAC 3000 mg/m2 Days 1–5, mitoxantrone 80 mg/m2 Day 1) (1992–1993) were included. HIDAC was defined as a cycle of at least 3000 mg/m2 × 5 days. Remission was defined according to standard criteria. The outcome analysis [CR and overall survival (OS)] was adjusted for the following factors: age, WBC at diagnosis, cytogenetic (CG) risk, immunophenotype, transplant, and prior HIDAC exposure. Results: Sixty-six pts were included (39 treated at CC, and 27 as part of SWOG protocol S9030). All pts received a vincristine/prednisone/anthracycline/steroid-based induction regimen (S8417, CALGB 19802, CALGB 8811) except for 1 pt who was treated with hyperCVAD. Seventeen pts treated at CC had HIDAC incorporated into their initial treatment (1: hyperCVAD; 16: CALGB 19802), but none of the SWOG pts did. The median age was 35 yrs (range 17 to 73). The median WBC at the time of diagnosis for CC pts was 21.4 K/uL (range 0.5–260.0) and median WBC at the time of study registration for SWOG patients was 17.6 K/uL (range 0.4–198.4). Three pts (5%) had a mixed (B/T) lineage leukemia. Three patients had lymphoblastic lymphoma (1 B-cell; 2 T-cell) at the time of initial diagnosis, and had ALL at the time of relapse. For the 39 CC pts, the median time from diagnosis to relapse was 12 mos (range 1–55 mos). CG risk was ascribed by CALGB criteria. Of the 50 pts with evaluable pre-study CG, 20 pts (40%) had normal CG, 18 (36%) miscellaneous, and 12 (24%) poor risk CG. Twenty pts (30%) received HIDAC alone, and 46 (70%) received HIDAC in combination with other drugs for relapsed ALL. The CR rate for all relapsed pts was 32% (CC 36% and SWOG 26%) and was not affected by the addition of other drugs to HIDAC. Twenty-nine patients (44%) were able to proceed to HSCT; and the median OS was 5.4 mos (95% CI: 4.8–6.0 mos). After adjusting for all baseline and demographic factors, the CR rate and OS between pts receiving or not receiving HIDAC during initial treatment was not significantly different. Five of 17 (29%: 95% CI 10%-56%) pts with prior exposure to HIDAC achieved CR while 16 of 49 (33%: 95% CI 20%-48%) pts without prior HIDAC exposure achieved a CR (p=0.80). The 1 year OS (from salvage) for pts treated with HIDAC for relapse who also were treated with prior HIDAC was 12% (95% CI: 0%-27%) and for pts not treated with prior HIDAC was 33% (95% CI: 20%-46%)(p=0.17). Since additional information was available on the CC pts, additional analyses were performed on this subgroup of pts. With the exception of lymphoblastic lymphoma at the time of diagnosis, no other factors correlated with achievement of CR. Achievement of CR was the only factor associated with proceeding to HSCT (79% vs. 36%, p=0.01). Variables associated with improved OS included: lymphoblastic lymphoma at the time of diagnosis (p=0.04; 2 of the 3 pts are still being followed at 80+ and 96+ mos), achievement of CR (p=0.0001), longer remission (> 30 mos, p=0.005), and transplantation (p=0.0001). Conclusion: The outcome of relapsed ALL with HIDAC salvage therapy is dismal, regardless of prior HIDAC exposure; and novel treatments are needed. There was a suggestion that the OS of pts with prior HIDAC exposure may be lower, but further study of 1 year OS with larger pt numbers will be needed to evaluate this. An interesting finding in this study was the favorable outcome of pts with lymphoblastic lymphoma at diagnosis, who subsequently relapsed in the leukemic phase and were treated with HIDAC. However, few pts carried this diagnosis and a larger number of pts are required before drawing firm conclusions. Disclosures: No relevant conflicts of interest to declare.
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Sarigumba, Marion Bagaloyos, and Monica Therese B. Cating-Cabral. "Hyperthyroidism and Immune Thrombocytopenia (ITP) Overlap Presenting as Hypoxic Ischemic Encephalopathy in a 38-Year-Old Filipino Female: A Case Report." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A934—A935. http://dx.doi.org/10.1210/jendso/bvab048.1910.
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Abstract Background: The coexistence of these two conditions can mimic severe sepsis in critically ill patients which may leave severe thyrotoxicosis unrecognized. Its higher incidence in Asian population suggests a possible genetic propensity. Clinical Case: A 38-year-old Filipino female sought consult due to changes in behavior. Two months prior, patient had persistent heavy menstrual bleeding but refused work-up. There was progressive weakness and pallor in the interim but no consult was done until she had an aggressive behavior hitting everyone she sees. Patient has Graves disease, maintained on methimazole 15 mg/day and propranolol 30 mg/day. Patient was advised to undergo radioactive iodine therapy but was lost to follow-up for 2 years. Likewise, no medication adjustment nor monitoring of biochemical parameters was done during the same period. On admission, patient was disoriented, tachycardic and febrile. She was generally pale with petechiae on the extremities and blood clots on her lips. Internal examination of the introitus revealed fresh blood with clots. Pregnancy test was negative. Initial laboratory evaluation revealed severe anemia (3.3 g/dl) and thrombocytopenia (3000/uL). Peripheral smear showed mild anisocytosis of red blood cells with no blasts nor atypical lymphocytes and platelet clumps seen. Patient received 1 unit platelet apherese and 2 units packed red blood cells (PRBC) and was started on broad spectrum antibiotic. Neurologic evaluation was negative for craniopathies. Baseline cranial CT scan was not done due to absence of lateralizing signs and was managed as a case of hypoxic ischemic encephalopathy from severe blood loss. Patient was biochemically hyperthyroid with TSH 0.065 uIU/ml, FT4 2.67 ng/dl and 10-fold elevated anti-TPO. Methimazole was then resumed at 20 mg/day and propranolol at 30 mg/day. Neck ultrasound showed an enlarged thyroid with diffuse parenchymal disease. Furthermore, patient had negative Coombs test, normal fibrinogen and procalcitonin. Patient was weakly positive for ANA at 1:160 dilution but negative for other markers in the lupus panel. Consistent with ITP, patient was started on IV hydrocortisone. In the interim, patient had less vaginal bleeding but with persistent bicytopenia which required multiple platelet and PRBC transfusions. A bone marrow biopsy was contemplated. However, on the 7th hospital day, patient had sudden onset of right sided paresthesia with dysarthria and hematomas on extremities. MRI of the brain revealed a large intraparenchymal hemorrhage and patient eventually succumbed to it. Conclusion: Bone marrow dysfunction secondary to the hyperthyroid state may explain the lack of response to standard therapy of ITP. There is short platelet lifespan, which is rather metabolic in nature, from increased reticuloendothelial phagocytic activity by upregulation of Fc receptor activity in patients with hyperthyroidism.
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Kumar, Sunil. "Drug Resistance due to Mutation in UL 97 and Certain Other Specific Genes in Cytomegalovirus Strains: An Overview." IOSR Journal of Pharmacy and Biological Sciences 8, no. 4 (2013): 101–12. http://dx.doi.org/10.9790/3008-084101112.
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Marquez, Félix Gibrant, Santiago Riviello-Goya, Angel Gabriel Vargas Ruiz, Edgar Ortíz Brizuela, Fernando Gil López, Alfredo Gutierrez Marín, María Fernanda Gonzalez Lara, Alfredo Ponce de Léon Garduño, José Sifuentes Osornio, and Juan Rangel-Patiño. "Low Rate of Thrombosis in Mexican Patients with COVID-19 Infection. a Benefit of Higher Doses Anticoagulants or a Sub Diagnosis?" Blood 136, Supplement 1 (November 5, 2020): 29–30. http://dx.doi.org/10.1182/blood-2020-136240.
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Background: Patients with COVID-19 have an increased risk of thromboembolic disease, this has been partly attributed to an excessive inflammatory response that is associated with hypercoagulability; patients develop thrombotic complications with rates of 6.4% in non-critically ill and 15 to 31 % in critically ill patients. With this data some clinicians have incorporated thromboprophylaxis with higher dose heparin into the management of this patients, to date there´s no information of the effect of this intervention. Methods: We conducted a prospective cohort, including consecutive critical and non-critical adults admitted to a referral center in Mexico City, between March 18 and May 19, all with a positive RT-PCR for SARS-CoV 2. Conventional coagulation test results were collected on admission and during hospitalization; use of anticoagulation, and patient outcomes were recorded, all patients had been discharged at the time of the final analysis. Thromboprophylaxis was administered according to institutional recommendations and individual medical criteria, we defined anticoagulant dose according to each medication. We compared the basal characteristics and outcomes in critical and non-critical patients. We evaluated the factors associated with thrombosis, bleeding, and mortality using the Cox Regression Model. Results: We evaluated 447 consecutive hospitalized patients with COVID-19, median age was 50 years (range,18-91), 62.6 % were male, 111 (24.8%) were critical. At admission 156 patients (34.9%) had D-dimer values above 3000 ng/mL, median fibrinogen was 651 mg/dL (range 130-1095), APTT was prolonged (> 3 seconds) in 179 patients (40%), and INR >1.2 in 26 patients (5.8%), median platelet value 215 X103/uL (range 33-666). Thromboprophylaxis' dosages were prophylactic in 267 (59.7%), intermediate in 75 (16.8%) and therapeutic in 91 (20.4%), 14 patients (3.1%) did not receive any medical thromboprophylaxis and 26 patients (5.8%) received aspirin during hospitalization. According to the International Society on Thrombosis and Hemostasis' criteria (ISTH criteria) 40 patients (8.9%) had overt-DIC, sepsis induced coagulopathy (SIC) was present in 28 patients (6.3%), and high risk for bleeding by IMPROVE score ≥7 points was found in 5 patients (1.1%). Overall thrombotic event (TE) was confirmed in five patients (1.1%), arterial thrombosis events in 0.4%, one stroke and one acute myocardial infarction; radiographically confirmed venous thrombosis in 0.67%, two with pulmonary embolism (PE) and one with deep venous thrombosis (DVT). The TE were more common in critical than in non-critical patients (3.6% vs 0.3%). The number of CT pulmonary angiogram or duplex ultrasounds performed when PE/DVT was suspected was eighteen (4%), eight (47%) non-critically ill and ten (53%) in the ICU; the rate of radiographically positive results was 22.2%. The overall major bleeding rate was 2.5%, of these 91% were in the ICU. Mortality was 23.5% in the cohort. Table 1. No factors were found to be associated with thrombosis. The factors associated with bleeding were an INR >1.2 (HR 9.0, 95% CI 1.2-67.3, p 0.03), IMPROVE score ≥7 (HR 81.3, 95% CI 11.9-555.6, p < 0.01), and mechanical ventilation (HR 33.1, 95% CI 4.1-262.2, p 0.01). Factors associated with mortality were: age >70 (HR 2.5, 95% CI 1.5-4.2, p <0.01), D-Dimer >3000 ng/mL (HR 2.0,95% CI 1.2-3.4, p <0.01), and mechanical ventilation (HR 1.7, 95% CI 1.01-2.8, p = 0.02). The presence of more than 450x109/L platelets was associated with reduced mortality (HR 0.31 95% CI 0.19-0.50). Figure 1 Discussion: The late outbreak of COVID-19 in Latin America had led to an empiric use of aggressive thromboprophylaxis. Our data shows a low TE rate as compared with other groups, nevertheless we cannot prove a direct impact of the aggressive thromboprophylaxis, firstly because of the low rate or events, and secondly, due to the limitations of an observational study. On the other hand, the incidence of PE/DVT is conditioned by the number of studies performed, yet radiological confirmation has proven difficult due to concerns about virus exposure. Regarding the security of the intervention, major bleeding rates were slightly higher to what has been otherwise reported, but with no bleeding related deaths. The benefit of higher anticoagulant doses most be shown in clinical trials before we can recommend their generalized use in COVID-19 patients. Disclosures No relevant conflicts of interest to declare.
