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A Zimran

Publications and source records attributed to A Zimran.

At least 19 recordsLinked to original sources
PubMed2000

The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease.

BACKGROUND: The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. METHODS: Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. RESULTS: Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. CONCLUSIONS: The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.

Adolescent↗
PubMed2000

Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.

BACKGROUND: Current treatment for Gaucher's disease involves administration of intravenous glucocerebrosidase to degrade glucocerebroside stored in lysosomes. Lowering the rate of biosynthesis of glucocerebroside should decrease accumulation of this substrate. We investigated the safety and efficacy of OGT 918 (N-butyldeoxynojirimycin), an inhibitor of glucosyltransferase, as a novel oral treatment for non-neuronopathic Gaucher's disease. METHODS: We recruited, into a 1-year open-label study, 28 adults (seven with previous splenectomies) from four national Gaucher's referral clinics, who were unable or unwilling to receive enzyme treatment. We measured liver and spleen volume by computed tomography or magnetic resonance imaging at baseline and at months 6 and 12, and biochemical and haematological variables monthly, including chitotriosidase activity (a sensitive marker of Gaucher's disease activity). Patients were started on 100 mg oral OGT 918 three times daily. FINDINGS: Baseline liver volumes were 1.1-2.7 times normal and spleen volumes 5.1-24.8 times normal. At 12 months, mean liver and spleen volumes were significantly lowered by 12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respectively (each p<0.001). Haematological variables improved slightly. Mean organ volume and blood counts improved continually between 6 months and 12 months of treatment. Mean chitotriosidase concentrations fell by 16.4% over 12 months (p<.0001). Six patients withdrew because of gastrointestinal complaints (two), personal reasons (two), or severe pre-existing disease (two). The most frequent adverse effect was diarrhoea, which occurred in 79% of patients shortly after the start of treatment. INTERPRETATION: Decrease of substrate formation by OGT 918 improves key clinical features of non-neuronopathic Gaucher's disease. The strategy justifies further trials in this and other glycosphingolipid storage disorders.

1-Deoxynojirimycin↗
PubMed2000

Withdrawal of enzyme replacement therapy in Gaucher's disease.

Although enzyme replacement therapy is safe and effective in ameliorating the signs and symptoms of Gaucher's disease, some patients have withdrawn from treatment. The purpose of this study was to evaluate the response to withdrawal and to discuss the implications for patients currently on unaltered therapy regimens since the advent of treatment. Fifteen patients, who had been treated with enzyme replacement for 5-56 months and then withdrew for 8-47 months, were assessed for changes in haematological parameters and in liver and spleen index volume. Despite non-uniformity of duration of on and off periods, degree of organomegaly, anaemia and thrombocytopenia, most patients did not revert to respective baseline values in most parameters after withdrawal. None of the patients suffered exacerbation of bone involvement or had new or aggravated pulmonary hypertension. Adult patients with stable Gaucher's disease may be withdrawn from therapy for circumscribed periods without forfeiting most gains accrued during enzyme therapy. Therefore, stopping and restarting may be considered in some patients. Alternatively, maintenance at reduced dosage and/or frequency may be appropriate in some adult patients who are stable or non-responsive after the first years of enzyme therapy. This caveat does not apply to children.

Adolescent↗
PubMed2000

Effect of ozone on red blood cell enzymes and intermediates.

Ozone autohemotherapy has been considered a form of alternative medicine and has not yet been subjected to the rigors of well-designed clinical trials. Despite encouraging anecdotal reports regarding the use of ozone in various disorders, there has been a concern that ozone per se may adversely affect red cell membranes and metabolites. The purpose of this study was to ascertain the effect of ozone administration at a concentration commonly used in autohemotherapy on a panel of red cell enzymes and intermediates, as well as its effect on red cell integrity. Since these parameters were unaffected by ozone, we suggest that clinical trials for the use of ozone autohemotherapy should be encouraged.

Adenosine Triphosphate↗
PubMed1999

Platelet function abnormalities in Gaucher disease patients.

Bleeding manifestations are common in Gaucher disease patients. Although usually attributed to thrombocytopenia, some patients with relatively high platelet counts and normal coagulation tests have hemorrhagic phenomena. To investigate whether perturbed platelet function could explain these bleeding manifestations we performed platelet aggregation tests on 32 type I adult Gaucher patients who were not severely thrombocytopenic (platelet counts >50 x 10(9)/L). Seven patients (22%) had abnormal platelet aggregation. In five, platelet aggregation was markedly reduced in response to collagen and ADP and virtually absent in response to epinephrine, whereas two patients had isolated severely impaired epinephrine-induced aggregation. In one patient platelet aggregation markedly improved following one year of enzyme replacement therapy. Incubating normal platelets with high concentrations of glucocerebroside did not impair their ability to aggregate, suggesting that plasma glucocerebroside does not directly interfere with platelet function. Platelet dysfunction is a hitherto unrecognised, relatively common cause of excessive bleeding in Gaucher patients.

Adolescent↗
PubMed1999

Two novel polymorphic sequences in the glucocerebrosidase gene region enhance mutational screening and founder effect studies of patients with Gaucher disease.

