[Inequity of compensation trajectories for victims of medical injuries. A survey in the French out-of-court settlement mechanism]. / Inégalités dans les parcours d'indemnisation des victimes d'accidents médicaux. Une enquête au sein du dispositif français de règlement amiable.

BACKGROUND: In France little is known about either the characteristics of people who take legal action because they believe themselves to be victims of harm caused by medical activity, or about their complaint trajectory. The law of 4th March 2002 created an out-of-court settlement mechanism which aims to reduce inequitable access to compensation experienced by victims faced with legal procedures that are both lengthy and costly. This mechanism now occupies a central position among the avenues of recourse available to patients and their families. METHODS: The study relates to the exhaustive database of 18,258 requests for compensation filed with the out-of-court settlement mechanism between 2003 and 2009. It takes 4 series of variables into account: (1) the characteristics of the people concerned by the request, (2) the recourse practices, (3) the result of the requests, (4) the characteristics of the commissions with whom they dealt. Univariate and multivariate analyses were performed, in particular to find factors relating to the different responses given to the requests. RESULTS: Of the requests filed with the out-of-court settlement mechanism, 34.5% led to compensation being awarded, 30.7% were deemed inadmissible and 34.8% were rejected on the basis of expert opinions. The risk of inadmissibility was greater when the victim was a woman, undeceased, or a minor aged between 1 and 17; it bore no relation to standard of living. Recourse to a lawyer (24%) depended on various characteristics, in particular the age and vital status of the victim. It is associated to the decrease of the risk of inadmissibility and to the increase of the chances of receiving compensation. There were significant differences in the ways requests were processed (depending on where they were filed), in the time it took to examine the case, and in the tendency to reject requests before or after expert medical opinion. CONCLUSION: This study offers the first ever description of the population of patients and families who accessed the out-of-court settlement mechanism for medical claims in France. It looks at how, within the mechanism, the diversity of practices impacts inequity and experiences during the compensation process.

Reference values for reticulocyte parameters and hypochromic RBC in healthy children.

INTRODUCTION: New erythrocyte and reticulocyte parameters available on modern hematology analyzers have shown to be useful markers in children. However, pediatric method-specific reference ranges for these indices are sparse. We aim to establish pediatric reference values for reticulocyte parameters and hypochromic red blood cells in healthy children with the ADVIA 2120 hematology analyzer. METHODS: Prospective study of 311 healthy children aged from 6 months to 18 years old with normal hematological parameters. ADVIA 2120 hematology analyzer (Siemens Healthcare Diagnostics, Amadora, Portugal) was used for whole-blood hematological measures. The sample population was grouped according to age into three cohorts, and gender distribution was used for participants aged ≥12 years. RESULTS: Age- and gender-specific reference limits of reticulocyte hemoglobin content (CHr or Ret-He), difference between the reticulocyte and erythrocyte hemoglobin content (Delta-He), immature reticulocyte fraction (IRF) and percentage of hypochromic red blood cells (%Hypo) are provided. Delta-He, IRF and %Hypo showed statistically significant gender differences in the 12-17 years group. CHr presented no significant gender variation within all age groups (median 30.8 ± 1.7 pg). CONCLUSION: Establishing reliable pediatric reference intervals for these novel hematological parameters may offer valuable prospects for clinical practice and research in the pediatrics field.

Normal red blood cells partially decrease diepoxybutane-induced chromosome breakage in cultured lymphocytes from Fanconi anaemia patients.

OBJECTIVES: Fanconi anaemia (FA) is a cancer-prone chromosome instability syndrome characterized by hypersensitivity to DNA cross-linking agents, such as diepoxybutane (DEB). Previous studies have shown that normal red blood cells (RBC) can protect cultured lymphocytes against chromosomal breaks induced by DEB. The present study was designed to analyse influence of RBCs from normal individuals on frequency of DEB-induced chromosome breaks in lymphocyte cultures from FA patients. MATERIALS AND METHODS: A comparative study was performed between DEB-induced chromosome breaks in cultures of FA lymphocytes with either autologous or heterologous RBCs. A further comparative study was carried out between whole blood cultures from FA patients performed on two occasions, before and 1 week after transfusion of RBCs. RESULTS: It was observed that normal RBCs compared to FA RBCs, partially reduced chromosome breaks in cultured FA lymphocytes. A significant reduction in DEB-induced breaks was also observed in FA cultured lymphocytes obtained 1 week after transfusion of RBCs, in comparison to those observed in the same patients before RBC transfusion. CONCLUSIONS: This study shows that DEB-induced chromosome instability in FA lymphocytes is partially reduced by normal RBCs. This effect may have some clinical relevance in vivo, whenever FA patients receive a RBC transfusion.

