Clinical implications of malnutrition in childhood cancer patients--infections and mortality.

PURPOSE: In childhood cancer patients, malnutrition has been proposed to increase infection rates and reduce survival. We investigated whether malnutrition at diagnosis and during treatment and weight loss during treatment are prognostic factors for infection rates and survival, within a heterogeneous childhood cancer population. METHODS: From two previous studies, all children ≤18 years of age diagnosed with cancer between October 2004 and October 2011 were included in this study. Data regarding BMI, infections, and survival were retrieved. Patients with a BMI z-score lower than -2.0 were classified as malnourished. Weight loss more than 5% was considered relevant. RESULTS: Two hundred sixty-nine childhood cancer patients were included in this study. At diagnosis, 5.2% of all patients were malnourished. These patients showed worse survival than those who were well nourished (hazard ratio (HR) = 3.63, 95% confidence interval (CI) = 1.52-8.70, p = 0.004). Malnourishment at 3 months after diagnosis (3.3% of all patients) also showed worse survival (HR = 6.34, 95% CI = 2.42-16.65, p < 0.001). Weight loss of more than 5% in the first 3 months after diagnosis was related to increased occurrence of febrile neutropenic episodes with bacteremia in the first year after diagnosis (odds ratio (OR) = 3.05, 95 % CI = 1.27-7.30, p = 0.012). CONCLUSION: We found that malnourishment in the initial phase of therapy is associated with worse survival in childhood cancer patients. In addition, we found for the first time that weight loss during treatment is associated with increased presence of febrile neutropenic episodes with bacteremia. This underlines the importance of optimal feeding designs in childhood cancer patients.

Polymorphisms in the TLR6 gene associated with the inverse association between childhood acute lymphoblastic leukemia and atopic disease.

Little is known about the etiology of childhood acute lymphoblastic leukemia (ALL). The presence of atopic disease has been shown to protect against developing childhood ALL. The aim of this study was to examine whether single nucleotide polymorphisms (SNPs) in innate immunity genes previously associated with atopic disease, can elucidate the inverse association between childhood ALL and atopic disease. We studied 525 children, including 192 with childhood ALL, 149 with atopic disease and 184 healthy control subjects. We compared genotype distributions of 29 SNPs in genes of TLR2, TLR4, TLR6, TLR9, TLR10 and CD14 between the three groups and corrected for multiple testing. The genotype distributions of two SNPs in the TLR6 gene, rs5743798 and rs6531666, differed significantly between children with ALL, children with atopic disease and control subjects. Particularly in children with atopic eczema, risk alleles for atopic disease were observed more often than in control subjects, and less often in children with ALL than in control subjects. These findings support the immune surveillance hypothesis as an explanation for the protective association of atopic disease on childhood ALL. Further investigation is warranted to examine in more detail the role of innate immunity in the development of childhood ALL.

Association of polymorphisms in the TLR4 gene with the risk of developing neutropenia in children with leukemia.

Infections are a major cause of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). Susceptibility to infections increases as the neutrophil count decreases. Despite identical treatment patients vary considerably in the number of neutropenic episodes. Toll-like receptor 4 (TLR4) has been shown to have a role in inhibiting apoptosis of neutrophils. Therefore, we hypothesized that polymorphisms in the TLR4 gene may influence the number of chemotherapy-induced neutropenic episodes. Eight single-nucleotide polymorphisms (SNPs) of the TLR4 gene were determined in 194 children aged 0-17 years, who were diagnosed with ALL. We compared the genotype distributions of the SNPs with the frequency of neutropenic episodes during treatment with chemotherapeutic regimens. The number of neutropenic episodes varied from 0 to 17, with a median of four neutropenic episodes. Four SNPs in the TLR4 gene (rs10759931, rs11536889, rs1927911 and rs6478317) were associated with an increased risk of developing chemotherapy-induced neutropenia, each sustaining correction for multiple testing. Further studies are required to elucidate whether pediatric patients with ALL with the particular SNPs in the TLR4 gene also experience more infections and would benefit from prophylactic antibiotic treatment, by a reduction of morbidity and mortality due to infections.

