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P Harmatz

Publications and source records attributed to P Harmatz.

16 recordsLinked to original sources
PubMed2005

Pharmacokinetic profile of recombinant human N-acetylgalactosamine 4-sulphatase enzyme replacement therapy in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): a phase I/II study.

AIM: Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme-N-acetylgalactosamine 4-sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double-blind, two-dose (0.2 and 1.0 mg/kg/week) phase I/II study (n = 7) followed by an open-label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. METHODS: Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp-up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. RESULTS: The area under the plasma concentration-time curve (AUC(0-t)) for the high-dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC(0-t) was observed between the low- and high-dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high-dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations. CONCLUSION: Pharmacokinetic parameters appear to be independent of the duration of treatment and are not linear between the 0.2 and 1.0 mg/kg/week doses. Antibodies to rhASB develop in most patients, but their concentration decreases over time. Antibody formation may influence pharmacokinetic parameters during the early phases of treatment, although it appears to have limited impact on biochemical efficacy.

Adolescent↗
PubMed2004

The new SQUID biosusceptometer at Oakland: first year of experience.

Liver iron measurements using biosusceptometers have been validated on two low-TC SQUID (Superconducting Quantum Interference Device) systems (New York and Hamburg) built in the 1980's. Recently, two new instruments have been installed in Torino, Italy (2001), and Oakland, California (2003). The design of the Oakland system is similar to those in Hamburg and Torino. Improvements were made to adjust for significant environmental noise, moreover, an active electronic noise cancellation, a computer controlled water coupling reference system using a pressure feedback and a faster data acquisition system using software lockin amplifiers have been implemented. All 3 systems (Hamburg, Torino, Oakland) are using the same standardized operational protocol. Presented herein are the data collected from 276 patients measured with the SQUID biosusceptometer at Oakland since installation. The results from 149 patients with beta-thalassemia (beta-Thal, age: 2-66 y), 76 patients with sickle-cell disease (SCD, age: 5-55 y), 35 patients with various rare diseases (RD, age: 2-80 y), and 16 patients with hereditary hemochromatosis (HHC, age: 6-74 y) are reported. The liver iron concentration in the different groups are 222 - 7570 (beta-Thal), 518 - 7918 (SCD), 511 - 6234 (RD), 258 - 2041 (HHC) microg/g-liver (in vivo wet weight). The long-term reproducibility (12 months) in a patient on constant treatment regimen demonstrated a mean liver iron of 1141 +/- 133 microg/g-liver. The new SQUID Ferritometer located on the US West coast will give more patients access to this non-invasive liver iron assessment.

Adolescent↗
PubMed2004

Interaction of artificial metallic objects with biosusceptometric measurements.

In human subjects, metallic objects cause distortions of the magnetic fields used by magnetic resonance imaging (0.5 - 3.0 T) or by SQUID biomagnetic liver susceptometry (0.1 - 30 mT) and may lead to artifacts in the measurement of the relaxation rate or the magnetic susceptibility. In biosusceptometry, the measured signal will depend not only on the magnetic susceptibility of the object, but also on its distance to the sensor assembly, and in case of ferromagnetic objects, on the direction of its remanent field. The magnetic susceptibility of a vascular access port-a-cath and of surgical clips have been measured by a SQUID biosusceptometer. Additionally, the impact from port-a-caths and dental braces on liver iron concentration (LIC) measurements was measured in vivo with respect to their radial distance from the gradiometer center axis. For the port-a-cath, a mean magnetic volume susceptibility of (83.5 +/- 0.3).10(-6) SI-units was found, which may be compared with the magnetic susceptibility of titanium at room temperature of (180 +/- 2).10(-6) SI demonstrating the absence of ferromagnetic contamination. At a radial distance of 5 cm from the gradiometer center axis, the voltage amplitude is similar to the signal generated by a normal liver. Modern surgical clips have nearly no impact on LIC measurements. However, dental braces although further away from the center axis, often superimpose the signal even from an iron overloaded liver. Depending on the Ni-content, these objects reveal ferromagnetic properties and contribute in first order with a one parameter reciprocal distance function to the measured liver iron signal.

Artifacts↗
PubMed2004

Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial of enzyme replacement therapy.

