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Biomedical subjects

B Z Yang

Publications and source records attributed to B Z Yang.

At least 19 recordsLinked to original sources
PubMed2005

Differentiation of long-chain fatty acid oxidation disorders using alternative precursors and acylcarnitine profiling in fibroblasts.

The differentiation of carnitine-acylcarnitine translocase deficiency (CACT) from carnitine palmitoyltransferase type II deficiency (CPT-II) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency from mitochondrial trifunctional protein deficiency (MTP) continues to be ambiguous using current acylcarnitine profiling techniques either from plasma or blood spots, or in the intact cell system (fibroblasts/amniocytes). Currently, enzyme assays are required to unequivocally differentiate CACT from CPT-II, and LCHAD from MTP. Over the years we have studied the responses of numerous FOD deficient cell lines to both even and odd numbered fatty acids of various chain lengths as well as branched-chain amino acids. In doing so, we discovered diagnostic elevations of unlabeled butyrylcarnitine detected only in CACT deficient cell lines when incubated with a shorter chain fatty acid, [7-2H3]heptanoate plus l-carnitine compared to the routinely used long-chain fatty acid, [16-2H3]palmitate. In monitoring the unlabeled C4/C5 acylcarnitine ratio, further differentiation from ETF/ETF-DH is also achieved. Similarly, incubating LCHAD and MTP deficient cell lines with the long-chain branched fatty acid, pristanic acid, and monitoring the C11/C9 acylcarnitine ratio has allowed differentiation between these disorders. These methods may be considered useful alternatives to specific enzyme assays for differentiation between these long-chain fatty acid oxidation disorders, as well as provide insight into new treatment strategies.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2005

Humoral and cellular immune responses to Fasciola gigantica experimental infection in buffaloes.

Humoral and cellular immune responses to Fasciola gigantica experimental infection in buffaloes were studied. The results showed that 33.4+/-9.1% of the infection dose was recovered as adult flukes from infected animals at necropsy. Significant differences of weight gain between infected and non-infected buffaloes was observed at 4 MPI (months post-infection). Anti F. gigantica excretory-secretory products (FgESP)-IgG levels increased significantly from 3 WPI (weeks post-infection) and displayed a peak at 13 WPI. Western blot indicated that in FgESP six major bands of 11.5, 19.0, 23.4, 29.8, 47.5 and 53.2kDa were recognized by F. gigantica-infected buffaloes sera after 0 WPI. Eosinophil numbers increased significantly from 3 WPI in F. gigantica-infected buffaloes and displayed a peak at 8 WPI. Peripheral blood mononuclear cells (PBMC) proliferation induced by FgESP increased from 2 WPI with a peak at 5 WPI. IFNgamma secretion by FgESP-stimulated PBMC appeared early from 1 WPI with three peaks at 2, 5 and 8 WPI, respectively. IL-10 production was observed from 2 WPI with two peaks at 4 and 9 WPI, respectively. Our results suggested that buffaloes were highly susceptible to F. gigantica infection, and this susceptibility could be associated with the late and weak cellular immune response in the early phase of infection and the Th0-like response throughout the infection.

Animals↗
PubMed2001

Carnitine/acylcarnitine translocase deficiency (neonatal phenotype): successful prenatal and postmortem diagnosis associated with a novel mutation in a single family.

The neonatal phenotype of carnitine-acylcarnitine translocase (CACT) deficiency is one of the most severe and usually lethal mitochondrial fat oxidation disorders characterized by hypoketotic hypoglycemia, hyperammonemia, cardiac abnormalities, and early death. In this study, the proband was the daughter of consanguineous Hispanic parents. At 36 h of life, she had bradycardia and died at 4 days of age without a specific diagnosis. In a subsequent pregnancy, prenatal counseling and amniocentesis were provided. Incubation of the amniocytes from this pregnancy and fibroblasts (from the dead proband) with [16-(2)H(3)]palmitic acid and analysis by tandem mass spectrometry revealed an increasedconcentration of [16-(2)H(3)]palmitoylcarnitine, suggesting the diagnoses of either CACT or carnitine palmitoyltransferase II (CPT-II) deficiency. CACT enzyme activity was absent in both cell lines. Molecular investigation of cDNA from the dead proband and her affected sibling revealed aberrant CACT cDNA species, including exon 3 skipping, both exon 3 and 4 skipping, and a 13-bp insertion at cDNA position 388. Investigation of these cell lines for mutations affecting CACT RNA processing by analysis of CACT gene sequences, including intron and exon boundaries, revealed a single nucleotide G deletion at the donor site in intron 3 which resulted in exon skipping and a 13-bp insertion. The proband and her affected sibling were homozygous for this deletion.

