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Biomedical subjects

F Peter

Publications and source records attributed to F Peter.

At least 19 recordsLinked to original sources

[Treatment of chronic viral hepatitis with recombinant interferon-alfa].

The antiviral treatment with alfa-interferon is the first proven therapeutic possibility in chronic viral hepatitis. The rate of improvement to alfa-interferon ranges between 15-40% depending on the type of hepatitis. The optimal dose is 5 MU/day three times a week for 6 months in chronic hepatitis B, while 3 MU/day three times a week for months in chronic hepatitis C. Results of therapy can be improved using combination treatment in selected cases.

Chronic Disease

Different sorting of Lys-Asp-Glu-Leu proteins in rat liver.

Most of the resident soluble proteins of the endoplasmic reticulum (ER) seem to be sorted into this compartment via their COOH-terminal tetrapeptide Lys-Asp-Glu-Leu (KDEL). This sorting is supposed to occur in a post-ER compartment. Three resident soluble ER glycoproteins belonging to the KDEL family are CaBP1, CaBP2, CaBP3 (= calreticulin), and CaBP4 (= grp94) (Nguyen Van, P., Peter, F., and Söling, H.-D. (1989) J. Biol. Chem. 264, 17494-17501). In rat liver, calreticulin possesses a carbohydrate moiety of the complex hybrid type with terminal galactoses (Nguyen Van, P., Peter, F., and Söling, H.-D. (1989) J. Biol. Chem. 264, 17494-17501). We can show now that practically all calreticulin molecules (and not only a fraction) possess terminal galactoses as well as the COOH-terminal KDEL sequence. This as well as pulse-chase experiments performed at 37 and 15 degrees C indicate that calreticulin must have passed through the trans-Golgi. Subcellular fractionations of post-mitochondrial supernatants from isolated rat hepatocytes by sucrose-Nycodenz gradient centrifugation revealed that calreticulin is confined mainly to the rough ER, grp94 mainly to the smooth ER. CaBP1, a member of the thioredoxin family, was recovered in fractions which most likely represent the intermediate compartment. This indicates that KDEL is a sorting signal which leads to the retention of these proteins in the pre-Golgi compartments. However, additional factors, most likely residing within the specific KDEL protein itself, determine the final location of the protein within the pre-Golgi compartments. This is underlined by experiments in which the density dependent distribution of total KDEL proteins was studied using a COOH-terminal KDEL-specific antibody.

Amino Acid Sequence

Intellectual assessment of hypothyroid children detected by screening.

The IQ was studied in 50 children with CH. Normal distribution of IQ was found in patients detected by neonatal screening. Close relationship was observed between subnormal IQ values (less than 90) and undetectable serum Tg levels (less than 0.3 ng/ml). The intellectual outcome in children with CH depends considerably from the intrauterine hypothyroidism.

Adolescent

Four intracisternal calcium-binding glycoproteins from rat liver microsomes with high affinity for calcium. No indication for calsequestrin-like proteins in inositol 1,4,5-trisphosphate-sensitive calcium sequestering rat liver vesicles.

It has been claimed that the inositol 1,4,5-trisphosphate-sensitive calcium pool in liver and pancreatic acinar cells is located in specified organelles ("calciosomes") which are characterized by their content of the calcium-binding protein calsequestrin (Volpe, P., Krause, K. H., Hashimoto, S., Zorzato, F., Pozzan, T., Meldolesi, J., and Lew, D. P. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 1091-1095). We show here that the inositol 1,4,5-trisphosphate-sensitive compartment of rat liver does not contain calsequestrin-like material. Instead four non-membraneous calcium-binding glycoproteins with approximate molecular masses of 59, 60, 80, and 90 kDa were found. The 59-, 80-, and 90-kDa proteins were of the high mannose-rich type, the carbohydrate moiety of the 60-kDa protein was of the complex hybrid type with terminal galactoses. All four proteins had high affinity binding sites for calcium (KD between 1 and 5 microM) and from 1 to 5 binding sites/molecule. The 80- and the 90-kDa proteins had also low affinity binding sites (KD 400 and 600 microM, respectively, with 13 and 15 binding sites/molecule, respectively). A comparison of the NH2-terminal sequences revealed that the 60-kDa calcium-binding protein represents the rat liver calregulin, whereas the 90-kDa calcium-binding protein represents grp94. The sequences did not reveal any relationship of the 80-kDa protein with grp78, or of the 59-kDa protein with protein disulfide isomerase.

Amino Acid Sequence

Intramuscular administration of iron during long-term chelation therapy with 2,3-dimercaptosuccinic acid in a man with severe lead poisoning.

