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Biomedical subjects

L C Tsui

Publications and source records attributed to L C Tsui.

At least 127 records · Page 7Linked to original sources
PubMed1996

Smooth pursuit eye movements in the evaluation of famotidine adjunctive therapy of schizophrenia: a preliminary report.

Smooth pursuit eye movements (SPEM) are often abnormal in schizophrenic patients and have been proposed as a trait marker of the disorder. We explored the use of SPEM as an outcome measure in an open-label clinical trial of famotidine, an H-2 antagonist, in patients with schizophrenia; famotidine has been proposed as an adjunctive medication, particularly for negative symptoms. Prior studies using SPEM as an outcome measure have not found a significant effect with "typical" neuroleptic medication, and one study found greater SPEM dysfunction with clozapine treatment. In this study, 19 schizophrenic subjects were stabilized for at least 1 week on conventional neuroleptic medications and then administered oral famotidine, 100 mg daily, for an additional 3 weeks. SPEM and clinical measures were assessed. Whereas Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessment of Negative Symptoms (SANS) scores decreased significantly with famotidine administration, there was no significant change in SPEM performance over the course of the study. Two subjects (11%) doubled their signal/noise ratio and maintained this increase after famotidine discontinuation, whereas three subjects (17%) approximately halved this ratio and returned to baseline after famotidine discontinuation. SPEM changes were not found to correlate significantly with changes in BPRS or SANS scores. These findings suggest that SPEM dysfunction reflects a "trait" rather than clinical "state" in schizophrenia, and changes in SPEM performance might not be expected always to parallel changes in clinical ratings.

Antipsychotic Agents↗
PubMed1996

An open-label study of the therapeutic efficacy of high-dose famotidine adjuvant pharmacotherapy in schizophrenia: preliminary evidence for treatment efficacy.

Histaminergic projections innervate brain areas implicated in the pathophysiology of schizophrenia. In a previous open-label study, there was the suggestion that famotidine, and H2 histamine-receptor antagonist, possessed adjuvant therapeutic properties when added to the stable neuroleptic medications regimens of 10 treatment-refractory patients. In that study, the maximal dosage of famotidine was limited to 40 mg/day, the recommended maximal dosage for the treatment of peptic ulcer disease. In this study, we examined 18 patients fulfilling DSM-III-R criteria for schizophrenia and schizoaffective disorder who had famotidine (100 mg/day) added to their stable neuroleptic medication regimen. Patients were rated on baseline, weekly thereafter, and 1 week after famotidine discontinuation, by using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Assessment of Negative Symptoms (SANS), and the Clinical Global Impression (CGI). On all of these outcome measures, statistically significant improvements suggestive of a beneficial adjunctive effect of famotidine were found. Famotidine (100 mg/day) was well tolerated by the study subjects. There was a wide range of famotidine blood levels achieved at the end of 3 weeks of famotidine adjunctive treatment, but these blood levels did not correlate with BPRS or SANS score changes. However, the patients with the greatest improvement in BPRS scores (and without concomitant deterioration in SAND scores) had some of the higher famotidine levels found in the study. Double-blind studies further assessing the potential adjunctive benefit of famotidine in the treatment of schizophrenia are indicated.

Adult↗
PubMed1996

Positional candidate genes for congenital chloride diarrhea suggested by high-resolution physical mapping in chromosome region 7q31.

Congenital chloride diarrhea affects intestinal transportation of electrolytes, resulting in potentially fatal diarrhea. Linkage disequilibrium analyses have suggested the congenital chloride diarrhea gene (CLD) to lie within 0.37 cM from D7S496 in human chromosome 7q31. To clone the CLD gene, we have constructed and refined a physical map based on a 2.7-Mb YAC contig around D7S496 and identified two candidate genes. The physical positions of 4 known genes (DRA, PRKAR2B, LAMB1, DLD), 7 polymorphic repeat markers, and 13 CpG islands were established. DRA (down-regulated in adenoma) is expressed in the gut and encodes a protein with sequence homology to anion transporters, whereas PRKAR2B encodes a regulatory subunit for protein kinase A. Both genes map within 450 kb from D7S496, making them functionally and positionally relevant candidates for CLD.

