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Biomedical subjects

C Y Yu

Publications and source records attributed to C Y Yu.

At least 19 recordsLinked to original sources
PubMed1999

Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations.

The frequent variations of human complement component C4 gene size and gene numbers, plus the extensive polymorphism of the proteins, render C4 an excellent marker for major histocompatibility complex disease associations. As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX module. Duplications of the RCCX modules occurred by the addition of genomic fragments containing a long (L) or a short (S) C4 gene, a CYP21A or a CYP21B gene, and the gene fragments TNXA and RP2. Four major RCCX structures with bimodular L-L, bimodular L-S, monomodular L, and monomodular S are present in the Caucasian population. These modules are readily detectable by TaqI RFLPs. The RCCX modular variations appear to be a root cause for the acquisition of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes. In a patient with congenital adrenal hyperplasia, we discovered a TNXB-TNXA recombinant with the deletion of RP2-C4B-CYP21B. Elucidation of the DNA sequence for the recombination breakpoint region and sequence analyses yielded definitive proof for an unequal crossover between TNXA from a bimodular chromosome and TNXB from a monomodular chromosome.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes.

The complement protein C4, encoded by two genes (C4A and C4B) on chromosome 6p, is the most polymorphic among the MHC III gene products. We investigated the molecular basis of C4 deficiency in a Finnish woman with systemic lupus erythematosus. C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected. This defect in C4 expression was specific in that synthesis of two other complement proteins was normal. Analysis of genomic DNA showed that the proposita had both deleted and nonexpressed C4 genes. Each of her nonexpressed genes, a C4A null gene inherited from the mother, a C4A null gene, and a C4B null gene inherited from the father, all contained an identical 2-bp insertion (TC) after nucleotide 5880 in exon 29, providing the first confirmatory proof of the C4B pseudogene. This mutation has been previously found only in C4A null genes. Although the exon 29/30 junction is spliced accurately, this frameshift mutation generates a premature stop at codon 3 in exon 30. These truncated C4A and C4B gene products were confirmed through RT-PCR and sequence analysis. Among the possible genetic mechanisms that produce identical mutations is both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele.

Adult↗
PubMed1999

Regulation by phosphorylation of the zinc finger protein KRC that binds the kappaB motif and V(D)J recombination signal sequences.

The DNA binding protein KRC (forkappaB binding andrecognitioncomponent of the V(D)J recombination signal sequence) belongs to a family of large zinc finger proteins that bind to the kappaB motif and contains two widely separated DNA binding structures. In addition to the kappaB motif, KRC fusion proteins bind to the signal sequences of V(D)J recombination to form highly ordered complexes. Here, we report that KRC may be regulated by post-translational modifications. Specific protein kinases present in the nucleus of pre-B cells phosphorylated a KRC fusion protein at tyrosine and serine residues. Such protein modifications increased DNA binding, thereby providing a mechanism by which KRC responds to signal transduction pathways. KRC is a substrate of epidermal growth factor receptor kinase and P34cdc2 kinase in vitro. Our results suggest that activation of the KRC family of transcription factors may provide a mechanism by which oncogenic tyrosine kinases regulate genes with kappaB-controlled gene regulatory elements.

Amino Acid Sequence↗
PubMed1999

Influence of incubation time, inoculum size, and glucose concentrations on spectrophotometric endpoint determinations for amphotericin B, fluconazole, and itraconazole.

We addressed the influence of the incubation time (24 h versus 48 h), starting inoculum size (standard inoculum size, approximately 10(3) CFU/ml, versus large inoculum size, approximately 10(4) CFU/ml), and supplementation with 2% glucose of RPMI 1640 medium on the spectrophotometric determination of the MICs of amphotericin B, fluconazole, and itraconazole. We compared the MICs determined spectrophotometrically with those determined by the standard broth macrodilution method (National Committee for Clinical Laboratory Standards approved guideline M27-A). The agreement between the results of the spectrophotometric and standard methods for amphotericin B testing was 100%; this agreement was independent of the inoculum size and incubation time. On the other hand, the agreement for the results for fluconazole testing and itraconazole testing was dependent on the inoculum size and incubation time. With large inoculum size, excellent agreement can be achieved at 24 h. With standard inoculum size, acceptable agreement can be achieved only at 48 h. In contrast to previous observations, the addition of 2% glucose did not have any significant impact on the growth density at 24 h, nor did it improve the agreement with the standard method. Furthermore, supplemental glucose might falsely elevate the MIC at 48 h.

