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.

Hematopoiesis of hereditarily asplenic-athymic (lasat) mice.

The hematopoiesis of athymic-asplenic (lasat) mice was compared with that of normal, asplenic, and athymic littermates with the same strain background. Erythrocyte blood volume, number and survival time were normal when related to the body weight of the animals. Peripheral blood showed leukopenia with absolute and relative lymphopenia, resembling the athymic rather than the asplenic pattern. The bone marrow was hypocellular as a consequence of a decrease in both lymphocytes and erythroid precursors, while thrombocytopoiesis and granulcytopoiesis-monocytopoiesis were essentially normal. Although the percentile value of femoral stem cells was high, their absolute number was, in fact, reduced by 35% as a result of the bone marrow hypocellularity. When lasat bone marrow cells were injected into normal, lethally irradiated mice, a rapid erythropoietic recovery was observed, whereas the restoration of the granlocytic compartment was impaired. It was concluded that: 1) lasat mice depict a normal hematopoiesis in spite of the congenital absence of the thymus and the spleen; 2) bone marrow stem cells may be defective when administered to lethally irradiated hosts; and 3) the athymic status predominates over the asplenic one.

Some aspects of iron metabolism during erythropoietic depression in the mouse.

Spleen and bone marrow patterns of response differ in mice subjected to erythropoietic depressors. Radioiron injected a few hours after a high dose of cyclophosphamide or x-irradiation is retained in the bone marrow. The magnitude of medullary retention is closely related to the number of cells able to synthesize hemoglobin at the moment of iron administration, and to the rate of cell death provoked by the cytotoxic agent. Depressors such as Actinomycin and transfusion, that block the differentiation of stem cells while allowing normal maturation of the erythroid cohort, do not induce marrow entrapment of iron. By contrast, retention is never observed in the spleen, where the 59-Fe turnover is not influenced by the mechanism and magnitude of aplasia. A functional lack of homogeneity of splenic and bone marrow erythropoiesis, hemoglobin metabolism and/or handling of iron stores is proposed. These results would be in agreement with other data from the literature reporting physiological differences among the various sectors of the reticuloendothelial system.

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.

[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.

[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.

[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.

[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.

[Dacie syndrome and other splenomegalies without apparent cause]. / El síndrome de Dacie y otras esplenomegalias sin causa aparente.

Some enlarged spleens do not seem to be related with known pathogenetic mechanisms (passive congestion, functional workload, malignant infiltration and inflammatory or storage disorders). Non-tropical idiopathic splenomegaly (Dacie's syndrome) is a form of hypersplenism of unknown origin that evolves into a non-Hodgkin lymphoma, after a variable interval, in 20% of the patients. Tropical idiopathic splenomegaly (or hyperreactive malarial splenomegaly) develops when a chronic malarial challenge triggers an abnormal immunological response consisting in decreased suppressor T lymphocytes and increased amounts of circulating immunoglobulin M and immunocomplexes, which are cleared by the splenic macrophages. This peculiar response to malaria seems to be linked to particular HLA antigens. Other confusing splenomegalies are seen in Felty's syndrome, in populations subjected to recurrent infections, and in some families. Overlapping findings and diseases suggest chronic antigenic stimulation as a common feature, with diverse responses depending on the host. A small percentage (probably less than 3%) of normal individuals has minimal splenomegaly without any clinical significance.

Postirradiation erythropoietic recovery in splenectomized mice.

The influence of splenectomy on erythropoietic recovery of lethally X-irradiated mice injected with different doses of syngeneic bone marrow was studied. Splenectomized animals showed less activation than unoperated controls in the lower dose range; however, by increasing the number of injected cells the response obtained was similar in both groups. Providing an adequate number of stem cells is administered to the splenectomized recipients, an enhanced erythropoietic activity of the graft may compensate for the absence of the spleen, which is an important organ in postirradiation recovery. Suggested explanations for this observation are lack of an haematopoietic inhibitory effect of the irradiated spleen, or changes in the environment provided by the spleenless host.

Effect of beta adrenergic blockade on surviving to acute hypoxia in mice.

A significant protection against the lethal effects of hypobaric and isobaric hypoxia is observed in mice treated with propranolol. Previous acclimatization to chronic hypoxia does not introduce variations on this protective effect of the beta adrenergic blocking drugs. Similar effects were found using histotoxic anoxia provoked by sodium azide administration. A significative reduction of body temperature is observed under the effects of the blockaders. These findings suggest a reduced need of oxygen in the treated animals. Neutralization of the effects of epinephrine released as a consequence of the hypoxic stress is proposed as the protection mechanism.