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Biomedical subjects

L S Chen

Publications and source records attributed to L S Chen.

At least 73 records · Page 4Linked to original sources
PubMed1993

Effects of myocardial fiber orientation on the electrical induction of ventricular fibrillation.

Although many studies have documented the importance of myocardial fiber orientation in the generation and maintenance of reentrant arrhythmia, its role in the induction of reentry by a single strong premature stimulus is held to be minimal. To study the importance of fiber orientation on the mechanisms of ventricular vulnerability to single strong premature electrical stimulation, computerized mapping studies using 56 closely (2. 5-5 mm) spaced epicardial bipolar electrodes were performed on six open-chest dogs to determine the patterns of activation after the application of a single strong premature stimulus. In an additional three dogs, both epicardial and endocardial mapping studies were performed with closely spaced electrodes. The baseline driving stimulus (S1) and the premature stimulus (S2) were given to the same or different sites on the right ventricular epicardium. When the line connecting the S1 and S2 (the electrical axis of stimulation) was roughly parallel to the fiber orientation, the vast majority of the early sites were found to lie between the S1 and S2 sites, with none of the early sites occurring on the side of the S2 site opposite to the S1 site. At the onset of ventricular fibrillation, figure-eight reentry was easily demonstrated. In comparison, when the S1 and S2 were given to the same site, or when the electrical axis of stimulation was roughly perpendicular to the fiber orientation, the early sites could occur on all sides of the S2 site. In these instances, a figure-eight reentry was not present at the onset of ventricular fibrillation, although this pattern could develop after the first few beats. These findings indicate that myocardial fiber orientation is an important factor in determining the patterns of activation during the electrical induction of ventricular fibrillation.

Animals↗
PubMed1993

Primary nasal melanoma with exclusive liver metastasis: a case report.

A 50-year-old male presented with a nasal mass causing obstruction and bleeding. The initial biopsy indicated a malignant lymphoma but the subsequent biopsy diagnosed an undifferentiated carcinoma. However, histopathological study and immunohistochemical study, made a final diagnosis of nasal melanoma. Six months after the diagnosis, the patient developed exclusive liver metastasis. He responded to 1 course of intensive chemotherapy with 200 mg/m2 cisplatin and 5000 mg/m2 dacarbazine for 6 months. For patients with nasal cavity malignancy, the possibility of primary melanoma should be considered. Combination chemotherapy with intensive dose of cisplatin and dacarbazine may be a viable treatment regimen for nasal melanoma with liver metastasis.

Humans↗
PubMed1993

Neoplastic transformation of a human keratinocyte cell line by the v-fos oncogene.

To analyze the role of the fos oncogene in the growth of human epithelial cells, we have transfected a non-tumorigenic human epidermal keratinocyte line (RHEK-1) immortalized by the Ad12-SV40 hybrid virus with a plasmid carrying the v-fos gene together with plasmid pSV2-neo which confers resistance to neomycin. Individual neomycin-resistant clones were isolated and characterized with respect to morphological alteration. Of 16 independent clones analyzed, two appeared morphologically transformed and formed foci in culture. Only the two clones with a transformed phenotype were found by Southern blot hybridization analysis to contain the transfected v-fos gene. These clones formed colonies in soft agar and induced tumors when transplanted into nude mice. Analysis of fos specific mRNA and protein demonstrated that the transfected v-fos gene was expressed in these two clonal lines. These findings suggest that expression of the v-fos gene might facilitate the process of neoplastic transformation of human epithelial cells in culture. This appears to represent the first demonstration of the transforming potential of the v-fos gene in human cells.

Animals↗
PubMed1992

Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs.