Base Sequence↗
PubMed2000

Identification of a novel mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency.

A novel mutation was identified in two unrelated patients with medium-chain acyl-CoA dehydrogenase deficiency. First, a 19-year-old Caucasian female presented with a devastating illness, resulting in sudden death in adulthood which is unusual. The second patient, now a 3.5-year-old male, presented at 17 months of age with a hypoglycemic seizure and dehydration. Sequence analysis revealed a novel mutation G617T in exon 8 resulting in an arginine to leucine substitution at codon 206 (R206L). Both patients were compound heterozygous for this G617T and the common mutation A985G.

Acyl-CoA Dehydrogenase↗
PubMed1999

Identification of two novel mutations in the hypoglycemic phenotype of very long chain acyl-CoA dehydrogenase deficiency.

Very long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of long chain fatty acid oxidation in the mitochondria. Patients with VLCAD deficiency have recently been observed with two clinical phenotypes. The cardiac form presents with an early onset cardiomyopathy and a high incidence of infant death, while the hypoglycemic form resembles medium chain acyl-CoA dehydrogenase (MCAD) manifesting with hypoketotic hypoglycemia. In our investigation on the molecular basis for these phenotypes, we identified two novel mutations in one VLCAD patient with the hypoglycemic form, a C953T (Pro318Leu) mutation in exon 10 resulting in a substitution of proline 318 by leucine on one allele, and a C1194A (Tyr398Stop) mutation in exon 12 which created a premature stop codon TAA on another allele. The Tyr398Stop mutation may result in a truncated protein or instable messenger RNA.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1999

Local fish consumption and serum PCB concentrations among Mohawk men at Akwesasne.

A study was conducted to assess local fish consumption patterns and their relationship to concentrations of total polychlorinated biphenyls (PCBs) in the serum of Mohawk men residing near three hazardous waste sites. From 1992 to 1995, 139 men were interviewed and donated a 20-ml venous blood sample. The results indicated that the men ate a mean of 21.2 local fish meals during the past year, compared with annual means of 27.7 meals 1-2 years before and 88.6 meals more than 2 years before (P<0.001 for test of trend). This change is probably a consequence of advisories issued against the consumption of local fish, since 97% of the men were aware of the advisories and two-thirds had changed their behavior as a result. Multiple regression analysis revealed that serum PCB levels increased with age (beta=0.036, P<0.001) and local fish consumption (beta=0.088, P=0.006). The data suggest that local fish consumption has contributed to body burdens in this population and that the advisories have been effective in modifying local fish consumption habits.

Adolescent↗
PubMed1999

Assessing environmental exposure to PCBs among Mohawks at Akwesasne through the use of geostatistical methods.

The Mohawk Nation at Akwesasne is a Native American community located along the St. Lawrence River in New York State, Ontario, and Quebec. One component of a multiphase human health study was to assess the impact of different pathways of human exposure resulting from the off-site migration of polychlorinated biphenyl (PCB) contamination in this area. This paper illustrates how mapped residential information and environmental sampling data can be united to assist in exposure assessment for epidemiologic studies using geographic information system (GIS) technology and statistical methods. A proportional sampling scheme was developed to collect 119 surface soils. Using a method of cross validation, the average estimated error can be computed and the best estimator can be selected. Seven spatial methods were examined to estimate surface soil PCB concentrations; the lowest relative mean error was 0.42% for Inverse 3 nearest neighbor weighted according to the inverse distance, and the highest relative mean error was 4.4% for Voronoi polygons. Residual plots indicated that all methods performed well except near some of the sampling points that formed the outer boundaries of the sampling distribution.

Environmental Exposure↗
PubMed1998

A novel mutation identified in carnitine palmitoyltransferase II deficiency.

