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Biomedical subjects

L Lin

Publications and source records attributed to L Lin.

At least 163 records · Page 9Linked to original sources
PubMed1998

Constitutive expression of HGF modulates renal epithelial cell phenotype and induces c-met and fibronectin expression.

Hepatocyte growth factor (HGF) is a potent renotropic factor that has been shown to play important roles in kidney development and recovery from acute renal injury. To examine the effects of HGF on renal tubular epithelium, we generated HGF-producing renal epithelial cells by stably transfecting mIMCD-3 and OK cells with an expression plasmid containing human HGF cDNA. Expression of HGF in the transfected cells was confirmed by detection of HGF mRNA by Northern blot analysis and detection of HGF secretion into the conditioned medium by ELISA. HGF-transfected cells exhibited fibroblast-like scattered morphology and increased cell motility. They formed branching tubules when grown in 3-D collagen gel. In addition, HGF-producing cells grew faster than their parental cells, but failed to form colonies in soft agar. These phenotypic changes were inhibited by a specific, neutralizing anti-HGF antibody. Interestingly, both c-met transcript and c-met protein were increased in HGF-transfected cells, suggesting that HGF amplifies its own action via stimulation of c-met expression. Autocrine expression of HGF and c-met in renal epithelial cells also stimulated fibronectin gene expression, which was totally blocked by incubation with a neutralizing anti-HGF but not a pan-specific anti-TGF-beta antibody, suggesting that it is independent of TGF-beta production. Our data demonstrate that HGF as a single factor stimulates renal epithelial cell proliferation, migration, differentiation, and extracellular matrix remodeling, making it uniquely suited to promote renal tubulogenesis during development, as well as to reconstitute tubular integrity following acute injury.

Animals↗
PubMed1998

Dopamine neurons make glutamatergic synapses in vitro.

Interactions between dopamine and glutamate play prominent roles in memory, addiction, and schizophrenia. Several lines of evidence have suggested that the ventral midbrain dopamine neurons that give rise to the major CNS dopaminergic projections may also be glutamatergic. To examine this possibility, we double immunostained ventral midbrain sections from rat and monkey for the dopamine-synthetic enzyme tyrosine hydroxylase and for glutamate; we found that most dopamine neurons immunostained for glutamate, both in rat and monkey. We then used postnatal cell culture to examine individual dopamine neurons. Again, most dopamine neurons immunostained for glutamate; they were also immunoreactive for phosphate-activated glutaminase, the major source of neurotransmitter glutamate. Inhibition of glutaminase reduced glutamate staining. In single-cell microculture, dopamine neurons gave rise to varicosities immunoreactive for both tyrosine hydroxylase and glutamate and others immunoreactive mainly for glutamate, which were found near the cell body. At the ultrastructural level, dopamine neurons formed occasional dopaminergic varicosities with symmetric synaptic specializations, but they more commonly formed nondopaminergic varicosities with asymmetric synaptic specializations. Stimulation of individual dopamine neurons evoked a fast glutamatergic autaptic EPSC that showed presynaptic inhibition caused by concomitant dopamine release. Thus, dopamine neurons may exert rapid synaptic actions via their glutamatergic synapses and slower modulatory actions via their dopaminergic synapses. Together with evidence for glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, the present results suggest that glutamatergic cotransmission may be the rule for central monoaminergic neurons.

Animals↗
PubMed1998

Cotranslational biogenesis of NF-kappaB p50 by the 26S proteasome.

The NFkappaB1 gene encodes two functionally distinct proteins termed p50 and p105. p50 corresponds to the N terminus of p105 and with p65 (RelA) forms the prototypical NF-kappaB transcription factor complex. In contrast, p105 functions as a Rel-specific inhibitor (IKB) and has been proposed to be the precursor of p50. Our studies now demonstrate that p50 is generated by a unique cotranslational processing event involving the 26S proteasome, whereas cotranslational folding of sequences near the C terminus of p50 abrogates proteasome processing and leads to p105 production. These results indicate that p105 is not the precursor of p50 and reveal a novel mechanism of gene regulation that ensures the balanced production and independent function of the p50 and p105 proteins.

Animals↗
PubMed1998

Inactivation of leukocytes in platelet concentrates by photochemical treatment with psoralen plus UVA.

