A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function

Mean platelet volume (MPV) and platelet count (PLT) are highly heritable and tightly regulated traits. We performed a genome-wide association study for MPV and identified one SNP, rs342293, as having highly significant and reproducible association with MPV (per-G allele effect 0.016 +/- 0.001 log fL; P < 1.08 x 10(-24)) and PLT (per-G effect -4.55 +/- 0.80 10(9)/L; P < 7.19 x 10(-8)) in 8586 healthy subjects. Whole-genome expression analysis in the 1-MB region showed a significant association with platelet transcript levels for PIK3CG (n = 35; P = .047). The G allele at rs342293 was also associated with decreased binding of annexin V to platelets activated with collagen-related peptide (n = 84; P = .003). The region 7q22.3 identifies the first QTL influencing platelet volume, counts, and function in healthy subjects. Notably, the association signal maps to a chromosome region implicated in myeloid malignancies, indicating this site as an important regulatory site for hematopoiesis. The identification of loci regulating MPV by this and other studies will increase our insight in the processes of megakaryopoiesis and proplatelet formation, and it may aid the identification of genes that are somatically mutated in essential thrombocytosis. (Blood. 2009; 113: 3831-3837)

Relationship between platelet phospholipid FA and mean platelet volume in healthy men

Increased mean platelet volume (MPV) has been suggested as an independent risk factor for acute myocardial infarction and the increased reactivity of large platelets. The aim of this study was to investigate the correlation between platelet phospholipid (PL) PUFA composition and MPV in 139 free-living healthy men ages 20-55 yr (vegans, n = 18; ovolacto vegetarians, n = 43; moderate meat-eaters, n = 60; and high meateaters, n = 18). Each subject completed a semiquantitative Food Frequency Questionnaire and gave a blood sample. Platelet PL FA composition and MPV were determined by standard methods. MPV was significantly greater in the vegans than in the ovolacto vegetarian, moderate, or high meat-eater groups (P < 0.01). Both vegan and ovolacto vegetarian groups had significantly higher platelet PL 18:2n-6 and 22:4n-6, and lower 20:5n-3 and 22:6n-3 compared with the moderate and high meat-eater groups. The vegans demonstrated a significant reduction in 20:4n-6 and 22:5n-3 compared with the ovolacto vegetarian, high meat-eater, and moderate meat-eater groups. Bivariate analysis results showed that MPV was significantly positively correlated with platelet PL 18:2n-6 (P = 0.048) and negatively correlated with 20:3n-6 (P = 0.02), 20:5n-3 (P = 0.005), and 22:5n-3 (P< 0.0001), respectively. In a multiple linear regression analysis, after controlling for potential confounding factors such as dietary group, age, exercise, body mass index, and dietary polyunsaturated and saturated fat, cholesterol, carbohydrate, and fiber intake, the MPV was still strongly negatively correlated with platelet PL 20:3n-6 (P = 0.003) and 22:5n-3 (P = 0.001). The present data suggest that 22:5n-3 and 20:3n-6 may play a role in the structural function of the platelet membrane.

The mean corpuscular volume and hydroxyurea in brazilian patients with sickle cell anemia: a surrogate marker of compliance

The suppression of erythropoiesis by Hydroxyurea (HU) therapy is associated with increase in mean corpuscular volume, in addition to the increase in Hb F. Monitoring the mean corpuscular volume values and the presence of macrocytosis are effective tools of adherence to the treatment with HU in patients with sickle cell anemia. The aim of this study is to monitor the mean corpuscular volume values after starting treatment with HU to determine if macrocytosis can be used as a surrogate marker of compliance with therapy. We conducted a prospective cohort study over one year with measurements of blood counts and mean corpuscular volume after starting therapy with HU in 95 patients with sickle cell anemia who were regularly followed in our ambulatory outpatient unit. In one-year of successful use of HU the mean value of the mean corpuscular volume increased significantly. The Andersen and Gill model demonstrated that the increase of one unit of MCV implies a 5% reduction in the risk of visiting the emergency room. Monitoring mean corpuscular volume values after prescribing HU alerts the provider of noncompliance in order to counsel the patient in question for better adherence to the use of HU that could improve the quality of care and to reduce morbidity and the frequency of acute pain crises and associated healthcare costs.