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of mitochondrial fatty-acid oxidation which presents as three distinct phenotypes (neonatal, infantile, and adult onset). CPT II exons from an adult-onset CPT II-deficient patient were amplified and directly sequenced to further investigate the molecular basis of this disorder. A novel mutation, C471T, in exon 4 of the carnitine palmitoyltransferase II gene was found which created a stop codon, TGA, at residue 124 of the protein (R124Stop). This mutation would result in severe protein truncation. This unique mutation was found on one allele while the S113L mutation, previously reported, was present on the other allele.

Adult↗
PubMed1998

Identification of four novel mutations in patients with carnitine palmitoyltransferase II (CPT II) deficiency.

Carnitine palmitoyltransferase II (CPT II) deficiency, an autosomal recessive disorder of fatty-acid oxidation, presents as three distinct phenotypes (neonatal, infantile, and adult onset). In order to investigate the molecular basis of these three phenotypes, six patients with CPT II deficiency have been studied. All six unrelated patients in this study experienced the clinical symptoms of CPT II deficiency. Three patients had the neonatal form, one had the milder infantile form, and the remaining two had the adult-onset form with "muscular" symptoms only. Their diagnoses were based upon in vitro analysis of the mitochondrial beta-oxidation pathway in fibroblasts and standard enzyme assays. We devised a method to screen the entire coding sequence and flanking splice junction of the CPT II gene. A total of six different mutations have been identified, including four novel mutations. Among them, the previously reported common mutation, S113L, was only found in 3 of 12 variant alleles. Three of the six mutations have been identified in a few unrelated patients, while the remaining three have been found in single families. This study, as well as those by others, indicates genetic heterogeneity in this disease. In addition to tabulating the mutations, the correlation of mutant genotype to clinical phenotype is briefly discussed.

Adult↗
PubMed1998

Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease.

Glycogen storage disease type II (GSDII; Pompe disease), caused by inherited deficiency of acid alpha-glucosidase, is a lysosomal disorder affecting heart and skeletal muscles. A mouse model of this disease was obtained by targeted disruption of the murine acid alpha-glucosidase gene (Gaa) in embryonic stem cells. Homozygous knockout mice (Gaa -/-) lack Gaa mRNA and have a virtually complete acid alpha-glucosidase deficiency. Glycogen-containing lysosomes are detected soon after birth in liver, heart and skeletal muscle cells. By 13 weeks of age, large focal deposits of glycogen have formed. Vacuolar spaces stain positive for acid phosphatase as a sign of lysosomal pathology. Both male and female knockout mice are fertile and can be intercrossed to produce progeny. The first born knockout mice are at present 9 months old. Overt clinical symptoms are still absent, but the heart is typically enlarged and the electrocardiogram is abnormal. The mouse model will help greatly to understand the pathogenic mechanism of GSDII and is a valuable instrument to explore the efficacy of different therapeutic interventions.

Animals↗
PubMed1997

Isolation and nucleotide sequence of human liver glycogen debranching enzyme mRNA: identification of multiple tissue-specific isoforms.

Glycogen storage disease type III (GSD-III) is caused by a deficiency of glycogen debranching enzyme (AGL) activity. Patients are found to have deficient AGL activity in both muscle and liver, and also enzyme deficiency in the liver, but not in muscle. To determine the molecular basis of enzymatic variability in GSD-III and to elucidate the mechanism for control of tissue-specific expression of AGL, we previously cloned and sequenced the human muscle AGL cDNA. Here we report the isolation and nucleotide sequence of liver AGL cDNA and the tissue distribution of the isoform mRNAs. The predominant form of human liver AGL cDNA (isoform 1) contained 400 bp of 5' untranslated region, 4596 bp of coding region, and 2371 bp of 3' untranslated region. The liver AGL mRNA sequence was identical to the previously published muscle sequence (isoform 5) for most of the length, except for the 5' end, in which the liver sequence diverged completely from the muscle sequence. The divergence began with the transcription start point and extended 82 nucleotides downstream from the translation initiation codon. Six isoforms of AGL mRNA were identified and sequenced from liver and muscle. These isoforms differed only at the 5' end. Tissue distribution studies showed that liver, kidney and lymphoblastoid cells expressed predominantly isoform 1; whereas muscle and heart expressed not only isoform 1, but also muscle-specific isoform mRNAs (isoforms 2, 3 and 4). Defining tissue-specific AGL isoform mRNAs is an important step toward understanding the molecular basis of enzymatic variability in GSD-III.