Single nucleotide polymorphisms in the apo(a) kringle IV type 8 domain are not associated with atherothrombotic serum lipoprotein (a) concentration, in a Portuguese paediatric population.

Lipoprotein (a) (Lp[a]) is a complex of apolipoprotein (a) (apo[a]) and low-density lipoprotein (LDL), associated with atherothrombotic disease. Most of the interindividual variations in plasma levels of Lp(a) can be attributed to sequence differences linked to the apo(a) gene locus. The aim of this study was to investigate a possible link between single nucleotide polymorphisms (SNPs) in the apo(a) kringle (K) IV type 8 domain and atherothrombotic serum Lp(a) concentrations. Direct sequencing of the two exons and flanking intronic sequences of the apo(a) K IV type 8 domain was performed in a group of 97 paediatric patients, 51 with serum Lp(a) concentration above and 46 with concentration below 30 mg/dl,. We found three SNPs, two in exon 1 (c.66A>C and c.133G>A) and one in intron 1 (c.160+1G>A). The c.66A>C polymorphism was the most common with a heterozygosity frequency of 15.46%. The c.133G>A and c.160+1G>A polymorphisms were found at a frequency of 5.15% and 1.03%, respectively. No statistically significant difference was found in the genotype distribution between the two groups of patients. Our results suggest that these SNPs in the apo(a) K IV 8 domain are not directly associated with atherothrombotic serum Lp(a) concentration in our population.

[Acute renal failure secondary to paroxysmal cold hemoglobinuria]. / Insuficiencia renal aguda secundaria a hemoglobinuria paroxística al frío.

Paroxysmal cold hemoglobinuria is a type of hemolytic anemia that mainly affects children. Tubular renal injury induced by the heme pigment in intravascular hemolysis is a rare cause of renal failure. We describe the case of a 5-year-old boy who presented with dehydration and dark urine a few hours after exposure to cold. The child had had an upper respiratory infection the previous week. He developed anemia and acute renal failure. The direct antiglobulin test was positive with anti-C3c and C3d. The diagnosis of paroxysmal cold hemoglobinuria was confirmed by the presence of biphasic antibody in the Donath-Landsteiner test.

Insuficiencia renal aguda secundaria a hemoglobinuria paroxística al frío / Acute renal failure secondary to paroxysmal cold hemoglobinuria

La hemoglobinuria paroxística al frío es una forma de anemia hemolítica que afecta principalmente a niños. La toxicidad tubular renal del pigmento hemo en situaciones de hemólisis intravascular constituye una etiología rara de insuficiencia renal. Se presenta el caso de un paciente de 5 años que presenta deshidratación y orina oscura horas después de exponerse al frío. Una semana antes había un antecedente de infección de las vías aéreas superiores. En su evolución desarrolla anemia e insuficiencia renal aguda. El test de Coombs directo es positivo con anti-C3c y C3d. La presencia de anticuerpos bifásicos queda demostrada con la prueba de Donath-Landsteiner, lo que confirma el diagnóstico de hemoglobinuria paroxística al frío

Paroxysmal cold hemoglobinuria is a type of hemolytic anemia that mainly affects children. Tubular renal injury induced by the heme pigment in intravascular hemolysis is a rare cause of renal failure. We describe the case of a 5-year-old boy who presented with dehydration and dark urine a few hours after exposure to cold. The child had had an upper respiratory infection the previous week. He developed anemia and acute renal failure. The direct antiglobulin test was positive with anti-C3c and C3d. The diagnosis of paroxysmal cold hemoglobinuria was confirmed by the presence of biphasic antibody in the Donath-Landsteiner test

Erythropoietin levels in the different clinical forms of hereditary spherocytosis.