Prognostic value of admission glucose and glycosylated haemoglobin levels in acute coronary syndromes.

BACKGROUND: Admission hyperglycaemia is associated with poorer prognosis in patients with an acute coronary syndrome (ACS). Whether hyperglycaemia is more important than prior long-term glucose metabolism, is unknown. AIM: To investigate the prognostic value of admission glucose and HbA(1c) levels in patients with ACS. METHODS: We measured glucose and HbA(1c) at admission in 521 consecutive patients with suspected ACS. Glucose was categorized as <7.8 (n = 305), 7.8-11.0 (n = 138) or > or =11.1 mmol/l (n = 78); HbA(1c) as <6.2% (n = 420) or > or =6.2% (n = 101). Mean follow-up was 1.6 +/- 0.5 years. RESULTS: The diagnosis of ACS was confirmed in 332 patients (64%), leaving 189 (36%) with atypical chest pain. In ACS patients, mortality by glucose category (<7.8, 7.8-11.0 or > or =11.1 mmol) was 9%, 8% and 25%, respectively (p = 0.001); mortality by HbA(1c) category (<6.2% vs. > or =6.2%) was 10% vs. 17%, respectively (p = 0.14). On multivariate analysis, glucose category was significantly associated with mortality (HR 3.0, 95% CI 1.1-8.3), but HbA(1c) category was not (HR 1.5, 95%CI 0.6-4.2). DISCUSSION: Elevated admission glucose appears more important than prior long-term abnormal glucose metabolism in predicting mortality in patients with suspected ACS.

Glucose and potassium derangements by glucose-insulin-potassium infusion in acute myocardial infarction.

BACKGROUND: High-dose glucose-insulin-potassium infusion (GIK) has been suggested to be beneficial in acute myocardial infarction (MI). Recently new large trials have shown no effect of GIK on mortality. To investigate whether metabolic derangement could have negated the potential beneficial effect, we studied the relation between systemic glucose and potassium levels and outcome. METHODS: Patients with signs and symptoms of ST-segment-elevation MI and treated with primary percutaneous coronary intervention (PCI) were randomised to no infusion or high-dose GIK, i.e. 80 mmol potassium chloride in 500 ml 20% glucose at a rate of 3 ml/kg/hour and 50 units short-acting insulin in 50 ml 0.9% sodium chloride for 12 hours. RESULTS: A total of 6991 glucose values and 7198 potassium values were obtained in 476 GIK patients and 464 controls. Mean serum glucose was significantly higher in the GIK group (9.3±4.5 mmol/l vs. 8.4±2.9 mmol/l, p<0.001). Mean potassium level was significantly higher in the GIK group (4.2±0.5 mmol/l vs. 3.9±0.4 mmol/l, p<0.001). Incidence of hyperglycaemia (glucose >11.0 mmol/l) occurred in 70.8% of GIK patients and 33.8% of controls (p<0.001). Hypokalaemia was less common in the GIK group (23.5 vs. 41.2%, p<0.001). Incidence of hyperkalaemia and hypoglycaemia did not differ significantly between the two groups. In multivariate analysis age, previous cardiovascular disease, Killip class >1, unsuccessful PCI and mean glucose after admission were associated with increased one-year mortality. CONCLUSION: In ST-segment-elevation MI patients treated with primary PCI, high-dose GIK induced hyperglycaemia and prevented hypokalaemia. Derangement of the glucose metabolism was related to one-year mortality.

[Diagnosis of diabetes mellitus: limited use for portable blood-glucose measuring devices]. / Diagnostiek van diabetes mellitus: beperkte plaats voor draagbare glucosemeters.