A photochemical treatment (PCT) process using a novel psoralen and long wavelength ultraviolet light (UVA, 320-400 nm) has been developed to inactivate bacteria and viruses in platelet concentrates. This study evaluated the efficacy of PCT for inactivation of leukocytes that contaminate platelet preparations. Three psoralens, 8-methoxypsoralen (8-MOP), 4'-aminomethyl 4,5', 8-trimethylpsoralen (AMT), and the novel psoralen S-59, were compared using the following four independent but complementary biological and molecular assays. (1) T-cell viability: Treatment with 150 mumol/L S-59 and 1.0 to 3.0 Joules/cm2 UVA inactivated >5.4 +/- 0.3 log10 of T cells in full-sized single-donor plateletpheresis units. Using 1.0 Joule/cm2 UVA, the lowest dose of S-59, AMT and 8-MOP required to reduce the number of T cells to the limit of detection was 0.05 micromol/L, 1.0 micromol/L, and 10.0 micromol/L, respectively. (2) Cytokine synthesis: Treatment with 1.9 Joules/cm2 UVA and 150 micromol/L S-59 or AMT completely inhibited synthesis of the cytokine IL-8 by contaminating leukocytes during 5 days of platelet storage. After treatment with 75 micromol/L 8-MOP and 1.9 Joules/cm2 UVA, only low levels of IL-8 were detected. (3) Psoralen-DNA adduct formation: The combination of 1.9 Joules/cm2 UVA and 150 micromol/L S-59, AMT, or 8-MOP induced 12.0 +/- 3.0, 6.0 +/- 0. 9, and 0.7 psoralen adducts per 1,000 bp DNA, respectively. (4) Replication competence: Polymerase chain reaction (PCR) amplification of small genomic DNA sequences (242-439 bp) after PCT was inhibited. The degree of PCR amplification inhibition correlated with the level of adduct formation (S-59 > AMT > 8-MOP). In contrast, 2,500 cGy gamma radiation, a dose that inactivates >5 log10 of T cells in blood products, had minimal effect on cytokine synthesis and did not induce sufficient DNA strand breaks to inhibit PCR amplification of the same small DNA sequences. These results demonstrate that leukocytes are sensitive to PCT with psoralens and among the psoralens tested S-59 is the most effective. Therefore, PCT has the potential to reduce the incidence of leukocyte-mediated adverse immune reactions associated with platelet transfusion.

Adult↗
PubMed1998

Chronic cognitive deficits and amyloid precursor protein elevation after selective immunotoxin lesions of the basal forebrain cholinergic system.

Alzheimer's disease (AD) is the most common neurodegenerative disorder that causes cognitive deficits in the elderly. Its neuropathology is characterized by amyloid deposition and specific cholinergic degeneration. To address the link between amyloid formation and cholinergic loss, we examined histologically the amyloid precursor protein (APP) changes following selective immunolesion of the basal forebrain cholinergic system with 192 IgG-saporin in rats at 6 months post-lesion. In such rats with cognitive deficits observed in Morris water maze tests, we found increased levels of APP by optical density measurements in regions of cholinergic denervation. APP elevation and performance in the water maze task correlate with reduction of acetyl-cholinesterase (AChE) activity in the frontal cortex and CA3 subfield of hippocampus. The data indicate that loss of cholinergic innervation can affect APP expression.

Acetylcholinesterase↗
PubMed1998

Pheromone-regulated genes required for yeast mating differentiation.

Yeast cells mate by an inducible pathway that involves agglutination, mating projection formation, cell fusion, and nuclear fusion. To obtain insight into the mating differentiation of Saccharomyces cerevisiae, we carried out a large-scale transposon tagging screen to identify genes whose expression is regulated by mating pheromone. 91,200 transformants containing random lacZ insertions were screened for beta-galactosidase (beta-gal) expression in the presence and absence of alpha factor, and 189 strains containing pheromone-regulated lacZ insertions were identified. Transposon insertion alleles corresponding to 20 genes that are novel or had not previously been known to be pheromone regulated were examined for effects on the mating process. Mutations in four novel genes, FIG1, FIG2, KAR5/ FIG3, and FIG4 were found to cause mating defects. Three of the proteins encoded by these genes, Fig1p, Fig2p, and Fig4p, are dispensible for cell polarization in uniform concentrations of mating pheromone, but are required for normal cell polarization in mating mixtures, conditions that involve cell-cell communication. Fig1p and Fig2p are also important for cell fusion and conjugation bridge shape, respectively. The fourth protein, Kar5p/Fig3p, is required for nuclear fusion. Fig1p and Fig2p are likely to act at the cell surface as Fig1:: beta-gal and Fig2::beta-gal fusion proteins localize to the periphery of mating cells. Fig4p is a member of a family of eukaryotic proteins that contain a domain homologous to the yeast Sac1p. Our results indicate that a variety of novel genes are expressed specifically during mating differentiation to mediate proper cell morphogenesis, cell fusion, and other steps of the mating process.

