Summary Background Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated ...donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate. Methods We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia. Data were available on 1525 patients transplanted between 2002 and 2006. 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n=10), or mismatched at one (n=40) or two (n=115) antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n=632 and n=332, respectively), or mismatched at one locus (n=256 and n=140, respectively). Findings Leukaemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (HR 1·62, 95% CI 1·18–2·23; p=0·003) or bone-marrow transplantation (HR 1·69, 95% CI 1·19–2·39; p=0·003). Grades 2–4 acute and chronic graft-versus-host disease (GvHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0·57, 95% 0·42–0·77; p=0·002 and HR 0·38, 0·27–0·53; p=0·003, respectively), while the incidence of chronic, but not acute GvHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0·63, 0·44–0·90; p=0·01). Interpretation These data support the use of UCB for adults with acute leukaemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently. Funding National Cancer Institute, National Heart Lung and Blood Institute, National Institute of Allergy and Infectious Disease ( U24-CA76518 ); Health Resources and Services Administration ( HHSH234200637015C ); Office of Naval Research, Department of Navy ( N00014-08-1-1207 ); Children's Leukemia Research Association; and a Scholar in Clinical Research Award from the Leukemia and Lymphoma Society.
It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart ...growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here, we show that a thyroid hormone surge activates the IGF-1/IGF-1-R/Akt pathway on postnatal day 15 and initiates a brief but intense proliferative burst of predominantly binuclear cardiomyocytes. This proliferation increases cardiomyocyte numbers by ∼40%, causing a major disparity between heart and cardiomyocyte growth. Also, the response to cardiac injury at postnatal day 15 is intermediate between that observed at postnatal days 2 and 21, further suggesting persistence of cardiomyocyte proliferative capacity beyond the perinatal period. If replicated in humans, this may allow novel regenerative therapies for heart diseases.
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•Murine cardiomyocytes continue to proliferate well after the neonatal period•A proliferative burst in preadolescence establishes the final cardiomyocyte number•Proliferation is initiated by the thyroid hormone/IGF-1/IGF-1-R/Akt pathway•Persistence of cardiomyocyte proliferation improves outcomes after cardiac injury
The heart adjusts to the increased circulatory demand in the postnatal period through a brief intense surge of cardiomyocyte proliferation during preadolescence, initiated by thyroid hormone signaling.
Recent robotic manipulation competitions have highlighted that sophisticated robots still struggle to achieve fast and reliable perception of task-relevant objects in complex, realistic scenarios. To ...improve these systems' perceptive speed and robustness, we present SegICP, a novel integrated solution to object recognition and pose estimation. SegICP couples convolutional neural networks and multi-hypothesis point cloud registration to achieve both robust pixel-wise semantic segmentation as well as accurate and real-time 6-DOF pose estimation for relevant objects. Our architecture achieves 1cm position error and <5^\circ$ angle error in real time without an initial seed. We evaluate and benchmark SegICP against an annotated dataset generated by motion capture.
The ESAs epoetin and darbepoetin were approved for treatment of chemotherapy-associated anemia in 1993 and 2002 and CKD-associated anemia in 1989 and 2001, respectively. In 2006, ESAs were the ...largest single pharmaceutical expenditure by the Center for Medicare and Medicaid Studies (CMS). Recently, a series of preclinical experiments, clinical trials, and meta-analyses of ESAs have been reported. The Food and Drug Administration (FDA), National Comprehensive Cancer Network (NCCN), American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO), and Kidney Disease Outcomes Quality Improvement (KDOQI) have issued guideline statements for ESAs, and CMS has implemented an ESA Monitoring Policy (EMP) to help ensure appropriate ESA claims. Herein, we analyze these actions and usage trends of ESAs for anemic cancer and CKD patients. Data sources included basic science studies, clinical trials, meta-analyses, notifications from CMS, ESA manufacturers, and the FDA, guidelines from the NCCN, ASH/ASCO, and KDOQI, and published reports regarding ESA usage reported between 2006 and 2008. Search terms included erythropoietin, darbepoetin, anemia, neoplasm, and CKD. Results from eight recent clinical trials and one 2008 meta-analysis for anemic cancer patients identified tumor progression and mortality risks with ESA versus placebo/control use. Analyses from one clinical trial and one 2008 meta-analysis for CKD patients identified mortality and cardiovascular risks when high hemoglobin levels were targeted. Guidelines, manufacturer notifications, and reimbursement policies have become increasingly conservative. ESA administration to anemic cancer and CKD patients has decreased. Among anemic cancer patients, red blood cell transfusions are increasing and ESA use is decreasing. Among anemic CKD patients, target and achieved hemoglobin levels and ESA doses have decreased. Regulatory, clinical and professional communities now advocate for conservative use of ESAs for anemic patients with cancer or CKD.