Base Sequence↗
PubMed1996

Genomic organization and FISH mapping of human Pmel 17, the putative silver locus.

The Pmel 17 gene is expressed preferentially in pigment cells. It has been mapped to human chromosome 12 pter-q21 and mouse chromosome 10, near the silver locus. The Pmel 17 gene contains an insertional mutation at its carboxyl terminus in the silver mouse, suggesting that the silver locus might correspond to the gene. In the current studies, we have isolated and characterized human Pmel 17 genomic clones and employed FISH mapping for a precise localization of this gene in the human chromosome. The FISH mapping placed the Pmel 17 gene at human chromosome 12 q12-q13. The human gene consists of nine exons and eight introns, and the entire coding region of the gene spans approximately 7.9 kb of the human chromosome 12. The putative functional domains, such as the signal sequence, histidine-rich, 26-amino acid repeats, cysteinerich, transmembrane and cytoplasmic domains, were encoded by separate exons. Cistranscription elements such as a TATA, a CAT and other potential elements for pigment cell-specific gene expression were found within 1100 base pairs of the 5' flanking region.

Amino Acid Sequence↗
PubMed1996

Localization of the human gene encoding the 13.3-kDa subunit of mitochondrial complex III (UQCRB) to 8q22 by in situ hybridization.

We have localized the human gene encoding the 13.3-kDa subunit of mitochondrial complex III (UQCRB) to chromosome 8 using both radioactive in situ hybridization and fluorescence in situ hybridization. The additional peak obtained with the former method is attributed to the higher sensitivity of this technique, which results in hybridization of the probe to the less conserved pseudogene. We therefore conclude that the functional gene is most likely located at 8q22.

Chromosome Mapping↗
PubMed1995

Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors.

We employed the polymerase chain reaction and genomic DNA library screening to clone novel human genes, GPR9 and GPR10, and a rat gene, GPR14. GPR9, GPR10, and GPR14 each encode G protein-coupled receptors. GPR10 and GPR14 are intronless within their coding regions, while GPR9 contains at least one intron. The receptor encoded by GPR9 shares the highest identity with human IL-8 receptor type B (38% overall and 53% in the transmembrane regions), followed by IL-8 receptor type A (36% overall and 51% in the transmembrane domains). GPR10 encodes a receptor that shares highest identity with the neuropeptide Y receptor (31% overall and 46% in the transmembrane domains). The receptor encoded by GPR14 shares highest identity with the somatostatin receptor SSTR 4 (27% overall and 41% in the transmembrane domains). Fluorescence in situ hybridization analysis localized GPR9 to chromosome 8p11.2-p12 and GPR10 to chromosome 10q25.3-q26.

Amino Acid Sequence↗
PubMed1995

Sequence analysis and chromosomal localization of human Cap Z. Conserved residues within the actin-binding domain may link Cap Z to gelsolin/severin and profilin protein families.

From a human retinal cDNA library, we have isolated cDNAs that are homologs for the alpha 2 and beta subunits of chicken Cap Z. The derived human alpha subunit shares 95% amino acid identity with the chicken alpha 2 subunit; the beta subunit is 99% identical to the chicken subunit residues 1-243. The remaining portion of the human beta subunit (244-272) diverges significantly with only 8 out of 29 C-terminal amino acids conserved between the two species. This lack of conservation is of particular interest because the chicken C terminus contains an actin-binding domain. Cosedimentation assays with F-actin show that human Cap Z binds actin with an affinity equal that of chicken Cap Z. These results point to the eight shared amino acids as critical for actin binding, three of which are regularly spaced leucines. These apolar residues and one outside the region of divergence align well with those residues of the actin-binding alpha-helix proposed for gelsolin segment 1. The apolar residues as well as three polar amino acids are also conserved in other capping, capping and severing, and monomer-binding proteins. Amino acid substitutions in the chicken beta subunit of the two most highly conserved leucines result in significant decreases in F-actin binding activity. The human alpha 2 gene (CAPZA2) has been mapped to chromosome 7 position q31.2-q31.3 and the beta gene (CAPZB) to chromosome 1 region p36.1.

Actins↗
PubMed1995

The cloning and chromosomal mapping of two novel human opioid-somatostatin-like receptor genes, GPR7 and GPR8, expressed in discrete areas of the brain.