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Kyvernitakis, Andreas, Thein H. Oo, Michael H. Kroll, Vahid Afshar-Kharghan, Parag Mahale, and Harrys A. Torres. "Incidence and Management of Hematological Toxicities Associated with Treatment of Hepatitis C Virus Infection in Cancer Patients." Blood 124, no. 21 (December 6, 2014): 4126. http://dx.doi.org/10.1182/blood.v124.21.4126.4126.
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Abstract Background Hematologic toxicity is a common treatment complication of chronic hepatitis C virus (HCV) infection, especially when interferon (IFN) and ribavirin are used. The side effects of treatment are often augmented in cancer patients due to baseline cytopenias. These adverse events often lead to dose reduction or discontinuation of antivirals. Hematopoietic growth factors (GF) and blood transfusions are used to counteract toxicities allowing patients to complete treatment. We aimed to evaluate the incidence and management of hematological toxicity associated with different types of HCV treatment in cancer patients. Methods Medical records of cancer patients treated for HCV infection at MD Anderson Cancer Center between 2009 and 2014 were reviewed. Those seen from 8/2009 to 10/2012 were analyzed retrospectively, whereas those seen from 11/2012 to 7/2014 were prospectively studied. Patients who received combination treatment with peg-IFN and ribavirin (PR), telaprevir or boceprevir plus PR (TBPR), sofosbuvir plus PR (SPR), sofosbuvir with simeprevir (SS) and sofosbuvir with ribavirin (SR) were included in the study. Data regarding treatment interventions (dose reductions and/or discontinuation of antivirals), use of GFs or blood transfusions in the management hematological side effects were analyzed. Categorical variables were analyzed using the χ2 or Fischer's exact test. Results Sixty-five patients were identified (Table). The need for treatment interventions, GFs or blood transfusions was comparable between patients with hematologic malignancies and solid tumors. Seventeen (81%) of the PR group, 13 (93%) of the TBPR group, 6 (67%) of the SPR group, 9 (64%) of the SR group and 0 of the SS group required treatment interventions (p <0.001) (Figure). Twelve (57%) of the PR group, 9 (64%) of the TBPR group, 3 (33%) of the SPR group, 2 (14%) of the SR group and 0 of SS group required the use of GFs (p <0.01). Six (29%) patients of the PR group, 9 (64%) from the TBPR group, 1 (11%) from the SPR group, 1 (7%) from the SR group and 0 from the SS group received blood transfusions (p <0.01). From patients who received GFs (N=26), 2 received epoetin alfa, 11 darbepoetin alfa, 2 filgrastim, 17 pegfilgrastim, 4 eltrombopag and 1 romiplostim. Ten of them (39%) required multiple GFs, with darbepoetin alfa and pegfilgrastim being the most common combination. Combined use of GFs was only needed in those receiving TBPR (56%), PR (33%) or SPR (33%). Overall, 82% of the patients who received treatment interventions, 77% of those who received GFs and 47% of those who received blood transfusions were able to complete HCV treatment. Thirteen patients (62%) from the PR group, 12 (86%) from the TBPR group, 3 (33%) from the SPR group, 2 (14%) from the SR group and 0 from the SS group developed grade 3 or 4 hematologic toxicities (p <0.001). One (25%) of 4 patients receiving eltrombopag developed portal vein thrombosis. No other patients developed side effects attributed to GF support. Conclusions Hematologic toxicity during HCV treatment in cancer patients is common. The use of GFs helps manage such toxicity, allowing completion of antiviral therapy. The newer HCV direct-acting antiviral agents are associated with less hematological toxicity, requiring fewer interventions, GFs and blood transfusions. No hematologic side effects were seen with the IFN-free, ribavirin-free combination of SS. Abstract 4126. Table Characteristics of HCV-infected cancer patients treated with different antiviral regimens PR (N=21)% TBPR (N=14)% SPR (N=9)% SR (N=14)% SS (N=7)% Age, median (range) 54.3 (45-68) 59.7 (49-69) 54.7 (35-75) 62.7 (33-82) 60.9 (46-64) Male gender 13 (62) 6 (43) 4 (44) 8 (57) 4 (57) Type of cancer Solid Hematologic 16 (76)5 (24) 10 (71)4 (29) 4 (44)5 (56) 6 (43)8 (57) 4 (57)3 (43) Cirrhosis 5 (24) 7 (50) 2 (22) 3 (21) 6 (86) Baseline labs, median (range) Hemoglobin (g/dL) Platelets (x1,000 K/uL) Absolute Neutrophil count (K/uL) 12.8 (10-15.9)165 (83-408)1385 (940-6120) 13.5 (9.6-16.3)112 (52-397)2360 (800-4900) 13.8 (8.8-14.2)183 (121-268)2680 (1650-5810) 13.1 (9.8-15.5)179 (57-390)2490 (1040-4040) 13.8 (12.3-16.1)141 (59-239)3000 (1390-5030) FDA-recommended duration of antiviral treatment, weeks 24-48 24-48 12 12-24 12 Duration of antiviral treatment, median (range) 24 (2-48) 19 (3-52) 12 (1-12)* 12 (3-24)* 6 (3-12)* *Patients may still be on treatment. Figure Management of hematologic toxicity during HCV treatment of cancer patients Figure. Management of hematologic toxicity during HCV treatment of cancer patients Disclosures Torres: Genentech,: Consultancy; Vertex Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc. : Consultancy, Research Funding; Gilead Sciences: Consultancy.
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Espinasse, Benjamin, Manali Joglekar, Giancarlo Valiente, and Gowthami M. Arepally. "Novel Techniques for Measurement of Variable Sized PF4/H Complexes." Blood 120, no. 21 (November 16, 2012): 2204. http://dx.doi.org/10.1182/blood.v120.21.2204.2204.
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Abstract Abstract 2204 Electrostatic interactions between Platelet factor 4 (PF4), a cationic protein, and heparin, an anionic carbohydrate result in the formation of ultra-large complexes (ULCs) that are immunogenic in mice (Suvarna, Blood 2007) and contribute to the immune pathogenesis of Heparin-induced thrombocytopenia (HIT). Previous studies (Rauova, Blood 2005; Greinacher, Arterioscler Thromb Vasc Biol, 2006) have shown that the size of ULCs is determined by the concentration and the molar ratios of PF4:H (PHRs) of each compound. Size determination of PF4/H complexes has been problematic due to technical limitations of two commonly employed methods for sizing complexes, photon correlation spectroscopy (PCS) and size exclusion chromatography (SEC). PCS is a technique for measuring particles in solution using laser illumination is based on principles of Brownian motion. PCS performs optimally with monodisperse populations and is biased by the presence of large aggregates. SEC, a liquid chromatography method, is technically cumbersome, requires sample labeling and not feasible for measuring large numbers of samples. To address these limitations, we examined two novel approaches for measuring a broad range of PF4/H complex size (100–3000 nm) in vitro: Nanosight and flow cytometry (FC). Nanosight (Nanosight Ltd, Wiltshire, United Kingdom),was employed for measuring small-sized complexes using physiologic concentrations of hPF4 (10 ug/mL). Nanosight uses proprietary software to track nanoparticles (range 10–1000nm) in solution by laser illumination with real-time tracking of the motion of individual particles by a camera. Analysis parameters provided by the software include: 1) Particle size distributions displayed as histograms 2) direct visualization of particles 3) particle counting and sizing and 4) particle scatter intensity vs. count and size. For measuring intermediate to large sized particles, formed at high hPF4 concentrations (95 ug/mL), we used flow cytometry calibrated with sizing beads on side scatter channel (SSC). FC was performed using a BD LSRII cell analyzer (Becton Dickinson, Franklin Lakes, NJ), a high throughput flow analyzer with the threshold channel for SSC set to 200 and a flow rate of 1 ul per second. The instrument was calibrated using sizing beads ranging from 0.3–6 μm in size (Figure A). For both techniques, PF4/H ULCs were formed by adding hPF4 (10 or 95 ug/mL)and various UFH concentrations in HBSS to yield the indicated PHRs. Complexes were incubated for 60 minutes and measured by NanoSight or FC. Results of experiments using Nanosight are shown in Table 1 with results showing size and particle counts for each PHR. Results of FC are shown in Figure B and Table 2 (median, 5% and 95% size in nm). Both studies showed reproducibility for measurements for a given concentration and showed changes in complex size as a function of PHR (Figure B). Both methodologies are technically simple and provide complementary approaches to PCS for PF4/H complex size determination. Disclosures: No relevant conflicts of interest to declare.
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Li, Mingjia, Aziz Nazha, Paul Elson, Sean Hobson, Mikkael A. Sekeres, Matt E. Kalaycio, Ronald M. Sobecks, et al. "A Prognostic Scoring System for Newly Diagnosed Adult Acute Lymphocytic Leukemia Patients." Blood 124, no. 21 (December 6, 2014): 5252. http://dx.doi.org/10.1182/blood.v124.21.5252.5252.