Erythropoietin (EPO), the main growth factor responsible for the regulation of red blood cell production, may be overproduced when blood loss or haemolysis occurs. Patients with mild hereditary spherocytosis (HS) are able to maintain normal haemoglobin concentration, whereas typical and severe HS patients develop an anaemic state. Splenectomy usually reverses anaemia. We aimed to clarify the role of EPO in the response to enhanced spherocyte destruction, and to look for a linkage with the broad clinical spectra of HS. EPO levels, reticulocyte count and production index (RPI), other parameters used to classify HS and the protein deficiencies underlying HS were evaluated in previously diagnosed unsplenectomised (n = 24) and splenectomised (n = 10) patients presenting mild, typical or severe HS. A significant increase in EPO was observed in all unsplenectomised HS patients. In the mild form, a significant correlation of EPO with reticulocyte count and RPI was observed; however, this correlation disappeared in typical HS patients. Splenectomised HS patients presented a correction in EPO levels in all forms of HS, although the reticulocyte count and RPI sustained slightly higher values. Our data show HS as a disease linked to an overproduction of EPO, according to the severity of the disease; however, a disturbance in erythropoiesis seems to occur in typical HS. Moreover, splenectomy leads to a correction in the EPO levels.

Protein deficiency balance as a predictor of clinical outcome in hereditary spherocytosis.

Vertical and horizontal interactions between membrane constituents account for integrity, strength and deformability of the erythrocyte. Disruption of vertical interactions caused by membrane protein deficiencies in hereditary spherocytosis (HS), favor membrane vesiculation with development of spherocytic cells. Our aim was to evaluate the hematological and clinical presentation of HS according to the type and amount of protein deficiency. We studied 81 Portuguese individuals, 71 belonging to 21 families plus 10 unrelated subjects, and found that 51 of them were HS patients. Patients were classified as presenting mild, typical or severe HS, according to laboratory results and clinical follow-up. We performed screening tests and the standardized electrophoretic membrane protein analysis to identify and quantify protein deficiencies. We found band 3 and ankyrin deficiencies as the major causes for HS. The ratios between the value of the primary and/or secondary protein deficiencies showed significantly different values according to the severity of HS, and a significant inverse correlation with the severity of HS was observed. In mild HS, the ratios between protein deficiencies reflected equivalent protein deficiencies, while an unbalance was observed in typical HS, which was enhanced in severe HS. Our data suggest that the relative quantification of each major membrane protein and of the ratios between the values of protein deficiencies may be helpful in providing additional data about the clinical outcome of HS.

[The identification of multiple thrombophilic risk factors in an infant with cerebrovascular accident]. / Múltiples factores de riesgo trombofílicos identificados en un lactante con accidente vascular cerebral.

INTRODUCTION: Neonatal stroke (NNS) incidence appears to be increasing over the last years. This is believed to be a consequence of diagnostic accuracy rather than a real amplification of this entity. Nowadays, NNS incidence is estimated to be 1:4000 full newborns. CASE REPORT: Child with left middle cerebral artery territory infarction in which several thromboembolic risk factors were documented both in the child (neonatal sepsis and factor V Leiden) and his mother (lupus anticoagulant, pre-eclampsy and factor V Leiden). CONCLUSIONS: This case supports the increasing evidence in recent reports that association of multiple prothrombotic risk factors (maternal and foetal) is present in NNS genesis. This way the authors agree that wide prothrombotic study may be of crucial interest in identifying subjacent thrombophilic disease, even when an exogenous risk factor is present.

Múltiples factores de riesgo trombofílicos identificados en un lactante con accidente vascular cerebral / The identification of multiple thrombophilic risk factors in an infant with cerebrovascular accident

Introducción. La frecuencia del accidente vascular cerebral (AVC) neonatal ha aumentado de manera significativa en los últimos años. Ello puede deberse no tanto a un aumento real del número de casos, como a una mayor certeza en su diagnóstico. Actualmente, su incidencia se ha calculado en un caso por cada 4.000 nacimientos. Caso clínico. Lactante con AVC en el área de la arteria cerebral media izquierda, del cual se disponía de información documentada sobre factores de riesgo (FR) tromboembólicos hereditarios y adquiridos, tanto en el niño (factor V de Leiden y sepsis neonatal) como en la madre (factor V de Leiden, lupus anticoagulante y preeclampsia). Conclusiones. Este caso apoya la evidencia, progresivamente observada en la literatura, de que el AVC neonatal es el resultado de una asociación de diversos FR trombótico (maternos y fetales). En este sentido, los autores consideran importante la investigación sistemática del niño y de su madre, teniendo en cuenta la identificación de una posible enfermedad trombofílica, incluso cuando se haya identificado un factor de riesgo exógeno