Chemotherapy-associated anemiaCKD-associated anemiaBasic ScienceESAs may be harmful: Erythropoietin receptors have been identified in tumor cells and have demonstrated downstream cellular effects including proliferation, anti-apoptosis, invasion, and chemotherapy resistance.ESAs may be beneficial: Studies have identified neurotrophic and neuroprotective effects of erythropoietin. Also, erythropoietin protects against hypoxia-induced apoptosis, ischemia-reperfusion injury, and promotes ventricular modeling.Clinical Trials and Meta-analysesEight clinical trials and one meta-analysis have identified increased risk of mortality and/or tumor progression associated with ESA use. Two meta-analyses have identified significantly increased risk of VTE and seven trials reported four-fold or greater increased risk of VTE.One trial and one meta-analysis have identified mortality and cardiovascular risks when ESAs were targeted to higher versus lower hemoglobin levels. A second trial did not identify clinical benefits with ESA administration targeted to normal versus lower hemoglobin levels.GuidelinesNCCN and ASH/ASCO guidelines support ESA administration targeted to between 10 and 12 g/dl and a trigger hemoglobin level to initiate ESA use at 10 g/dl.KDOQI supports hemoglobin levels targeted to between 11 and 12 g/dl and avoiding levels > 13 g/dl.Recent Manufacturer NotificationsThe FDA mandated that product labels state that ESAs are not indicated for patients receiving myelosuppressive therapy with curative intent, the trigger hemoglobin should be <10 g/dl, and ESAs should be withheld if the hemoglobin exceeds a level necessary to avoid transfusion.Revised labels indicated hemoglobin levels should be targeted to between 10 and 12 g/dl and that high ESA doses should be avoided.Reimbursement PoliciesTarget and trigger hemoglobin levels of < 10 g/dl and a maximum duration of 8 weeks of treatment are supported by CMS.Target hemoglobin levels < 13 g/dl are supported by CMS. Reimbursement is reduced when hemoglobin levels > 13 g/dl are recorded for 3 or more consecutive billing cycles.Usage TrendBetween November 2006 and October 2007, usage of ESAs declined from 42% to 15% per patient at risk while transfusions increased from 24% to 28% per patient at risk.ESA use among CKD patients not on hemodialysis decreased from 54% to 42% from 2007 to 2008.
To determine whether solar load distribution pattern on a solid nondeformable ground surface is the product of contact erosion and is the mirror image of load distribution on a deformable surface in ...horses.
30 clinically normal horses.
Solar load distribution was compared among 25 clinically normal horses during quasistatic loading on a solid nondeformable surface and on a highly deformable surface. Changes in solar load distribution patterns were evaluated in 5 previously pasture-maintained horses housed on a flat nondeformable surface. Changes in solar load distribution created by traditional trimming and shoeing were recorded.
Unshod untrimmed horses had a 4-point (12/25, 48%) or a 3-point (13/25, 52%) wall load distribution pattern on a flat solid surface. Load distribution on a deformable ground surface was principally solar and located transversely across the central region of the foot. Ground surface contact areas on solid (24.2 +/- 8.62 cm2) and deformable (69.4 +/- 22.55 cm2) surfaces were significantly different. Maintaining unshod horses on a flat nondeformable surface resulted in a loss of the 3- and 4-point loading pattern and an increase in ground surface contact area (17.9 +/- 2.77 to 39.9 +/- 12.77 cm2). Trimming increased ground surface contact area (24.2 +/- 8.60 to 45.7 +/- 14.89 cm2).