Amino Acid Sequence↗
PubMed1996

Improved detection of the G1528C mutation in LCHAD deficiency.

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, an autosomal recessive disorder of fatty-acid oxidation, is clinically characterized by skeletal myopathy, Reye-like syndrome, or sudden unexplained infant death. A common mutation, G1528C, has recently been reported. To avoid nonspecific amplification from a "pseudogene" and potential complications, we have developed a nested PCR/PstI digestion method. Here, we report mutation studies in 11 additional unrelated patients with LCHAD deficiency. Genomic DNA fragments (117 bp) were amplified by the nested PCR, digested with PstI, and subjected to electrophoresis on 12% polyacrylamide gel. Four patients were found to be homozygous for the G1528C mutation; 7 patients were compound heterozygous, indicating significant genetic heterogeneity. The G1528C mutation has been found on at least one allele in all patients with isolated LCHAD deficiency, suggesting that it is an excellent marker for this disease. This DNA test combined with tandem mass-spectrometric in vitro probe analysis easily identifies affected individuals and carriers in families which are compound heterozygous for G1528C.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1994

Studies on structural changes of collagen in silicosis.

In order to provide scientific information on the prevention and treatment of silicosis, studies about changes of silicotic collagen in lungs were carried out. In this paper, we present experiments about the structural changes of collagen in silicotic lungs of rats and patients. These included electron microscopy, circular dichroism and infrared spectroscopy studies of collagen fibers. The results indicated that fibers of silicotic collagen were shorter in length, smaller in diameter and decreased in alpha-helix content. The -Si-O-R- group and -OH group were found increased and -C-C- backbone shortened. The increase of -Si-O-R- group indicated that silica formed linking bridges between collagens which may be the cause of progressive enlargement of nodules.

Animals↗
PubMed1992

Molecular cloning and nucleotide sequence of cDNA encoding human muscle glycogen debranching enzyme.

cDNA comprising the entire length of the human muscle glycogen debranching enzyme was cloned and its nucleotide sequence determined. The debrancher mRNA includes a 4545-base pair coding region and a 2371-base pair 3'-nontranslated region. The calculated molecular mass of the debrancher protein derived from cDNA sequence is 172,614 daltons, consistent with the estimated size of purified protein (Mr 165,000 +/- 500). A partial amino acid sequence (13 internal tryptic peptides with a total of 213 residues) determined on peptides derived from purified porcine muscle debrancher protein confirmed the identity of the cDNA clone. Comparison of the amino acid sequence predicted from the human glycogen debrancher cDNA with the partial protein sequence of the porcine debrancher revealed a high degree (88%) of interspecies sequence identity. RNA blot analysis showed that debrancher mRNA in human muscle, lymphoblastoid cells, and in porcine muscle are all similar in size (approximately 7 kilobases). Two patients with inherited debrancher deficiency had a reduced level of debrancher mRNA, whereas two other patients had no detectable abnormality in RNA blots. The isolation of the debrancher cDNA and determination of its primary structure is an important step toward defining the structure-function relationship of this multifunctional enzyme and in understanding the molecular basis of the type III glycogen storage disease.

Amino Acid Sequence↗
PubMed1992

Assignment of the human glycogen debrancher gene to chromosome 1p21.

Glycogen debranching enzyme is a monomeric protein containing two independent catalytic activities of glycantransferase and glucosidase that are both required for glycogen degradation. Its deficiency causes type III glycogen storage disease. A majority of the patients with this disease have deficient enzyme activity in both liver and muscle (type IIIa) but approximately 15% of them lack enzyme activity only in the liver (type IIIb); however, the enzyme is a monomer and appears to be identical in all the tissues. The cDNA coding for the complete human muscle debranching enzyme has recently been isolated. Using the cDNA clones, the debrancher gene was localized to human chromosome 1 by somatic cell hybrid analysis. Regional assignment to chromosome band 1p21 was determined by in situ hybridization. Mapping of the debrancher gene to a single chromosome site is consistent with our hypotheses that a single gene encodes both liver and muscle debrancher protein.

Animals↗