Gaucher disease, an inherited glycolipid storage disorder, is caused by a deficiency of the catabolic enzyme glucocerebrosidase (EC 3.2.1.45). The gene for human glucocerebrosidase is located on chromosome 1q21 and has a highly homologous pseudogene situated 16 kb downstream. We report two novel polymorphic sequences in the glucocerebrosidase gene region: the first consists of a variable number of dinucleotide (CT) repeats located 3.2 kb upstream from the glucocerebrosidase gene, and the second is a tetranucleotide (AAAT) repeat found between the glucocerebrosidase gene and its pseudogene, 9.8 kb downstream from the functional gene. These polymorphic sequences, along with a previously reported PvuII polymorphism in intron 6 of the glucocerebrosidase gene, were analyzed in patients with Gaucher disease (n=106) and in two normal control populations, one of Ashkenazi Jewish ancestry (n=72) and the second comprising non-Jewish individuals (n=46). In these samples, strong linkage disequilibrium was found between mutations N370S, c.84-85insG, and R463C and specific haplotypes; no significant linkage disequilibrium was found when examining haplotypes of patients with the L444P mutation. Studies of these polymorphic sites in several instances also led to the recognition of genotyping errors and the identification of unusual recombinant alleles. These new polymorphic sites provide additional tools for mutational screening and founder effect studies of Gaucher disease.

Amino Acid Substitution↗
PubMed1999

Is there a correlation between degree of splenomegaly, symptoms and hypersplenism? A study of 218 patients with Gaucher disease.

Despite the prevalence of splenomegaly as a sign in many disorders, there have been no studies that correlate the degree of organomegaly with the symptoms generally ascribed to splenic enlargement. The degree of splenomegaly was compared with five overt symptoms of mechanical displacement, i.e. chronic abdominal pain, abdominal discomfort, early satiety, pain while lying on the side, or attacks of acute (colicky) left upper quadrant pains. We have also employed splenomegaly as seen in Gaucher disease as a paradigm to determine whether there is a correlation between the degree of splenomegaly and the parameters of hypersplenism. Although there was a statistically significant correlation between degree of splenomegaly and blood counts, this proved to be clinically negligible. Surprisingly, there was also no correlation between degree of splenomegaly and any of symptoms investigated.

Abdominal Pain↗
PubMed1999

Gaucher's disease with valve calcification: possible role of Gaucher cells, bone matrix proteins and integrins.

Gaucher's disease, an autosomal recessive storage disease, leads to deposition of glucocerebrosides in various organs, especially those of the reticuloendothelial system. The heart is not thought to be frequently involved and studies of patients with cardiac involvement have concentrated on myocardial involvement. Despite careful prior investigation Gaucher cells have never been detected in the valves of these patients. Pathological findings of a patient with Gaucher's disease, type IIIc, with prominent cardiac valvular involvement are reported and, for the first time, the presence of Gaucher cells in the valve tissue is documented. There is evidence that the pathogenesis of the valvular injury may be by way of a cell-mediated mechanism involving bone matrix proteins and integrins.

Adolescent↗
PubMed1999

Cytokines in Gaucher's disease.

Gaucher's disease (GD) is characterized by hepatosplenomegaly, bone marrow infiltration, osteonecrosis, which may all be associated with the presence of pathological macrophages that contain undegraded glycosphingolipids. Levels of serum cytokines, which are soluble products of mononuclear phagocytes (MNP), were evaluated in 24 GD patients. Levels of interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and soluble interleukin-2 receptor (sIL-2R) in GD patients were significantly higher than in normal controls. We attempted to correlate cytokine levels with disease severity. Type I GD patients with more severe clinical manifestations had significantly higher levels of IL-1beta, IL-1Ra and IL-6, relative to type I patients with milder disease. Three patients homozygous for the 1448C mutation with neuropathic type III disease, had significantly higher levels of sIL-2R than type I patients or controls. We speculate that cytokine over-expression may relate to the pathophysiology of some of the clinical manifestations of GD. Thus, the elevated IL-1beta, TNF-alpha and IL-6 levels may induce the bone manifestations, the neutrophil chemotaxis and the increased incidence of hyper-gammaglobulinemia present in GD patients.

Chemotaxis, Leukocyte↗
PubMed1998

Echocardiographic assessment of pulmonary hypertension in Gaucher's disease.

BACKGROUND: Enzyme therapy has been shown to decrease the signs and symptoms of Gaucher's disease. A few patients, however, develop pulmonary hypertension on such treatment. We investigated the frequency of pulmonary hypertension in Gaucher's disease. METHODS: We studied 134 adults with type 1 Gaucher's disease, including 73 patients on enzyme replacement, with echocardiography. We measured tricuspid incompetence (TI) with continuous-wave doppler. Pulmonary hypertension was indicated by a TI gradient of more than 30 mm Hg. FINDINGS: Nine (7%) patients had pulmonary hypertension: all were treated and six had undergone splenectomy. Chest radiographs confirmed the presence of pulmonary hypertension in these patients as well as in most patients with TI gradients of 25-29 mm Hg. INTERPRETATION: The confounding effects of disease severity and splenectomy in many treated patients precluded definitive conclusion of cause and effect. Nonetheless, we found an unexpectedly high rate of pulmonary hypertension and recommended routine echocardiographic monitoring of all treated and untreated patients with type 1 Gaucher's disease. We also suggest consideration of treatment withdrawal if the TI gradient progresses to more than 30 mm Hg.

Adult↗