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Abstract Introduction: Traditional prognostic factors for adult acute lymphocytic leukemia (ALL) include age, white blood count at diagnosis, and cytogenetic (CG) risk. We sought to identify a more detailed prognostic risk score for newly diagnosed adult patients (pts) based on these and other pre-treatment characteristics. Methods: 82 newly diagnosed ALL pts given induction chemotherapy (IC) at our institution between the years 2003-2011 were included, and data were obtained by chart review. Institutional review board approval was obtained. Variables examined included: gender, age, immunophenotype, CG risk, pre-IC body mass index (BMI), pre-IC and day 28 serum albumin, absolute lymphocyte (ALC) and neutrophil (ANC) counts, positive culture (blood or other) during IC, positive imaging suggestive of infection (during IC), and allogeneic hematopoietic cell transplant (AHCT). CG risk was ascribed by CALGB criteria (Blood 1999; 93: 3983). BMI was defined by: underweight (≤ 18.5), normal (> 18.5-25.0), overweight (> 25.0-30.0), moderately obese (> 30.0-35.0), severely obese (> 35.0-40.0), and very severely obese (> 40.0). The primary endpoint was overall survival (OS) which was measured from IC to death or last follow-up. Proportional hazards models were used for univariable and multivariable analyses. In the multivariable analysis stepwise variable selection was used to identify independent predictors. Results were internally validated using a bootstrap algorithm. For convenience measured factors were discretized using a recursive partitioning algorithm. Prognostic groups were formed by assigning “points” to each factor that were based on the magnitude of the estimated regression coefficients of the final model, and then summing the total number of points present. Results: Median age at diagnosis was 43 yrs (range 18-78); 58% male. 71% of pts (58/82) had a B-cell immunophenotype. CG risk included: normal: 15 pts (18%), high: 41 pts (50%), miscellaneous: 9 pts (11%), and unknown: 17 pts (21%). Twenty-four pts (29%) were Ph+. The majority of pts (70%: 57/82) received the CALGB 19802 regimen (Cancer 2013; 119: 90) for IC +/- a tyrosine kinase inhibitor (if they were Ph+). 27% of pts (22/ 82) received AHCT in CR1. Estimated median OS is 41.5 months (95% CI: 15.5-N/A). In univariable analysis age, pre-induction BMI, Day 28 ALC, pre- and Day 28 albumin, Day 28 ANC, Day 28 platelet count, evidence of infection, and CG risk were all seen to impact outcome. In multivariable analysis pre-IC BMI and albumin, age, and Day 28 ALC were identified as independent predictors. Assigning 1 “points” each for age >50, albumin prior to IC ≤ 3.2 g/dL, or Day 28 ALC ≤ 50 /uL and 2 points for BMI ≥ 35, 3 prognostic groups were defined: favorable (0 points) 32% of pts (26/80): estimated 5-yr OS of 68% +/-11%; intermediate (1 points) (29% of pts, 23/80): estimated 5 yr OS of 39% +/-11%, and unfavorable (≥ 2 points) (39% of pts, 31/80) with estimated 5 yr OS of 17% +/- 7% (Figure 1). Conclusion: We have constructed a simple prognostic model for newly diagnosed adults with ALL. This model will need to be validated in a larger group of uniformly treated patients. Table 1 Prognostic Factors for OS in Univariable and Multivariable Analysis Factor Univariable (HR (95% C.I.)) Multivariable (HR (95% C.I.)) Age at dx (≤50 vs. >50) 3.29 (1.80-5.99), p=.0001 2.83 (1.45-5.53), p=.002 Pre-IC BMI (<35 vs. >35) 2.95 (1.57-5.52), p=0.0008 3.88 (1.84-8.17), p=.0004 Pre-IC albumin (≥ 3.2 vs. < 3.2 g/dl) 2.61 (1.43-4.77), p=0.002 2.66 (1.33-5.30), p=.0006 Day 28 ALC (> 50/uL vs. ≤50/uL) 3.57 (1.61-7.91), p=0.002 3.11 (1.33-7.28), p=.009 CG risk 2.03 (0.98-4.22); p=0.06 ------ Day 28 albumin (>2.3 vs. ≤2.3 g/dl) 3.37 (1.66-6.83), p=0.0008 ------ Day 28 ANC (>200/uL vs. ≤200/uL) 4.51 (1.94-10.51), p=.0005 ------ Day 28 platelets (>75K/uL vs. ≤75K/uL) 2.44 (1.26-4.72), p=.008 ------ Any positive culture (no vs. yes) 2.19 (1.19-4.04), p=0.01 ------ Blood culture positive for bacteria (no vs. yes) 2.34 (1.28-4.30), p=0.006 ------ Positive imaging suggestive of infection (no vs. yes) 2.44 (1.34-4.46), p=0.004 ------ Positive blood culture and image (no vs. yes) 1.96 (1.07-3.57), p=0.03 ------ Figure 1 Prognostic Groups Figure 1. Prognostic Groups Disclosures No relevant conflicts of interest to declare.
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Morris, Morris David. "REVIEWMahbub ul Haq.Human Development in South Asia, 1997. New York: Oxford University Press, 1997. Pp. ix+1153. $30.00 (cloth); $23.00 (paper)." Economic Development and Cultural Change 48, no. 2 (January 2000): 433–39. http://dx.doi.org/10.1086/452470.
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Advani, Anjali S., Hongli Li, Laura C. Michaelis, Bruno C. Medeiros, Michaela Liedtke, Alan F. List, Kristen O'Dwyer, Megan Othus, Harry P. Erba, and Frederick R. Appelbaum. "Report of the Relapsed/Refractory Cohort of SWOG S0919: A Phase 2 Study of Idarubicin and Cytarabine in Combination with Pravastatin for Acute Myelogenous Leukemia." Blood 126, no. 23 (December 3, 2015): 3803. http://dx.doi.org/10.1182/blood.v126.23.3803.3803.
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Abstract Background: Inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy (Blood 104: 1816, 2004). A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)] in relapsed AML (British Journal of Haematology 2014; 167: 233-7). However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥ 3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi < 6 months following their last induction regimen or with refractory disease. Here, we report the results in this poor risk group. Methods: Pts were treated at SWOG institutions from April 2013 through November 2014. The protocol was approved by each institution's review board. Pravastatin was supplied by Bristol-Meyers Squibb. Eligibility: age ≥ 18 yrs, relapsed/refractory AML, cardiac ejection fraction ≥ 45%, CR/CRi following most recent chemotherapy < 6 months, no prior hematopoietic transplant. Treatment: oral pravastatin 1280 mg Days 1-8, idarubicin 12 mg/m2 IV Days 4-6, and cytarabine 1.5 g/m2/day continuous IV infusion Days 4-7. Pts achieving a CR could receive 2 cycles of consolidation. CR and CRi were defined by International Working Group criteria. Thirty-seven pts were to be accrued. If ≥ 12 pts achieved CR or CRi, the regimen would be considered sufficiently effective (critical level=5% if the true CR rate is 20% and power of 87% if the true CR rate is 40%). Results: Forty-one pts with a median age of 54 yrs (range 23-75) were enrolled. Nineteen pts (46%) were male and the median WBC was 3000/ uL (range 200-450,000). The median time from initial diagnosis to registration was 4.1 months (range 0.7-49.5). Disease status: primary refractory (63%), relapsed (37%). Cytogenetic risk defined by NCCN criteria: 41% poor, 54% intermediate, 5% missing. The response rate was 34% CR/CRi (95% CI: 20.1%, 50.6%). The p-value comparing 34% to 20% (the null response rate) is 0.024 at a one-sided alpha level of 0.05. The estimated median overall survival is 3.6 months and the median relapse-free survival is 2.6 months. No clinical factors (age, WBC, cytogenetic risk, disease status, time from diagnosis, AML onset) were associated with response. Nine pts proceeded to allogeneic hematopoietic stem cell transplant (AHSCT) and the median overall survival for these patients has not been reached with a median follow-up of 10 months. Conclusions: The CR/CRi rate in this poor risk relapsed/refractory population is encouraging and suggests that targeting the cholesterol pathway may have therapeutic impact. However, these pts still have rapidly relapsing disease. Pts who were able to proceed quickly to AHSCT achieved prolonged survival. Disclosures Off Label Use: pravastatin in the treatment of AML. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. List:Celgene Corporation: Honoraria, Research Funding. Erba:Millennium/Takeda: Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celator: Research Funding; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Amgen: Consultancy, Research Funding; Astellas: Research Funding; Millennium/Takeda: Research Funding; Sunesis: Consultancy; Celator: Research Funding; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding; Ariad: Consultancy; Sunesis: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees; Pfizer: Consultancy; Jannsen (J&J): Other: Data Safety and Monitoring Committees.
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Bender, H., A. Schomburg, F. Grün wald, G. Schöneich, P. Zamorra, K. Reichmann, C. Dierke-Dzierzon, P. Mallmann, H. J. Biersack, and H. Pal medo. "Schmerztherapie mit Rhenium-186 HEDP bei multiplen Knochenmetastasen." Nuklearmedizin 35, no. 02 (1996): 63–67. http://dx.doi.org/10.1055/s-0038-1629697.
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Zusammenfassung Ziel: Die effiziente, medikamentöse Behandlung von Patienten mit schmerzhaften, disseminierten Knochemmetastasen stellt ein therapeutisches Problem dar. Die systemische Radionuklidtherapie kommt als Alternative in Frage. In der vorliegenden Studie wurde die Effektivität von Rhenium-186 HEDP zur Schmerztherapie bei disseminierten Knochenmetastasen evaluiert. Methoden: 30 Patienten, die wegen schmerzhafter Knochenmetastasen analgetisch behandelt wurden, erhielten -teilweise mehrfach- Injektionen von jeweils 1295 MBq 186Re HEDP zur Schmerzbehandlung. Ergebnisse: Bei 70% der Patienten ließ sich eine Schmerzreduktion erreichen. Die Dauer des Ansprechens auf die Therapie betrug im Mittel 4 Wochen (1 Wo-2,5 Mon). Die wesentlichen Nebenwirkungen bestanden in einem geringen Abfall der Thrombozyten (durchschnittl. 30000/ul) und einer kurzzeitigen Verstärkung der Schmerzsymptomatik (Flare-Effekt). Schlußfolgerung: Bei Patienten mit schmerzhaften, disseminierten Knochenmetastasen kann die Schmerztherapie mit Rhenium-186 HEDP komplementär zur medikamentösen Therapie eingesetzt werden.
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Poudyal, Bishesh Sharma, Binaya Sapkota, Gentle Sunder Shrestha, Sujan Thapalia, Bishal Gyawali, and Sampurna Tuladhar. "Safety and Efficacy of Azathioprine as a Second Line Therapy for Primary Immune Thrombocytopenic Purpura." Journal of Nepal Medical Association 55, no. 203 (September 30, 2016): 16–21. http://dx.doi.org/10.31729/jnma.2832.