In the Netherlands, guidelines for the diagnosis of diabetes mellitus are confusing and differ from the international guidelines. Capillary blood-glucose testing using a blood-glucose device is allowed used as a diagnostic tool, although this test is imprecise. The Dutch laboratories measure blood-glucose concentrations by a more precise accurate method, but sometimes measure glucose levels in capillary whole blood and sometimes in venous plasma. These results are not comparable, because the results of capillary measurements are lower than the plasma measurements. In daily practice, health-care professionals are using different methods and are often not aware of the differences in glucose values that may result. They do not realise that glucose devices and laboratory glucose measurements may differ and that capillary- and plasma-glucose values are not interchangeable. Uniformity within the Dutch laboratories with regard to the glucose measurements is urgently needed, as is revision of the Dutch guidelines concerning the diagnosis of diabetes mellitus. This should be based solely on venous plasma-glucose values determined in a laboratory. Portable blood-glucose devices should not be used as a diagnostic tool for diabetes mellitus. These should only be used for blood-glucose control monitoring during treatment or as a screening tool.

Dysglycemia in suspected acute coronary syndromes.

BACKGROUND: Apart from diabetes itself, even minor glycometabolic dysregulation may be associated with an increased risk of cardiovascular disease. We analyzed the prevalence and predictive value of glycometabolic disturbances in patients with a suspected acute coronary syndrome (ACS). METHODS: In a prospective follow-up study, admission glucose and Hba1C levels in all consecutive patients with suspected ACS were measured. Dysglycemia was defined as a Hba1C of 5.6-6.1% with a non-fasting glucose above 7.8 mmol/L. Both predictors of glycometabolic disturbances and the predictive value of glycometabolic disturbances were studied. RESULTS: Of the 521 patients with a suspected ACS who were included in the study, 332 (64%) had an ACS and 189 (36%) had atypical chest pain. A total of 115 patients (22%) had diabetes and 65 (13%) had dysglycemia. Patients with diabetes or dysglycemia had an increased risk of a confirmed diagnosis of ACS (RR 2.3, 95% CI 1.5-3.4). Multivariate analyses did not change these findings. CONCLUSIONS: One in three patients with suspected ACS had a glucose metabolism disturbance. Glycometabolic disturbance was strongly associated with a confirmed diagnosis of ACS. Whether intensive treatment of patients with disturbed glucose metabolism may improve long-term prognosis needs to be assessed.

Towards worldwide standardisation of HbA1c determination.

Haemoglobin A(1)c (HbA(1)c) or glycohaemoglobin is one of the most important parameters in the management of patients with diabetes mellitus, but to date there is no international standard for determining HbA(1)c. Most of the routine HbA(1)c assays are standardised against one of the local standardisation schemes like the NGSP (USA) and other schemes (Japan, Sweden). Still, results of HbA(1)c tests diverge considerably, as do the accompanying clinical decision limits. The IFCC Working Group on HbA(1)c Standardisation has developed a reference method and also set up a reference system for HbA(1)c, in which the analyte is defined as beta-N-glycated haemoglobin. This reference system consists of a network of reference laboratories that uses the reference methods and certified reference materials for optimal measurement of HbA(1)c in human blood. The main task of the network is to assign values to secondary reference materials, to be used by manufacturers of routine HbA(1)c assays to calibrate their assays. The high specificity of the reference method results in lower HbA(1)c values in blood samples, since the unspecific components falsely identified as HbA(1)c in routine methods are not measured by the reference method. The reference range for the new reference method was determined as 3 to 4% and the clinical decision limits were translated from existing guidelines: goal of treatment 5% HbA(1)c, change of therapy advised at HbA(1)c greater than 6%. Despite these lower values, worldwide implementation of the IFCC reference system for HbA(1)c is recommended, in order to end the great divergence in HbA(1)c results, with which physicians and patients are confronted today.

Impaired platelet inhibitory effect of a single dose of acetylsalicylic acid in patients with unstable coronary artery syndrome in comparison with healthy volunteers.