Mucopolysaccharidosis type VI (MPS VI), or Maroteaux-Lamy syndrome, is a lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (ARSB). Seven MPS VI patients were chosen for the initial clinical trial of enzyme replacement therapy. Direct sequencing of genomic DNA from these patients was used to identify ARSB mutations. Each individual exon of the ARSB gene was amplified by PCR and subsequently sequenced. Nine substitutions (c.289C>T [p.Q97X], c.629A>G [p.Y210C], c.707T>C [p.L236P], c.936G>T [p.W312C], c.944G>A [p.R315Q], c.962T>C [p.L321P], c.979C>T [p.R327X], c.1151G>A [p.S384N], and c.1450A>G [p.R484G]), two deletions (c.356_358delTAC [p.Y86del] and c.427delG), and one intronic mutation (c.1336+2T>G) were identified. A total of 7 out of the 12 mutations identified were novel (p.Y86del, p.Q97X, p.W312C, p.R327X, c.427delG, p.R484G, and c.1336+2T>G). Two of these novel mutations (p.Y86del and p.W312C) were expressed in Chinese hamster ovary cells and analyzed for residual ARSB activity and mutant ARSB protein. The two common polymorphisms c.1072G>A [p.V358M] and c.1126G>A [p.V376M] were identified among the patients, along with the silent mutation c.1191A>G. Cultured fibroblast ARSB mutant protein and residual activity were determined for each patient, and, together with genotype information, were used to predict the expected clinical severity of each MPS VI patient.

Alternative Splicing↗
PubMed2001

Characterization of glycated hemoglobin in diabetic patients: usefulness of electrospray mass spectrometry in monitoring the extent and distribution of glycation.

A combination of chromatographic and mass spectrometric techniques was used to evaluate the extent and distribution of glycation within the glycated hemoglobin (GHb) molecule. Studies on quantification of hemoglobin (Hb) glycation by electrospray ionization mass spectrometry (ES-MS) of intact globins employed specimens from 10 diabetic individuals and five normal controls. Detailed structural analysis of the phenylboronate affinity chromatography/ion-exchange (IE) HPLC-separated sub-populations of GHb was performed on a specimen carrying 13.7% GHb. An efficient protocol for mapping glycation sites within alpha and beta globins was developed, e.g., Glu-C/Asp-N proteolytic digestion followed by LC-ES-MS. Relative site occupancy within discrete components of GHb was evaluated. A correlation between the degree of glycation measured at Hb level (by affinity chromatography) and at globin level (measured by ES-MS) was carried out. The above studies led us to conclude that during the process of phenylboronate chromatography GHb dimers, rather than tetramers, are bound to the affinity resin so a fraction of glycated dimers rather than tetramers is measured. This finding implies that a process of glycation affects a much higher number of native Hb tetramers than was previously contemplated. No glycation sites appear to be missed by phenylboronate affinity chromatography. We have found no evidence of the presence of multiple glycations within a single globin chain. While glycation of both globins within a dimer cannot be excluded, it is unlikely to be a significant phenomenon. According to ES-MS data, an equivalent of about one globin per alphabeta dimer of the affinity chromatography-isolated GHb carried glycation.

Amino Acid Sequence↗
PubMed2001

Correlation of abnormal intracranial vessel velocity, measured by transcranial Doppler ultrasonography, with abnormal conjunctival vessel velocity, measured by computer-assisted intravital microscopy, in sickle cell disease.

The Stroke Prevention Trial has confirmed that utilization of transcranial Doppler ultrasonography (TCD), which examines blood flow in large intracranial vessels, can identify children with sickle cell disease (SCD) who are at high risk of developing a premature stroke. It is not known to what extent the vasculopathy in SCD involves small vessels and whether the abnormalities, if present, correlate with large-vessel vasculopathy. Eighteen children with SCD were examined with TCD to determine middle cerebral artery (MCA) velocity and computer-assisted intravital microscopy (CAIM) to determine bulbar conjunctival vessel velocity during the same visit for vasculopathy correlation. High MCA velocity (> or = 200 cm/sec) was found by TCD in 4 patients who also showed abnormal conjunctival velocity (< 0.2 mm/sec or intermittent trickle flow) by CAIM. Three patients had conditional (> or = 170 cm/sec and < 200 cm/sec) MCA velocity: 2 showed abnormal (trickle) and 1 showed normal conjunctival velocity (1.9 mm/sec). One patient with unmeasurable MCA velocity had abnormal (trickle) conjunctival velocity. Of the remaining 10 patients who had normal MCA velocity, 2 showed abnormal (0.05 mm/sec and 0.1 mm/sec) and 8 showed normal conjunctival velocities (1.1-2.4 mm/sec). The MCA velocities correlated significantly with bulbar conjunctival flow velocities (P < or =.008, Fisher exact test). A correlation exists between MCA (large-vessel) and conjunctival (small-vessel) flow velocities. CAIM is a noninvasive quantitative technique that might contribute to the identification of SCD patients at high risk of stroke. Small-vessel vasculopathy might be an important pathological indicator and should be further explored in a large-scale study. (Blood. 2001;97:3401-3404)

Adolescent↗
PubMed2000

Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy.

Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 +/- 6.64 mg/g dry weight; R = 0.350, P =.142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P <.001), but serum ferritin at biopsy did not correlate with months of transfusion (R = 0.308, P =.200). Sixteen patients had abnormal biopsies showing mild to moderate changes on evaluation of inflammation or fibrosis. Liver iron was correlated with fibrosis score (R = 0.50, P =.042). No complications were associated with the liver biopsy. Our data suggest that, in patients with sickle cell disease, ferritin is a poor marker for accurately assessing iron overload and should not be used to direct long-term chelation therapy. Despite high levels of liver iron, the associated liver injury was not severe.

Anemia, Sickle Cell↗
PubMed1999

Validation of the Natus CO-Stat End Tidal Breath Analyzer in children and adults.

OBJECTIVE: The performance of a point-of-care, noninvasive end tidal breath carbon monoxide analyzer (CO-Stat End Tidal Breath Analyzer, Natus Medical Inc.) that also reports end tidal carbon dioxide (ETCO2) and respiratory rate (RR), was compared to established, marketed (predicate) devices in children (n = 39) and adults (n = 48) who are normal or at-risk of elevated CO excretion. METHODS: Concentrations of end tidal breath CO (ETCO), room air CO, ETCO corrected for inhaled CO (ETCOc), ETCO2, and RR were measured with the CO-Stat analyzer and the data compared to those obtained from the same subjects using the Vitalograph BreathCO monitor (Vitalograph, Inc.) for ETCOc and the Pryon CO2 monitor (SC210 and SC300, Pryon Corp) for ETCO2 and RR. Adults and children were studied at three medical centers. The data were analyzed by paired t-tests and linear regression. Bias and imprecision between the CO-Stat analyzer and the predicate devices was calculated by the method of Bland and Altman. RESULTS: Paired t-tests, performed on the three parameters measured with the CO-Stat analyzer and predicate devices showed that only the ETCOc values in the adults and the ETCO2 values in the children were significantly different (lower, p < or = 0.0001, and higher, p < or = 0.0001, respectively). The mean bias and imprecision of the CO-Stat analyzer for adult ETCOc and children ETCO2 measurements were -0.9 +/- 1.2 ppm and 0.4 +/- 0.6%, respectively. Linear regression analysis for the ETCOc results in children and adults had a high degree of correlation (r = 0.91 and 0.98, respectively). CONCLUSIONS: We conclude that in a clinical environment the Natus CO-Stat End Tidal Breath Analyzer performs at least as well as predicate devices for the measurements of ETCOc, ETCO2, and RR.

Adolescent↗
PubMed1999

Effects of red blood cell transfusion on resting energy expenditure in adolescents with sickle cell anemia.

BACKGROUND: Previous studies indicate that resting energy expenditure is elevated in children with sickle cell anemia, possibly caused in part by hemolysis and increased erythropoietic activity. The purpose of the present investigation was to determine whether erythrocyte transfusion normalizes resting energy expenditure in sickle cell anemia. METHODS: Five adolescents with sickle cell anemia (12-16 years old; 4 boys, 1 girl) were studied before and 1 week after erythrocyte transfusion before elective surgery or at the initial transfusion for growth failure. Resting energy expenditure was measured by indirect calorimetry, and laboratory measures were determined by routine, validated methods. Data comparisons were by nonparametric analysis. RESULTS: After erythrocyte transfusion, total hemoglobin levels increased (difference (D) = 15 g/l; p < 0.05), whereas hemoglobin S (D = -0.36; p < 0.05) and reticulocyte count (D = -0.12; p < 0.05) decreased. Mean pretransfusion resting energy expenditure was elevated to 124% above predicted levels (p < 0.05) and increased further to 134% above prediction (p < 0.05 vs. pretransfusion levels). Plasma triiodothyronine (T3) levels increased (D = 0.17 nmol/l; p < 0.05), reverse T3 (rT3) levels tended to decline (D = -0.04 nmol/l; p = 0.14), and rT3/T3 decreased (D = -0.03; p < 0.05). Plasma insulin-like growth factor-I (IGF-I) levels were low-normal before transfusion and did not change, despite the change in resting energy expenditure. CONCLUSIONS: The results confirm that resting energy expenditure is elevated in patients with sickle cell anemia. However, resting energy expenditure further increased after transfusion, despite decreased erythropoietic activity. A posttransfusion decrease in rT3/T3 may contribute to the increased resting energy expenditure. That there was no change in IGF-I implies that the growth hormone-IGF system is not involved in posttransfusion regulation of resting energy expenditure. Therefore, our data are not consistent with the hypothesis that increased resting energy expenditure in sickle cell anemia is directly related to erythropoietic activity. The mechanisms by which resting energy expenditure increases after transfusion in sickle cell anemia require additional investigation.

