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D Elstein

Publications and source records attributed to D Elstein.

67 records · Page 4Linked to original sources
PubMed1994

HCG contamination of alglucerase: clinical implications in low-dose regimen.

Alglucerase (Ceredase) is currently the treatment of choice for patients with symptomatic Gaucher disease. The contamination of this placental enzyme with human chorionic gonadotropin (hCG) has raised concern regarding possible endocrinological complications. We examined 32 patients treated with low-dose alglucerase and 27 untreated patients as controls, and found no significant clinical differences between the two groups: no prepubertal children were affected, no menstrual irregularities were reported, and all hCG levels were well within normal range. Conversely, our finding of a statistically significant difference between the groups underscores the importance of initiating parallel studies of hCG contamination in patients receiving high-dose protocol.

Adult↗
PubMed1994

Low-dose enzyme replacement therapy for Gaucher's disease: effects of age, sex, genotype, and clinical features on response to treatment.

Although alglucerase therapy has become the treatment of choice for symptomatic patients with Gaucher's disease, the low-dose/high-frequency regimen introduced as a means to reduce the high cost of treatment has raised major controversy. We evaluated the efficacy and safety of low-dose alglucerase in 29 patients with Gaucher's disease who completed 6 to 28 months of therapy. All received intravenous alglucerase at a monthly dose of 30 units/kg, given usually in equal doses 3 times a week. All patients responded well to treatment. The hematological improvement and the reduction in organomegaly were satisfactory. No correlation was found between age, sex, genotype, previous splenectomy, or severity score index and the response to treatment. Patients with a greater degree of hepatomegaly tended to have a more pronounced decrease in liver size, although this reduction did not reach statistical significance. We confirmed that a low-dose/high-frequency regimen of alglucerase was as effective as a high-dose/low-frequency protocol in the treatment of Gaucher's disease, even in the severely ill. Whenever cost is an issue, we recommend using this low-dose regimen.

Adolescent↗
PubMed1991

Anomalous mobilities of Na,K-ATPase alpha subunit isoforms in SDS-PAGE: identification by N-terminal sequencing.

Three isoforms of the alpha subunit of Na,K-ATPase, alpha 1, alpha 2, and alpha 3 have been characterized at the DNA, mRNA and protein levels. In admixtures, isoforms migrate as doublets (i.e. alpha 1 and another band originally designated alpha +, comprising alpha 2 + alpha 3) when analyzed by SDS-PAGE. As deduced from cDNA sequences their masses range from 111.7 to 112.6 kDa. With conventional protein standards, however, SDS-PAGE yields nominal masses of 85-105 kDa. In this system, the presence of a doublet that reacted with a polyclonal anti-Na,K-ATPase antibody in the kidney was interpreted as indicating two molecular or conformational species of the kidney alpha sub-unit (Siegel, G.J. and Desmond, T.J. (1989) J. Biol. Chem. 264, 4751-4754). We report that Na,K-ATPase purified from dog, guinea pig and rat kidney medulla or from rat brain, can yield two distinct bands when analyzed by SDS-PAGE or STS-PAGE, migrating between 85 and 105 kDa. An additional band migrating at 117 and 120 kDa appears often in enzyme purified from rat and guinea pig kidney medulla. The apparent molecular weights and relative intensities of these bands vary with temperature and duration of incubation during sample preparation. N-terminal sequencing and monospecific antibody probes revealed that the two distinct bands obtained from the kidney enzyme consist only of the alpha 1 isoform. The band appearing at 117-120 kDa also contains only the alpha 1 N-terminal sequence. In contrast, as reported earlier (Sweadner, K.J. (1979) J. Biol. Chem. 254, 6060-6067), the doublet seen in brain preparations consists of alpha 1 and alpha 2 or (alpha 2 + alpha 3). We conclude that monospecific antibody probes or N-terminal sequencing must be used to identify Na,K-ATPase isoforms by SDS- or STS-PAGE. In addition, gel conditions that may affect the mobilities of the isoforms are discussed.

Amino Acid Sequence↗
PubMed1986

Na,K-ATPase activity and 25(OH)vitamin D3 hydroxylation in rat proximal tubules.

The proximal tubule is the target site for parathyroid hormone (PTH), and conversion of 25(OH)vitamin D3 hormones which impinge on calcium (Ca) homeostasis, as well as a major site for sodium (Na) reabsorption. The effect of changes in PTH and vitamin D status on Na,K-ATPase activity, as a measure of Na transport, were studied in the proximal tubules of adult rat kidneys where Na and Ca reabsorption rates are in parallel. Na,K-ATPase activity and 25(OH)D3 metabolism were determined in cortical and juxtamedullary proximal tubule segments from normal, parathyroidectomized (PTX), and vitamin D-deficient (-D) rats. Na,K-ATPase activity was highest in cortical segments. PTX led to a decrease in activity in convoluted segments but increased activity in straight segments. In -D rats, Na,K-ATPase activity decreased in cortical segments but increased in juxtamedullary segments. 25(OH)D3 was metabolized more to 24,25(OH)2D3 than to 1,25(OH)2D3 in all normal segments. Juxtamedullary segments were more sensitive to PTX and -D conditions. These findings suggest that cortical and juxtamedullary nephrons are inherently different in basal Na,K-ATPase activity, in conversion of 25(OH)D3 to active metabolites, and in response to altered PTH and vitamin D3 status.