BACKGROUND AND AIM: Controversial reports have been published about the efficiency of potent platelet inhibitors in patients with coronary artery syndrome (CAS). We therefore questioned whether a functional change in platelets affects the patient's response to ASA. STUDY DESIGN AND METHODS: Nineteen consecutive patients presenting with unstable coronary syndrome and 15 healthy volunteers were included. No platelet inhibitory drugs or coumarin were used in either group before the study. Platelet aggregation tests were performed on baseline samples and after a single dose of ASA. Afterwards, all patients underwent coronary angiography to exclude non-CAS. RESULTS: In the patient group (n=15 after exclusion) no significant increase in bleeding constant was found after ASA, using a PFA analyser, in contrast to the control group. The maximal velocity and the maximal percentage optical platelet aggregation using ADP was significantly more reduced in the control group. ASA did not significantly reduce the thromboxane B2 production in the patient group. CONCLUSION: ASA has less platelet inhibitory effects in patients with unstable CAS in comparison with healthy volunteers. Platelets, in the hyperactive state of unstable CAS, prove to be less subject to inhibition. This might add to the explanation of the lack of efficiency of platelet inhibitory drugs to prevent thrombotic complications after PTCA and platelet aggregation onto stent surfaces in patients with acute CAS.

[The troponin assay in a cardiac emergency unit: especially to exclude severe cardiac risk]. / De troponinebepaling op een Eerste Harthulp: vooral ter uitsluiting van ernstig cardiaal risico.

OBJECTIVE: To determine the value in daily practice of a troponin assay for triage of patients with chest pain. DESIGN: Retrospective and descriptive. METHOD: All patients in whom troponin T was measured after at least six hours after complaints began during the first three months of 2001 in the cardiac emergency unit of the Isala Clinics, location Weezenlanden, Zwolle, the Netherlands, were included. Cardiac events occurring within 30 days after the troponin assay were recorded retrospectively. RESULTS: All 350 included patients were followed for 30 days. An elevated troponin level was found in 51 patients (15%). At 30 days, 27 of these 51 patients had had a myocardial infarction or had died. Apart from these 27 patients, a revascularisation procedure was performed in nine patients. In the remaining 15 patients with an elevated troponin level, another reason for myocardial damage was found. In 40 patients in whom the troponin assay was negative, coronary artery disease was diagnosed later. The negative predictive value for myocardial infarction or death within 30 days was 98%. CONCLUSION: A troponin assay, performed six hours or more after the onset of cardiac symptoms, appears to be a safe method to exclude patients with severe coronary artery disease resulting in myocardial necrosis and an elevated risk of death. An elevated troponin level was always associated with myocardial damage, but not always with coronary artery disease. Therefore, there must be a clear indication for requesting a troponin assay, and one should always keep in mind that a normal troponin level does not exclude coronary artery disease.

Prognostic importance of left ventricular function after angioplasty or thrombolysis for acute myocardial infarction.

OBJECTIVES: To compare long-term clinical outcome after acute myocardial infarction treated with primary coronary angioplasty or thrombolytic therapy, and to study the determinants of survival. BACKGROUND: Primary coronary angioplasty results in a higher patency rate and a better short-term survival when compared with thrombolytic therapy, but so far limited information has been available regarding long-term clinical outcome. METHODS: Patients with acute myocardial infarction (n=395) were randomised to treatment with either intravenous streptokinase or primary angioplasty, and were followed for up to eight years. RESULTS: A total of 105 patients died, 42 patients in the primary coronary angioplasty group compared with 63 patients in the streptokinase group (p=0.03). Death and nonfatal reinfarction occurred in 53 patients in the angioplasty group, compared with 94 patients in the streptokinase group (p<0.001). The major cause of long-term mortality is sudden death. Multivariate analysis showed that left ventricular function was the most important predictor for both total mortality and sudden death. CONCLUSION: The benefits of primary coronary angioplasty compared with streptokinase are well sustained during long-term follow-up.

Clinical characteristics and outcome of patients with acute myocardial infarction and preinfarction angina.

