High incidence of autoantibodies in Fabry disease patients.

Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism that results from a deficiency of the lysosomal enzyme alpha-galactosidase A. This defect leads to the accumulation of its substrates, mainly globotriaosylceramide, in lysosomes of cells of different tissues. Different studies have shown the involvement of immunopathologies in different sphingolipidoses. The coexistence of FD and immune disorders such as systemic lupus erythematosus, rheumatoid arthritis and IgA nephropathy, has been described in the literature. The aim of this study was to evaluate the prevalence of a group of autoantibodies in a series of Argentine FD patients. Autoantibodies against extractable nuclear antigens (ENAs), double-stranded DNA, anticardiolipin and phosphatidylserine were assayed by ELISA. Lupus anticoagulants were also tested. Fifty-seven per cent of the samples showed reactivity with at least one autoantigen. Such reactivities were more frequent among males than among females. Antiphospholipid autoantibodies were detected in 45% of our patients. The high rate of thrombosis associated with FD could be related, at least in part, to the presence of antiphospholipid autoantibodies in Fabry patients. We found the presence of ENAs, which are a characteristic finding of rheumatological diseases, previous a frequent misdiagnosis of FD, in around 39% of the cases. The detection of a high level of autoantibodies must be correlated clinically to determine the existence of an underlying autoimmune disease. With the recent development of therapy, the life expectancy in FD will increase and autoimmune diseases might play an important role in the morbidity of FD.

Estudios para evaluar el hierro corporal / Studies for evaluation of body iron

Objetivos: Evaluar el estado del hierro del organismo mediante estudios multiparamétricos combinando el receptor de transferrina soluble (RTfs) con Ferritina, hemoglobina, saturación de transferrina (%).Materiales y Métodos: Adultos Sanos (AS)(n=51) y Anémicos Ferroprivos (AF)(n=50). RTfs y Ferritina se determinaron por ELISA. Resultados: El intervalo de confianza de la media del RTfs IC95( µ) fue 15.5-18.1 nmol/L con un 95% de probabilidad en AS. En el grupo AF el mv y rango del RTfs fueron 66.3 nmol/L y 16.1-148.4 nmol/L, ( α) ) 0.05, respectivamente, y el índice RTfs/F fue mayor (75.8) que en AS (nivel de significación 5%).El estudio de la relación RTfs/Hb (p<0.001), 71% (r2) y Ferritina/Hb (p<0.001), 70 % (r2), mostró que para valores de Hb <120g/L, el RTfs es más sensible que la Ferritina. El índice RTfs/F (p<0,001), 72% (r2) mostró aumentos significativos para valores de Ferritinas <12µg/L. Conclusiones: Nuestros estudios confirman que el RTfs detecta con eficiencia diagnóstica cambios sensibles del hierro funcional. El uso combinado del RTfs con parámetros convencionales permite una rápida evaluación del estado del hierro

Objetive: Multi-parameter studies combining serum Transferrin Receptor (sTfR) with Ferritin, hemoglobin, transferrin saturation percentage for an assessment of iron status. Materials and Methods.Subjects: Healthy Adults (HA)(n=51) and Iron-Deficient Anemic Patients (IDAP) (n=50). sTfR and Ferritin were measured by ELISA. Results: Mean confidence interval IC95( µ) showed that the mean value for sTfR was 15.5-18.1 nmol/L (95% probability) in HA group. In IDAP both the sTfR mv and range (66.3 nmol/L, 16.1-148.4 nmol/L, ( α) ) 0.05), and the sTfR/F Index (75.8) were greater than in HA (5% significance level). TfR/Hb (p<0.001), 71% (r2), and Ferritin/Hb (p<0.001), 70 % (r2), showed that for Hb <120g/L, sTfR is more sensitive than Ferritin. sTfR/Ferritin (p<0.001), 72% (r2) showed significant sTfR increases for ferritins <12µg/L. Conclusion: Our studies confirm that the sTfR detects iron-sensitive changes with a diagnostic accuracy. The combined use of sTfR and conventional parameters allows for easier iron status assessment

Serum erythropoietin and its relation with soluble transferrin receptor in patients with different types of anaemia in a locally defined reference population.