Mean corpuscular volume as a marker for adherence to antiretroviral therapy among HIV infected children and adolescents in Uganda

Mean corpuscular volume, which is an inexpensive and widely available measure to assess, increases in HIV infected individuals receiving zidovudine and stavudine raising the hypothesis that it could be used as a surrogate for adherence.^ The aim of this study was to examine the association between mean corpuscular volume and adherence to antiretroviral therapy among HIV infected children and adolescents aged 0–19 years in Uganda as well as the extent to which changes in mean corpuscular volume predict adherence as determined by virologic suppression.^ The investigator retrospectively reviewed and analyzed secondary data of 158 HIV infected children and adolescents aged 0–19 years who initiated antiretroviral therapy under an observational cohort at the Baylor College of Medicine Children's Foundation - Uganda. Viral suppression was used as the gold standard for monitoring adherence and defined as viral load of < 400 copies/ml at 24 and 48 weeks. ^ Patients were at least 48 weeks on therapy, age 0.2–18.4 years, 54.4% female, 82.3% on zidovudine based regimen, 92% WHO stage III at initiation of therapy, median pre therapy MCV 80.6 fl (70.3–98.3 fl), median CD4% 10.2% (0.3%–28.0%), and mean pre therapy viral load 407,712.9 ± 270,413.9 copies/ml. For both 24 and 48 weeks of antiretroviral therapy, patients with viral suppression had a greater mean percentage change in mean corpuscular volume (15.1% ± 8.4 vs. 11.1% ± 7.8 and 2.3% ± 13.2 vs. -2.7% ± 10.5 respectively). The mean percentage change in mean corpuscular volume was greater in the first 24 weeks of therapy for patients with and without viral suppression (15.1% ± 8.4 vs. 2.3% ± 13.2 and 11.1% ± 7.8 vs. -2.7% ± 10.5 respectively). In the multivariate logistic regression model, percentage change in mean corpuscular volume ≥ 20% was significantly associated with viral suppression (adjusted OR 4.0; CI 1.2–13.3; p value 0.02). The ability of percentage changes in MCV to correctly identify children and adolescents with viral suppression was higher at a cut off of ≥ 20% (90.7%; sensitivity, 31.7%) than at ≥ 9% (82.9%; sensitivity, 78.9%). Negative predictive value was lower at ≥ 20% change (25%; specificity, 84.8%) than at ≥ 9% change (33.3%; specificity, 39.4%).^ Mean corpuscular volume is a useful marker of adherence among children and adolescents with viral suppression. ^

Mean Platelet Volume (MPV), Platelet Distribution Width (PDW), Platelet Count and Plateletcrit (PCT) as predictors of in-hospital paediatric mortality: a case-control Study.

Background: Thrombocytopenia has been shown to predict mortality. We hypothesize that platelet indices may be more useful prognostic indicators. Our study subjects were children one month to 14 years old admitted to our hospital. Aim: To determine whether platelet count, plateletcrit (PCT), mean platelet volume (MPV) and platelet distribution width (PDW) and their ratios can predict mortality in hospitalised children. Methods: Children who died during hospital stay were the cases. Controls were age matched children admitted contemporaneously. The first blood sample after admission was used for analysis. Receiver operating characteristic (ROC) curve was used to identify the best threshold for measured variables and the ratios studied. Multiple regression analysis was done to identify independent predictors of mortality. Results: Forty cases and forty controls were studied. Platelet count, PCT and the ratios of MPV/Platelet count, MPV/PCT, PDW/Platelet count, PDW/PCT and MPV x PDW/Platelet count x PCT were significantly different among children who survived compared to those who died. On multiple regression analysis the ratio of MPV/PCT, PDW/Platelet count and MPV/ Platelet count were risk factors for mortality with an odds ratio of 4.31(95% CI, 1.69-10.99), 3.86 (95% CI, 1.53-9.75), 3.45 (95% CI, 1.38-8.64) respectively. In 67% of the patients who died MPV/PCT ratio was above 41.8 and PDW/Platelet count was above 3.86. In 65% of patients who died MPV/Platelet count was above 3.45. Conclusion: The MPV/PCT, PDW/Platelet count and MPV/Platelet count, in the first sample after admission in this case control study were predictors of mortality and could predict 65% to 67% of deaths accurately.