Loteprednol etabonate, a new glucocorticoid soft drug with a characteristic chloromethyl ester function in the 17 beta-position, is currently in the early phases of clinical development. As the basis for human trials, this study describes a new reversed-phase high-performance liquid chromatographic method for the determination of levels of drug in plasma and urine samples and assesses the pharmacokinetic properties of loteprednol etabonate in dogs and rats. Intravenous administration of loteprednol etabonate (5 mg/kg) to dogs revealed a terminal half-life of 2.8 h, a volume of distribution of 3.7 L/kg, and a total body clearance of 0.9 L/h/kg. Intact loteprednol etabonate was not detectable in the urine. After oral administration of the drug (5 mg/kg) to dogs, only metabolites, but no intact drug, were found in the plasma, an indication for a high first-pass effect. A pronounced binding of the drug to plasma protein (> 90%) and a high erythrocyte-buffer partition coefficient of 7.8 were determined in vitro. Preliminary information about tissue distribution and possible metabolic pathways were obtained in rats after oral administration of a 14C-labeled loteprednol etabonate suspension (5 mg/kg). pH-selective extraction into ethyl acetate revealed three distinguishable fractions: (1) a neutral lipophilic fraction, presumably intact drug, (2) an acidic, lipophilic fraction, and (3) a hydrophilic nonextractable fraction. Levels of intact drug and metabolites were highest in liver and kidney, whereas significantly lower levels were found in other investigated organs (lung, brain, heart).(ABSTRACT TRUNCATED AT 250 WORDS)

Androstadienes↗
PubMed1992

Maintenance of amelogenin gene expression by transformed epithelial cells of mouse enamel organ.

Electroporation was used to introduce foreign genes into cells derived from the mouse enamel organ epithelia (EOE). Optimal conditions for this electroporation were established. The introduction of a plasmid construct bearing the coding region for the large T-antigen from polyoma virus into EOE cells permitted the establishment of a derivative cell line that has the following characteristics: (1) the cells could be passaged many times; (2) they expressed a keratin-containing cytoskeleton; and (3) approx. 60% of the cells expressed amelogenin, a tissue-specific gene product unique to ameloblasts. Potential uses for such a cell line include analysis of: (1) the upstream regulatory regions required for temporally and spatially restricted expression of amelogenin; (2) the post-translational modification of amelogenin in synchronized cells and (3) the organization and biomineralization of enamel extracellular matrix in monolayer culture.

Amelogenin↗
PubMed1992

Cytokine regulation of nerve growth factor-mediated cholinergic neurotrophic activity synthesized by astrocytes and fibroblasts.

The neurotrophic activity of astrocytes and fibroblasts and its regulation by various cytokines were investigated. Astrocyte conditioned medium (ACM) enhanced the survival of neurons and the proliferation of astrocytes in embryonic cortical cultures grown in serum-free defined medium. However, these results were not affected by acidic fibroblast growth factor, interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF alpha), and transforming growth factor-beta 1. In contrast, ACM induced choline acetyltransferase expression in septal cholinergic neurons via nerve growth factor (NGF)-dependent and -independent mechanisms. However, neither acidic nor basic fibroblast growth factor is involved in this biological activity in ACM. The cytokines listed above mainly stimulate NGF-mediated cholinergic neurotrophic activity in ACM. A combination of IL-1 beta and TNF alpha significantly enhanced choline acetyltransferase activity in septal neurons co-cultured with astrocytes, and this effect was found to be mediated by NGF produced by activated astrocytes. Effects of astrocytes on GABAergic neurons were also examined. ACM was found to increase glutamate decarboxylase activity in neuronal cultures from septum in the presence of Ara-C. However, the cytokines did not enhance this activity in ACM. Moreover, a combination of IL-1 beta and TNF alpha had no effect on glutamate decarboxylase activity in septal neurons co-cultured with astrocytes. In a final set of experiments, cholinergic neurotrophic activity in skin-derived fibroblast conditioned medium (FCM) was examined. FCM was found to possess biological activity similar to that of ACM on septal neurons grown in serum-free defined medium with Ara-C. The cytokines also enhanced NGF-mediated cholinergic neurotrophic activity in FCM. Astrocytes and fibroblasts were found to possess NGF-type and non-NGF-type cholinergic neurotrophic activity, and various cytokines were found to regulate the NGF-type cholinergic neurotrophic activity in both types of cells. NGF produced by astrocytes and fibroblasts that are activated by cytokines is likely to be important for development and regeneration of NGF-sensitive neurons in the central and peripheral nervous systems.

Animals↗
PubMed1992

Radioiodine-131 therapy for well-differentiated thyroid cancer--a quantitative radiation dosimetric approach: outcome and validation in 85 patients.

