Lower incidence of clinical allergy with PEG-asparaginase upfront versus the sequential use of native E. coli asparaginase followed by PEG-ASP in pediatric patients with acute lymphoblastic leukemia.

Asparaginase (ASP) is an essential component for the acute lymphoblastic leukemia (ALL) treatment, but toxicities, such as allergy, frequently limit its use. Although the potentially lower PEG-ASP formulation immunogenicity, few studies with conflicting results have compared the allergy incidence between Escherichia coli-ASP and PEG-ASP in the same protocol. We aimed at comparing the allergy incidence in children receiving native E. coli-ASP versus PEG-ASP within the same clinical protocol (Spanish Society of Pediatric Hematology and Oncology ALL-SEHOP-PETHEMA 2013). One hundred and twenty-six children (1-19 years) diagnosed with ALL from 2013 to 2020 were included. Patients in group 1 received a sequential scheme of native E. coli-ASP 10,000 IU/m2 intramuscularly (IM) followed by PEG-ASP 1000 IU/m2 IM. Patients in group 2 received PEG-ASP 1000 IU/m2 IM upfront. Clinical allergy incidence was compared between both groups. Serum ASP activity (SAA) was measured in a subgroup of patients, and silent inactivation was recorded. The cumulative incidence of clinical allergy was significantly higher in group 1 (native followed by PEG-ASP) than in group 2 (PEG-ASP upfront), 24.7% versus 4.1% (p = 0.0085). Adequate ASP activity was achieved with PEG-ASP 1000 IU/m2 dose in most patients (median SAA 412.5 and 453.0 IU/L at days 7 and 14). The incidence of silent inactivation in PEG-ASP upfront patients was very low. PEG-ASP-used upfront was associated with a lower incidence of clinical allergy than that observed in the sequential use of native E. coli-ASP followed by PEG-ASP. PEG-ASP at 1000 IU/m2 was effective in achieving enough ASP activity in most patients.

Physicochemical Stability and Sterility of Standard Parenteral Nutrition Solutions and Simulated Y-Site Admixtures for Neonates.

BACKGROUND: Parenteral nutrition (PN) is frequently needed in neonatal intensive care. The use of standard PN has emerged as an easy-to-prescribe approach that allows one to have on-site, ready-to-use PN. The aim of this study was to test the physicochemical stability and sterility of 2 specific PN solutions as well as simulate Y-site compatibility with lipid injectable emulsions (ILE). METHODS: Our study considered 2 standard ILE-free PN solutions according to neonatal weight. These solutions were prepared in duplicate and stored at 4°C. The following physicochemical parameters were tested: visual alterations, turbidity, pH, osmolarity, and calcium concentration. Sterility was assessed by means of agar blood culture and glucose concentration determination. In addition, we assessed the stability of simulated Y-site admixtures. For each standard ILE-free PN solution, 2 3-in-1 PN admixtures were designed, considering extreme values of fluid requirements (50 and 150 ml/kg/d) and a fat supply of 2 g/kg/24 h. The physicochemical parameters tested were phase separation and fat mean droplet size distribution. RESULTS: No alterations were detected by visual inspection. Calcium concentrations, turbidity, pH, and osmolarity values remained stable in all the determinations. All agar blood cultures were negative and glucose concentration was constant over time. Physical stability of simulated Y-site admixtures was considered acceptable as mean droplet size distribution remained below 500 nm in all the emulsions. CONCLUSION: The 2 tested standard ILE-free PN solutions for neonates are physicochemically stable and sterile for 31 days under refrigeration (4°C). These solutions are also stable in case of Y-site administration with ILE at the conditions tested.

Analysis of peptidome profiling of serum from patients with early onset symptoms of ischemic stroke.

BACKGROUND: We sought to identify new serum biomarkers for the early diagnosis of ischemic stroke. METHODS: We collected 63 serum samples from patients with neurologic disease (45 patients with ischemic stroke, 18 patients with other neurologic disorders, and 56 healthy controls). Serum peptides were extracted using immobilized copper ion chromatography on a robotic platform. Mass spectra were acquired by matrix-assisted laser desorption/ionization-time of flight mass spectrometry using an Autoflex II spectrometer (Bruker Daltonics, Billerica, MA). Statistical analyses were performed with Clinprotools 2.2 software (Bruker Daltonics) and SPSS software (version 15.0; SPSS, Inc., Chicago, IL). RESULTS: No peptide biomarker or panel of peptide biomarkers was identified to differentiate between ischemic stroke and other neurologic disease, but ischemic stroke patients were differentiated from healthy controls with a single feature of the peptidome (sensitivity 88.6%; specificity 96.4%). CONCLUSIONS: Analysis of peptidome profiling of serum could be a useful tool in the search for early diagnostic biomarkers of ischemic stroke.