Adolescent↗
PubMed1995

Elevated plasma ceruloplasmin in insulin-dependent diabetes mellitus: evidence for increased oxidative stress as a variable complication.

Ceruloplasmin (Cp) is an acute-phase-responsive oxidase enzyme. Prior reports suggest that Cp is increased in diabetes mellitus, perhaps reflecting greater oxidant stress. However, the situation in insulin-dependent diabetes mellitus (IDDM) per se remains unclear. Furthermore, vitamin C can interfere with one indirect assay for Cp, and vitamin C metabolism is altered in IDDM. We measured Cp levels by both a direct radial immunodiffusion (RID) assay and an indirect oxidase assay in 10 subjects with IDDM and 10 nondiabetics, both at baseline and after 30 days of vitamin C supplementation (100 or 600 mg daily, five subjects per group). Plasma copper level was measured independently also. Our data show that circulating levels of Cp are significantly increased in IDDM subjects as a group, and specifically that Cp is abnormally high in a subset of IDDM individuals. Vitamin C supplementation at either dose interfered with the oxidase assay for Cp in both groups, but vitamin C did not alter the RID assay. The observed increase in plasma copper suggests that circulating holo-Cp is increased. The finding of increased Cp in some individuals with IDDM supports the hypothesis of increased oxidant stress as a variable factor in the spectrum of chronic complications in diabetes. Measurements of Cp level by the oxidase assay must be considered unreliable for subjects taking vitamin C supplements of > or = 100 mg/d.

Acute-Phase Reaction↗
PubMed1989

Prolactin is transported across the epithelium of the jejunum and ileum of the suckling rat.

Milk prolactin is transferred from the gastrointestinal tract to the circulation of the suckling rat. To identify the site of prolactin penetration and to determine the mechanism by which the hormone traverses the mucosal barrier, we followed the uptake of prolactin from ligated loops of jejunum or ileum in vivo by three methods: autoradiography, transport of prolactin-gold conjugates, and immunocytochemistry. Autoradiographic studies demonstrated specific binding sites for 125I-prolactin on apical membranes of the jejunum and ileum. Excess cold prolactin reduced radiolabel in apical and basal compartments. Gel autoradiography of portal sera showed the presence of intact prolactin and a prolactin fragment following jejunal transport but only a prolactin fragment following ileal transport. Uptake of prolactin-gold conjugates demonstrated that, in the jejunum, label was present at the luminal surface, within endosomal compartments and lysosomes, in basal coated and smooth vesicles, within basal coated pits, and beyond the basolateral surface. In the ileum, label was found at the luminal surface; within the tubulocisternae, endosomal vesicles, lysosomes, and basal smooth vesicles; and beyond the basolateral surface. Immunoreactive prolactin was present throughout the transepithelial pathways. This study demonstrates that prolactin is selectively and nonselectively absorbed in the jejunum and ileum and that the hormone is directed either to the lysosome for degradation or across the epithelium by means of a transcellular pathway.

Animals↗
PubMedDate not supplied

Burn severity, copper dose, and plasma ceruloplasmin in burned children during total parenteral nutrition.

Copper (Cu) is an essential nutrient with known metabolic roles in wound healing. Ceruloplasmin (CP), the primary Cu-transport protein, responds as an acute-phase reactive protein after trauma. However, for severe burn trauma, this response is absent in the early catabolic phase despite Cu provision. We report data for 14 severely burned children receiving Cu in total parenteral nutrition (TPN-Cu) ranging from 7 to 26 micrograms Cu.kg-1 x day-1. All patients manifested low plasma levels of CP. The reduction in CP reflected burn severity but also appeared to be dependent on the Cu dose. Increasing Cu supplementation to improve CP raises a concern for hepatotoxicity, which is accompanied by an elevation in the plasma nonceruloplasmin Cu (nonCP-Cu). The calculated plasma nonCP-Cu in our series is consistent with a lack of increased risk and suggests that TPN-Cu at the general pediatric guideline of 20 micrograms.kg-1 x day-1 is safe and reasonable for severely burned children. Cu supplementation > 20 micrograms/kg may be beneficial; however, monitoring of both CP and total Cu should continue as standard practice in the management of these patients.

Burns↗