Serum erythropoietin (Epo) and soluble transferrin receptor (sTR) were measured in a locally defined reference population (n=100): healthy volunteers (n=50); iron- deficiency anaemia (n=41) and haemolytic anaemia (n=9) (beta-thalassaemia, n = 4; autoimmune, n=5). Our data demonstrated an inverse relationship between erythroid activity and Epo levels. The regression line between Ln Epo and haemoglobin (Hb) was highly significant: P < 0.0001, r2=0.8275, Ln Epo=8.5346-0.04275 Hb, confidence limit 95%. The mean observed/predicted (O/P) ratio of Ln (Epo) was 1.01 +/- 0.11. We demonstrated that the serum Epo concentration in this particular population correlated consistently with clinical measures of erythropoietic activity. sTR, a new index of erythropoiesis, varied from 16.1 to 148 nmol/l, mean 62.0 nmol/l in the anaemic patients' group. The relationship between Ln Epo and Ln sTR was highly significant: P < 0.0001. We conclude that locally defined regression analyses are crucial for correct data interpretation and can indicate whether or not Epo production is appropriate or inappropriate. Serial determinations of sTR could help in the assessment of response to therapeutic doses of Epo.

[Multiparametric analysis for the diagnosis of iron deficiency anemia]. / Análisis multiparametricos para el diagnóstico de la anemia ferropriva.

The serum transferrin receptor (sTR) as a marker of iron depletion was evaluated in two groups: 50 normal adults of both sexes living at sea level and 50 iron deficiency anemias (secondary to nutritional, gastrointestinal or gynecologic diseases). Mean values were 16.6 nmol/L (interval of reference 8.8 to 26.2), for controls, without variations related to age and sex, and 66.3 nmol/L (16.1 to 148.8) for anemic patients. Statistical analysis (receiver operating characteristics, ROC) determined an optimal reference interval of 8.8 to 25.8 nmol/L. Predictive values as a diagnostic tool were 97.5%, PV (+) and 97.7%, PV (-); diagnostic efficiency was 97.7%. In both controls and anemics it was observed: 1) an inverse relationship between sTR and serum ferritin (F) (r2 72%; p < 0.001); 2) wide variations of sTR when plasma hemoglobin (Hb) was < 100 g/L (r2 71%; p < 0.001); 3) values for the sTR/logarithm of serum ferritin ratio (sTR/F index) much higher in anemics (75.8) than in controls (9.6). In the former group, iron supplementation normalized sTR levels but did not change ferritin values. We conclude that sTR is a specific and sensitive index of functional iron deficiency and therefore a quick, accurate and non invasive quantitative parameter for the diagnosis of iron deficient erythropoiesis.

Análisis multiparametricos para el diagnóstico de la anemia ferropriva. / [Multiparametric analysis for the diagnosis of iron deficiency anemia]

The serum transferrin receptor (sTR) as a marker of iron depletion was evaluated in two groups: 50 normal adults of both sexes living at sea level and 50 iron deficiency anemias (secondary to nutritional, gastrointestinal or gynecologic diseases). Mean values were 16.6 nmol/L (interval of reference 8.8 to 26.2), for controls, without variations related to age and sex, and 66.3 nmol/L (16.1 to 148.8) for anemic patients. Statistical analysis (receiver operating characteristics, ROC) determined an optimal reference interval of 8.8 to 25.8 nmol/L. Predictive values as a diagnostic tool were 97.5

, PV (+) and 97.7

, PV (-); diagnostic efficiency was 97.7

. In both controls and anemics it was observed: 1) an inverse relationship between sTR and serum ferritin (F) (r2 72

; p < 0.001); 2) wide variations of sTR when plasma hemoglobin (Hb) was < 100 g/L (r2 71

; p < 0.001); 3) values for the sTR/logarithm of serum ferritin ratio (sTR/F index) much higher in anemics (75.8) than in controls (9.6). In the former group, iron supplementation normalized sTR levels but did not change ferritin values. We conclude that sTR is a specific and sensitive index of functional iron deficiency and therefore a quick, accurate and non invasive quantitative parameter for the diagnosis of iron deficient erythropoiesis.