Amino Acid Sequence↗
PubMed1998

Quantitative analysis of antibiotics by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Comparative studies of the matrix-assisted laser desorption/ionization (MALDI) of 30 antibiotics were made using alpha-cyano-4-hydroxycinnamic acid (HCCA), 2,5-dihydroxybenzoic acid (DHB), 5,10,15,20-tetrakis(4-hydroxyphenyl)-21H,23H-porphyrin and meso-tetra(N-methyl-4-pyridyl)porphyrin matrices. Most antibiotics generated intense protonated molecules in HCCA and DHB matrices, and sodium or potassium adduct ions in porphyrin matrices. Using sulfonamide antibiotics as model compounds, DHB was found to be the most suitable matrix for quantitative analysis. Detection limits were about 1 picomole. Linear correlation (R2 > 0.97), between the sample quantity over the range 1 to 100 picomole and the signal response, was obtained when ratios of the sum of peak areas of protonated molecules and sodium adduct ions, with reference to that of a structurally analogous internal standard (acetaminophen), were measured. The precision was found to be in the range of 4 to 32% relative standard deviation, dependent on the type and concentration of the analyte. A simple acylation derivatization process was developed to confirm the presence of suspected antibiotic residues. It is demonstrated that MALDI is a viable technique for the quantitative analysis of low molecular weight antibiotics.

Anti-Bacterial Agents↗
PubMed1998

Characterization of 12 microsatellite loci of the human MHC in a panel of reference cell lines.

The human genome contains a large number of interspersed microsatellite repeats which exhibit a high degree of polymorphism and are inherited in a Mendelian fashion, making them extremely useful genetic markers. Several microsatellites have been described in the HLA region, but allele nomenclature, a set of broadly distributed controls, and typing methods have not been standardized, which has resulted in discrepant microsatellite data between laboratories. In this report we present a detailed protocol for genotyping microsatellites using a semi-automated fluorescence-based method. Twelve microsatellites within or near the major histocompatibility complex (MHC) were typed in the 10th International Histocompatibility Workshop homozygous typing cell lines (HTCs) and alleles were designated based on size. All loci were sequenced in two HTCs providing some information on the level of complexity of the repeat sequence. A comparison of allele size obtained by genotyping versus that obtained by direct sequencing showed minor discrepancies in some cases, but these were not unexpected given the technical differences in the methodologies. Fluorescence-based typing of microsatellites in the MHC described herein is highly efficient, accurate, and reproducible, and will allow comparison of results between laboratories.

Alleles↗
PubMed1998

Beta-casomorphins stimulate and enterostatin inhibits the intake of dietary fat in rats.

The effects of beta-casomorphins 1-7, 1-5 and 1-4 on food intake of rats adapted to either a high fat (HF) or high carbohydrate (HC) diet have been studied and compared to the effects of enterostatin. Intracerebroventricular (icv) beta-casomorphin1-7 (beta-CM1-7) stimulated intake of HF diet in overnight fasted rats, but beta-CM1-5 and beta-CM1-4 were ineffective. Peripheral injection of beta-CM1-7 also increased the intake of a high fat diet, but reduced the intake of HC diet in satiated rats. Intracerebroventricular (ICV) beta-CM1-7 caused a dose-dependent increase in the intake of HF diet, but a dose-dependent inhibition of HC ingestion in satiated rats. Enterostatin (ICV) inhibited the beta-CM1-7 stimulation of HF intake, as did the general opioid antagonist naloxone. Ligand binding studies with [3H-pro] enterostatin identified on low affinity binding site (Kd 100nM) on a crude brain membrane preparation. This binding was displaced by beta-CM1-7, beta-CM1-5 and beta-CM1-4. These data suggest that at high doses enterostatin and beta-CM1-7 may interact with the same low affinity receptor to modulate intake of dietary fat.

Amino Acid Sequence↗
PubMed1998

Changes in the microstructure of feeding after administration of enterostatin into the paraventricular nucleus and the amygdala.

The effects of enterostatin (ENT) injected into the paraventricular nucleus (PVN) and the amygdala (AMYG) on the microstructure of feeding was studied by using an automated feeding apparatus. In rats adapted to a 6-h meal feeding regime, ENT reduced the size and duration of the first meal after injection in both the PVN and the AMYG. Similar effects were observed when ENT was given at the beginning of the dark cycle in rats fed ad libitum although the onset of feeding was also delayed in this situation. The number of meals and the size of subsequent meals was unaffected by ENT but the eating rate within the first meal was reduced after ENT injection into the AMYG of meal-fed rats. Enterostatin injected into the AMYG at a dose that suppressed feeding did not produce a conditioned taste aversion. ENT given centrally therefore appears to reduce food intake by delaying the initiation of feeding and/or advancing meal termination suggesting that it affects both appetite and satiation mechanisms.