Aortic Intima-Media Thickness and Mean Platelet Volume in Children With Type 1 Diabetes Mellitus

Background: Diabetes mellitus type 1 is the most common endocrine metabolic disorder occurring in childhood and adolescence due to the autoimmune destruction of pancreatic beta cells as a result of various environmental factors interacting with an underlying genetic predisposition. Diabetes is a risk factor for early onset atherosclerosis, and the high mortality rate seen in these patients is partially related to cardiovascular diseases. Objectives: This study was conducted to compare mean platelet volume as a marker of early atherosclerosis with aortic intima-media thickness in children with type 1 diabetes and to identify its correlation with known cardiovascular risk factors. Patients and Methods: The study included 27 patients between age range of 6 and 17 years that were diagnosed with type 1 diabetes and 30 healthy children of the same age range who did not have any chronic disease. In both groups, we used the color Doppler ultrasound to measure children’s aortic intima-media thickness and identify their mean platelet volumes. Results: There was no significant difference between the groups regarding gender distribution, age, High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL) cholesterol levels (P > 0.05). Also no significant difference could be documented between the patient and control groups regarding the aortic intima-media thickness and mean platelet volume (P > 0.05). However, there was a significant correlation between aortic intima-media thickness and mean platelet volume (r = 0.351; P < 0.05). Conclusions: In the present study, there was no evidence of early atherosclerosis in children with type 1 diabetes. However, mean platelet volume having a significant correlation with aortic intima-media thickness may be useful as an early marker of atherosclerosis.

Abordagens estereológica e imunohistoquímica no câncer de próstata: uma reavaliação diagnóstica e possível terapêutica

Os esforços para melhorar o diagnóstico, o prognóstico e a vigilância do câncer de próstata (CaP) são relevantes. A superestimação do Escore de Gleason (GSC) pode submeter os indivíduos a um tratamento agressivo desnecessário. Foi tido como objetivo utilizar a estereologia em avaliações do CaP e investigar se o volume nuclear médio (VNM) correlaciona-se com o padrão primário de Gleason (Gpp), a fim de buscar um método alternativo devido à subjetividade do Escore de Gleason, que seja aquele, um método confiável e objetivo, sem discordância interobservador. Para isso, identificamos 74 amostras de prostatectomia radical, que foram divididos em seis grupos com base no Gpp, de 3 a 5. Controles (C) foram adquiridos em regiões não tumorais pareadas das mesmas amostras. O VNM foi estimado utilizando o método de "intersecção dos pontos amostrados". Diferenças estatísticas do VNM entre os grupos C e os grupos Gpp foram testadas utilizando o teste de Kruskall-Wallis e pós- teste de Dunn. As diferenças entre cada grupo Gpp e seus homólogos foram testados com o teste de Wilcoxon. As correlações foram avaliadas com a correlação de Spearman (R [Spearman]). As correlações entre o antígeno prostático específico (PSA) e o GSC (R [Spearman] de 0,76) e entre o PSA e o VNM (R [Spearman] de 0,78) foram moderadamente forte e altamente significativa, e a correlação entre o VNM e o Gpp (R [Spearman] de 0,53) foi moderada e altamente significativa. O VNM foi significativamente maior em regiões cancerígenas em comparação as regiões de controle-pareado. O planejamento adequado de um estudo, bem como a disponibilidade de equipamentos e softwares para a quantificação morfológica, pode proporcionar incentivo para rapidez e precisão para estimar o VNM como parâmetro auxiliar na avaliação do câncer de próstata. A reprodutibilidade falha interobservador do GSC tem mostrado possíveis conduções equivocadas dos pacientes portadores de CaP. O VNM representa um método reprodutível de classificação objetiva para o câncer de próstata. Portanto, os dados atuais favorecem o uso de VNM associado com GSC e o PSA na avaliação do câncer de próstata.