Cistatina C en la evaluación de la función renal / Assessment of renal function using cystatin C

La medición del filtrado glomerular es el mejor índice de valoración de la función renal. La creatinina sérica es el marcador de filtrado glomerular más utilizado, a pesar de estar sometido a diferentes fuentes de variabilidad. La cistatina C es una proteína de bajo peso molecular propuesta como marcador de función renal más sensible que la creatinina al detectar de forma precoz alteraciones en la función renal. La medida de cistatina C en suero en determinados grupos de pacientes como ancianos, niños o diabéticos parece aportar mayor información que la creatinina. Sin embargo, presenta alteraciones en su concentración sérica por factores diferentes al filtrado glomerular. Actualmente no hay evidencia científica suficiente que justifique el cambio de las ecuaciones de estimación del filtrado glomerular basadas en la concentración sérica de creatinina por la medida de la concentración sérica de cistatina C en la evaluación de la función (AU)

Glomerular filtration is the best index for assessing renal function. Despite being subjected to several sources of variability, serum creatinine is the most common glomerular filtration marker in use. Cystatin C is a low molecular weight protein which is more sensitive than creatinine, particularly for the identification of initial small decreases in renal function. The use of cystatin C in certain groups of patients such as elderly, children or diabetics appears to provide more information than creatinine. However, serum cystatin C can be influenced by non-renal factors. Currently, there is not enough scientific evidence to recommend the use of cystatin C to assess renal function instead of creatinine and creatinine equations (AU)

Standardized peptidome profiling of human serum for the detection of pancreatic cancer.

OBJECTIVE: To establish new biomarkers for accurate diagnosis of pancreatic cancer (PC) using a standardized serum peptidome profiling and compare the results with those from the tumor marker, CA 19-9. METHODS: Serum samples from 102 patients (55 with chronic pancreatitis and 47 with PC) and 56 healthy controls were collected and analyzed following a protocol that was rigorously designed to prevent preanalytical variation. Serum peptides were extracted using immobilized copper ion chromatography on a robotic platform. Mass spectra were acquired by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry on an Autoflex II spectrometer (Bruker Daltonics, Bremen, Germany). Statistical analysis was performed using the Clinprotools 2.2 software (Bruker Daltonics) and the SPSS 15.0 software (SPSS Inc, Chicago, Ill). RESULTS: Standardized peptidome profiling showed a median coefficient of variation of 11.6% calculated using all the extracted peptides and negligible influence of sex and age on peptidome profiles. The diagnostic sensitivity was 89.9%, and the diagnostic specificity was 92.7%, using 2 serum features and CA 19-9 serum concentration. Healthy controls were differentiated from patients with PC and chronic pancreatitis, with the use of 3 features of the peptidome (diagnostic sensitivity, 98.2%; diagnostic specificity, 97.1%). CONCLUSIONS: Standardized serum peptidome profiling could be a useful tool to improve biochemical diagnosis of PC in combination with the classic tumor marker, CA 19-9.

Nuevos marcadores en el síndrome coronario agudo / New biomarkers in acute coronary syndrome