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Introduction: Immune thrombocytopenic purpura remains common blood disease in Nepal. Azathioprine is an oral immunosupressive medicine which has been used widely in various autoimmune disease and solid organ transplant patients. It is inexpensive, easily available and well tolerated medicine. This study was carried out to evaluate efficacy and safety of azathioprine as a second line medicine for primary ITP patients who were refractory to steroid therapy.Methods: The observational, pre-post study was conducted at Government of Nepal Civil Service Hospital, Kathmandu from January to October 2014. Twenty four primary ITP patients who were steroid refractory were treated with Azathioprine. Patients were termed steroid refractory if platelet counts were less than 30,000/ul on day 21st of steroid therapy. From day 22 onwards oral azathioprine 2mg/kg was started and steroids were tapered 10mg/week and stopped. Platelet counts of more than 30000/ul after one month of stopping steroid, while still on azathioprine, were termed response to azathioprine. Platelet count of more than 100,000/ul was termed complete response. The associations among age, gender, duration and platelets counts were analyzed by chi square test and Fisher's exact test (when individual cell frequency was less than 5). The comparison of platelets counts among the start and day 90 of Azathioprine therapy was performed by the paired t-test. Results: The study showed that there was not significant association among age and gender of the patients and their platelets count on the start of Azathioprine therapy (p value 0.354 and 0.725 respectively) and on day 90 of Azathioprine therapy (p value 0.082 and 0.762 respectively). The duration-wise comparisons of platelets count on both the start and day 90 of Azathioprine therapy were significant (p values 0.029 and 0.008 respectively). The paired comparison among platelets count on the start and day 90 of Azathioprine therapy was highly significant (p value 0.000).Conclusions: The study showed the therapeutic implication of azathioprine in ITP patients. It also showed that efficacy of azathioprine was comparable with other modes of treatment. In low income countries like Nepal azathioprine can be considered as second line treatment for steroid refractory ITP patients.Keywords: Immune thrombocytopenic purpura; autoimmune disease; steroids; azathioprine; Nepal. | PubMed
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Mitrani, Robert, Kandace Gollomp, Michele P. Lambert, and Amrom Obstfeld. "The Immature Reticulocyte Fraction As an Aid in the Diagnosis and Prognosis of Parvovirus B19 Infection in Sickle Cell Disease." Blood 132, Supplement 1 (November 29, 2018): 3678. http://dx.doi.org/10.1182/blood-2018-99-117152.
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Abstract Background Sickle cell disease (SCD) is characterized by hemoglobin polymerization leading to vaso-occlusion, chronic hemolysis and vasculopathy. Parvovirus B19 (B19) infection causes an acute arrest of erythropoiesis leading to reticulocytopenia and potentially life-threatening anemia in patients with chronic hemolysis such as SCD. Diagnosis of B19 infection relies on clinical history in combination with expensive and often belated serological and molecular testing. The immature reticulocyte fraction (IRF) is a relatively new reticulocyte parameter available on automated hematology analyzers that assesses the maturity of circulating reticulocytes by quantifying the fraction that stain strongest for RNA. Aims We hypothesized that the IRF could provide diagnostic information in the evaluation and management of patients with SCD who are being evaluated for B19 infection. Specifically, given that the IRF quantifies the fraction of circulating reticulocytes that have just exited the bone marrow and are least mature, we speculated that changes in IRF would precede changes seen in the reticulocyte counts in aplastic crisis and recovery. Methods We performed a retrospective analysis of records at the Children's Hospital of Philadelphia of complete blood count (CBC) and reticulocyte indices in patients with sickle cell disease in whom B19 infection by PCR testing was assessed between January 1, 2015 and October 31, 2017. CBC testing was performed on the Sysmex XN 3000 analyzer. Medical records were reviewed to verify that the B19 testing was sent during an acute aplastic episode. Diagnostic performance of reticulocyte percent (RET%) and count (RET) compared to the IRF and the absolute IRF count (AIR) was assessed by receiver-operator characters (ROC) curves on GraphPad Prism. For recovery studies, an increasing IRF was defined as an increase of 10 per 24 hour period and a recovering reticulocyte count was defined as an increase of 50,000 cells/uL per 24 hour period. Results At baseline, patients with SCD have an average IRF of 27.2% (16.7 - 37.7%), far higher than the reference interval (9.3 - 17.4%). This parallels the elevations in reticulocyte counts in this population and relates to their chronically high RBC turnover. A total of 119 patients had B19 testing performed in the study period of which 26 were found to have acute infection. The most common diagnoses amongst the B19 negative patients were unspecified fever/viral syndrome, vaso-occlusion/pain crisis, and acute chest syndrome. ROC curve analysis demonstrates that RET%, RET, IRF, and AIR lab values are predictive of B19 infection on the day that B19 PCR testing was sent with an AUC of 0.73, 0.76, 0.76, and 0.83 (p < 0.001 for all) respectively. The AUC for each parameter increased when the respective minimum value was analyzed; RET%, RET, IRF, and AIR showed an AUC of 0.83, 0.87, 0.87, and 0.91 (p < 0.0001 for all, figure 1 and table 1). In particular, an IRF value below 2.45% demonstrated a sensitivity of 50% and a specificity of 99% for B19 infection in the study population. Finally, amongst B19 positive patients we found that an increasing IRF was strongly associated with a reticulocyte recovery within the following 48 hour period (chi-square p-value = 0.015). A rising IRF was associated with a higher mean reticulocyte increase in the following assessment (2,500/24 hour period vs. 33,000/24 hour period, p < 0.05, figure 2). Moreover, an increasing IRF had a sensitivity of 31% and a specificity of 92% for a recovery in reticulocyte count. These results were consistent amongst all aplastic patients who were tested for B19 as well (data not shown). These data suggest that a high IRF is closely associated with a rising reticulocyte count within the following 24-48 hours. Conclusions Our data confirms that amongst a cohort of complicated patients with SCD and other causes for reticulocytopenia, the IRF is highly specific for detecting the severe aplasia caused by B19 infection in this group. This additional data may be useful in better triaging patients with SCD and reticulocytopenia and potentially in improving utilization of the more expensive B19 diagnostic testing. Furthermore our study suggests that an increasing IRF predicts reticulocyte recovery in reticulocytopenic patients with SCD and could have utility in clinical decision making such as whether to transfuse packed red blood cells or whether they can be safely discharged from the hospital. Disclosures Lambert: Amgen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Educational Concepts in Medicine: Consultancy; Summus: Consultancy; Rigel: Consultancy; Shionogi: Consultancy; CSL: Consultancy.
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Chaudhury, Ateefa, Rami S. Komrokji, Najla H. Al Ali, Ling Zhang, Pardis Vafaii, and Jeffrey E. Lancet. "Prognosis and Outcomes in MDS-MPN Unclassifiable: Single Institution Experience of a Rare Disorder." Blood 126, no. 23 (December 3, 2015): 1698. http://dx.doi.org/10.1182/blood.v126.23.1698.1698.
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Abstract Introduction: The 2008 World Health Organization (WHO) classification has recognized a unique overlap category that has features of proliferation found in myeloproliferative neoplasms (MPN) and also dysplasia found in myelodysplastic syndrome (MDS). The least well characterized of the 4 MDS/MPN overlap diseases is a rare entity known as MDS/MPN Unclassifiable (MDS/MPN-U), comprising <5% of myeloid disorders. Furthermore, given the rarity of this disorder, there is no validated risk stratification scoring system, although there are several commonly used prognostic models for MDS, including the International Prognostic Scoring System (IPSS), the Revised International Prognostic Scoring System (IPSS-R), and the M.D. Anderson Cancer Center model (MDAS). The objectives of this study were to evaluate the natural history of this very uncommon diagnosis and to determine which of the current scoring symptoms used for MDS best discriminates outcomes. Methods: The Moffitt Cancer Center database of over 3000 MDS patients was used to identify patients with MDS/MPN-U and to subsequently perform a comprehensive chart/pathology review. We then applied IPSS, IPSS-R, and the MDAS scores to each patient in order to compare differences in overall survival (OS) amongst different risk groups within each scoring system. Finally, we compared outcomes in the MDS/MPN-U group with a large number of matched MDS cases from within our database, using the MDAS. Descriptive statistical analyses were utilized. Chi square analysis and t- test were performed to compare categorical and continuous variables. Akaike information criteria (AIC) were used to assess the relative goodness of fit of the models. All data was analyzed using SPSS version 21.0 statistical software. Results: Forty three patients were identified with MDS/MPN-U and were pathologically confirmed to meet WHO criteria. Median age was 71 years (range 55 - 91) and the M:F = 26.17. Median baseline laboratory parameters: WBC 11.2 x 103/dL (range 0.9 - 84.8); Hb 9.7 g/dL (range 5.8-14.4); platelets 137 x 103/uL. Table 1 summarizes risk stratification per current validated MDS scoring systems. The majority of patients had lower risk disease by all the models. Forty of 42 (95%) patients evaluable for prognostic scoring were classified as low/Int-1 by IPSS. However, 11 out of the 40 pts (28%) classified as lower risk by IPSS were upgraded to Int-2 or high risk by MDAS. Twenty-two patients received hypomethylating agents (HMA) as first line treatment after supportive care. Per IWG 2006, 8 of 22, (36%) had complete response, partial remission, or hematologic improvement, 7 (32%) had stable disease, and 6 (27%) had progressive disease. The median OS for all MDS/MPN-U patients was 33 months (95% Confidence Interval 22 - 45). Within each MDS scoring system, statistically significant survival differences were detected between risk stages (table 1). The IPSS-R did not improve the IPSS prognostic value. Patients categorized as lower-risk (low/Int-1) by MDAS had superior survival compared to IPSS. Lastly, we compared outcomes between the 43 MDS/MPN-U patients and 1117 IPSS low/Int-1 matched controls within the MDS database. Median overall survival was inferior in MDS/MPN-U vs. MDS (33.4 mo vs. 57 mo, p = 0.005). In addition, using the MDAS, stage-by-stage, survival was significantly worse in the MDS/MPN-U group. Table 1. Risk Stratification Based on MDS Scoring Systems MDS/MPN-Un (%) Median Overall Survival (mo) P-value IPSS Low Int-1 Int-2 High 15 (35.7)25 (59.5)1 (2.4)1 (2.4) 33.433.312.86.0 < 0.001 IPSS-R Very Low Low Intermediate High Very High 6 (14.3)21 (50)10 (23.8)4 (9.5)1 (2.4) 18.2333.425.112.86.0 0.001 MDAS Low Int-1 Int-2 High 6 (14.3)20 (47.6)13 (31.0)3 (7.1) 52.433.425.16.0 < 0.001 Conclusions: MDS/MPN-U appears to have a variable disease course but with generally poor outcomes, even amongst lower-risk patients classified by MDS scoring systems, and despite a moderate rate of response to treatment. Matched comparisons indicate inferior outcomes compared with similarly staged MDS patients. The MDAS may offer increased discriminatory capacity for determining prognosis based on disease stage. Further work with a larger patient population and cross comparisons to other MDS/MPN diseases will assist further understanding of this rare disorder. Integration of somatic mutations data may compliment the clinical models. Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Pharmacylics: Speakers Bureau; Incyte: Consultancy. Lancet:Kalo-Bios: Consultancy; Celgene: Consultancy, Research Funding; Pfizer: Research Funding; Amgen: Consultancy; Seattle Genetics: Consultancy; Boehringer-Ingelheim: Consultancy.
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Karakonstantis, Stamatis, Mina Koulouridi, Kyriakos Pitsillos, Eirini Kalokyri, Anna Kozyri, Galateia Gourniezaki, and Charalampos Lydakis. "A prospective study of hospitalized patients with leukemoid reaction; causes, prognosis and value of manual peripheral smear review." Romanian Journal of Internal Medicine 57, no. 3 (September 1, 2019): 241–47. http://dx.doi.org/10.2478/rjim-2019-0006.