Introduction. Neonatal stroke (NNS) incidence appears to be increasing over the last years. This is believed to be a consequence of diagnostic accuracy rather than a real amplification of this entity. Nowadays, NNS incidence is estimated to be 1:4000 full newborns. Case report. Child with left middle cerebral artery territory infarction in which several thrombo-embolic risk factors were documented both in the child (neonatal sepsis and factor V Leiden) and his mother (lupus anticoagulant, pre-eclampsy and factor V Leiden). Conclusions. This case supports the increasing evidence in recent reports that association of multiple prothrombotic risk factors (maternal and foetal) is present in NNS genesis. This way the authors agree that wide prothrombotic study may be of crucial interest in identifying subjacent thrombophilic disease, even when an exogenous risk factor is present

Determination of neutrophil Fcgamma receptor IIIb antigens (HNA-1a, HNA-1b and HNA-1c) by fluorescence-primed allele-specific polymerase chain reaction.

We evaluate a technique for genotyping HNA-1a, -1b and -1c antigens, resorting to fluorescence-primed allele-specific polymerase chain reaction (FPAS-PCR), and determine the frequency of the different genotypes in a normal Portuguese population. Our results indicate that the FPAS-PCR system is a reliable and simple tool for genotyping the neutrophil Fcgamma receptor IIIB antigens. The HNA-1a, -1b and -1c gene frequencies of 42.98, 84.21 and 6.14%, respectively, found in this study are similar to those reported for other white populations.

Coexistence of congenital red cell pyruvate kinase and band 3 deficiency.

The authors report the case of a 9-year-old Caucasian girl, born in northern Portugal, with chronic nonspherocytic haemolytic anaemia and without family history of anaemia. The aethiological study of this anaemia revealed pyruvate kinase deficiency (PKD), because of two previously described mutations (426Arg-->Trp and 510Arg-->Gln). Since the blood smear revealed features not fully compatible with PKD diagnosis, additional tests were performed for the propositus and her parents, namely red blood cell membrane protein analysis. A decrease in proteins band 3 (15%) and 4.2 (18%) was found in the propositus. Her father presented only a decrease in band 3 (11%). Coexistence of PKD and erythrocyte membrane proteins deficiency in the same patient is very uncommon. Our findings suggest that a careful blood smear observation may lead to the identification of a combined deficiency in erythrocyte membrane proteins and enzymopathies.

Properties and microstructure of thermo-pressed wheat gluten films: a comparison with cast films.

Wheat gluten films were prepared by thermo-pressing, and their mechanical properties were compared to those of cast films. The stress-strain relationship was established for films with various amounts of glycerol. Both relationships were quite different, revealing a different network organization. Thermo-pressed films presented higher stress values than cast films, but the effect of the glycerol amount was similar in both cases, an increase of the glycerol amount leading to a decrease of both films stress. The glycerol influence on the strain at break of thermo-pressed films was very limited, with strain values reaching a maximum around 200%. The role of disulfide bridges on themomoulded films mechanical properties was investigated, and it was shown that some rearrangements and a significative protein insolubilization occurred during the process. The effective flow porosity of the protein network for thermo-pressed films was estimated by water capillary rise measurements to about 7%. Scanning electron microscopy was used to obtain some information about the microstructure of both cast and thermo-pressed films.

Molecular determinants of the influence of hydrophilic plasticizers on the mechanical properties of cast wheat gluten films.

The influence of a set of hydrophilic plasticizers varying in their chain length (ethyleneglycol and longer molecules) on the tensile strength and elongation at break of cast gluten films was studied. When considered on a molar basis (moles of plasticizer per mole of amino acid), the effect of the different plasticizers depended on their respective molecular weights for plasticizer/amino acid ratios in the range from 0.10 to 0.40. However, above a ratio of 0.40-0.50 mol/mol of amino acid, these differences were abolished and both stress and strain reached a plateau value, with all plasticizers studied. In fact, when a homologous series of molecules was considered, the ability for plasticizer to decrease stress and increase strain was closely related to the number of hydrogen bonds the molecule was able to share with the protein network. Ethyleneglycol's efficiency was, however, lower than expected from its hydrogen-bonding potential; a comparison with other diols demonstrated that this was due to the small size of this molecule. The particular effect of glycerol concentration on the films' mechanical properties suggested that other molecular features of the plasticizer, such as the number and position of hydroxide groups in the molecule, were involved in the plasticization mechanism.