Amygdala↗
PubMed1998

Applying human factors to the design of medical equipment: patient-controlled analgesia.

OBJECTIVE: Medical instruments commonly have poorly designed user interfaces that promote human errors with life-threatening consequences. The primary hypothesis of this study was that a specific user interface could be made safer and more efficient if redesigned using human factors techniques and principles. METHODS: The user interface of a commercially available patient-controlled analgesia (PCA) pump, the Abbott Lifecare 4100 PCA Plus II infuser, was evaluated using a cognitive task analysis of bench tests and field observations. Based on this analysis, the user interface was redesigned. Important elements of the new design include a dialog structure with fewer steps, a dialog overview showing the user's location in the programming sequence, better command feedback, easier error recovery, and clearer labels and messages. The changes were evaluated by comparing a computer prototype of the new interface with a computer simulation of the old one. Twelve student nurses performed six programming tasks with each interface. Task completion time, number of errors, and subjective mental workload were collected for each trial. RESULTS: The results showed significantly faster programming times (F(1,11) = 6.85, P < 0.025), lower mental workload ratings (chi2(1) = 4.45, p < 0.025, one-tailed), and fewer errors (chi2(1) = 3.33, p < 0.05, one-tailed) with the new interface. CONCLUSION: Adopting a human factors approach to redesigning the PCA interface led to significantly faster, easier, and more reliable performance. These findings have important implications for improving the design of other computer-based medical equipment.

Analgesia, Patient-Controlled↗
PubMed1998

Maternal uniparental meroisodisomy in the LAMB3 region of chromosome 1 results in lethal junctional epidermolysis bullosa.

Herlitz junctional epidermolysis bullosa (OMIM#226700) is a lethal, autosomal recessive blistering disorder caused by mutations in one of the three genes LAMA3, LAMB3, or LAMC2, encoding the constitutive polypeptide subunits of laminin 5. In this study, we describe a patient homozygous for a novel nonsense mutation Q936X in exon 19 of LAMB3, which has been mapped to chromosome 1q32. The patient was born with extensive blistering and demonstrated negative immunofluorescence staining for laminin 5, and transmission electron microscopy revealed tissue separation within lamina lucida of the dermal-epidermal junction, diagnostic of Herlitz junctional epidermolysis bullosa. The mother of the proband was found to be a heterozygous carrier for this mutation, whereas the father demonstrated the wild-type LAMB3 allele only. Nonpaternity was excluded by 13 microsatellite markers in six different chromosomes. Genotype analysis using 28 microsatellite markers spanning chromosome 1 revealed that the patient had maternal primary heterodisomy, as well as meroisodisomy within two regions of chromosome 1, one on 1p and the other one on 1q, the latter region containing the maternal LAMB3 mutation. These results suggest that Herlitz junctional epidermolysis bullosa in this patient developed as a result of reduction to homozygosity of the maternal LAMB3 mutation on chromosome 1q32.

Cell Adhesion Molecules↗
PubMed1998

The effects of a high fat diet on leptin mRNA, serum leptin and the response to leptin are not altered in a rat strain susceptible to high fat diet-induced obesity.

Osborne-Mendel (OM) and S5B/Pl rats differ in their sensitivity to develop obesity when fed a high fat (HF) diet; OM rats become obese, whereas S5B/Pl rats remain thin. We have investigated the possibilities that either an impaired leptin response or resistance to leptin action underlies the sensitivity to this form of obesity in OM rats. In Experiment 1, OM and S5B/Pl rats fed a nonpurified diet were killed at d 0 or were fed either a HF (56% fat energy) or a low fat (LF, 10% fat energy) diet for 2 or 7 d. The HF diet increased serum leptin significantly by d 2 to levels that were similar in both rat strains. At 7 d, leptin levels were lower than at d 2 but remained higher than levels in the d 0 control groups. The leptin mRNA:18S RNA ratio in epididymal adipose tissue increased to higher levels in HF-fed OM rats than in S5B/Pl rats fed that diet. However, although the LF diet had no effect in S5B/Pl rats, it increased leptin mRNA levels in epididymal adipose tissue of OM rats compared with the controls fed the nonpurified diet. In Experiment 2, OM and S5B/Pl rats were fed HF or LF diets for 5 wk. At that time, their feeding response to a range of leptin doses (0, 1, 5 or 10 microgram) given intracerebroventricularly was tested after overnight food deprivation. There was a similar dose-dependent reduction in energy intake in response to leptin in both OM and S5B/Pl rats. These responses were independent of the diet. The data suggest that the susceptibility of OM rats to HF diet-induced obesity is not related to either a loss of central sensitivity to leptin or a failure to enhance leptin production acutely, although the failure to maintain chronically increased levels of serum leptin could contribute to the obesity.