2,3-Dimercaptosuccinic acid (DMSA) an investigational chelant structurally similar to dimercaptopropanol (BAL), offers the advantage of not depleting iron stores on which basis it would not seem to form a toxic chelate with iron. We report the case of a man with a formidable body burden of lead (Pb) and depleted iron stores who was given iron intramuscularly during a defined period of long-term retreatment with DMSA. Initiation of retreatment with DMSA, 30 mg/kg/day given orally in three divided doses for the first 7 days markedly enhanced Pb diuresis, entailed a pronounced fall in blood Pb and abolished symptoms of Pb poisoning. Continuation of retreatment with two-thirds the initial DMSA dose for an added 15 days maintained blood Pb at sustained low levels. Iron sorbitol administered intramuscularly during this period in individual doses of 100 mg of elemental iron given 3 days apart to a conservative total of 400 mg produced no untoward effects, suggesting that a toxic chelate between iron and DMSA was not formed. Serum ferritin entered the normal range and there was virtually an immediate significant decrease in erythrocyte protoporphyrin. Together with discernible increases in haemoglobin, haematocrit and MCV, this pointed to enhanced iron utilization. Since iron utilization is curtailed by high concentrations of Pb, the immediacy and magnitude of the post-chelation rebound in blood Pb precluded iron administration at any other stage. From these data, DMSA emerges as a uniquely versatile new chelant. Suitable for long-term administration, it permits the simultaneous parenteral administration of iron during dose-related sustained decreases in blood Pb.

Adult

Protoporphyrinaemia and decreased activities of 5-aminolevulinic acid dehydrase and uroporphyrinogen I synthetase in erythrocytes of a Vitamin B6-deficient epileptic boy given valproic acid and carbamazepine.

Carbamazepine (CBMZP) has been implicated as an inhibitor of the activities of 5-aminolaevulinic acid dehydratase (ALA-D) and uroporphyrinogen I synthetase (URO-S). In an epileptic boy undergoing long-term treatment with valproic acid (VPA), 1.3 g/d, CBMZP, 0.9 g/d and folic acid, 7.5 mg/d, decreased activities of ALA-D and URO-S coincided with increased levels of erythrocyte protoporphyrin (EP) in the absence of Pb poisoning, iron depletion and erythropoietic protoporphyria. A progressive fall in plasma pyridoxal 5'-phosphate (B6-P) to 7.7 nmol/L (lower reference limit, 14.6 nmol/L) prompted implementation of pyridoxine HCl (B6-HCl), 87.5 mg/d followed by administration of both B6-HCl and preformed B6-P (50 mg/d each). This permitted the eventual withdrawal of VPA and a net reduction of CBMZP to 450 mg/d. During these manipulations, ALA-D and URO-S activities, EP and urinary porphyrins and their precursors were measured serially. An assay system utilizing red cell ALA-D for generation of porphobilinogen (PBG) from added ALA at pH 7.4 was used for determination of ALA-D and URO-S activities in separate aliquots of the same assay mixture both in the absence and presence of Zn and dithiothreitol (DTT). One unit (U) for ALA-D = 1 nmol PBG/L RBC/s; for URO-S = 1 nmol porphyrin/L/s; minimum normal level for ALA-D = 135 U; for URO-S = 6 U. B6-HCl alone entailed increases in ALA-D and URO-S prior to any reduction of CBMZP. After administration of both B6-HCl and B6-P and withdrawal of VPA, the overall increase in ALA-D was from 54.59 to 197.2 U (-Zn; -DTT) and from 50.76 to 217.3 U (+Zn; +DTT). The overall increase in URO-S was from 2.67 to 8.90 U (-Zn; -DTT) and from 3.02 to 8.66 U (+Zn; +DTT). During stepwise reduction of VPA, EP remained elevated to values as high as 2.48 mumol/L (upper reference limit, 1.33 mumol/L). Only after permanent withdrawal of VPA did concentrations of EP fall to normal levels. Values for porphyrins and their precursors in urine were normal throughout. Since both VPA and B6-P are strongly protein-bound, it is suggested that VPA displaced B6-P from protective protein binding sites and that the resulting deficit in B6-P (rather than CBMZP) reduced ALA-D and URO-S activities via primary reduction of ALA-synthetase activity. Increases in EP emerge as a hitherto unappreciated effect of VPA warranting further investigation.

Ammonia-Lyases

The lead program at CPRI.

A lead (Pb) screening program in operation at CPRI in London, Ontario, since 1977 involves simultaneous measurement of blood Pb and erythrocyte protoporphyrin (EP) in a randomized population of physically and/or mentally handicapped children and adolescents on admission, discharge and during outpatient visits. This 11-year study has yielded a large database for computerized evaluation. Based upon log normal transformation of data obtained from the admission and outpatient groups, the normal curve yielded a mean and standard deviation (SD) for blood Pb of 0.36 +/- 0.27 mumol/L (n = 4188). This fosters a downward revision of the upper reference limit to 0.89 mumol/L (95% confidence level). The overall mean for EP was 0.35 +/- 0.37 mumol/L and suggests an upper reference limit of 1.09 mumol/L. The direct correlation between annual means of blood Pb and EP retained its significance (r = 0.80; P less than 0.004). For both blood Pb and EP, there was no significant difference in values between admissions (n = 1455), discharges (n = 1310) and outpatient visits (n = 2963). Only in the case of blood Pb was the overall mean value of males (n = 3822) higher (0.46 +/- 0.34 mumol/L) than that of females (0.39 +/- 0.25 mumol/L; n = 1906), but by t-test the difference was not significant. Although annual means of both blood Pb and EP were highest in 1978 and 79 and lowest in 1987, there was no significant difference between any two years.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

Microsampling technique and determination of blood lead by Zeeman atomic absorption spectrophotometry.