OBJECTIVES/BACKGROUND: Preinfarction angina is associated with reduced myocardial infarct size in patients treated with thrombolysis. Our objective was to assess the relation between preinfarction angina and infarct size, left ventricular function and clinical outcome in patients treated with primary angioplasty (PTCA) and compare this with patients treated with thrombolysis. METHODS: In the Zwolle Infarction Study, 953 patients were treated for acute myocardial infarction between 1990 and 1996; 761 patients underwent primary PTCA and 192 patients received thrombolysis as reperfusion therapy. RESULTS: Preinfarction angina was present in about 50% of the patients, who were categorised into angina ≤24 hours and angina >24 hours before infarction. Patients in both treatment groups have a longer ischaemic time when preinfarction angina is present. In patients treated with thrombolysis, preinfarction angina ≤24 hours results in a smaller enzymatic infarct. Thrombolysis seems to be more effective when preinfarction angina occurs within the 24 hours prior to myocardial infarction. Collateral filling of the infarct-related artery is more often seen in patients with preinfarction angina. In the primary PTCA group, a longer ischaemic time in patients with preinfarction angina does not result in increased infarct size, and this effect remains after excluding patients with collateral filling. CONCLUSIONS: The protective effect of preinfarction angina is likely to be due to better collateral filling of the infarct-related artery and to ischaemic preconditioning of the myocardium.

Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction.

BACKGROUND: As compared with thrombolytic therapy, primary coronary angioplasty results in a higher rate of patency of the infarct-related coronary artery, lower rates of stroke and reinfarction, and higher in-hospital or 30-day survival rates. However, the comparative long-term efficacy of these two approaches has not been carefully studied. METHODS: We randomly assigned a total of 395 patients with acute myocardial infarction to treatment with angioplasty or intravenous streptokinase. Clinical information was collected for a mean (+/-SD) of 5+/-2 years, and medical charges associated with the two treatments were compared. RESULTS: A total of 194 patients were assigned to undergo primary angioplasty, and 201 to receive streptokinase. Mortality was 13 percent in the angioplasty group, as compared with 24 percent in the streptokinase group (relative risk, 0.54; 95 percent confidence interval, 0.36 to 0.87). Nonfatal reinfarction occurred in 6 percent and 22 percent of the two groups, respectively (relative risk, 0.27; 95 percent confidence interval, 0.15 to 0.52). The combined incidence of death and nonfatal reinfarction was also lower among patients assigned to angioplasty than among those assigned to streptokinase, with a relative risk of 0.13 (95 percent confidence interval, 0.05 to 0.37) for early events (within the first 30 days) and a relative risk of 0.62 (95 percent confidence interval, 0.43 to 0.91) for late events (after 30 days). The rates of readmission for heart failure and ischemia were also lower among patients in the angioplasty group than among patients in the streptokinase group. Total medical charges per patient were lower in the angioplasty group (16,090 dollars) than in the streptokinase group (16,813 dollars, P=0.05). CONCLUSIONS: During five years of follow-up, primary coronary angioplasty for acute myocardial infarction was associated with lower rates of early and late death and nonfatal reinfarction, fewer hospital readmissions for ischemia or heart failure, and lower total medical charges than treatment with intravenous streptokinase.

RADHA--a new male germ line-specific chromosomal protein of Drosophila.

A new chromosomal protein - RADHA - of Drosophila is described that is specific for the male germ line. It is encoded by a single-copy gene, located in the region 96C-D of D. melanogaster polytene chromosomes. Transcription of the radha gene is restricted to the primary spermatocyte stage. The protein initially accumulates in some of the Y-chromosomal lampbrush loops. After meiosis it is found in the nuclei of spermatids and might be involved in chromatin rearrangement processes in the male germ line. RADHA is a basic protein with a C-terminal leucine zipper region and several segments capable of forming coiled-coil structures.

Preparation of a candidate primary reference material for the international standardisation of HbA1c determinations.

