Alloimmunization to platelets in heavily transfused patients with sickle cell disease

Bone marrow transplantation (BMT) is now an option for some patients with sickle cell disease (SCD). Many SCD patients are multiply transfused with red blood cells (RBCs), and may be immunized to alloantigens other than erythrocyte antigens. Because platelet refractoriness is a significant complication during BMT, we wished to determine the prevalence of alloimmunization to platelets in transfused SCD patients. Sera collected from 47 transfused and 14 untransfused SCD patients were screened for HLA and platelet-specific antibodies. Transfusion and RBC antibody histories were reviewed. A subset of the patients were rescreened 1 year later. Eighty-five percent of patients with at least 50 RBC transfusions (22 of 26), 48% of patients with less than 50 transfusions (10 of 21), and none of 14 untransfused patients demonstrated platelet alloimmunization (P < .05). Platelet alloimmunization was more prevalent than RBC alloimmunization (20% to 30%). Half of the platelet reactivity was chloroquine-elutable. Eighteen of 22 patients (82%) on chronic RBC transfusion remained platelet-alloimmunized 11 to 22 months after initial testing. In summary, 85% of heavily transfused SCD patients are alloimmunized to HLA and/or platelet-specific antigens. These patients may be refractory to platelet transfusion, a condition that would increase their risk during BMT. Leukodepletion in the transfusion support of SCD patients should be considered to prevent platelet alloimmunization.     

The effect of lithium on growth factor production in long-term bone marrow cultures

We have previously reported that lithium chloride (LiCl) stimulates the production of granulocyte-macrophage colony-forming cells (GM-CFC), pluripotent stem cells (CFU-S), and differentiated granulocytes, macrophages and megakaryocytes in murine Dexter marrow cultures and that this effect appears to be mediated indirectly by a radioresistant adherent marrow cell. In this study we have established that exposure of murine Dexter cultures to LiCl (4 mEq/L) causes an increase of colony-forming cell megakaryocytes (CFU-meg) over 1 to 6 weeks of culture in both supernatant (188% to 611%) and stromal phases (123% to 246%). Moreover, we have shown that lithium treatment of either irradiated (1,100 rad) or unirradiated stromal cells increased production of activities stimulating formation of megakaryocyte, granulocyte, macrophage, and mixed lineage colonies and proliferation of the factor-dependent cell line, FDC-P1. This FDC-P1 stimulatory activity was completely blocked by an antibody to purified recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF). The baseline or lithium-induced--stromal-derived bone marrow colony stimulating activity was partially blocked by the antibody to rGM-CSF and by an antibody to purified colony stimulating factor I (CSF-1); the two antibodies combined resulted in greater than 90% inhibition of the lithium-induced marrow stimulatory activity. In addition, radioimmunoassay (RIA) showed that although CSF-1 was detectable in supernatants of these cultures, exposure to lithium did not increase CSF-1 levels. These data indicate that Dexter stromal cells produce CSF- 1 and GM-CSF and that lithium appears to exert its stimulatory effects on in vitro myelopoiesis by inducing production of GM-CSF.     

Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.     

A statistical analysis of murine stem cell suicide techniques

The clinical application of soft agar cloning techniques for granulocyte-macrophage stem cells (CFU-C) has resulted in a number of contradictory reports that may in part be due to an inadequate data base. Growth of murine CFU-C is more reproducible and less variable than that of human CFU-C. We utilized in vivo hydroxyurea suicide of murine marrow CFU-C to address the question of how many experiments are needed to detect a specific difference with a p of less than 0.05. In 66 experiments the mean marrow CFU-C hydroxyurea kill was 23.3%; 6-9 separate experiments were necessary to detaect differences of 25%-30%. In order to be sure that a 25%-30% difference is not present, 15-21 experiments were required. Using a Dec-20 computer, 1000 samples of sample size 3, 4, or 10 were drawn from the 66 experiments; it was found that with 3 experiments and a true value of 23%, the actually observed value was below 10%, 17% of the time, and was over 40% in 10% of the samplings. In a smaller number of experiments similar results were obtained analyzing 3HTdR suicide of pluripotent stem cells and CFU- C. These data could provide a base from which to judge the validity of studies utilizing the CFU-C technique.     

Performance and Limitations of Administrative Data in the Identification of AKI

Background and objectives

Billing codes are frequently used to identify AKI events in epidemiologic research. The goals of this study were to validate billing code–identified AKI against the current AKI consensus definition and to ascertain whether sensitivity and specificity vary by patient characteristic or over time.

Design, setting, participants, & measurements

The study population included 10,056 Atherosclerosis Risk in Communities study participants hospitalized between 1996 and 2008. Billing code–identified AKI was compared with the 2012 Kidney Disease Improving Global Outcomes (KDIGO) creatinine-based criteria (AKI_cr) and an approximation of the 2012 KDIGO creatinine- and urine output–based criteria (AKI_{cr_uop}) in a subset with available outpatient data. Sensitivity and specificity of billing code–identified AKI were evaluated over time and according to patient age, race, sex, diabetes status, and CKD status in 546 charts selected for review, with estimates adjusted for sampling technique.