The hemopoietic system: a phylogenetic approach.

Nomadism is a true hemopoietic characteristic during vertebrate phylogeny and ontogeny. This work reviews the mechanism and developmental steps of hemopoiesis, from a phylogenetic point of view. A summary of the principal hemopoietic "foci" along the evolutionary line is also presented.

[Large granular lymphocytic leukemia. Case report with scarce expression in peripheral blood]. / Leucemia de linfocitos grandes granulares. Presentación de un caso con escasa expresión en sangre periférica.

The case of a 33 year old woman with a large granular lymphocytic leukemia is presented. The main symptoms were neutropenia and recurrent respiratory bacterial infections. No enlargement of the liver, spleen or lymph nodes was noted. Circulating lymphocytes averaged 3000/microliter with 35% of large granular cells. The bone marrow biopsy showed lymphatic infiltration with both nodular and interstitial pattern. Lymphocytes bore the T suppressor phenotype (CD8+, CD45 RO+, CD20-, kappa-, lambda-). Cytogenetic studies revealed a low expression clone with 7q-: del (7)(q36). Gene rearrangements for immunoglobulins or T-cell receptors could not be demonstrated by Southern Blot. Bone marrow cultures grew normally while both normal and patient bone marrow showed marked inhibition when incubated with patients serum. Normalization of the peripheral granulocytic count was obtained with prednisone, while granulocytic-stimulating factors, chlorambucil, and cyclosporine A were partially active or inactive. We suggest that this case represents a form of the lymphoproliferative disease of granular lymphocytes. To our knowledge, the deletion of the long arm of chromosome 7 has not been described in this disease.

[Enzyme replacement therapy in type 1 Gaucher's disease]. / Terapia de reemplazo enzimático en la enfermedad de Gaucher Tipo 1.

Gaucher disease is a sphingolipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GC) and the consequent deposition of glucocerebrosides into the cells of the macrophagic system. Among the three types of clinical disease, type 1 leads to hepatosplenomegaly, hypersplenism and skeletal abnormalities including bone pain, osteopenia and fractures. Two pediatric female patients with moderately severe type 1 Gaucher disease were treated with commercially available GC, mannose terminated to be macrophage-targeted. GC was given by intravenous infusion (30 to 60 units per kilogram of body weight every two weeks) for 8 and 18 months. The hemoglobin concentration increased and the serum acid phosphatase decreased in both patients. In the most affected child, hepatic volume decreased significantly and bony symptoms disappeared. Infusions were uneventful except for an episode of anaphylaxis that subsided rapidly, allowed resumption and did not affect efficacy. These observations are in agreement with the international experience in approximately 800 cases, with good tolerance in all type 1 patients who show objective clinical improvement; patterns of response are variable from patient to patient, independent from previous splenectomy, and dose-dependent; the dose can be tapered after a period of time. Antibodies anti-GC are seen in 13% of the patients, but their presence does not have clinical consequences. The cost of the enzyme makes it crucial to define precise indications, optimal dosing schedules, duration of treatment and cost-benefit ratio.

[Incidence and probable etiology of toxic agranulocytosis in a definite population in the province of Buenos Aires (1963-1976)]. / Incidencia y etiología probable de agranulocitosis tóxica en una población definida de la provincia de Buenos Aires (1963-1976).

The medical records of 55 patients with toxic agranulocytosis (unrelated to radiation, anticancer drugs or known industrial toxics) were reviewed in a well defined population of the Province of Buenos Aires during 1963-1976. There were 65 episodes in 30 women and 25 men, age average 49 years. Nine patients repeated the episode by reexposure to the same drug. The annual incidence rate was 8.4 cases per million/year. Nineteen (35.5%) of the patients died. Forty-three episodes (64.3%) were associated with analgesic-antipyretics, mainly dipyrone (34 cases). In most situations, drugs were prescribed for mild complaints such as pharyngitis, arthralgias or abdominal pain. Although toxic agranulocytosis is an infrequent disease, its relationship with drugs is well known and its mortality remains high.