We prepared a candidate primary reference material for the forthcoming international standardisation of beta-N-terminal glycated hemoglobin A measurements. It consists of well-defined mixtures of purified beta-N-terminal glycated hemoglobin A and non-glycated hemoglobin A. First, beta-N-terminal glycated hemoglobin A and non-glycated hemoglobin A were isolated, purified to homogeneity, and characterised. The techniques used were cation exchange and affinity chromatography for the purification, and high performance liquid chromatography, capillary isoelectric focusing, electrospray ionisation mass spectrometry, and peptide mapping for the characterisation. Hemoglobins from blood of healthy, non-diabetic volunteers were obtained with a purity of > 99.5% for non-glycated hemoglobin A and of > 98.5% for beta-N-terminal glycated hemoglobin A. However, results from peptide mapping indicate that the beta-N-terminal glycated hemoglobin A preparations still contain some non-beta-N-terminal glycated hemoglobins, co-eluting with beta-N-terminal glycated hemoglobin A. The exact content of beta-N-terminal glycated hemoglobin A in these preparations could be determined by a procedure consisting of standard addition, enzymatic cleavage and quantification of the resulting beta-N-terminal peptides to be in the range from 95-97.5%. Since the beta-N-terminal glycated hemoglobin A and non-glycated hemoglobin A content could be exactly determined in the materials prepared, mixtures of both components could be successfully used to calibrate the candidate reference methods.

Naturally occurring testis-specific histone H3 antisense transcripts in Drosophila.

While analysing the transcription of the cluster of cell-cycle regulated histone genes in Drosophila hydei, we have found transcripts spanned both histone H3 and H4 genes and were antisense for histone H3. As the two histone genes are in opposite orientation, these transcripts contained the sense strand of the histone H4 gene. Such transcripts were present in both poly(A)+ and poly(A)- RNA fractions. The polyadenylated molecules contained a poly(A) tail at the 3' end of the stem-loop structure, which is characteristic for cell-cycle regulated histone mRNAs. The antisense RNA of histone H3 is synthesized exclusively in testes. By developing an improved protocol of in situ hybridization to Drosophila testis squashes, we could demonstrate that the antisense transcripts are localized in the nuclei of primary spermatocytes. Possible functions of this RNA are discussed.

Candidate reference methods for hemoglobin A1c based on peptide mapping.

A reference method that specifically measures hemoglobin (Hb) A1c is an essential part of the reference system for the international standardization of Hb A1c/glycohemoglobin. We have developed a new method for quantification, based on the specific N-terminal residue of the hemoglobin beta-chains. Enzymatic cleavage of the intact hemoglobin molecule with endoproteinase Glu-C has been optimized to obtain the beta-N-terminal hexapeptides of Hb A1c and Hb A0. These peptides have been separated by reversed-phase HPLC and quantitated by electrospray ionization-mass spectrometry (method A) or by capillary electrophoresis (method B). With these peptides and hyphenated separation techniques, it has been possible to overcome the insufficient resolution of currently used protein separation systems for Hb A1c.

Evaluation of the Menarini-Arkray HA 8140 hemoglobin A1c analyzer.

We describe a multinational evaluation of the Menarini-Arkray HA 8140 hemoglobin (Hb) A1c analyzer, which utilizes a high degree of automation, including bar code reading, cap piercing, and whole-blood sampling. With-in- and between-batch CVs were < 2%. Linearity was confirmed throughout the working range of the analyzer. Common Hb variants, including Hb S, Hb C, and Hb F, did not interfere with the Hb A1c separation, and the potentially interfering labile Schiff base was effectively removed during the chromatographic procedure. The HA 8140 analyzer displayed good correlation to the Bio-Rad Variant analyzer, Tinaquant immunoassay, affinity chromatography, and an optimized "in-house" HPLC Hb A1c method. The methods when compared by Altman and Bland plots showed bias (upper, lower 95% confidence limits) of: Variant minus HA 8140 = 0.99 (0.23, 1.74), Tinaquant minus HA 8140 = 0.14 (-0.71, 0.98); affinity minus HA 8140 (after log transformation) = 1.13 (0.90, 1.41), and "in house" HPLC minus HA 8140 (after log transformation) = 0.91 (0.82, 1.01).