Results

A total of 34,179 hospitalizations were identified; 1353 had a billing code for AKI. The sensitivity of billing code–identified AKI was 17.2% (95% confidence interval [95% CI], 13.2% to 21.2%) compared with AKI_cr (n=1970 hospitalizations) and 11.7% (95% CI, 8.8% to 14.5%) compared with AKI_{cr_uop} (n=1839 hospitalizations). Specificity was >98% in both cases. Sensitivity was significantly higher in the more recent time period (2002–2008) and among participants aged 65 years and older. Billing code–identified AKI captured a more severe spectrum of disease than did AKI_cr and AKI_{cr_uop}, with a larger proportion of patients with stage 3 AKI (34.9%, 19.7%, and 11.5%, respectively) and higher in-hospital mortality (41.2%, 18.7%, and 12.8%, respectively).

Conclusions

The use of billing codes to identify AKI has low sensitivity compared with the current KDIGO consensus definition, especially when the urine output criterion is included, and results in the identification of a more severe phenotype. Epidemiologic studies using billing codes may benefit from a high specificity, but the variation in sensitivity may result in bias, particularly when trends over time are the outcome of interest.     

Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds

Aims/hypothesis

There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA_1c and the risks of vascular complications and death in such patients.

Methods

Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA_1c measurements during follow-up and prior to the first event. Adjusted risks for each HbA_1c decile were estimated using Cox models. Possible differences in the association between HbA_1c and risks at different levels of HbA_1c were explored using linear spline models.

Results

There was a non-linear relationship between mean HbA_1c during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA_1c studied (5.5?C10.5%), there was evidence of ??thresholds??, such that below HbA_1c levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p?>?0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA_1c level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p?Conclusions/interpretation In patients with type 2 diabetes, HbA_1c levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.

Trial Registration:

ClinicalTrial.gov NCT00145925

Funding:

Servier and the National Health and Medical Research Council of Australia (project grant ID 211086 and programme grant IDs 358395 and 571281)     

小唾液腺癌治疗新进展

该文旨在对小唾液腺癌的治疗进行回顾。小唾液腺癌可发生在头颈部很多位置,通常表现为黏膜下肿块。影像学检查是对肿瘤发病部位及病变范围内解剖结构的关系进行评估的基础。切取活检或穿吸活检可以决定肿瘤的病理类型和分级。随着分子生物学技术的不断进步,小唾液腺癌的诊断     

Assessing education in pulmonary rehabilitation: the Understanding COPD (UCOPD) questionnaire

There is currently no questionnaire available that comprehensively assesses patients' understanding, self-efficacy and satisfaction with the education component of pulmonary rehabilitation. The aim of this study was to develop the Understanding COPD (UCOPD) questionnaire. The key stages in the development of the UCOPD questionnaire were: (i) Generation of questions, and assessment of face and content validity, user-centredness, acceptability and feasibility; (ii) Assessment of plain English and readability; (iii) Assessment of structural validity; (iv) Assessment of test-retest reliability and internal consistency; (v) Assessment of the responsiveness, convergent validity and floor and ceiling effects. The UCOPD questionnaire assesses understanding, self-efficacy and use of key self-management skills (Section A) and satisfaction (Section B). It has good validity and practical properties, and readability was acceptable. It has good test-retest reliability (Section A: ICC range: 0.87 to 0.96; Section B: Wilcoxon: p > 0.05) and internal consistency (Cronbach's Alpha range: 0.78 to 0.95). It is responsive to pulmonary rehabilitation (Mean change: About COPD: 18.26 [12.12 to 24.40]%, Managing Symptoms 20.94 [13.86 to 28.01]%, Accessing Help and Support 24.06 [14.53 to 33.60]%, Total 20.59 [14.43 to 26.75]%, p < 0.001). It had a moderate correlation with the Bristol COPD Knowledge Questionnaire (BCKQ): pre-pulmonary rehabilitation: r = 0.41, p = 0.02; post-pulmonary rehabilitation: r = 0.35, p = 0.047. In conclusion, the UCOPD questionnaire offers the opportunity to assess the benefit of the education component of pulmonary rehabilitation in terms of its effect on understanding, self-efficacy and satisfaction. Further research is needed across different pulmonary rehabilitation settings to demonstrate the robustness of the UCOPD questionnaire, and to establish the minimum clinically important difference.     

Higher order aberrations,refractive error development and myopia control: a review

Evidence from animal and human studies suggests that ocular growth is influenced by visual experience. Reduced retinal image quality and imposed optical defocus result in predictable changes in axial eye growth. Higher order aberrations are optical imperfections of the eye that alter retinal image quality despite optimal correction of spherical defocus and astigmatism. Since higher order aberrations reduce retinal image quality and produce variations in optical vergence across the entrance pupil of the eye, they may provide optical signals that contribute to the regulation and modulation of eye growth and refractive error development. The magnitude and type of higher order aberrations vary with age, refractive error, and during near work and accommodation. Furthermore, distinctive changes in higher order aberrations occur with various myopia control treatments, including atropine, near addition spectacle lenses, orthokeratology and soft multifocal and dual-focus contact lenses. Several plausible mechanisms have been proposed by which higher order aberrations may influence axial eye growth, the development of refractive error, and the treatment effect of myopia control interventions. Future studies of higher order aberrations, particularly during childhood, accommodation, and treatment with myopia control interventions are required to further our understanding of their potential role in refractive error development and eye growth.