Nuclear charge radii of light isotopes based on frequency comb measurements

Optical frequency comb technology has been used in this work for the first time to investigate the nuclear structure of light radioactive isotopes. Therefore, three laser systems were stabilized with different techniques to accurately known optical frequencies and used in two specialized experiments. Absolute transition frequency measurements of lithium and beryllium isotopes were performed with accuracy on the order of 10^(−10). Such a high accuracy is required for the light elements since the nuclear volume effect has only a 10^(−9) contribution to the total transition frequency. For beryllium, the isotope shift was determined with an accuracy that is sufficient to extract information about the proton distribution inside the nucleus. A Doppler-free two-photon spectroscopy on the stable lithium isotopes (6,7)^Li was performed in order to determine the absolute frequency of the 2S → 3S transition. The achieved relative accuracy of 2×10^(−10) is improved by one order of magnitude compared to previous measurements. The results provide an opportunity to determine the nuclear charge radius of the stable and short-lived isotopes in a pure optical way but this requires an improvement of the theoretical calculations by two orders of magnitude. The second experiment presented here was performed at ISOLDE/CERN, where the absolute transition frequencies of the D1 and D2 lines in beryllium ions for the isotopes (7,9,10,11)^Be were measured with an accuracy of about 1 MHz. Therefore, an advanced collinear laser spectroscopy technique involving two counter-propagating frequency-stabilized laser beams with a known absolute frequency was developed. The extracted isotope shifts were combined with recent accurate mass shift calculations and the root-mean square nuclear charge radii of (7,10)^Be and the one-neutron halo nucleus 11^Be were determined. Obtained charge radii are decreasing from 7^Be to 10^Be and increasing again for 11^Be. While the monotone decrease can be explained by a nucleon clustering inside the nucleus, the pronounced increase between 10^Be and 11^Be can be interpreted as a combination of two contributions: the center-of-mass motion of the 10^Be core and a change of intrinsic structure of the core. To disentangle these two contributions, the results from nuclear reaction measurements were used and indicate that the center-of-mass motion is the dominant effect. Additionally, the splitting isotope shift, i.e. the difference in the isotope shifts between the D1 and D2 fine structure transitions, was determined. This shows a good consistency with the theoretical calculations and provides a valuable check of the beryllium experiment.

Common variants in TMPRSS6 are associated with iron status and erythrocyte volume

We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791, combined P = 1.5 x 10(-20)), transferrin saturation (combined P = 2.2 x 10(-23)) and erythrocyte mean cell volume (MCV, combined P = 1.1 x 10(-10)). We also find suggestive evidence of association with blood hemoglobin levels (combined P = 5.3 x 10(-7)). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis.

Gamma Knife Radiosurgery as a Therapeutic Strategy for Intracranial Sarcomatous Metastases

Purpose: To determine the indication and outcomes for Gamma Knife stereotactic radiosurgery (GKSRS) in the care of patients with intracranial sarcomatous metastases. Methods and Materials: Data from 21 patients who underwent radiosurgery for 60 sarcomatous intracranial metastases (54 parenchymal and 6 dural-based) were studied. Nine patients had radiosurgery for solitary tumors and 12 for multiple tumors. The primary pathology was metastatic leiomyosarcoma (4 patients), osteosarcoma (3 patients), soft-tissue sarcoma (5 patients), chondrosarcoma (2 patients), alveolar soft part sarcoma (2 patients), and rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, neurofibrosarcoma, and synovial sarcoma (1 patient each). Twenty patients received multimodality management for their primary tumor, and 1 patient had no evidence of systemic disease. The mean tumor volume was 6.2 cm 3 (range, 0.07-40.9 cm 3), and a median margin dose of 16 Gy was administered. Three patients had progressive intracranial disease despite fractionated whole-brain radiotherapy before SRS. Results: A local tumor control rate of 88% was achieved (including patients receiving boost, up-front, and salvage SRS). New remote brain metastases developed in 7 patients (33%). The median survival after diagnosis of intracranial metastasis was 16 months, and the 1-year survival rate was 61%. Conclusions: Gamma Knife radiosurgery was a well-tolerated and initially effective therapy in the management of patients with sarcomatous intracranial metastases. However, many patients, including those who also received fractionated whole-brain radiotherapy, developed progressive new brain disease. © 2010 Elsevier Inc. All rights reserved.

Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer.

Red blood cell (RBC) parameters such as morphology, volume, refractive index, and hemoglobin content are of great importance for diagnostic purposes. Existing approaches require complicated calibration procedures and robust cell perturbation. As a result, reference values for normal RBC differ depending on the method used. We present a way for measuring parameters of intact individual RBCs by using digital holographic microscopy (DHM), a new interferometric and label-free technique with nanometric axial sensitivity. The results are compared with values achieved by conventional techniques for RBC of the same donor and previously published figures. A DHM equipped with a laser diode (lambda = 663 nm) was used to record holograms in an off-axis geometry. Measurements of both RBC refractive indices and volumes were achieved via monitoring the quantitative phase map of RBC by means of a sequential perfusion of two isotonic solutions with different refractive indices obtained by the use of Nycodenz (decoupling procedure). Volume of RBCs labeled by membrane dye Dil was analyzed by confocal microscopy. The mean cell volume (MCV), red blood cell distribution width (RDW), and mean cell hemoglobin concentration (MCHC) were also measured with an impedance volume analyzer. DHM yielded RBC refractive index n = 1.418 +/- 0.012, volume 83 +/- 14 fl, MCH = 29.9 pg, and MCHC 362 +/- 40 g/l. Erythrocyte MCV, MCH, and MCHC achieved by an impedance volume analyzer were 82 fl, 28.6 pg, and 349 g/l, respectively. Confocal microscopy yielded 91 +/- 17 fl for RBC volume. In conclusion, DHM in combination with a decoupling procedure allows measuring noninvasively volume, refractive index, and hemoglobin content of single-living RBCs with a high accuracy.

State-dependent volume isotope shifts of low-lying states of group-IIa and -IIb elements

Results of relativistic multiconfiguration Dirac-Fock calculations with an extended nucleus are used to analyze the volume isotope shifts of the resonance transitions in the group-IIa and -IIb elements as well as in Yb. This is done together with a review of the isotope shift theory, including a critical evaluation and comparison of the semiempirical calculation of volume isotope shifts commonly used today. Electronic factors F_i, proportional to differences of electronic densities over the nuclear volume, are discussed within various approximations and compared with experimental results.

Glass transition and free volume behaviour of poly(acrylonitrile)/LiCF3SO3 polymer-in-salt electrolytes compared to poly(ether urethane)/LiClO4 solid polymer electrolytes

Measurements of the glass transition temperature (T_g) and free volume behaviour of poly(acrylonitrile) (PAN) and PAN/lithium triflate (LiTf), with varying salt composition from 10 to 66 wt% LiTf, were made by positron annihilation lifetime spectroscopy (PALS). Addition of salt from 10 to 45 wt% LiTf resulted in an increase in the mean free volume cavity size at room temperature (r.t.) as measured by the orthoPositronium (oPs) pickoff lifetime, τ₃, with little change in relative concentration of free volume sites as measured by oPs pickoff intensity, I₃. The region from 45 to 66 wt% salt displayed no variation in relative free volume cavity size and concentration. This salt concentration range (45 wt%<[LiTf]<66 wt%) corresponds to a region of high ionic conductivity of order 10⁻⁵ to 10⁻⁶ S cm⁻¹ at T_g as measured by PALS. A percolation phenomenon is postulated to describe conduction in this composition region. Salt addition was shown to lower the T_g as measured by PALS; T_g was 115°C for PAN and 85°C for PAN/66 wt% LiTf. The T_g and free volume behaviour of this polymer-in-salt electrolyte (PISE) was compared to a poly(ether urethane)/LiClO₄ where the polymer is the major component, i.e. traditional solid polymer electrolyte (SPE). In contrast to the PISE, the T_g of the SPE was shown to increase with increasing salt concentration from 5.3 to 15.9 wt%. The relative free volume cavity size and concentration at r.t. were shown to decrease with increasing salt concentration. Ionic conductivity in this SPE was of order 10⁻⁵ S cm⁻¹ at r.t., which is over 60°C above T_g, 10⁻⁸ S cm⁻¹ at 25°C above T_g, and conductivity was not measurable at T_g.