Amphotericin B↗
PubMed1999

An unequal crossover between the RCCX modules of the human MHC leading to the presence of a CYP21B gene and a tenascin TNXB/TNXA-RP2 recombinant between C4A and C4B genes in a patient with juvenile rheumatoid arthritis.

The RCCX module of the human MHC class III region is comprised of four genes arranged in tandem: RP, complement C4, steroid 21-hydroxylase (CYP21), and tenascin X (TNX). Variations in the number and genes of the RCCX modules may lead to genetic and/or autoimmune diseases. Restriction fragment length polymorphism (RFLP) analysis was utilized to determine the RCCX modular variation in patients with juvenile rheumatoid arthritis (JRA). In JRA patient L1, RFLP analysis suggested the presence of a bimodular RCCX structure containing both C4A long and C4B short genes, yet missing the markers for the CYP21A and TNXA genes usually located between the C4A and C4B genes. The 7.5-kb genomic fragment spanning the CYP21-TNX-RP2 genes was cloned and sequenced, revealing that a genetic recombination occurred between TNXA of a bimodular RCCX chromosome and TNXB of a monomodular RCCX chromosome. This recombination results in a new MHC haplotype with a CYP21B gene and a TNXB/TNXA-RP2 recombinant between the two C4 genes. Elucidation of the breakpoint region provides further evidence for the instability of the MHC class III gene region as a result of the RCCX modular variation.

Amino Acid Sequence↗
PubMed1998

Four ubiquitously expressed genes, RD (D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1 (D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA.

The association of the HLA class III region with many diseases motivates the investigation of unidentified genes in the 30-kb segment between complement component genes Bf and C4. RD, which codes for a putative RNA binding protein, is 205 bp downstream of Bf. SKI2W (HGMW-approved symbol SKIV2L), a DEVH-box gene probably involved in RNA turnover, is 171 bp downstream of RD (HGMW-approved symbol D6S45). RP1 (HGMW-approved symbol D6S60E) is located 611 bp upstream of C4. The DNA sequence between human RD and RP1 was determined and the exon-intron structure of SKI2W elucidated. SKI2W consists of 28 exons. The putative RNA helicase domain of Ski2w is encoded by 9 exons. Further analysis of the 2.5-kb intergenic sequence between SKI2W and RP1 led to the discovery of DOM3Z. The full-length cDNA sequence of DOM3Z encodes 396 amino acids with a leucine zipper motif. Dom3z-related proteins are present in simple and complex eukaryotes. In Caenorhabditis elegans, Dom3z-related protein could be involved in the development of germ cells. Human RD-SKI2W and DOM3Z-RP1 are arranged as two head-to-head oriented gene pairs with unmethylated CpG sequences at the common 5' regulatory region of each gene pair. The ubiquitous expression pattern suggests that these four genes are probably housekeeping genes.

Amino Acid Sequence↗
PubMed1998

The human DEVH-box protein Ski2w from the HLA is localized in nucleoli and ribosomes.

The human helicase gene SKI2W is located between RD and RP1 in the class III region of the major histocompatibility complex. Transcripts of SKI2W are detectable in RNA samples isolated from multiple tissues. The protein product Ski2w shares striking amino acid sequence similarities to the yeast antiviral protein Ski2p that controls the translation of mRNAs, probably based on the mRNA structural integrity. Whether this translational regulation mechanism for cellular and viral RNAs exists in mammals is under investigation. Antisera against human Ski2w were generated using fusion proteins produced in bacteria or insect cells. Western blot analysis showed that the endogenous Ski2w protein is approximately 140 kDa in size and is enriched in polysomal fractions of cytoplasmic extracts from HeLa cells. Ribosomal profile studies revealed that Ski2w distributed throughout the entire sucrose gradient in the presence of Mg2+, but co-sedimented with the 18S rRNA-containing 40S subunit and the small ribosomal subunit protein S27a in the presence of EDTA. The co-sedimentation of Ski2w with the 40S subunit is not affected by RNase A treatment of the cell extract, or the addition of KCl to 0.5 M, suggesting that Ski2w is associated with the 40S ribosomal subunit. Indirect immunofluorescence experiments showed that human Ski2w is localized in the nucleoli and in the cytoplasm. In essence, human Ski2w is present at the sites of ribosome biogenesis and protein synthesis.

Amino Acid Sequence↗
PubMed1998

Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired.