For almost five decades, 131I treatment of thyroid cancer has been based empirically on administered activity rather than on actual radiation doses delivered. In 1983, we defined radiation dose thresholds for successful treatment. This report is concerned with the subsequent validation of those thresholds in 85 patients. The successful ablation of thyroid remnants occurred after a single initial 131I administration in 84% of inpatients and in 79% of outpatients when treatment was standardized to a radiation dose of at least 30,000 cGy (rad). Administered activities low enough to permit outpatient therapy could be used in 47% of the patients. Lymph node metastases were treated successfully in 74% of patients with a single administration of 131I calculated to deliver at least 8,500 cGy (rad). For athyrotic patients with nodal metastases only, success was achieved in 86% of patients at tumor doses of at least 14,000 cGy (rad). These success rates are equal to or better than those reported with empiric methods of 131I administration. The individualized treatment planning selectively allocates hospitalization and higher exposures to 131I to those patients who require them.

Adenocarcinoma↗
PubMed1991

Hippocampal grafts into the intact brain induce epileptic patterns.

Spontaneous hippocampal EEG activity and evoked field potentials were investigated in intact rats and in animals with fetal hippocampal grafts. Pieces of hippocampal grafts, derived from 15- to 16-day-old fetuses, were used to prepare cell suspensions and grafted directly into the intact hippocampus. Control animals received suspension grafts of the cerebellum derived from fetuses of identical age. Host hippocampal electrical patterns were monitored with chronic single electrodes or with a 16-microelectrode probe from 7 to 10 months after grafting. In contrast to previously reported high survival rates of fetal grafts in studies with damage to the host brain prior to grafting, survival of both hippocampal (60%) and cerebellar grafts (20%) was very poor in the intact hippocampus. In animals with cerebellar transplants or without surviving grafted neurons the electrical activity of the host hippocampus was indistinguishable from normal controls. In rats with hippocampal grafts short duration, large amplitude EEG spikes (up to 10 mV) were recorded, predominantly during immobility. When the EEG spikes (putative interictal spikes) were of large amplitude and contained population spikes, test evoked responses delivered to the perforant path were suppressed after the spontaneous events. In contrast, evoked responses were facilitated by interictal spikes without population spikes. The threshold of electrically induced afterdischarges did not differ significantly between groups of intact rats and animals with or without hippocampal grafts. However, in three rats with hippocampal grafts the evoked afterdischarges were associated with behavioral seizures. In two of these rats spontaneously occurring seizures were also observed. Synaptophysin-immunoreactivity demonstrated growth of the host mossy fibers into the graft.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1991

Cellular replacement therapy for neurologic disorders: potential of genetically engineered cells.

Neural transplantation, a mode of cellular replacement, has been used as a therapeutic trial for Parkinson's disease. Studies indicate that tonic release of the metabolites from the graft that can be utilized by the host brain, is likely to be the major mechanism responsible for the therapeutic effect. The use of fetal tissue is complicated by ethical controversy and immunological incompatibility. Autografting adult tissue has not been successful mainly due to poor survival. Genetically engineered cells are promising alternative sources of donor cells. We have investigated the potential of primary skin fibroblasts as donor cells for intracerebral grafting. Primary skin fibroblasts survive in the brain and remain in situ. A number of genes (nerve growth factor, tyrosine hydroxylase, glutamic acid decarboxylase, and choline acetyltransferase) have been successfully introduced and expressed in the primary fibroblasts. The L-dopa-secreting primary fibroblasts exhibited a behavioral effect in a rat model of Parkinson's disease up to 8 weeks after being grafted into denervated striatum. Factors that can maximize gene transfer, transgene expression, and fibroblast survival in the brain make up the future direction of investigation.

Animals↗
PubMed1991

Timing of flagellar gene expression in the Caulobacter cell cycle is determined by a transcriptional cascade of positive regulatory genes.

The Caulobacter crescentus flagellar (fla) genes are organized in a regulatory hierarchy in which genes at each level are required for expression of those at the next lower level. To determine the role of this hierarchy in the timing of fla gene expression, we have examined the organization and cell cycle regulation of genes located in the hook gene cluster. As shown here, this cluster is organized into four multicistronic transcription units flaN, flbG, flaO, and flbF that contain fla genes plus a fifth transcription unit II.1 of unknown function. Transcription unit II.1 is regulated independently of the fla gene hierarchy, and it is expressed with a unique pattern of periodicity very late in the cell cycle. The flaN, flbG, and flaO operons are all transcribed periodically, and flaO, which is near the top of the hierarchy and required in trans for the activation of flaN and flbG operons, is expressed earlier in the cell cycle than the other two transcription units. We have shown that delaying flaO transcription by fusing it to the II.1 promoter also delayed the subsequent expression of the flbG operon and the 27- and 25-kDa flagellin genes that are at the bottom of the regulatory hierarchy. Thus, the sequence and timing of fla gene expression in the cell cycle are determined in large measure by the positions of these genes in the regulatory hierarchy. These results also suggest that periodic transcription is a general feature of fla gene expression in C. crescentus.