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Abstract Introduction. Several diagnoses have been associated with leukemoid reaction (LR). In patients with LR the diagnostic and prognostic value of detailed manual blood smear counts (such as the percentage of band cells or grading of neutrophil toxic changes) has not been studied previously. Methods. We prospectively recorded all hospitalized adult (> 18 years old) patients with LR (≥ 30000/ul) of neutrophilic predominance, excluding patients with pre-existing leukocytosis due to hematological malignancies. We examined the diagnoses and prognosis (in-hospital mortality and post-discharge mortality up to a year after the end of the study) of these patients as well as the value of manual peripheral smear review. Results. We recorded a total of 93 patients with LR from January 2017 to December 2017. Infection was the most common diagnosis (70%), followed by malignancy (7.5%) and bleeding (6.5%). In-hospital mortality (45%) and post-discharge mortality (35% of those discharged) were very high. Among blood smear findings, only neutrophil vacuolation was significantly more common in patients with infections (34%), although it was also observed in many patients without any infection (13%). Blood smear findings were not associated with prognosis. Conclusion. Detailed manual smear review is a labor-intensive procedure and it has limited diagnostic and prognostic value in unselected hospitalized patients with neutrophilic LR.
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Falola, O. O., and O. O. Olufayo. "Rumen characteristics and blood parameters of West African dwarf goats fed vetiver grass (Chrysopogon zizanoides. L. Roberty) ensiled with cassava peels at different ratio." Nigerian Journal of Animal Production 44, no. 3 (January 2, 2021): 366–70. http://dx.doi.org/10.51791/njap.v44i3.654.
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Vetiver is a perennial grass of tropical origin, commonly used as edge row plants for the control of erosion. Being leafy and with a high tillering ability, it has not been properly integrated as forage for ruminants. Thus, an experiment was carried out to determine the effect of ensiling a four week re-growth of vetiver grass with cassava peels on rumen and blood metabolites of West African dwarf goats. Sixteen goats were used for the study. A completely randomized design was used with four animals per treatment. Vetiver grass was ensiled with cassava peels at ratio (A) 80:20, (B) 70:30, (C) 60:40 and (D) 50:50 were provided ad-libtum at 5% body weight. Rumen and blood samples were collected at the end of the experiment which lasted for 90 days. Results of the study showed rumen ammonia nitrogen (NH3-N) concentration of 7.25-7.93mg/100mL, and pH of 6.75-6.81. Variations among the treatments were within the acceptable range for rumen microbial activity. There was a uniformly low plasma urea (4.36-5.16mm/l). Glucose (85.36-89.04g/dL), total protein (6.42- 7.50g/dL), cholesterol (60.95-66.19g/dL), haemoglobin (10.9-12.7g/100ml), packed cell volume (30.0-31.0%) and white blood cell (10.25-10.67×103/ul) were within the range reported for healthy goats. Ensiled vetiver grass with cassava peels had no detrimental effects on the rumen and blood parameters of the experimental animals.
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Zhao, Yanmin, Yi Luo, Yamin Tan, Jimin Shi, Lizhen Liu, Kangni Wu, Jingsong He, and He Huang. "Prior Treatment with Dasatinib Followed by Stem Cell Transplantation In Patients with CML In Advanced Phases with BCR-ABL Mutation." Blood 116, no. 21 (November 19, 2010): 4485. http://dx.doi.org/10.1182/blood.v116.21.4485.4485.
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Abstract Abstract 4485 Background: The prognosis for patients with chronic myeloid leukemia (CML) in advanced phases remains dismal, especially for those who develop ABL mutation. Administration of second-generation tyrosine kinase inhibitors (TKI) might provide an effective approach for patients with BCL-ABL mutation, but it only offers short-tem benefit in most cases. Allogeneic stem cell transplantation (allo-SCT) seems the only curative therapy for advanced CML, and limited data exist on the effectiveness of allo-SCT following prior treatment with new TKI dasatinib. Objective and Methods: To evaluate the efficacy of this combination therapy, patients with advanced disease harboring BCL-ABL mutation were enrolled between May 2009 and May 2010, and given dasatinib for a predetermined period, and then referred to myeloablative allo-SCT. All the patients were conditioned with busulfan/cyclophosphamide based regimens. ATG was used for those who received HLA-haploidentical transplantation. Cyclosporin, mycophenolate mofetil and short-term methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Results: (1) Five patients with accelerated phase (n=1) and blast crisis (n=4) were enrolled. The median age was 37 years (range, 11–42 years). All the patients had a history of chronic phase (CP) before enrollment. Three patients progressed to advanced phases on imatinib. The other two patients didn't receive any TKIs during the CP. When progressing to blast crisis, imatinib was administered but showed no response. BCR-ABL mutations were detected at the beginning of enrollment. The mutations were F359C, D296G, E459G, Y253H, Y253F. (2) After enrollment, patients were treated with dasatinib for 1–3months (median, 2 months). At the time of transplant, all patients achieved complete hematological response and returned to CP, and two patients achieved partial cytogenetic response. Dasatinib was well-tolerated expect one patient who developed pleural effusion. (3) Donors were HLA-haploidentical related in two cases,HLA-identical related in one case, and HLA-identical unrelated in two cases, respectively. All patients engrafted successfully, with a median time to neutrophil (>500/ul) and platelet (>30000/ul) recovery of 15 and 17 days respectively. Two patients experienced grade III-IV acute GVHD). Chronic GVHD (cGVHD) was observed in three patients, including two with extensive cGVHD. The relapse rate after transplantation was 0. Only one patient died from pulmonary fungal infection while in complete molecular remission. After a median follow-up of 6.5 months, four patients were alive with complete cytogenetic remission, including three in complete molecular remission. Conclusion: Dasatinib given before allo-HSCT do not negatively affect transplant engraftment and response rate. Myeloablative transplantation for imatinib-resistant CML may have a satisfactory outcome when combined with dasatinib, which could provide a good quality of remission prior to transplantation and a curable opportunity after transplantation. Disclosures: No relevant conflicts of interest to declare.
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Lee, Sang-Hoon, Seung-Won Oh, Young-Hee Lee, Il-Jin Kim, Dong-Jin Lee, Jae-Chun Lim, Cha-Cheol Park, and Han-Do Kim. "Preparation and properties of flame-retardant epoxy resins containing reactive phosphorus flame retardant." Journal of Engineered Fibers and Fabrics 15 (January 2020): 155892502090132. http://dx.doi.org/10.1177/1558925020901323.
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To prepare flame-retardant epoxy resin, phosphorus compound containing di-hydroxyl group (10-(2,5-dihydroxyphenyl)-9,10-dihydro-9-oxa-10-phospha phenanthrene-10-oxide, DOPO-HQ) was reacted with uncured epoxy resin (diglycidyl ether of bisphenol A, YD-128) and then cured using a curing agent (dicyandiamide, DICY). This study focused on the effect of phosphorus compound/phosphorus content on physical properties and flame retardancy of cured epoxy resin. The thermal decomposition temperature of the cured epoxy resins (samples: P0, P1.5, P2.0, and P2.5, the number represents the wt% of phosphorus) increased with increasing the content of phosphorus compound/phosphorus (0/0, 19.8/1.5, 27.8/2.0, and 36.8/2.5 wt%) based on epoxy resin. The impact strength of the cured epoxy resin increased significantly with increasing phosphorus compound content. As the phosphorus compound/phosphorus content increased from 0/0 to 36.8/2.5 wt%, the glass transition temperature (the peak temperature of loss modulus curve) increased from 135.2°C to 142.0°C. In addition, as the content of phosphorous compound increased, the storage modulus remained almost constant up to higher temperature. The limiting oxygen index value of cured epoxy resin increased from 21.1% to 30.0% with increasing phosphorus compound/phosphorus content from 0/0 to 36.8/2.5 wt%. The UL 94 V test result showed that no rating for phosphorus compounds less than 19.8 wt% and V-1 for 27.8 wt%. However, when the phosphorus compound was 36.8 wt%, the V-0 level indicating complete flame retardancy was obtained. In conclusion, the incorporation of phosphorus compounds into the epoxy chain resulted in improved properties such as impact strength and heat resistance, as well as a significant increase in flame retardancy.
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Xu, Buqin, Guilong Xu, Hui Qiao, Yun Liang, Jin Yang, and Jian Hu. "Preparation and flame retardancy of epoxy resin phosphoric acid modified poly-acrylate resin." Pigment & Resin Technology 48, no. 3 (May 7, 2019): 197–201. http://dx.doi.org/10.1108/prt-04-2018-0041.
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Purpose The flammability of poly-acrylate (PA) resin is a major disadvantage in applications that require flame resistance. It has been reported that a flame-retardant PA resin could be prepared by covalent incorporate phosphorous containing monomer with vinyl group via free radical polymerization, and the prepared modified PA resin is expected to exhibit better flame resistance than those by an additive approach. However, the phosphorus-containing monomers reported previously are made from expensive or toxic materials, and the production procedure is tedious and under harsh reaction conditions, which are not feasible for industrial application. Therefore, the purpose of this paper is the preparation of flame-retardant PA resin modified by epoxy resin phosphorous acid (EPPA) and the study of its flame retardancy. Design/methodology/approach EPPA is first prepared by epoxy resin E-51 and phosphorous acid and then used to prepare phosphorous containing PA resin by free radical polymerization. The flame retardancy of the prepared EPPA-modified PA (EPPA-PA) resin is studied. Findings The results show that EPPA can graft onto the PA polymer chain by free radical polymerization, the flame retardancy of the EPPA-PA resin increases as the EPPA content increasing. The flame retardancy of EPPA-PA resin prepared reaches 27.8% and can pass the V-0 rating in the UL-94 test when EPPA content is 30.0%. SEM and EDS results indicate that phosphorous element in the EPPA-PA resin shows a condensed-phase flame retardant effect. Research limitations/implications The grafting degree of EPPA cannot be accurately tested. Practical implications It is expected that the large-scale production of this epoxy resin phosphoric acid modified PA resin will enable practical industrial applications. Originality/value This method for synthesis of epoxy resin phosphoric acid modified PA resin is newfrangled.
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Luskin, Marlise R., Campbell L. Stewart, Jennifer JD Morrissette, David Lieberman, David J. Margolis, Alexander E. Perl, and Misha A. Rosenbach. "Next Generation Sequencing (NGS) Identifies an Association Between NPM1 Mutation and Leukemia Cutis." Blood 124, no. 21 (December 6, 2014): 2341. http://dx.doi.org/10.1182/blood.v124.21.2341.2341.