Holoprosencephaly (HPE) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a series of patients with hemizygous deletions of the long arm of chromosome 13, we have defined a discrete region in band 13q32 where deletion leads to major developmental anomalies (the 13q32 deletion syndrome). This approximately 1-Mb region lies between markers D135136 and D13S147. Patients in which this region is deleted usually have major congenital malformations, including brain anomalies such as HPE or exencephaly, and digital anomalies such as absent thumbs. We now report that human ZIC2 maps to this critical deletion region and that heterozygous mutations in ZIC2 are associated with HPE. Haploinsufficiency for ZIC2 is likely to cause the brain malformations seen in 13q deletion patients.

Amino Acid Sequence↗
PubMed1998

Effects of early postnatal dexamethasone therapy on calcium homeostasis and bone growth in preterm infants with respiratory distress syndrome.

The effects of dexamethasone therapy on calcium homeostasis and bone growth were evaluated in 49 infants (24 placebo and 25 dexamethasone) who participated in a double-blind trial of early dexamethasone therapy for the prevention of chronic lung disease. Dexamethasone (0.25 mg kg(-1) b.i.d. on d 1-7; 0.12 mg kg(-1) b.i.d. on d 8-14; 0.05 mg kg(-1) b.i.d. on d 15-21; 0.02 mg kg(-1) b.i.d. on d 22-28) or saline placebo was given i.v. Serum calcium (Ca), phosphorus (P) and parathyroid hormone (PTH), and the corresponding urinary excretion of calcium (FECa) and phosphorus (FEP) were measured on d 2, 3, 7, 10, 14, 21 and 28 after starting the study. Radiographic evaluations of bone growth were also evaluated. Infants in the dexamethasone group had significantly higher PTH on d 2 (p < 0.01), 7 and 14 (p < 0.05) than infants in the placebo group. The dexamethasone-treated infants also had significantly higher FEP on d 2, 7 and 14 (p < 0.05) and lower FECa on d 7 and 14 (p < 0.05) than control infants. There was no significant difference between the groups in bone growth during the study. It was concluded that early dexamethasone therapy causes a transient elevation in PTH without apparent change in bone growth. The long-term effect remains to be evaluated further.

Age Factors↗
PubMed1998

Voriconazole against fluconazole-susceptible and resistant candida isolates: in-vitro efficacy compared with that of itraconazole and ketoconazole.

We compared the in-vitro activity of fluconazole, itraconazole, ketoconazole and voriconazole against 67 blood isolates of Candida spp. exhibiting a wide range of fluconazole MICs (0.125 to >64 mg/L). Voriconazole was the most potent in vitro, followed by itraconazole, ketoconazole and fluconazole. Itraconazole and voriconazole had in-vitro activity against fluconazole-susceptible and -resistant candida isolates. Higher itraconazole and voriconazole MICs were observed in isolates exhibiting higher fluconazole MICs, suggesting cross-resistance. Itraconazole and voriconazole MICs of > or =16 mg/L were observed only in Candida albicans and Candida tropicalis. Candida krusei and Candida glabrata exhibited itraconazole MICs of 0.5-1 mg/L and voriconazole MICs of 0.25-0.5 mg/L.

Antifungal Agents↗
PubMed1998

In vitro comparative efficacy of voriconazole and itraconazole against fluconazole-susceptible and -resistant Cryptococcus neoformans isolates.

In vitro susceptibility testing for 50 clinical isolates of fluconazole-susceptible or -resistant Cryptococcus neoformans was performed with itraconazole and voriconazole. Voriconazole was more potent than itraconazole for fluconazole-susceptible isolates and as potent as itraconazole for fluconazole-susceptible dose-dependent isolates and for fluconazole-resistant isolates. For fluconazole-resistant isolates, the voriconazole and itraconazole MICs ranged from 1 to 2 microg/ml.

Antifungal Agents↗
PubMed1998

Molecular genetics of the human MHC complement gene cluster.