[Influence of Gilbert's syndrome on serum bilirubin levels and gallstone formation in children with chronic hemolytic disease]. / Influencia del síndrome de Gilbert en los valores de bilirrubina sérica y presencia de litiasis vesicular en pacientes con hemólisis crónica congénita.

To determine whether Gilbert's syndrome increases the risk of gallstone formation in children with chronic hemolytic disease, we studied 44 children with this diagnosis. Gallstones were detected by abdominal ultrasonography. This took place annually in scheduled examinations or in the context of acute abdominal pain. In all patients, the mean values of hemoglobin, reticulocyte and serum bilirubin in the chronic phase were recorded. In addition, TA insertion in the A(TA)nTATAA motif within the promoter region of the enzyme uridine-diphosphate-glucuronyl transferase (UGT1A1) was screened, since this is typically associated with GS.We found 10 (22.7 %) homozygotes for the mutated allele TA*7/TA*7, 12 (27.3 %) TA*6/TA*6 heterozygotes and 22 (50 %) homozygotes for the wild-type allele TA*6/TA*6. No statistically significant differences were found in the values of hemoglobin (Kruskal-Wallis test 2.496; p > 0.05) or in reticulocyte count (Kruskal-Wallis test 1.696; p > 0,05) between the three groups of patients, suggesting a similar degree of hemolysis. Patients with the UGT1A1 TA*7/TA*7 genotype showed higher mean serum bilirubin levels than did patients who were homozygous for the wild-type allele (Mann-Whitney test 35.5; p < 0.05). None of the patients with the TA*6/TA*6 genotype developed gallstones, whereas this complication was found in 2 of 12 (16.6 %) heterozygotes and 6 of 10 (60 %) homozygotes for the allele with TA insertion. In this latter group, 4 patients presented acute pancreatitis as a consequence of gallstone formation.The association between increased bilirubin load due to chronic hemolytic disease and diminished hepatic conjugation leads to raised serum bilirubin levels and consequently to an increased risk of gallstone formation. Therefore, we recommend screening for Gilbert's syndrome in children in the initial phases of chronic hemolytic diseases.

[Transient erythroblastopenia in the context of Epstein-Barr virus infection]. / Eritroblastopenia transitoria en el contexto de infección por el virus de Epstein-Barr.

The authors report the case of a previously healthy 5-year-old boy who, 1 month after tonsillitis, presented severe aregenerative anemia, macrocytosis, and increased hemoglobin F associated with mild thrombocytopenia. Peripheral blood smear showed no significant alterations and bone marrow aspirate revealed markedly decreased red blood cell precursors. Etiological investigation showed elevated titers of Epstein-Barr virus antibodies (IgM anti-viral capsid antigen). Bone marrow biopsy showed no criteria for red cell aplasia and in situ hybridization revealed intracellular Epstein-Barr virus. Reticulocytosis emerged from days 10-17 of follow-up, together with rising hemoglobin. Mean corpuscular volume and hemoglobin F returned to normal 2 months later. Immunological study revealed partial IgG3 deficit that persisted after 1 year of follow-up.

Eritroblastopenia transitoria en el contexto de infección por el virus de Epstein-Barr / Transient erythroblastopenia in the context of Epstein-Barr virus infection

Los autores describen el caso clínico de un niño varón de 5 años de edad, previamente sano que, 1 mes después de una amigdalitis, presentó una anemia arregenerativa grave con macrocitosis y hemoglobina F aumentada, asociada a una trombocitopenia ligera. El frotis de la sangre periférica no presentaba alteraciones significativas y el aspirado de medula ósea revelaba una hipoplasia eritroide marcada. La investigación etiológica reveló la presencia de un título elevado de anticuerpos anti-viral capsid antigen IgM para el virus Epstein-Barr. En la biopsia ósea, sin criterios de aplasia medular, se comprobó la presencia intracelular del virus por hibridación in situ. El día 17 de seguimiento fue posible documentar la aparición de reticulocitosis y el incremento del valor de hemoglobina. El volumen globular medio y el porcentaje de hemoglobina F se normalizaron a los 2 meses. El estudio inmunológico reveló un déficit parcial de IgG3, que mantiene después de 1 año de seguimiento (AU)