The epidemiology of red cell transfusion.

BACKGROUND AND OBJECTIVES: Understanding of the clinical usage of red cells is limited despite its importance in transfusion practice improvement and planning for blood supply requirements. Previous studies have described red cell use based upon ICD and hospital discharge codes; however, such approaches are open to misclassification. This study addresses this limitation by undertaking an epidemiological analysis of red cell use using case note review. MATERIALS AND METHODS: Patient, disease and contextual factors were extracted from the medical records of a randomly selected sample of hospital patients in Northern Ireland who received a red cell transfusion during 2005 (n=1474). RESULTS: Transfused patients received a total of 3804 units (median of two units per transfusion episode). Most transfusions occurred in a medical setting (71%). Patients undergoing treatment for gastrointestinal conditions were responsible for the majority of the demand (29% of transfusion episodes; 34% of red cell units). The presence of bleeding and abnormal tests of coagulation were associated with receiving larger transfusions (≥ 3 units), while patients undergoing orthopaedic surgery and those with a haemoglobin level over 7 g/dl had the lowest risk of receiving ≥ 3 units in any one transfusion episode. CONCLUSION: The majority of red cells are now prescribed in a medical setting. With an ageing population and increasing therapeutic interventions, the demand for blood is likely to increase despite efforts to reduce usage by eliminating inappropriate transfusions through education and behaviour change. The post-transfusion target (and therefore the number of units to transfuse) for any given clinical situation as well as guidance on a 'safe' transfusion threshold should be considered in future guidelines.

Homocysteine and methylmalonic acid as indicators of folate and vitamin B12 deficiency in pregnancy.

Deficiency of folate during pregnancy is associated with megaloblastic anaemia. Lower levels of folate and vitamin B12 have been reported in mothers whose offspring had neural tube defects compared to unaffected controls. Increased methylmalonic acid levels are a sensitive indicator of mild vitamin B12 deficiency and elevated homocysteine levels denote vitamin B12 or folate deficiency. We have investigated the relationship between serum concentration of total homocysteine, methylmalonic acid, vitamin B12 and folate in pregnancy. A significant inverse correlation was found between homocysteine and red cell folate and, to a lesser extent, serum folate. In addition, a significant inverse correlation was found between methylmalonic acid and vitamin B12. No significant relationship was found between homocysteine and vitamin B12. The relationship between red cell folate and serum folate and homocysteine may be useful for detecting borderline folate deficiency in pregnancy and indicate pregnancies at risk of neural tube defect. These sensitive assays are useful tools for the further investigation of folate vitamin B12 and metabolism in normal and abnormal pregnancy.

High bax expression is a good prognostic indicator in acute myeloid leukaemia.

Most cytotoxic drugs kill cells by instigating the process of apoptosis and it has been suggested that apoptotic markers may provide an indication of tumour chemosensitivity. The aim of this study was to determine if such a relationship exists in acute myeloid leukaemia (AML). The levels of spontaneous apoptosis, bcl-2 and bax were evaluated in 56 newly diagnosed AML patients to determine if they correlated with a response to cytotoxic therapy. Spontaneous apoptosis was lower, but bcl-2, bax and the bcl-2/bax ratio were higher in AML compared with normal individuals. AML patients with high bax expression at diagnosis had significantly better prognosis for disease-free survival, event-free survival and overall survival (P = 0.016). In the standard risk group, high bax expression was in keeping with significantly improved survival. Multivariate analysis revealed bax to be an independent predictor of survival. There was a significant reduction in bcl-2 and bax expression when AML patients entered complete remission and also in relapsed AML patients who entered a second remission. This study suggests that bax is a useful prognostic indicator in AML and may assist with therapeutic decision-making for patients in the standard risk category.

Granulocyte and granulocyte-macrophage colony-stimulating factors in cord and maternal serum at delivery.

Impaired neutrophil responses contribute to the neonate's increased susceptibility to infection. Because granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhance granulocyte and macrophage number and function, their use in the management of neonatal sepsis may be beneficial. Little is known about the endogenous levels of G-CSF and GM-CSF. In adults, raised values for G-CSF, but not GM-CSF, have been demonstrated in patients with infection, and conflicting data has emerged regarding CSF levels in neonates. We have used an ELISA to measure maternal and cord serum G-CSF and GM-CSF at the time of delivery, with gestational age between 25 and 42 wk. In mothers, an inverse linear relationship between gestational age and GM-CSF levels (p = 0.049) was found, but no association with G-CSF levels was observed. In neonates, a quadratic association was found between GM-CSF levels and gestational age (p = 0.019), whereas G-CSF levels showed an inverse linear association (p = 0.015). In addition, an association was found between maternal and cord GM-CSF (p = 0.007) but not G-CSF levels in paired samples. The effect of gestational age on the cytokine levels could not be explained by the white cell count, the absolute neutrophil count, pregnancy-induced hypertension, or the presence of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Accumulation of Maillard reaction products in skin collagen in diabetes and aging.