In horses, the solar surface is the primary weight-loading surface, and deformability of ground surface may have a role in foot expansion during loading. Increased surface area induced by loading on deformable surfaces, trimming, and shoeing protects the foot.
The pivotal role of phytohormones during fruit development and ripening is considered established knowledge in plant biology. Perhaps less well-known is the growing body of evidence suggesting that ...organic acids play a key function in plant development and, in particular, in fruit development, maturation and ripening. Here, we critically review the connection between organic acids and the development of both climacteric and non-climacteric fruits. By analyzing the metabolic content of different fruits during their ontogenetic trajectory, we noticed that the content of organic acids in the early stages of fruit development is directly related to the supply of substrates for respiratory processes. Although different organic acid species can be found during fruit development in general, it appears that citrate and malate play major roles in this process, as they accumulate on a broad range of climacteric and non-climacteric fruits. We further highlight the functional significance of changes in organic acid profile in fruits due to either the manipulation of fruit-specific genes or the use of fruit-specific promoters. Despite the complexity behind the fluctuation in organic acid content during fruit development and ripening, we extend our understanding on the importance of organic acids on fruit metabolism and the need to further boost future research. We suggest that engineering organic acid metabolism could improve both qualitative and quantitative traits of crop fruits.
We screened anonymously all mothers and infants born during a 3 1/2-month period to determine the prevalence of intrapartum cocaine use, test the maternal characteristics that are specific predictors ...of intrauterine cocaine exposure (IUCE), and compare the sensitivity of infant urine versus meconium samples for identification of IUCE. Of 1237 live births during the study period, a sample was obtained from 1201 mother-infant pairs. The overall prevalence of documented intrapartum cocaine exposure was 66 (5.5%) of 1201 pairs. Previously developed drug screening guidelines had a sensitivity of 89% for detecting IUCE in infants. Direct comparisons of samples from the same mother-infant pair revealed that there were no cases in which cocaine was found in infant urine but not in meconium; however, infant urine testing missed 25% of the infants who had positive findings in meconium. We conclude that (1) meconium testing was more likely than urine testing to identify an infant with IUCE, detecting an additional 33%; (2) there was significant maternal cocaine use (5.5%) in a teaching hospital with a mixed patient population; (3) maternal characteristics known to identify infants at risk of having IUCE were useful in our population; and (4) IUCE of neonates admitted to the neonatal intensive care unit was more common than that of infants admitted to the regular newborn nursery.
OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in older people with diabetes mellitus.
DESIGN: Cross‐sectional, population‐based study.
SETTING: Three ...homecare agency areas in Boston, Massachusetts.
PARTICIPANTS: Two hundred ninety‐one homebound people aged 60 and older; 40% with diabetes mellitus.
MEASUREMENTS: Demographic data; evidence of diabetes mellitus and other diseases; Mini‐Mental State Examination and tests of memory and executive function; ADLs.
RESULTS: Executive and visuospatial functions were more impaired in individuals with diabetes mellitus than in those without, as assessed using Block Design (mean score±standard deviation 17.1±8.6 vs 20.5±9.6, P=.003) and Trails B (median seconds to accomplish the task: 255 vs 201, P=.03). For memory, word retention score was lower in those with diabetes mellitus than without (39.1±28.9 vs 48.0±29.7, P=.01), but the other memory tests did not show a difference between these two subgroups. More individuals with diabetes mellitus suffered from depressive symptoms than those without (55% vs 42%, P=.03). The ADL scores of those with diabetes mellitus were higher than those without.
CONCLUSION: The pattern of cognitive deficits in people with diabetes mellitus suggests frontal‐subcortical dysfunction, as seen in microvascular disease of the brain. The impairment in ADLs may be associated with this executive dysfunction, which cerebral microvascular disease in diabetes mellitus may cause.
Bacillus anthracis
strains previously isolated from Bulgaria form a unique subcluster within the A1.a cluster that is typical for isolates from southeastern Europe. Here, we report the draft genome ...sequences of two Bulgarian
B. anthracis
strains belonging to the A branch (A.Br.)008/009 canonical single nucleotide polymorphism (SNP) group of the major A branch.
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