Following the cloning of the opioid receptors mu, kappa, and delta, we conducted a search for related receptors. Using oligonucleotides based on the opioid and also the structurally related somatostatin receptors, we amplified genomic DNA using the polymerase chain reaction and isolated fragments of novel G protein-coupled receptor genes. Two of these gene fragments designated clones 12 and 11 were used to isolate the full-length genes. The intronless coding sequences of these genes, named GPR7 and GPR8, shared 70% identity with each other, and each shared significant similarity with the sequences encoding transmembrane regions of the opioid and somatostatin receptors. GPR7 was mapped to chromosome 10q11.2-q21.1 and GPR8 to chromosome 20q13.3. Northern blot analysis using human mRNA demonstrated expression of GPR7 mainly in cerebellum and frontal cortex, while GPR8 was located mainly in the frontal cortex. In situ hybridization revealed expression of GPR7 in the human pituitary. A partial sequence of the mouse orthologue of GPR7 was obtained, and in situ hybridization demonstrated expression in discrete nuclei of brain, namely suprachiasmatic, arcuate, and ventromedial nuclei of hypothalamus. A stable cell line expressing the GPR7 gene was created, but expression levels of the receptor were low. The available pharmacology indicated binding to several opioid drugs such as bremazocine, levorphanol, and beta-FNA, but not to the opioid receptor subtype-selective mu, delta, or kappa agonists.

Amino Acid Sequence↗
PubMed1995

Identification of six mutations (R31L, 441delA, 681delC, 1461ins4, W1089R, E1104X) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Six new mutations have been identified in the CFTR gene. These mutations, representing three different categories--missense (R31L, W1098R), nonsense (E1104X), and frameshift (441delA, 681delC, 1461ins4)--are located in exons 2, 4, 5, 9, and 17b of the gene and presumed to cause cystic fibrosis (CF) in patients. All these mutations are probably rare in the population, as no additional examples were found for any of them in a cohort of 545 CF patients. Our study also revealed a benign sequence variation (3499 + 45T-->C) in intron 17b.

Adult↗
PubMed1995

Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations.

OBJECTIVE: To compare differences in epithelial chloride conductance according to class of mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: We evaluated the relationship between the functional classes of CFTR mutations and chloride conductance using the first diagnostic sweat chloride concentration in a large cystic fibrosis (CF) population. RESULTS: There was no difference in sweat chloride value value between classes of CFTR mutations that produce no protein (class I), fail to reach the apical membrane because of defective processing (class II), or produce protein that fails to respond to cyclic adenosine monophosphate (class III). Those mutations that produce a cyclic adenosine monophosphate-responsive channel with reduced conductance (class IV) were associated with a significantly lower, intermediate sweat chloride value. However, patients with the mutations that cause reduced synthesis or partially defective processing of normal CFTR (class V) had sweat chloride concentrations similar to those in classes I to III. CONCLUSION: Studies of differences in chloride conductance between functional classes of CFTR mutations provide insight into phenotypic expression of the disease.

Child↗
PubMed1995

Isolation of three novel human genes encoding G protein-coupled receptors.

We have cloned and mapped the chromosomal location of three novel human genes encoding G protein-coupled receptors that we have named GPR6, GPR5, and GPR4. The entire coding region for each of these genes was contained on single exons. Gene GPR6 encoded a receptor that shared closest identity (71% in the transmembrane regions) with the human orphan receptor GPR3 and was localized to chromosome 6 (q21-q22.1). Northern blot analysis revealed that GPR6 transcripts were abundant in the human putamen and to a lesser extent in the frontal cortex, hippocampus, and hypothalamus. Gene GPR5 encoded a receptor that most closely resembled the orphan receptor RBS11 (48% in the transmembrane regions) and the MIP 1 alpha/RANTES receptor (45% in the transmembrane regions) and was localized to chromosome 3 (p21.3-p21.1). Gene GPR4 shared identity (40% in the transmembrane regions) with the human platelet-activating factor receptor and was localized to chromosome 19 (q13.2-q13.3).