Incidencia y etiología probable de agranulocitosis tóxica en una población definida de la provincia de Buenos Aires (1963-1976) / Incidence and probable etiology of toxic agranulocytosis in a definite population of the Buenos Aires province (1963-1976

Se revisaron las historias clínicas de 55 enfermos com agranulocitosis tóxica (no relacionada con antineoplásicos, irradiación o tóxicos industriales conocidos), procedentes de la zona de influencia sanitaria de la ciudad de Bahía Blanca, entre 1963 y 1976. Hubieron 65 episodios en 30 mujeres y 25 hombres, con una edad promedio de 49 años. Nueve enfermos repitieron el episodio por reexposición al mismo fármaco. La incidencia anual media fue de 8,4 casos por millón de habitantes por año. Diecinueve pacientes (34,5 por ciento) murieron. Cuarenta y tres episodios (64,3 por ciento se asociaron con analgésicos-antipiréticos, en especial dipirona (34 episodios). En la mayoría de los casos, los fármacos se indicaron por problemas banales tales como faringitis, artralgias o dolor abdominal. Aunque la agrunulocitosis tóxica es una enfermedad infrecuente, su relación con fármacos es bien conocida y su mortalidad es relativamente alta

Terapia de reemplazo enzimático en la enfermedad de Gaucher Tipo 1 / Enzyme replacement therapy in type 1 Gaucher's disease

La enfermedad de Gaucher es una deficiencia de glucocerebrosidasa (GC) con acumulación de glucocerebrósidos en el sistema macrofágico, y da lugar a tres formas clínicas diferentes. De ellas, el tipo 1 se caracteriza por infiltración del bazo, hígado y médula ósea e incluye además alteraciones esqueléticas, evidenciadas por dolor óseo, osteopenia y fracturas. Se trataron dos niñas con GC disponible comercialmente, usando dosis bimensuales entre 30 y 60 U/Kg. En ambas pudo observarse tendencia a la normalización de la hemoglobina y fosfatasa ácida sérica, y en la más afectada menor hepatomegalia y desaparición de los síntomas esquelético. Un episódio de anafilaxia observado en esta misma enferma cedió rápidamente, y pudo continuar el tratamiento sin que ocurriera disminución de la respuesta. Los resultados coincidentes con la experiencia mundial, confirman que el tratamiento con GC es racional y efectivo en la enfermedad de Gaucher tipo I. La tolerancia es buena y no se describen fenómenos de resistencia. La modalidad de respuesta es variable, pero todos los enfermos responden y al cabo de un tiempo se puede disminuir lentamente la dosis. Aun así, el precio de la enzima impone una precisa definición de las indicaciones en función de una óptima relación conto-beneficio

Incidencia y etiología probable de agranulocitosis tóxica en una población definida de la provincia de Buenos Aires (1963-1976). / [Incidence and probable etiology of toxic agranulocytosis in a definite population in the province of Buenos Aires (1963-1976)]

The medical records of 55 patients with toxic agranulocytosis (unrelated to radiation, anticancer drugs or known industrial toxics) were reviewed in a well defined population of the Province of Buenos Aires during 1963-1976. There were 65 episodes in 30 women and 25 men, age average 49 years. Nine patients repeated the episode by reexposure to the same drug. The annual incidence rate was 8.4 cases per million/year. Nineteen (35.5

) of the patients died. Forty-three episodes (64.3

) were associated with analgesic-antipyretics, mainly dipyrone (34 cases). In most situations, drugs were prescribed for mild complaints such as pharyngitis, arthralgias or abdominal pain. Although toxic agranulocytosis is an infrequent disease, its relationship with drugs is well known and its mortality remains high.