Animals↗
PubMed1985

Regulation of 25-OH-D3 1 alpha-hydroxylase and 24-hydroxylase activities along the rat nephron and in isolated kidney cells.

The regulation of 25-OH-D3 metabolism in isolated cells of one kidney and microdissected single nephron segments from the contralateral kidney was studied. Preparations from rats fed a normal diet produced only 24,25-OH2-D3, in isolated cells (7.9 pmol/1.25 X 10(6) cells/min; 5 micron 25-OH-D3), in proximal convoluted tubules (PCT; 1.9 pmol/mm/min; 0.1 mM 25-OH-D3), and proximal straight tubules (PST; 1.5 pmol/mm/min; 0.1 mM 25-OH-D3). Distal tubules (DT) did not metabolize 25-OH-D3. Rats pretreated with 1,25-(OH)2-D3 produced more 24,25-(OH)2-D3 in PST (2.49 pmol/mm/min), with no change of metabolism in the isolated cells, PCT and DT. Preparations from vitamin D deficient rats produced both 24,25-(OH)2-D3 and 1,25-(OH)2-D3: 7.2 and 4.6 pmol/1.25 X 10(6) cells/min, respectively, in the cells, 0.9 and 0.3 pmol/mm/min in PCT and 1.2 and 0.4 in PST. These results confirm that rat PCT and PST have 24-hydroxylase activity, that in vitamin D deficiency, rat renal cells, PCT and PST all have both 24-hydroxylase and 1 alpha-hydroxylase activity, and that 1,25-(OH)2-D3 pretreatment increases the 24-hydroxylase activity in the PST but not in the PCT.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMedDate not supplied

Viral infections and phenotypic heterogeneity in Gaucher disease.

Gaucher disease, the most common lysosomal storage disorder, is remarkable for its tremendous phenotypic heterogeneity even among patients with the same genotype. Beyond mutations at the 1q21 locus, there may be other genetic and environmental factors that impact on the natural course of Gaucher disease and indeed may trigger symptoms and signs. Among candidate events are viral infections such as the Epstein-Barr virus (EBV) or cytomegalovirus (CMV). The purpose of this study was to ascertain if indeed prior infection with EBV or CMV in patients homozygous for the most common mutation, N370S (1226G), is predictive of a more severe phenotype. Evidence for an EBV virus was IgG and IgM antibodies to early antigen and IgG anti-EBNA. For CMV infection, IgG and IgM antibodies were sought. This study failed to demonstrate any correlation between prior EBV or CMV infection and clinical course of Gaucher disease in patients homozygous for the N370S (1226G) mutation. The only positive finding was a higher level of anti-EBNA antibodies among patients with moderate/severe disease. In conclusion, other than a small subset of patients who showed a pattern comparable to immunosuppression, there was no association between severity of Gaucher disease and prior EBV or CMV infection.

Cytomegalovirus Infections↗
PubMedDate not supplied

Chitotriosidase deficiency in survivors of Candida sepsis.

The existence of chitotriosidase, a human chitinolytic enzyme, hydrolyzes artificial chitotrioside substrates, but its specific function in humans is unknown. The homologous chitinases have an anti-fungal action in plants. In patients with Gaucher disease, chitotriosidase activity is markedly elevated and is a marker for response to specific treatment. In all populations, 6% of individuals are enzyme deficient but completely healthy. It was hypothesized that chitotriosidase deficient persons may be more vulnerable to fungal infections. Thus, the objective of the study was to ascertain the prevalence of homozygosity for the mutation of chitotriosidase among survivors of Candida sepsis. The prevalence of homozygosity among survivors was similar to that in the normal population. Although the cohort is the largest of its kind, since only survivors were tested, further studies should include all patients with Candida sepsis for comparison of survival rates among deficient versus sufficient individuals, and thereby elucidate if this enzyme has an anti-fungal function in man. Several theories are considered to explain the results.

Adult↗
PubMedDate not supplied

The 1226G (N370S) Gaucher mutation among patients with Legg-Calve-Perthes disease.

Legg-Calve-Perthes disease (LCPD) is an avascular necrosis of the femoral head with an annual incidence of 5-15/100,000. The estimated incidence of Gaucher disease, a lysosomal recessive storage disease, is 1:850, with a carrier rate of 1:17.5 for the 1226G (N370S) mutation among Ashkenazi Jews in whom there is a predilection. Since clinical and radiological findings of avascular hip necrosis due to either Gaucher disease or LCPD may be indistinguishable, misdiagnosis may occur. The purpose of this study was to evaluate the incidence of 1226G Gaucher mutation in a cohort of radiologically confirmed LCPD patients (diagnosed 1986-2000) in Israel. Enzyme assay was performed for confirmation of affected versus carrier status in patients with the 1226G mutation. In all, 78 LCPD patients, 86% males, 51% with severe bone disease, were studied. Family history was negative for Gaucher disease. Ethnic origin was 39% Ashkenazi Jewish, 6% Arab, and 55% other ethnicities. One Ashkenazi Jewish LCPD patient was homozygous for the 1226G mutation, and 4 LCPD patients were carriers: 3 Ashkenazi Jewish and 1 Arab patient. The frequency of the 1226G mutation among the LCPD patients was increased relative to historical Ashkenazi Jewish Israeli controls (P = 0.01). Since Gaucher disease may be misdiagnosed as LCPD, glucocerebrosidase enzyme testing is recommended among Ashkenazi Jewish children diagnosed with LCPD.

Clinical Enzyme Tests↗