Quality control materials and participation in proficiency testing programmes were used for assessing the long-term performance of our blood lead analysis. The accuracy and precision of the blood controls, Metals 1 and 2 from the Behring Institute, were evaluated over a 1-year period. The accuracy of the method was also monitored by the Centers for Disease Control (CDC) Blood Lead Proficiency Testing Programme over a 3-year period. Nearly 85% (28 out of 33 samples) of our results were within +/- 5% of the CDC reference values. There were excellent correlations between our results and the target values of several proficiency testing samples, with correlation coefficient values of 0.9959-0.9970. The method was used for the screening of blood lead in children in conjunction with microsampling techniques.

Child

A comparison of fatty acid composition of cholesteryl esters in subjects at various concentrations of serum lipid.

We have evaluated the fatty acid composition of high density lipoprotein (HDL) cholesteryl esters in serum specimens of 83 male subjects, divided into 2 groups: one with a mean HDL cholesterol of 0.75 mmol/L and the other with 1.25 mmol/L. The specimens with low HDL cholesterol concentrations had an increase in the proportion of palmitic acid (6%) and stearic acid (67%) compared with specimens and high HDL cholesterol concentration. When the fatty acid composition of the same specimens was evaluated in groups corresponding to the four major phenotypes (normolipidemic, hypercholesterolemic, hypertriglyceridemic and hyperlipidemic), we found statistically no significant differences between these groups in the HDL cholesteryl ester fraction. There were, however, statistically significant differences between the hyperlipidemic group and the other three groups in the proportions of palmitoleic, oleic and stearic acids, and in the ratio of oleic/linoleic acids of total cholesteryl esters.

Adult

Fluorometric determination of erythrocyte protoporphyrin in blood, a comparison between direct (hematofluorometric) and indirect (extraction) methods.

We measured the concentration of erythrocyte protoporphyrin in 43 blood samples by two fluorometric methods. In the indirect method, protoporphyrin was extracted from blood and the fluorescence of the free acid in the extract was determined with a filter-fluorometer. These results were compared with results of direct determination of protoporphyrin in the same samples. In the direct assay the fluorescence of protoporphyrin, present in blood as the zinc salt, was measured without extraction, with the use of a hematofluorometer. Comparison of the results of the direct and indirect methods showed an excellent correlation (r = 0.986), but the hematofluorometric values (y) were approximately 9% lower than the fluorometric values (y = 0.911x). The slope of the regression line (0.911) is likely to be different for each hematofluorometer-fluorometer combination. Therefore, hematofluorometric values can only be compared with fluorometric values if the slope of the regression line is known and is used as a correction factor.

Erythrocytes

Lead-erythrocyte protoporphyrin correlation in blood of exposed workers.

A systematic survey of blood samples from 174 industrial workers occupationally exposed to lead fumes and lead dust, revealed some poor correlations between the lead (Pb) level and the free erythrocyte protoporphyrin (FEP) level. In addition to those workers who had an expected correlation (normal Pb-normal FEP or elevated Pb-elevated FEP) there were two groups with atypical correlations. In one group a normal Pb level was associated with an elevated FEP level and in the other group an elevated Pb level was associated with a normal FEP level. This shows that neither the Pb nor the FEP test can substitute for the other. Since the individual FEP response to Pb absorption is unpredictable, both tests should be carried out routinely. This would make it possible to determine simultaneously the degree of absorption (Pb level) and the degree of intoxication (FEP level) and would improve significantly the assessment of undue lead absorption of occupationally exposed workers. If, however, only one of these tests is used for screening the other test should always be carried out as a confirmatory test when the screening detects an elevated Pb or FEP level.

Environmental Exposure

Quantitative analysis of human serum cholesterol by thin-layer chromatographic spot test.

A fast, inexpensive, simple method is described for the determination of the total cholesterol concentration in human serum. The cholesterols (free and esterified) are extracted from serum by a double extraction procedure, using isopropanol-water-10 N sodium hydroxide (250:125:10) and then n-octane. An aliquot of the octane extract is spotted on a thin-layer plate and the cholesterol in the spot is rendered visible using an aqueous phosphomolybdic acid staining solution and a heat treatment for the color development. The colored spot is scanned with a densitometer.

1-Propanol