The human major histocompatibility complex (MHC) complement gene cluster (MCGC) is a highly variable region that is characterized by polymorphisms, variations in gene size and gene number, and associations with diseases. Deficiencies in complement C2 are either due to abolition of C2 protein synthesis by mini-deletions that caused frameshift mutations, or blocked secretion of the C2 protein by single amino acid substitutions. One, two or three C4 genes may be present in a human MCGC haplotype and these genes may code for C4A, C4B, or both. Deficiencies of C4A or C4B proteins are attributed to the expression of identical C4 isotypes or allotypes from the C4 loci, the absence or deletion of a C4 gene, 2-bp insertion at exon 29 or 1-bp deletion at exon 20 that caused frameshift mutations. The C4 genes are either 21 or 14.6 kb in size due to the presence of endogenous retrovirus HERV-K(C4) in the intron 9 of long C4 genes. A deletion or duplication of a C4 gene is always accompanied by its neighboring genes, RP at the 5' region, and CYP21 and TNX at the 3' region. These four genes form a genetic unit termed the RCCX module. In an RCCX bimodular structure, the pseudogene CYP21A, and partially duplicated gene segments TNXA and RP2 are present between the two C4 loci. The RCCX modular variations in gene number and gene size contributed to unequal crossovers and exchanges of polymorphic sequences/mutations, resulting in the homogenization of C4 polymorphisms and acquisitions of deleterious mutations in RP1, C4A, C4B, CYP21B and TNXB genes. RD, SKI2W, DOM3Z and RP1 are the four novel genes found between Bf and C4. RD and Ski2w proteins may be related to RNA splicing, RNA turnover and regulation of translation. The functions of Dom3z and RP1 are being investigated. The complete genomic DNA sequence between C2 and TNX is now available. This should facilitate a complete documentation of polymorphisms, mutations and disease associations for the MCGC.

Chromosome Mapping↗
PubMed1998

Technetium-99m-HMPAO brain SPECT in neonates with hypoglycemic encephalopathy.

Regional brain injury in three neonates with hypoglycemic encephalopathy are presented using serial 99mTc-hexamethyl propyleneamine oxime (HMPAO) SPECT and, for comparison, MRI. During the acute stage, both 99mTc-HMPAO SPECT and MRI reveal abnormalities in the posterior cerebrum. Technetium-99m-HMPAO SPECT reveals further areas of insult, for example the frontal lobes. The degree of hypoperfusion correlates with the clinical severity of hypoglycemia during the neonatal period and subsequent neurological sequelae. Follow-up with HMPAO SPECT several months after insult demonstrates persistent hypoperfusion in some areas, mainly in the occipital and posterior parietal regions. MRI can depict morphological changes with superior resolution. Because morphological change generally follows slowly after functional change, MRI is less sensitive than HMPAO SPECT in detecting and predicting the extent of hypoglycemic cerebral injury during the acute phase. HMPAO SPECT during the acute stage is a valuable tool for evaluating the extent and severity of brain injury in neonates with hypoglycemic encephalopathy.

Brain↗
PubMed1997

Characterization of focal hepatic masses by dynamic contrast-enhanced MR imaging: findings in 311 lesions.

This study aimed to determine the overall accuracy of known enhancement patterns for the characterization of a large series of focal hepatic masses on dynamic contrast-enhanced magnetic resonance (MR) images. Breath-hold T1-weighted images of the liver acquired before intravenous gadolinium administration and serially over 6-10 min after contrast injection were acquired in < 25 a using FLASH or rapid spin-echo pulse sequences. A total of 311 proven focal hepatic masses in 128 patients were analyzed, including 192 malignant lesions (166 metastases and 26 hepatomas) and 119 benign lesions (48 cavernous hemangiomas, 45 hepatic cysts, and 26 other abnormalities). The lesions were evaluated for a variety of characteristics independently by two reviewers who were blinded to results. Cavernous hemangiomas showed early peripheral nodular enhancement (80% sensitivity and 99% specificity) and hepatic cysts showed no enhancement (100% sensitivity and 95% specificity). Hepatic metastases showed variable, moderate enhancement (47% by one reviewer and 74% by the other). Metastatic lesions from hypervascular primary neoplasms displayed peak enhancement during the hepatic artery dominant (bolus) phase, while other malignant neoplasms showed later peak enhancement (72% sensitivity and 77% specificity). Five metastatic foci with early homogeneous enhancement showed a delayed peripheral washout of contrast (rim sign), while no nonmetastatic foci displayed this finding (3% sensitivity and 100% specificity). Characteristic enhancement patterns of focal hepatic lesions were described in a large series of patients. This study confirms results of previous investigators who have shown that early nodular peripheral enhancement was highly specific for hemangiomas and lack of enhancement was highly specific for hepatic cysts. Hypervascular metastatic foci show earlier peak enhancement than other malignant lesions. Some (2-3%) metastatic lesions display a peripheral washout of contrast on serial images, with 100% specificity.

Adolescent↗