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Abstract Background:Leukemia cutis (LC) occurs in 10-30% of AML cases and may be a marker of poor prognosis. However, outside of monocytic AML (FAB M4/M5), no clinical or genetic predictors of LC are known. Recently, a number of somatic molecular mutations have been described in AML. Using amplicon-based next-generation sequencing (NGS) of a panel of recurrent, hematologic malignancy-associated mutations, we sought to determine potential molecular markers associated with the development of LC. Methods: A cohort of non-M3 AML patients treated at the University of Pennsylvania was identified in which NGS had been performed on either leukemic blasts obtained during clinical care or from the institutional tissue bank.Average read depth for 33 hematologic malignancy-associated genes was approximately 3000X, minimal depth was 250x, and reporting frequency cutoff for variants was 5%. Mutations were reported as pathogenic or variants of uncertain significance (VUS, further sub-classified internally as likely disease associated, VUS, or likely benign) based on the University’s Center for Personalized Diagnostics (CPD) review of publically available data; only pathogenic or likely disease-associated mutations were included in this analysis. A database maintained by dermatopathology was reviewed to identify cases of leukemia cutis at any time during the disease course. Independent dermatopathology review was obtained for indeterminate cases. Association between presence of each of the 3 most common molecular mutations (FLT3-ITD, DNMT3A, and NPM1) and development of LC was assessed by logistic regression, with adjustment for FAB M4/M5, as appropriate. The association between presence of a molecular mutation in different functional classes (tumor suppressors, activated signaling, chromatin modifiers, transcription factors, splicing machinery) and the development of LC was also assessed. Results:279 adult patients with AML with known molecular genotype were identified. Molecular profile was determined from AML diagnosis in (243, 88%) with the remainder undergoing assessment after prior therapy (relapsed or refractory). 56% were male with median age of 60 years (range 18-87) and median WBC count at diagnosis of 22 K/uL (range 0.4 -388 K/uL; 17% ≥100K/uL). The majority of patients had intermediate cytogenetic risk (12% favorable, 59% intermediate, 23% unfavorable, 6% unknown) and 41% of patients had FAB M4/M5 AML (9% unknown). The three most common mutations were NPM1 (29%), DNMT3A (25%), and FLT3-ITD (23%). NPM1mutations were enriched in patients with FAB M4/M5 AML (41% vs 23%, p=0.003). Leukemia cutis was present in 26 (9%) of patients. NPM1 mutant status was present in 14 of 26 cases of leukemia cutis (OR 3.17, 95% CI 1.40-7.20, p=0.006). No association was detected for LC and the presence of mutant FLT3-ITD (OR 1.27, p=0.613), mutant DNMT3A (OR 1.7, p=0.224), or a mutation in any functional class of AML mutations (all p-values NS). The impact of NPM1 mutant status remained significant after adjustment for association with M4/M5 AML (OR 3.91, p=0.005). As the histologic subtype of AML might modify the association between NPM1 mutations and leukemia cutis, we next examined the impact of NPM1 mutant status on patients with FAB M4/M5 AML and non-M4/M5 AML. Among patients with M4/M5 AML, 10/12 (80%) patients with LC were NPM1 mutant compared to 32/91 (35%) without LC suggesting that the presence of mutated NPM1 was significantly associated with the development of LC (OR 9.22, p=0.006). Among patients with non-M4/M5 AML, 3/9 (33%) of patients with leukemia cutis were NPM1 mutant compared to 32/142 (22.5%) without LC indicating no association in the non-M4/M5 subgroup (OR 1.72, p=0.461). Interestingly, M4/M5 AML was not associated with LC in the NPM1 WT cohort (OR 0.65, p=0.6). Conclusion: Using NGS, we identify a novel association between NPM1 mutation status and the presence of leukemia cutis, particularly within monocytic AML. Confirmation of these observations in a larger dataset is planned. Our data suggest potential cellular effects of NPM1 mutation affecting homing of leukemic blasts to skin and support the World Health Organization’s provisional classification of NPM1-mutated AML as a distinct biologic entity. Disclosures No relevant conflicts of interest to declare.
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Kato, Harumi, Takakazu Kawase, Shinichi Kako, Shuichi Mizuta, Kazuteru Ohashi, Mineo Kurokawa, Koji Iwato, et al. "Favorable Outcomes of Autologous Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Remission: On Behalf of the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)." Blood 120, no. 21 (November 16, 2012): 2021. http://dx.doi.org/10.1182/blood.v120.21.2021.2021.
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Abstract Abstract 2021 Background: Postremission treatment for adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-)ALL] in first remission remains elucidated and the role of autologous stem cell transplantation (auto-SCT) is still controversial in the application for Ph(-)ALL patients. We retrospectively analyzed the consolidative role of auto-SCT as a postremission therapy for adult Ph(-)ALL in first remission. Patients and Methods: Among 1962 adult Ph(-)ALL patients registered in the JSHCT database, we selected cases receiving auto-SCT with myeloablative preparative regimens in first complete remission from 1983 to 2009. Results: A total of 155 patients with 86 male patients were analyzed. The median age was 25 years (range: 16 to 74) and 79% of patients were less than 45 years of age at transplant. The number of patients having white blood cell (WBC) count <30000/ul and ≥30000/ul at diagnosis was 81 and 21, respectively. The number of patients showing B- and T-cell phenotypes was 80 and 21, respectively. Cytogenetic data were available in 96 patients, of which 69 patients had normal karyotypes. Most patients (84%) underwent auto-SCT before 2002, and 42 out of 155 patients received TBI combined conditioning regimens. With a median follow-up of 10 years, the 10-year overall survival rate of all 155 patients was 41% (95%CI: 33 to 49). Among patients younger than 45 years, the survival rate of adolescent and young adult (AYA) patients (aged 24 years or less) was comparable to that of patients aged 25 to 44 years (p= 0.110). Cumulative incidence of relapse and non-relapse mortality (NRM) at 10 year after auto-SCT was 47% (95%CI: 39 to 55) and 10% (95%CI: 6 to 16), respectively. In univariate analysis, factors associated with worse overall survival were age 45 years or more [Hazard ratio (HR): 1.67, p=0.038] and usage of conditioning regimens without total body irradiation (TBI) (HR: 1.51, p=0.110). Factors associated with decreasing relapse rates were usage of TBI conditioning regimens (HR: 0.35, p=0.069) and transplant year 2000 and later (HR: 0.35, p=0.141). In multivariate analysis, factors correlated with increasing the overall survival rate and decreasing the relapse rate were age less than 45 years [HR: 0.59 (95%CI: 0.36 to 0.96), p=0.034] and usage of TBI conditioning regimens [HR: 0.55 (95%CI: 0.31 to 0.99), p=0.048], respectively. There were no significant factors associated with NRM in univariate and multivariate analyses. We next performed comparison of auto-SCT with allogeneic stem cell transplantation (allo-SCT) in adult Ph(-)ALL patients. Patients undergoing allo-SCT were selected from the same JSHCT database. A total of 921 patients were identified as cases receiving allo-SCT with myeloablative preparative regimens in first complete remission. With a median follow-up of 4.95 years, the 4-year overall survival rate was 63% (95%CI: 51 to 59). Allo-SCT yielded better overall survival rate than that of auto-SCT (63% vs. 48% at 4 year, p=0.0004). In subset analyses, we limited analyses to the groups of patients younger than 45 years and receiving TBI regimens followed by auto-SCT (n=31) or allo-SCT (n=685). There were no differences in baseline patients' characteristics between the two groups except age [auto-SCT: 20 years (range: 16 to 40) vs. allo-SCT: 28 years (range: 16 to 44), p<0.001]. The 4-year overall survival rates in patients undergoing auto-SCT and allo-SCT were 71% (95%CI: 52 to 84) and 66% (95% CI: 62 to 70), respectively (p=0.510, Figure. 1). No statistically significant factors were found in the analyses of relapse and NRM. Conclusions: Our analyses demonstrated that auto-SCT produced excellent results showing a plateau in long-term survival and that clinical outcome of auto-SCT was comparable to that of allo-SCT in some part of patients. Candidates who obtained most benefit from auto-SCT was those younger than 45 years and well tolerated with TBI combined myeloablative conditioning regimens. Since optimal timing of postremission therapy is critical for adult Ph(-)ALL patients, auto-SCT in first complete remission could be one of promising treatment strategies for the patients. Disclosures: No relevant conflicts of interest to declare.
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López-González, Guillermo, Charles F. LeMaistre, Carlos Bachier, Brad Smith, Ka Wah Chan, Michael Grimley, Wilma Cain, Elina Delgado, Shawn Kaleel, and Paul Shaughnessy. "Clinical and Cost Outcomes of Double Umbilical Cord Blood Versus Bone Marrow and Peripheral Blood Unrelated Hematopoietic Stem Cell Transplants." Blood 112, no. 11 (November 16, 2008): 967. http://dx.doi.org/10.1182/blood.v112.11.967.967.
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Abstract Umbilical cord blood (UCB) is a viable source of hematopoietic stem cells (HSC) however, because of the increased risk of nonengraftment associated with low total nucleated cell counts (TNC) per kg, double UCB (DCB) transplants are used in larger patients (pts). Minimal data has been collected on cost analysis and clinical outcomes comparing DCB to peripheral blood (PB) and bone marrow (BM) unrelated donor (UD) transplants. Thus, we conducted a retrospective review of DCB transplants (n=30) from January 2004 through April 2008 compared to BM (n= 23, 30%) and PB (n = 54, 70%) UD transplants during the same time period. Median age was 21 yrs (range 13–66) for DCB recipients and 45 yrs (range 0.4–67) for UD pts. UD pts were HLA typed at A, B, C, DR, and DQ and matched with donors at 9(10) (21%) and 10(10) (79%) loci [all mismatches at class I alleles]. Pts were considered for DCB transplant if a suitable 10/10 or 9/10 donor could not be identified. DCB recipients had HLA matches of 6/6, 5/6/, 4/6 and 3/6 as follows: (cord 1/ cord 2): (0.0%/6.7%), (20.0%/30.0%), (76.7%/63.3%), (3.3%/0.0%) [HLA disparity between each UCB unit and recipient was not necessarily at the same loci]. The median TNC/kg in DCB pts was 2.03x107 (range 7.9x106 – 9.3x108). Full intensity preparative regimens (BuCY2 or TBI³ 1200 cGy based) were used in 43% of UD and 50% of DCB pts. Median day to ANC>500/ul for DCB and UD pts was 23 days (range 6–66) and 15 days (range 7–52), and platelet >20,000/ul was 52 days (range 7–130) and 19 days (range 9–63), respectively. Incidences of acute GVHD ≥2 and chronic GVHD in the UD and DCB pts were 61.0% and 51% vs. 53.3% and 45%, respectively. Median follow-up was 143 days (range 12–847) for the DCB group and 242 days (range 34–1506) for the UD pts. Estimated overall survival (OS) at 1 year was 61% (95% CI: 48% to 71%) for UD pts vs. 55% (95% CI: 34% to 72%) in DCB pts (p = NS). Estimated transplant related mortality (TRM) at 100 days for UD pt was 6.5% (95% CI: 2.8% to 14.9%) and 16.7% (95% CI: 7.3% to 35.5%) (p=0.09) in DCB pts. There were 48 total deaths; 14 (46.7%) in the DCB pts and 34 (44.2%) in the UD pts. In both the DCB and UD groups, disease relapse (21.4% and 23.5%) and infection (28.6% and 14.7%) caused the majority of deaths. All facility transplant related costs were reviewed from the transplant center thru the first year post transplant, excluding pretransplant workup and care not received at the transplant center. The total median costs for DCB transplants were significantly more than the UD costs at D30, D100 and 1yr post transplant by differences of $42,067, $50,806, and $52,297, respectively (p<0.05 for each time interval). The median length of stay for initial hospitalization at start of preparative regimen was 22 days (2–144) in the UD pts and 29 days (6–103) in the DCB pts, and 60% of total median costs occurred by D30 in the DCB group compared to 52% in the UD group. In conclusion, DCB provides a viable option for HSC with comparable clinical outcomes to UD transplants, however DCB transplants are more expensive primarily because of inpatient costs in the first 30 days.