To investigate the contribution of glycation and oxidation reactions to the modification of insoluble collagen in aging and diabetes, Maillard reaction products were measured in skin collagen from 39 type 1 diabetic patients and 52 nondiabetic control subjects. Compounds studied included fructoselysine (FL), the initial glycation product, and the glycoxidation products, N epsilon-(carboxymethyl) lysine (CML) and pentosidine, formed during later Maillard reactions. Collagen-linked fluorescence was also studied. In nondiabetic subjects, glycation of collagen (FL content) increased only 33% between 20 and 85 yr of age. In contrast, CML, pentosidine and fluorescence increased five-fold, correlating strongly with age. In diabetic patients, collagen FL was increased threefold compared with nondiabetic subjects, correlating strongly with glycated hemoglobin but not with age. Collagen CML, pentosidine and fluorescence were increased up to twofold in diabetic compared with control patients: this could be explained by the increase in glycation alone, without invoking increased oxidative stress. There were strong correlations among CML, pentosidine and fluorescence in both groups, providing evidence for age-dependent chemical modification of collagen via the Maillard reaction, and acceleration of this process in diabetes. These results support the description of diabetes as a disease characterized by accelerated chemical aging of long-lived tissue proteins.

Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus.

Glycation, oxidation, and browning of proteins have all been implicated in the development of diabetic complications. We measured the initial Amadori adduct, fructoselysine (FL); two Maillard products, N epsilon-(carboxymethyl) lysine (CML) and pentosidine; and fluorescence (excitation = 328 nm, emission = 378 nm) in skin collagen from 39 type 1 diabetic patients (aged 41.5 +/- 15.3 [17-73] yr; duration of diabetes 17.9 +/- 11.5 [0-46] yr, [mean +/- SD, range]). The measurements were related to the presence of background (n = 9) or proliferative (n = 16) retinopathy; early nephropathy (24-h albumin excretion rate [AER24] > or = 20 micrograms/min; n = 9); and limited joint mobility (LJM; n = 20). FL, CML, pentosidine, and fluorescence increased progressively across diabetic retinopathy (P < 0.05, P < 0.001, P < 0.05, P < 0.01, respectively). FL, CML, pentosidine, and fluorescence were also elevated in patients with early nephropathy (P < 0.05, P < 0.001, P < 0.01, P < 0.01, respectively). There was no association with LJM. Controlling for age, sex, and duration of diabetes using logistic regression, FL and CML were independently associated with retinopathy (FL odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.01-1.12, P < 0.05; CML OR = 6.77, 95% CI = 1.33-34.56, P < 0.05) and with early nephropathy (FL OR = 1.05, 95% CI = 1.01-1.10, P < 0.05; CML OR = 13.44, 95% CI = 2.00-93.30, P < 0.01). The associations between fluorescence and retinopathy and between pentosidine and nephropathy approached significance (P = 0.05). These data show that FL and Maillard products in skin correlate with functional abnormalities in other tissues and suggest that protein glycation and oxidation (glycoxidation) may be implicated in the development of diabetic retinopathy and early nephropathy.

Decrease in skin collagen glycation with improved glycemic control in patients with insulin-dependent diabetes mellitus.

Glycation, oxidation, and nonenzymatic browning of protein have all been implicated in the development of diabetic complications. The initial product of glycation of protein, fructoselysine (FL), undergoes further reactions, yielding a complex mixture of browning products, including the fluorescent lysine-arginine cross-link, pentosidine. Alternatively, FL may be cleaved oxidatively to form N(epsilon)-(carboxymethyl)lysine (CML), while glycated hydroxylysine, an amino-acid unique to collagen, may yield N(epsilon)-(carboxymethyl)hydroxylysine (CMhL). We have measured FL, pentosidine, fluorescence (excitation = 328 nm, emission = 378 nm), CML, and CMhL in insoluble skin collagen from 14 insulin-dependent diabetic patients before and after a 4-mo period of intensive therapy to improve glycemic control. Mean home blood glucose fell from 8.7 +/- 2.5 (mean +/- 1 SD) to 6.8 +/- 1.4 mM (P less than 0.005), and mean glycated hemoglobin (HbA1) from 11.6 +/- 2.3% to 8.3 +/- 1.1% (P less than 0.001). These changes were accompanied by a significant decrease in glycation of skin collagen, from 13.2 +/- 4.3 to 10.6 +/- 2.3 mmol FL/mol lysine (P less than 0.002). However, levels of browning and oxidation products (pentosidine, CML, and CMhL) and fluorescence were unchanged. These results show that the glycation of long-lived proteins can be decreased by improved glycemic control, but suggest that once cumulative damage to collagen by browning and oxidation reactions has occurred, it may not be readily reversed. Thus, in diabetic patients, institution and maintenance of good glycemic control at any time could potentially limit the extent of subsequent long-term damage to proteins by glycation and oxidation reactions.