La cardiopatía isquémica supone el 1,3% de los casos de atención en un servicio de urgencias hospitalario en España. El manejo del paciente es complejo por el riesgo de producir una alta médica incorrecta, el beneficio de instaurar una revascularización rápida y el gasto excesivo por admisiones injustificadas. La última década ha permitido un importante avance en el desarrollo de nuevos marcadores cardíacos. Tradicionalmente los marcadores del síndrome coronario agudo han sido indicadores de necrosis cardíaca. Esta función se ha ampliado actualmente. Aún hay muchas limitaciones en la medición de estos marcadores, como la falta de un procedimiento estandarizado o materiales de referencia certificados. Además de las troponinas cardíacas y el electrocardiograma, medir la albúmina modificada por isquemia puede ayudar a excluir un síndrome coronario agudo en pacientes con baja probabilidad de isquemia miocárdica. La proteína fijadora de ácidos grasos-H es un marcador de necrosis útil en el diagnóstico precoz del infarto agudo de miocardio. En el pronóstico del síndrome coronario agudo, la proteína C reactiva, los péptidos natriuréticos y la mieloperoxidasa complementan el valor pronóstico de la troponina. El ligando soluble CD40 permite la clasificación e individualización del tratamiento del síndrome coronario agudo. Actualmente no hay suficiente evidencia para que ningún nuevo marcador sustituya a los que recomiendan las sociedades científicas ni se dispone de procedimientos de medición rápidos para algunos de ellos. Deben establecerse paneles utilizando la evidencia científica disponible y tomando como objetivo su contribución a una mejor evolución del paciente(AU)

Myocardical ischemia involves 1.3% of the patients attending emergency departments in Spain. The management of these patients is complex, due to the risk of an incorrect discharge diagnosis, the benefit of rapid revascularization and the excessive cost due to unnecessary admissions. There has been a significant improvement in the development of new cardiac biomarkers over the last ten years. Biomarkers traditionally used for identifying acute coronary syndrome were indicators of myocardial necrosis. This role has currently been expanded. There are still some limitations in the measurement of these biomarkers, due to lack of standardised assays or certified calibrators. Ischemia-modified albumin in conjunction with cardiac troponin and electrocardiogram, can help to rule out an acute coronary syndrome in patients with a low probability of having myocardical ischemia. Heart-type fatty acid-binding protein is a strong necrosis biomarker in the early diagnosis of acute myocardical infarction. C-reactive protein, natriuretic peptides and myeloperoxidase have been shown to complement cardiac troponin in the prognosis of acute coronary syndrome. Soluble CD40 ligand enables the identification of a subgroup of patients who will benefit from a treatment in acute coronary syndrome. There is currently not enough evidence to replace new biomarkers with any of these already been recommended by the scientific societies. Also, the assays of some of them are not sufficiently rapid. A multimarker strategy must be created to take into account the existing scientific-based evidence, with the aim of improving outcomes in patients(AU)

Multicentric evaluation of the homogeneous LDL-cholesterol Plus assay: comparison with beta-quantification and Friedewald formula.

OBJECTIVES: To evaluate the analytical and clinical performance of a new version of the LDL-C Plus assay and compare it with the beta-quantification (BQ) method in a multicenter study. DESIGN AND METHODS: Direct LDL-C was measured in 169 fresh pooled samples and in 830 clinical samples with known LDL-C by BQ. The reactivity of lipoproteins and the effect of hemoglobin, bilirubin and chylomicrons (CM) were studied. RESULTS: Direct LDL-C total imprecision was <2.2%; inaccuracy <+/-2.5% (unaffected by triglycerides up to 9.5 mmol/L); and total error 9.8%. Direct assay reacted with 95%, 50% and 25% of the cholesterol in the LDL, intermediate (IDL) and VLDL fractions, respectively. A significant association was observed with BQ. Icteric samples showed a negative bias and the effect of CM was variable. A positive bias was observed when VLDL-cholesterol/triglyceride ratio was >0.57. CONCLUSIONS: LDL-C Plus assay represents a valid alternative to BQ for clinical laboratories.

Differential intestinal mucosal protein expression in hypercholesterolemic mice fed a phytosterol-enriched diet.

The molecular mechanisms involved in the phytosterol-induced decrease in intestinal cholesterol absorption remain unclear. Further, other biological properties such as immunomodulatory activity and protection against cancer have also been ascribed to these plant compounds. To gain insight into the mechanisms underlying phytosterol actions, we conducted a proteomic study in the intestinal mucosa of phytosterol-fed apolipoprotein E-deficient hypercholesterolemic (apoE-/-) mice. With respect to control-fed apoE-/- mice, nine differentially expressed proteins were identified in whole-enterocyte homogenates using 2-D DIGE and MALDI-TOF MS. These proteins are involved in plasma membrane stabilization, cytoskeleton assembly network, and cholesterol metabolism. Four of these proteins were selected for further study since they showed the highest abundance change or had a potential functional relationship with known effects of phytosterols. Annexin A2 (ANXA2) and beta-actin decrease and annexin A4 (ANXA4) and annexin A5 (ANXA5) increase were confirmed by Western blot analysis. Intestinal gene expression of ANXA2 and A5 and beta-actin was reduced, whereas that of ANXA4 was unchanged. The main results were retested in normocholesterolemic C57BL/6J mice. ANXA4 and ANXA5 protein upregulation and ANXA2 and beta-actin downregulation were reproduced in these animals. However, no changes in gene expression were found in C57BL/6J mice in either of the four proteins selected. ANXA2, A4, and A5 and beta-actin are proteins of special interest given their pleiotropic functions that include cholesterol-ester transport from caveolae, apoptosis, and anti-inflammatory properties. Therefore, the protein expression changes identified in this study might be involved in the biological effects of phytosterols.