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Thorsten, Vanessa, Donald Dudley, Corette Parker, Matthew Koch, Carol Hogue, Barbara Stoll, Robert Silver, et al. "Stillbirth, Inflammatory Markers, and Obesity: Results from the Stillbirth Collaborative Research Network." American Journal of Perinatology 35, no. 11 (April 2, 2018): 1071–78. http://dx.doi.org/10.1055/s-0038-1639340.
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Background Obesity is associated with increased risk of stillbirth, although the mechanisms are unknown. Obesity is also associated with inflammation. Serum ferritin, C-reactive protein, white blood cell count, and histologic chorioamnionitis are all markers of inflammation. Objective This article determines if inflammatory markers are associated with stillbirth and body mass index (BMI). Additionally, we determined whether inflammatory markers help to explain the known relationship between obesity and stillbirth. Study Design White blood cell count was assessed at admission to labor and delivery, maternal serum for assessment of various biomarkers was collected after study enrollment, and histologic chorioamnionitis was based on placental histology. These markers were compared for stillbirths and live births overall and within categories of BMI using analysis of variance on logarithmic-transformed markers and logistic regression for dichotomous variables. The impact of inflammatory markers on the association of BMI categories with stillbirth status was assessed using crude and adjusted odds ratios (COR and AOR, respectively) from logistic regression models. The interaction of inflammatory markers and BMI categories on stillbirth status was also assessed through logistic regression. Additional logistic regression models were used to determine if the association of maternal serum ferritin with stillbirth is different for preterm versus term births. Analyses were weighted for the overall population from which this sample was derived. Results A total of 497 women with singleton stillbirths and 1,414 women with live births were studied with prepregnancy BMI (kg/m2) categorized as normal (18.5–24.9), overweight (25.0–29.9), or obese (30.0 + ). Overweight (COR, 1.48; 95% confidence interval [CI]: 1.14–1.94) and obese women (COR, 1.60; 95% CI: 1.23–2.08) were more likely than normal weight women to experience stillbirth. Serum ferritin levels were higher (geometric mean: 37.4 ng/mL vs. 23.3, p < 0.0001) and C-reactive protein levels lower (geometric mean: 2.9 mg/dL vs. 3.3, p = 0.0279), among women with stillbirth compared with live birth. Elevated white blood cell count (15.0 uL × 103 or greater) was associated with stillbirth (21.2% SB vs. 10.0% live birth, p < 0.0001). Histologic chorioamnionitis was more common (33.2% vs. 15.7%, p < 0.0001) among women with stillbirth compared with those with live birth. Serum ferritin, C-reactive protein, and chorioamnionitis had little impact on the ORs associating stillbirth with overweight or obesity. Adjustment for elevated white blood cell count did not meaningfully change the OR for stillbirth in overweight versus normal weight women. However, the stillbirth OR for obese versus normal BMI changed by more than 10% when adjusting for histologic chorioamnionitis (AOR, 1.38; 95% CI: 1.02–1.88), indicating confounding. BMI by inflammatory marker interaction terms were not significant. The association of serum ferritin levels with stillbirth was stronger among preterm births (p = 0.0066). Conclusion Maternal serum ferritin levels, elevated white blood cell count, and histologic chorioamnionitis were positively and C-reactive protein levels negatively associated with stillbirth. Elevated BMIs, both overweight and obese, were associated with stillbirth when compared with women with normal BMI. None of the inflammatory markers fully accounted for the relationship between obesity and stillbirth. The association of maternal serum ferritin with stillbirth was stronger in preterm than term stillbirths.
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Gundabolu, Krishna, Catalina C. Amador, Allison M. Cushman-Vokoun, Vijaya R. Bhatt, Lori J. Maness, and Timothy C. Greiner. "Concurrent Somatic Mutations in Exon 14 of Janus KINASE2 (JAK2) and Exon 10 of Myeloprolifeative Leukemia Virus Oncogene (MPL) in Myeloproliferative Neoplasms (MPN) and Myelodysplastic Syndromes (MDS)/MPN." Blood 126, no. 23 (December 3, 2015): 5211. http://dx.doi.org/10.1182/blood.v126.23.5211.5211.
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Abstract INTRODUCTION: JAK2 p.V617F mutations are common in Polycythemia Vera (>90%), Essential Thrombocythemia (50%; ET) and Primary Myelofibrosis (30-50%; PMF). Somatic mutations of codons 515 or 505 in MPL Exon 10 are present in 5% of non-JAK2-mutated ET and 1% of PMF. MPL p.W515L mutation has also been identified in patients with Refractory Anemia with Ring Sideroblasts associated with Thrombocytosis (RARS-T). MPL mutation in Exon 10 codon 505 (S505N) was originally identified as a germ line mutation associated with hereditary thrombocytopenia, but was subsequently reported in ET and PMF. Most current evidence suggests that JAK2 and MPL mutations are mutually exclusive. Pardanani et al had reported 6 cases out of 1182 patients with concurrent JAK2 and MPL mutations, using assays of different sensitivities. In the reported cases the more frequent allele mutated is MPL and less frequent allele is JAK2 as a possible second hit. Here, we report 2 cases with concurrent JAK2 and MPL mutations. METHODS: DNA was extracted and subjected to library preparation using the 50 gene Ion AmpliSeq™ Cancer Hotspot Panel v2, clonal amplification and Ion Sphere™ Particle enrichment on the Ion One Touch™ 2 and One Touch™ ES, and Next Generation Sequencing (NGS) on the Ion Torrent PGM System™. Data was analyzed using Variant Caller Software v.4.0 and NextGENe software v.2.3.4. The original target region BED file for the Ion AmpliSeq™ Cancer Hotspot Panel v2 was modified to include only MPL exon 10 and JAK2 exon 14 amplicons. Assay coverage averaged approximately 3000X. RESULTS: From February 2015, JAK2/MPL NGS was performed on 105 specimens to determine somatic mutations in possible MPN and MDS/MPN cases. 2/105 (1.9%) of the specimens harbored concurrent JAK2 and MPL mutations compared to 6/1182 patients reported previously (0.5%). One patient had RARS-T and one had PMF. Mean age (69 and 74 years) was 71 years, hemoglobin (8.3 and 10.3 gm/dL) 9.3 gm/dL, hematocrit (25 and 26%) 25%, Mean Corpuscular Volume (92 and 92 fL) 92 fL, platelet count (171 and 1320 x 10E3/cmm) 745 x 10E3/cmm, White blood count-WBC (6.2 and 10.3 x 10E3/UL) 8.25 x10E3/cmm, monocytes (3-5%) 4%, Basophils (1 and 2%) 2%, Neutrophils (61 and 66%) 64%, Bands (3and 15%) 9%, Eosinophils (0 and 2%) 1%, peripheral blood blasts (0 and 4%) 2%, bone marrow fibrosis grade of 2 in a grading scale of 1-3. Both were males. Spleen was not palpable at diagnosis in either patient. The case with RARS-T had 4.5% MPL p.W515L mutation allele frequency and 22.7% JAK2 p.V617F mutation allele frequency. The case with PMF had 3.3% MPL p.S505N mutation allele frequency and 2.4% JAK2 p.V617F mutation allele frequency (detected at the follow up 6 months bone marrow in May 2015). They were treated with EPO analogues/Anagrelide and Ruxolitinib respectively. None had thrombosis or bleeding complications. At a mean follow-up of 366 days (113 and 620 day), both patients are alive. CONCLUSION: MPL (codons 505 and 515) and JAK2 p.V617F mutations are not always mutually exclusive. NGS panels with dual gene coverage and high sensitivity identify coexistent mutations that would not be identified by single gene assays. The clinical significance of concurrent mutations remains unclear. Disclosures No relevant conflicts of interest to declare.
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Nguyen, Julia, Fuad Abdulla, Chunsheng Chen, Phong Nguyen, Minh Nguyen, Benjamin Tittle, Gerard O'Sullivan, John D. Belcher, and Gregory M. Vercellotti. "Phenotypic Characterization the Townes Sickle Mice." Blood 124, no. 21 (December 6, 2014): 4916. http://dx.doi.org/10.1182/blood.v124.21.4916.4916.