Amino Acid Sequence↗
PubMed1995

Localization to chromosome 7q36.1 of the human XRCC2 gene, determining sensitivity to DNA-damaging agents.

The identification of genes controlling cellular response to DNA damage is of considerable importance, and cell lines showing hypersensitivity to DNA-damaging agents can be used as vehicles to map and clone these genes. In this study the hamster cell line irs1, showing hypersensitivity to a number of different DNA-damaging agents, was fused to normal human cells to complement the defect. The resultant hybrids were analysed by Alu-PCR, chromosome painting, and with DNA markers to map the complementing gene (named XRCC2) to a specific chromosomal region. These hybrids showed correction of sensitivity to both X-rays and to mitomycin-C, and contained human chromosome 7, often as their only human component. Hybrids showing unstable retention of human chromosomes were sub-cloned to show that loss of chromosome 7 and loss of resistance to mitomycin-C occurred concordantly. Two separate hybrids were found to have a smaller piece of chromosome 7, and specific DNA probes and microsatellite markers defined this as a contiguous region at 7q35-36. Hybrid irradiation-fusion methods were used to further reduce the size of the complementing genomic region and to localize the gene to an approximately 3-5 Mb region at 7q36.1.

Animals↗
PubMed1995

Famotidine adjunctive pharmacotherapy of schizophrenia: a case report.

Recent reports suggest some utility for famotidine, a histamine type 2 (H2) antagonist, in the treatment of schizophrenia. The current report describes a treatment-resistant patient with chronic undifferentiated schizophrenia whose most dramatic symptomatic improvements were temporarily related to the open-label addition of famotidine (40-100 mg/day) to conventional neuroleptic treatment (molindone 150-200 mg/day) over the course of approximately 10 months. During one 2-week interval, his symptoms were controlled with famotidine (40 mg/day) alone. The case suggests that some adjuvant efficacy exists for famotidine in at least some patients with schizophrenia. Placebo-controlled trials are needed to more fully evaluate the utility of famotidine in the treatment of schizophrenia.

Famotidine↗
PubMed1995

A YAC-based contig of 1.5 Mb spanning the human multidrug resistance gene region and delineating the amplification unit in three human multidrug-resistant cell lines.

A contig of 21 nonchimeric yeast artificial chromosomes (YACs) has been assembled across 1.5 Mb of the multidrug resistance (MDR) gene region located at 7q21, and formatted with four previously reported probes, six newly isolated probes, and three sequence-tagged sites (STSs) from internal and end fragments of YACs. A physical map of rare cutter restriction enzyme sites across the region was also constructed by pulsed-field gel electrophoretic (PFGE) analysis of four overlapping YAC clones. The amplification unit of this region in different cell lines was then determined by Southern blot analysis on the basis of the physical map and probes. Amplified DNA was located in extrachromosomal elements in human MDR cell lines studied here, and the size of the amplification unit was determined to be discrete in one MDR amplification but variable in others.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1995

Skipping of exon 12 as a consequence of a point mutation (1898 + 5G-->T) in the cystic fibrosis transmembrane conductance regulator gene found in a consanguineous Chinese family.

A point mutation (1898 + 5G-->T) located five base pairs downstream from the donor splice site in intron 12 of the CFTR gene has been identified in a consanguineous CF patient of Chinese origin. To determine if this nucleotide substitution could affect mRNA splicing, PCR analysis was performed with RNA isolated from the lymphoblastoid cell line of the mother of the deceased patient. While exon 12-minus transcript was detected in this sample, it was also found in individuals without 1898 + 5G-->T, albeit in a smaller proportion. Using a sequence polymorphism associated with each of the two alleles in the mother, however, we showed that mutant transcript was almost exclusively produced by the 1898 + 5G-->T allele. Skipping of exon 12 would result in the deletion of 29 amino acids from the first nucleotide binding domain of CFTR, rendering the protein non-functional. The possibility of a low level (< or = 2.5%) of normal transcript from the mutant allele cannot be excluded and it may explain the pancreatic sufficient phenotype of the patient. The 1898 + 5G-->T mutation was found in two other CF patients of Chinese origin, but it was not detected in 192 CF chromosomes of Caucasian origin and 30 other chromosomes from Chinese individuals without a family history of CF.

Base Sequence↗