Adipose Tissue↗
PubMed1998

The dose-effect relationships between torture and psychiatric symptoms in Vietnamese ex-political detainees and a comparison group.

The purpose of this study was to determine in Vietnamese ex-political detainees newly arrived into the United States a) the prevalence of torture and psychiatric symptoms and b) the dose-effect relationships between cumulative torture experience and the psychiatric symptoms of posttraumatic stress disorder (PTSD) and major depression. The study population included Vietnamese ex-political detainees (N = 51) and a comparison group (N = 22). All respondents received culturally validated instruments with known psychometric properties including Vietnamese versions of the Hopkins Symptom Checklist-25 and the Harvard Trauma Questionnaire. The ex-political detainees, in contrast to the comparison group, had experienced more torture events (12.2 SD = 4.2 vs. 2.6 SD = 3.1) and had higher rates of PTSD (90% vs. 79%) and depression (49% vs. 15%). Dose-effect relationships between cumulative torture experience and psychiatric symptoms were positive with the PTSD subcategory of "increased arousal" revealing the strongest association. These findings provide evidence that torture is associated with psychiatric morbidity in Vietnamese refugees. The demonstration of significant dose-effect responses supports the hypothesis that torture is a major risk factor in the etiology of major depression and PTSD. The generalizability of these results to other torture survivor groups is unknown. The interaction between torture and other pre- and post-migration risk factors over time in different cultural settings still needs to be examined.

Adult↗
PubMed1998

Diversity of HLA-B61 alleles and haplotypes in East Asians and Spanish Gypsies.

The distribution of HLA-B61 alleles and their association with HLA-C and DRB1 alleles were investigated in six East Asian populations (South Korean, Chinese Korean, Man (Manchu), Northern Han, Mongolian and Buryat) and Spanish Gypsies and compared to our previous report on the Japanese population. The alleles were identified using a group-specific polymerase chain reaction (PCR) and genomic DNA followed by hybridization with sequence-specific oligonucleotide probes (SSOP). Both HLA-B*4002 and B*4006 were commonly detected in the South Korean, Chinese Korean, Man, Northern Han and Japanese populations, while HLA-B*4002 was predominant in the Mongolian and Buryat populations. Strong associations of B*4002 with Cw*0304 and of B*4006 with Cw*0801 were commonly observed in these East Asian populations. In contrast, in Spanish Gypsies, only HLA-B*4006 was found and the allele exhibited a strong association with Cw*1502. HLA-B*4003 was also identified in the South Korean, Chinese Korean, Northern Han, Mongolian and Japanese populations at relatively low frequencies, and exhibited an association with Cw*0304. Moreover, the association of these B61 alleles with the DRB1 alleles revealed considerable diversity among the different populations. HLA-B*4004 and B*4009 were not observed in these populations. Consequently, the frequencies of the B61 alleles varied among the different East Asian populations, but the individual B61 alleles were carried by specific haplotypes often regardless of the ethnic differences.

Alleles↗
PubMed1998

Microsatellite single nucleotide polymorphisms in the HLA-DQ region.

Sequencing studies were performed in three previously described microsatellite and minisatellite markers located within the HLA-DQ region, DQCAR, DQCARII and G51152. Multiple nucleotide substitutions that did not change size polymorphisms were observed in all three markers. In all loci, the number of core repeats did not correlate with neighboring DQ allele sequence motifs while single nucleotide changes within or flanking the microsatellite sequence did. This result indicates higher mutation rates for microsatellite expansions/contractions than for nucleotide substitutions in these loci. Further analysis indicated an almost complete phylogenetic correspondence between DQCAR single nucleotide polymorphisms (SNPs) and DQB1 sequences on one side (1.0-1.5 kb apart) and a complete relationship between DQCARII and DQA1 sequences on the other (4.5 kb apart). In contrast, G51152 sequences did not correspond perfectly with DQB1 allelic sequences, thus suggesting the existence of several ancestral crossovers between this marker and DQB1 (20-25 kb). Sequencing microsatellites might be useful in disease mapping studies by increasing marker informativeness and by helping in the interpretation of association study results. It is also proposed that SNPs within the flanking region of CA repeats could be used to develop biallelic markers from already available mapped microsatellite markers.

Alleles↗