Terapia de reemplazo enzimático en la enfermedad de Gaucher Tipo 1. / [Enzyme replacement therapy in type 1 Gauchers disease]

Gaucher disease is a sphingolipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GC) and the consequent deposition of glucocerebrosides into the cells of the macrophagic system. Among the three types of clinical disease, type 1 leads to hepatosplenomegaly, hypersplenism and skeletal abnormalities including bone pain, osteopenia and fractures. Two pediatric female patients with moderately severe type 1 Gaucher disease were treated with commercially available GC, mannose terminated to be macrophage-targeted. GC was given by intravenous infusion (30 to 60 units per kilogram of body weight every two weeks) for 8 and 18 months. The hemoglobin concentration increased and the serum acid phosphatase decreased in both patients. In the most affected child, hepatic volume decreased significantly and bony symptoms disappeared. Infusions were uneventful except for an episode of anaphylaxis that subsided rapidly, allowed resumption and did not affect efficacy. These observations are in agreement with the international experience in approximately 800 cases, with good tolerance in all type 1 patients who show objective clinical improvement; patterns of response are variable from patient to patient, independent from previous splenectomy, and dose-dependent; the dose can be tapered after a period of time. Antibodies anti-GC are seen in 13

of the patients, but their presence does not have clinical consequences. The cost of the enzyme makes it crucial to define precise indications, optimal dosing schedules, duration of treatment and cost-benefit ratio.

Incidencia y etiología probable de agranulocitosis tóxica en una población definida de la provincia de Buenos Aires (1963-1976) / Incidence and probable etiology of toxic agranulocytosis in a definite population of the Buenos Aires province (1963-1976

Se revisaron las historias clínicas de 55 enfermos com agranulocitosis tóxica (no relacionada con antineoplásicos, irradiación o tóxicos industriales conocidos), procedentes de la zona de influencia sanitaria de la ciudad de Bahía Blanca, entre 1963 y 1976. Hubieron 65 episodios en 30 mujeres y 25 hombres, con una edad promedio de 49 años. Nueve enfermos repitieron el episodio por reexposición al mismo fármaco. La incidencia anual media fue de 8,4 casos por millón de habitantes por año. Diecinueve pacientes (34,5 por ciento) murieron. Cuarenta y tres episodios (64,3 por ciento se asociaron con analgésicos-antipiréticos, en especial dipirona (34 episodios). En la mayoría de los casos, los fármacos se indicaron por problemas banales tales como faringitis, artralgias o dolor abdominal. Aunque la agrunulocitosis tóxica es una enfermedad infrecuente, su relación con fármacos es bien conocida y su mortalidad es relativamente alta (AU)

Terapia de reemplazo enzimático en la enfermedad de Gaucher Tipo 1 / Enzyme replacement therapy in type 1 Gauchers disease

La enfermedad de Gaucher es una deficiencia de glucocerebrosidasa (GC) con acumulación de glucocerebrósidos en el sistema macrofágico, y da lugar a tres formas clínicas diferentes. De ellas, el tipo 1 se caracteriza por infiltración del bazo, hígado y médula ósea e incluye además alteraciones esqueléticas, evidenciadas por dolor óseo, osteopenia y fracturas. Se trataron dos niñas con GC disponible comercialmente, usando dosis bimensuales entre 30 y 60 U/Kg. En ambas pudo observarse tendencia a la normalización de la hemoglobina y fosfatasa ácida sérica, y en la más afectada menor hepatomegalia y desaparición de los síntomas esquelético. Un episódio de anafilaxia observado en esta misma enferma cedió rápidamente, y pudo continuar el tratamiento sin que ocurriera disminución de la respuesta. Los resultados coincidentes con la experiencia mundial, confirman que el tratamiento con GC es racional y efectivo en la enfermedad de Gaucher tipo I. La tolerancia es buena y no se describen fenómenos de resistencia. La modalidad de respuesta es variable, pero todos los enfermos responden y al cabo de un tiempo se puede disminuir lentamente la dosis. Aun así, el precio de la enzima impone una precisa definición de las indicaciones en función de una óptima relación conto-beneficio (AU)