Kinetics of sickle cell biorheology and implications for painful vasoocclusive crisis

We developed a microfluidics-based model to quantify cell-level processes modulating the pathophysiology of sickle cell disease (SCD). This in vitro model enabled quantitative investigations of the kinetics of cell sickling, unsickling, and cell rheology. We created short-term and long-term hypoxic conditions to simulate normal and retarded transit scenarios in microvasculature. Using blood samples from 25 SCD patients with sickle hemoglobin (HbS) levels varying from 64 to 90.1%, we investigated how cell biophysical alterations during blood flow correlated with hematological parameters, HbS level, and hydroxyurea (HU) therapy. From these measurements, we identified two severe cases of SCD that were also independently validated as severe from a genotype-based disease severity classification. These results point to the potential of this method as a diagnostic indicator of disease severity. In addition, we investigated the role of cell density in the kinetics of cell sickling. We observed an effect of HU therapy mainly in relatively dense cell populations, and that the sickled fraction increased with cell density. These results lend support to the possibility that the microfluidic platform developed here offers a unique and quantitative approach to assess the kinetic, rheological, and hematological factors involved in vasoocclusive events associated with SCD and to develop alternative diagnostic tools for disease severity to supplement other methods. Such insights may also lead to a better understanding of the pathogenic basis and mechanism of drug response in SCD.National Institutes of Health (U.S.) (R01HL094270)National Institutes of Health (U.S.) (U01HL114476

Prominent Role Of Platelets In The Formation Of Circulating Neutrophil-red Cell Heterocellular Aggregates In Sickle Cell Anemia.

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Order from disorder in lattice QCD at high density

We investigate the properties of the ground state of strong coupling lattice QCD at finite density. Our starting point is the effective Hamiltonian for color singlet objects, which looks at lowest order as an antiferromagnet, and describes meson physics with a fixed baryon number background. We concentrate on uniform baryon number backgrounds (with the same baryon number on all sites), for which the ground state was extracted in an earlier work, and calculate the dispersion relations of the excitations. Two types of Goldstone boson emerge. The first, antiferromagnetic spin waves, obey a linear dispersion relation. The others, ferromagnetic magnons, have energies that are quadratic in their momentum. These energies emerge only when fluctuations around the large-N_c ground state are taken into account, along the lines of ``order from disorder'' in frustrated magnetic systems. Unlike other spectrum calculations in order from disorder, we employ the Euclidean path integral. For comparison, we also present a Hamiltonian calculation using a generalized Holstein-Primakoff transformation. The latter can only be constructed for a subset of the cases we consider.Comment: 24 pages, 6 figures, 1 tabl

Formation of Spherical D2-brane from Multiple D0-branes

We study D-branes in SU(2) WZW model by means of the boundary state techniques. We realize the ``fuzzy sphere'' configuration of multiple D0-branes as the boundary state with the insertion of suitable Wilson line. By making use of the path-integral representation we show that this boundary state preserves the appropriate boundary conditions and leads to the Cardy state describing a spherical D2-brane under the semi-classical approximation. This result directly implies that the spherical D2-brane in SU(2) WZW model can be well described as the bound state of D0-branes. After presenting the supersymmetric extension, we also investigate the BPS and the non-BPS configurations of D-branes in the NS5 background. We demonstrate that the non-BPS configurations are actually unstable, since they always possess the open string tachyons. We further notice that the stable BPS bound state constructed by the tachyon condensation is naturally interpreted as the brane configuration of fuzzy sphere.Comment: 36 pages, no figure, v2: typos corrected, references added, v3: minor corrections, some discussions added in Sec. 2, v4: references added, v5: appendix added, accepted for publication in Nuclear Physics

The XMM-Newton survey of the Small Magellanic Cloud: XMMUJ005011.2-730026 = SXP214, a Be/X-ray binary pulsar