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Abstract The HbSS-Townes mouse model, developed in Dr. Tim Townes laboratory, University of Alabama, Birmingham (and kindly provided by him to our laboratory) were created on a mixed genetic background in which the murine adult α-globin genes were replaced with the human α-globin gene (genotype: Hba hα/hα) and the murine adult β-globin genes were replaced with human sickle βS- and fetal Aγ-globin gene fragments linked together (genotype: Hbb hAγβS/hAγβS) (Wu LC et al. Blood 2006;108: 1183-1188). HbSS-Townes mice have anemia, a shortened RBC half-life of 2.5 days and a severe disease phenotype. Control HbAA-Townes mice were created by replacing the murine globin genes with human α-globin gene (genotype: Hba hα/hα) and linked human βA- and fetal Aγ-globins (genotype: Hbb hAγβA/hAγβA), while HbAS-Townes heterozygous mice were developed by breeding HbAA and HbSS mice. Many laboratories are utilizing these mice but complete phenotypic description of these three models has not been described including: hematology, kidney and liver function, inflammatory markers, haptoglobin and hemopexin levels, red cell half-lives, organ histopathology and vascular responses to vaso-occlusive stimuli. Table 1 summarizes our findings. There was a clear difference in histopathology between the HbSS and other groups (HbAA and HbAS). HbSS mice had hepatic necrosis, increased erythropoiesis and increased hemosiderin within the liver and some subtle lesions involving the glomeruli in the kidneys. Additional findings were a marked increase in size of spleen (7.0-7.6 x by % body weights) attributed to severe congestion and increased erythropoiesis. No lesions were observed in the lungs and other tissues. The tissues evaluated in the HbAS and HbAA groups were essentially normal. In contrast, HbSS mice had multifocal irregular areas of necrosis within the liver, with reactive leukocyte infiltrates (mainly neutrophils in the more acute lesions with a greater proportion of mononuclear cells (macrophages etc.) in more chronic lesions. MPO immunohistochemistry confirmed the presence of neutrophils in the liver. There was a substantial increase in iron (and hemosiderin) in the livers of HbSS mice, confirmed by a Prussian Perls stain and low, but detectable, levels of iron in the proximal convoluted tubules of the kidney. This is consistent with increased red cell turnover in the HbSS mice. Total iron mass in the markedly enlarged spleen is very high. There is a somewhat subtle glomerulopathy present in the kidney, with enlarged glomeruli with variable ectasia of vessels, and mesangial derangement. In conclusion the Townes mouse models provide a spectrum of severe hemolytic disease that in many ways mimic the human disease albeit imperfectly. TableTable 1 HbAAHbASHbSSHb (g/dL)12.0 ± 0.610.6 ± 0.59.5 ± 1.4*Hematocrit (%)49.6 ± 2.345.0 ± 4.2*29.2 ± 0.9*#WBC (K/µL)10.8 ± 1.213.2 ± 4.038.2 ± 4.9*#Platelet Counts (K/uL)854 ± 78889 ± 1421004 ± 179Monocytes (%)8.0 ± 1.17.6 ± 1.77.4 ± 1.0Lymphocytes (%)60 ± 3.063.8 ± 5.667.5 ± 9.1Neutrophils (%)28.6 ± 5.926.1 ± 8.727.8 ± 2.2Reticulocytes (%)7.8 ± 1.78.6 ± 4.556.8 ± 2.6*#RBC Half-Life (days)15.710.62.4Expired CO (nmoles/h/g)0.92 ± 0.241.27 ± 0.236.33 ± 1.08*Serum Bilirubin (mg/dl)3.5 ± 0.94.3 ± 0.65.6 ± 0.4*Urine Creatinine (mg/dL)44.1 ± 3.845.9 ± 3.856.2 ± 7.0*Urine Osmolality (mOsm/kg H2O)2147 ± 761707 ± 2651361 ± 32*Serum Haptoglobin (µg/ml)39.3 ± 3.80.5 ± 0.2*2.3 ± 1.4*Serum Hemopexin (µg/ml)802 ± 266169 ± 51*124 ± 35*Serum SAP (µg/ml)20.9 ± 7.214.1 ± 12.086.7 ± 20.2*#Stasis at 1h in Response to Hb (%)10.0 ± 3.219.8 ± 2.7*30.0 ± 3.4*#Mortality at 24h in Response to Heme (%)00100*#Liver % of Body Weight4.95 ± 0.484.39 ± 0.356.22 ± 0.21*#Spleen % of Body Weight0.79 ± 0.140.87 ± 0.396.61 ± 0.75*#Kidney % of Body Weight0.65 ± 0.270.72 ± 0.190.73 ± 0.24Liver Necrosis Score0.0 ± 0.00.25 ± 0.502.38 ± 0.25*Liver Fe Score0.0 ± 0.00.25 ± 0.53.0 ± 0.0*Lung Fe Score0.0 ± 0.00.0 ± 0.0*1.0 ± 0.0*#Spleen Fe Score3.0 ± 0.03.0 ± 0.02.0 ± 0.0*#Kidney Fe Score0.0 ± 0.00.25 ± 0.51.75 ± 0.5*#Liver Gr1 Score1.0 ± 0.01.25 ± 0.52.25 ± 0.5*Lung Gr1 Score1.0 ± 0.01.0 ± 0.01.25 ± 0.5Spleen Gr1 Score1.5 ± 0.62.0 ± 0.02.0 ± 0.0Kidney Gr1 Score0.25 ± 0.50.25 ± 0.50.75 ± 0.5* p<0.05 vs HbAA; # p<0.05 vs HbAS Disclosures No relevant conflicts of interest to declare.
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Bush, Adam M., Matthew Borzage, Soyoung Choi, Thomas Coates, and John C. Wood. "Elevated Cerebral Metabolic Oxygen Consumption in Sickle Cell Disease." Blood 124, no. 21 (December 6, 2014): 2706. http://dx.doi.org/10.1182/blood.v124.21.2706.2706.
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Abstract Introduction Stroke occurs when cerebral blood flow (CBF) is inadequate to the metabolic needs of the brain. In sickle cell disease (SCD) stroke is common, however accurate quantification of basal cerebral oxygen consumption (CMRO2) has not been performed. Early PET studies suggested CMRO2 was decreased in SCD patients, but these studies lacked data regarding brain volume and gray-white matter fractions; lower CMRO2 may simply have reflected brain loss from prior stroke. In contrast, NIRS and global resting energy expenditure studies have demonstrated elevated peripheral metabolic rate in SCD patients at baseline, with further increases during painful crisis. In those studies, oxygen consumption was correlated with markers of inflammation, particularly white blood cell count, consistent with metabolic consequences of neutrophil activation. Characterizing CMRO2 in SCD provides insight into better prevention and management of stroke in the SCD population. Accordingly, we measured CBF and cerebral venous saturation (SvO2) via a recently developed magnetic resonance imaging (MRI) technique: T2 Relaxation Under Spin Tagging (TRUST). Using the Fick Principle, this allowed for quantification of oxygen extraction fraction (OEF) and the first quantitative measurements of CMRO2in SCD patients. Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. Fifteen patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetery. TRUST was used to measured T2 relaxation of blood within the sagittal sinus; T2 relaxation was converted to SvO2 using established calibration curves. OEF represented the difference of SaO2 andSvO2 .Phase Contrast (PC) of the carotid and vertebral arteries was used to measure global CBF. CMRO2 was calculated as the product of CBF and OEF. High resolution, 3D, T1 weighted images were used for grey-white segmentation and brain volume calculations using BrainSuiteñ software. Relative grey matter CMRO2 and white matterCMRO2 were estimated by assuming that (gm) CMRO2 was three-fold higher than (wm) CRMRO2. Complete blood count, cell free hemoglobin, LDH, and hemoglobin electrophoresis were measured at the study visit. Results Table 1 summarizes the results. To compensate for their chronic anemia, SCD patients had 67% greater CBF than control subjects, producing a normal SvO2 and OEF. Oxygen delivery also trended higher than for controls leading to higher total CMRO2 in the SCD patients. CMRO2 increases remained significant even after correction for differences in grey and white matter volumes. We found no correlation between WBC and CMRO2when tested by population. Discussion Our study demonstrates elevated cerebral metabolism in SCD, mirroring increases in global resting energy expenditure and peripheral metabolic rate described by other groups. The etiology of the increased CMRO2 is unknown but could reflect neuroinflammation or energy demands from chronic injury/repair. Regardless, our observation at least partially explains the increase of CBF beyond predicted by anemia alone. By excluding patients with overt stroke and by correcting for differences in brain volume and composition, our results are the first CMRO2 measurements in SCD that are unconfounded by brain volume loss. Given the age differences between our study and control populations, we cannot exclude developmental differences in CMRO2 among patients and controls. However, in general, CMRO2 increases with age, which would tend to lessen rather than increase the CMRO2 differences seen in our study. Table 1 Controls SCD p Age (years) 37.2 + 2.8 20.3 + 2.6 <0.05 Sex 9 F, 3 M 9 F, 6 M ns Hemoglobin (g/dl) 13.5 + 1.2 9.6 + 1.1 <0.05 WBC (103/uL) 6.1 + 2.2 11.0 + 4.2 <0.05 Sa O2 (%) 95.7 + 1.5 94.1 + 4.1 ns Sv O2 (%) 65.6 + 6.7 63.6 + 8.4 ns OEF 30.0 + 7.1 32.3 + 7.4 ns CBF (ml/100g/min) 70.0 + 4.6 116.8 + 19.1 <0.05 Cerebral O2 delivery (umol O2/100g/min) 193.0 + 44.9 239.0 + 35.7 ns Grey Matter Mass (ml) 499.6 + 72.0 528.4 + 58.1 ns White Matter Mass (ml) 444.6 + 58.2 422.9 + 59.5 ns CMRO2 (umol O2/100g/min) 193.1 + 44.9 239.0 + 35.7 <0.05 (gm)CMRO2 250.7 + 58.7 292.7 + 39.7 <0.05 (wm) CMRO2 175.5 + 41.1 204.9 + 27.8 <0.05 Disclosures Coates: Novartis: Honoraria, Speakers Bureau; Apo Pharma: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; SHire: Consultancy, Honoraria.
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"UL expands plastics certification programme with RoHS and non-halogenated options." Additives for Polymers 2015, no. 2 (February 2015): 5. http://dx.doi.org/10.1016/s0306-3747(15)30006-3.
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Morotti, Andrea, Sandro Marini, Michael J. Jessel, Kristin Schwab, Alison M. Ayres, Christina Kourkoulis, Edip M. Gurol, et al. "Abstract TP326: Lymphopenia, Infectious Complications and Outcome in Spontaneous Intracerebral Hemorrhage." Stroke 48, suppl_1 (February 2017). http://dx.doi.org/10.1161/str.48.suppl_1.tp326.
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Background and Purpose: lymphopenia is increasingly recognized as a consequence of acute illness and may predispose to infections. We investigated whether admission lymphopenia (AL) is associated with increased risk of infectious complications and poor outcome in patients with spontaneous intracerebral hemorrhage (ICH). Methods: we analyzed a prospectively collected cohort of ICH patients ascertained between 1994 and 2015. Subjects were included if they had a lymphocyte count obtained within 24 h from onset and AL was defined as lymphocyte count<1000/uL. Infectious complications were assessed through retrospective chart review and the association between AL, infectious complications and mortality was investigated with a multivariable Cox regression and logistic regression respectively. Results: 2014 patients met the inclusion criteria (median age 75, males 54.0%) of whom 548 (27.2%) had AL and 605 (30.0%) experienced an infectious complication. Overall case fatality at 90 days was 36.9%. Patients with AL were more severely affected, as highlighted by larger hematoma volume, higher frequency of intraventricular hemorrhage and lower Glasgow Coma Scale score (all p<0.001). AL was independently associated with increased risk of pneumonia (Hazard Ratio [HR] 1.65, 95% confidence interval [CI] 1.32-2.05, p<0.001) and multiple infections (HR 1.75, 95% CI 1.22-2.51, p=0.002). The association with urinary tract infection, sepsis or other infections was not significant. AL was also an independent predictor of 90-day mortality (odds ratio 1.55, 95% CI 1.18-2.04, p=0.002) after adjusting for confounders. Conclusions: AL is common in ICH and associated with increased risk of infectious complications and poor outcome. Further studies will be needed to determine whether prophylactic antibiotics in ICH patients with AL can improve outcome.