Diagnóstico precoz del cáncer mediante análisis proteómicos del suero: ¿ficción o realidad? / Early diagnosis of cancer by proteomic analysis of serum: fiction or reality?

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A cause of falsely low HDL concentrations in HIV-infected patients: increased polyclonal serum immunoglobulin.

OBJECTIVE: To describe the interference of polyclonal hypergammaglobulinemia in a direct HDL-c method. METHODS: HDL-c was measured by a direct method (Roche Diagnostics) in four HIV-infected patients showing polyclonal hypergammaglobulinemia and also by precipitation with phosphotungstic acid and ultracentrifugation at a density of 1.063 kg/L. In addition, an electrophoretic lipid profile was performed by an automated electrophoretic system. RESULTS: Direct HDL-c concentration was very low or even nondetectable in all hyperglobulinemic samples. Ultracentrifugation showed a higher HDL-c concentration, and the electrophoretic lipid profile showed a band corresponding to HDL particles whose cholesterol concentration was in concordance with that of ultracentrifugation. Kinetic monitoring of the absorbance for the direct HDL-c method showed a high reading after the first reagent addition and a final absorbance quite close to or even lower than the initial absorbance. CONCLUSION: Although interference by any HIV therapy drug cannot be completely ruled out, our results showed that when high immunoglobulin concentrations existed in the patient's serum, the direct HDL-c method yielded low or undetectable HDL-c values. The high initial absorbance observed suggested an interaction between immunoglobulins and the first reagent of the method, producing a complex that scattered light and falsely decreased HDL-c concentrations.

N-terminal probrain natriuretic peptide (NT-proBNP) in the emergency diagnosis and in-hospital monitoring of patients with dyspnoea and ventricular dysfunction.

OBJECTIVE: To evaluate the utility of NT-proBNP in the emergency diagnosis and in-hospital monitoring of patients with acute dyspnoea and ventricular dysfunction. BACKGROUND: Misdiagnosis of heart failure (HF) is common in the urgent care setting using clinical diagnostic tests. Reports show that BNP is useful to diagnose HF in patients with acute dyspnoea. METHODS: Prospective study of 100 patients attending the Emergency Department (ED) for acute dyspnoea. Final diagnosis was determined on the basis of ED data sheets, echocardiography and pulmonary function tests. NT-proBNP levels were obtained on admission, at 24 h and at day 7. RESULTS: Patients with ventricular dysfunction were sub-classified into decompensated HF and masked HF, defined as HF with concomitant signs of pulmonary disease. Decompensated and masked HF patients had significantly higher NT-proBNP values than patients with non-cardiac dyspnoea (normal ventricular function) (920+/-140 and 978+/-363 vs. 50+/-15 pmol/L; P<0.001 and P<0.01, respectively). The mean area under the ROC curve for NT-proBNP was 0.957 (95% CI, 0.918 to 0.996, P<0.001). In multiple logistic-regression analysis NT-proBNP>115 pmol/l was the strongest independent predictor of ventricular dysfunction (odds ratio 45.4; 95% CI: 4.5-452.3). At day 7, a significant and similar reduction in NT-proBNP was observed in the two groups of patients with ventricular dysfunction (P<0.001 vs. admission values), but complete clinical resolution was less frequent in masked HF patients (P<0.05 vs. decompensated HF). CONCLUSIONS: NT-proBNP is a new candidate marker for the detection and exclusion of ventricular dysfunction in patients attending the ED for acute dyspnoea. NT-proBNP may also serve to monitor outcome during hospitalization.

Glucemia: una magnitud analítica polivalente / Glycemia: a polyvalent analytical magnitude

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