In the course of the XMM-Newton survey of the Small Magellanic Cloud (SMC), a region to the east of the emission nebula N19 was observed in November 2009. To search for new candidates for high mass X-ray binaries the EPIC PN and MOS data of the detected point sources were investigated and their spectral and temporal characteristics identified. A new transient (XMMUJ005011.2-730026= SXP214) with a pulse period of 214.05 s was discovered; the source had a hard X-ray spectrum with power-law index of ~0.65. The accurate X-ray source location permits the identification of the X-ray source with a ~15th magnitude Be star, thereby confirming this system as a new Be/X-ray binary.Comment: 8 pages 11 figures. Accepted for publication in MNRA

Tricuspid regurgitation velocity and other biomarkers of mortality in children, adolescents and young adults with sickle cell disease in the United States: The PUSH study

In the US, mortality in sickle cell disease (SCD) increases after age 18- 20- years. Biomarkers of mortality risk can identify patients who need intensive follow- up and early or novel interventions. We prospectively enrolled 510 SCD patients aged 3- 20- years into an observational study in 2006- 2010 and followed 497 patients for a median of 88- months (range 1- 105). We hypothesized that elevated pulmonary artery systolic pressure as reflected in tricuspid regurgitation velocity (TRV) would be associated with mortality. Estimated survival to 18- years was 99% and to 25- years, 94%. Causes of death were known in seven of 10 patients: stroke in four (hemorrhagic two, infarctive one, unspecified one), multiorgan failure one, parvovirus B19 infection one, sudden death one. Baseline TRV - ¥2.7 m/second (>2 SD above the mean in age- matched and gender- matched non- SCD controls) was observed in 20.0% of patients who died vs 4.6% of those who survived (P =- .012 by the log rank test for equality of survival). The baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. Additional biomarkers associated with mortality were ferritin - ¥2000- μg/L (observed in 60% of patients who died vs 7.8% of survivors, P <- .001), forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80 (71.4% of patients who died vs 18.8% of survivors, P <- .001), and neutrophil count - ¥10x109/L (30.0% of patients who died vs 7.9% of survivors, P =- .018). In SCD children, adolescents and young adults, steady- state elevations of TRV, ferritin and neutrophils and a low FEV1/FVC ratio may be biomarkers associated with increased risk of death.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155951/1/ajh25799_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155951/2/ajh25799.pd

Severe painful vaso-occlusive crises and mortality in a contemporary adult sickle cell anemia cohort study.

BACKGROUND: Frequent painful vaso-occlusive crises (VOCs) were associated with mortality in the Cooperative Study of Sickle Cell Disease (CSSCD) over twenty years ago. Modern therapies for sickle cell anemia (SCA) like hydroxyurea are believed to have improved overall patient survival. The current study sought to determine the relevance of the association between more frequent VOCs and death and its relative impact upon overall mortality compared to other known risk factors in a contemporary adult SCA cohort. METHODS: Two hundred sixty four SCA adults were assigned into two groups based on patient reported outcomes for emergency department (ED) visits or hospitalizations for painful VOC treatment during the 12 months prior to evaluation. RESULTS: Higher baseline hematocrit (p = 0.0008), ferritin (p = 0.005), and HDL cholesterol (p = 0.01) were independently associated with 1 or more painful VOCs requiring an ED visit or hospitalization for acute pain. During a median follow-up of 5 years, mortality was higher in the ED visit/hospitalization group (relative risk [RR] 2.68, 95% CI 1.1-6.5, p = 0.03). Higher tricuspid regurgitatant jet velocity (TRV) (RR 2.41, 95% CI 1.5-3.9, p \u3c 0.0001), elevated ferritin (RR 4.00, 95% CI 1.8-9.0, p = 0.001) and lower glomerular filtration rate (RR=2.73, 95% CI 1.6-4.6, p \u3c 0.0001) were also independent risk factors for mortality. CONCLUSIONS: Severe painful VOCs remain a marker for SCA disease severity and premature mortality in a modern cohort along with other known risk factors for death including high TRV, high ferritin and lower renal function. The number of patient reported pain crises requiring healthcare utilization is an easily obtained outcome that could help to identify high risk patients for disease modifying therapies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00011648 http://clinicaltrials.gov