Bacterial Proteins↗
PubMed1991

Overexpression of transforming growth factor-beta in transgenic mice carrying the human T-cell lymphotropic virus type I tax gene.

Human T-cell lymphotropic virus type I (HTLV-I) has been associated with an adult form of T-cell leukemia as well as tropical spastic paraparesis, a neurodegenerative disease. Adult T-cell leukemia patients express high levels of the type 1 isoform of transforming growth factor-beta (TGF-beta 1), which is mediated by the effects of the HTLV-I Tax transactivator protein on the TGF-beta 1 promoter. To understand further the regulation of TGF-beta 1 expression by Tax, we examined its expression in transgenic mice carrying the HTLV-I tax gene. We show that tumors from these mice and other tissues, such as submaxillary glands and skeletal muscle, which express high levels of tax mRNA selectively express high levels of TGF-beta 1 mRNA and protein. Moreover, TGF-beta 1 significantly stimulated the incorporation of tritiated thymidine into one of three cell lines derived from neurofibromas of tax-transgenic mice, which suggests that the excessive production of TGF-beta 1 may play a role in tumorigenesis and that these mice may serve as a useful model for studying the biological effects of TGF-beta in vivo.

Animals↗
PubMed1990

Spatial organization of physiological activity in the hippocampal region: relevance to memory formation.

Based on a review of anatomical and physiological findings, we suggest that the hippocampus may be viewed as a positive feedback device (autoassociator), which is capable of modifying the activity of the neocortical neurons. We examine the three-dimensional organization of evoked and spontaneous physiological patterns of the hippocampus and suggest rules how these patterns emerge during different behaviors from a hard-wired structural network. The high spatial coherence of theta activity is due to an external pacemaker, while the high synchrony of population bursts underlying hippocampal sharp waves is explained by the similar probability of recruitment of neurons by the burst-initiator cells along the whole extent of the hippocampus. We suggest that the burst-initiator cells are a group of CA3 neurons whose excitability is increased by a transient potentiation action of the neocortical activity during theta-concurrent exploratory behaviors. We hypothesize that sharp wave-concurrent population bursts result in a highly synchronous hippocampal output, converging preferentially on those entorhinal neurons which were instrumental in the creation of the burst-initiator neurons. The feedback action of population activity thus provides a selective mechanism for potentiation of connections between information-carrying neurons in the hippocampus and entorhinal cortex. The state-dependent operations of the anatomical hardware also point to the importance and advantage of studying the physiological activity of the intact brain.

Action Potentials↗
PubMed1990

Cloning, expression, and characterization of the Escherichia coli K-12 rfaD gene.

The rfaD gene encodes ADP-L-glycero-D-mannoheptose-6-epimerase, an enzyme required for the biosynthesis of the lipopolysaccharide precursor ADP-L-glycerol-D-mannoheptose. The precise localization of the rfaD gene on a 1.3-kilobase SspI-HpaI fragment is reported. The rfaD gene and the flanking regions were completely sequenced. The location of the rfaD gene on the physical map of the Escherichia coli chromosome was determined. Primer extension studies were used to define the regulatory region of the rfaD gene. The cloned rfaD gene directed the synthesis of a 37,000-dalton polypeptide in several in vivo and in vitro expression systems. N-terminal analysis of purified ADP-L-glycero-D-mannoheptose-6-epimerase confirmed the first 34-amino-acid sequence deduced from the nucleotide sequence of the rfaD gene coding region. The primary structure of the rfaD protein contains the sequence fingerprint for the ADP-binding beta alpha beta fold at the N terminus.

Adenosine Diphosphate↗
PubMed1990

Biochemical and radiohistochemical analyses of alpha-2 adrenergic receptors in the kindling model of epilepsy.

Biochemical and radiohistochemical methods were used to study alterations in alpha-2 adrenergic receptors in the kindling model of epilepsy. The radioligands used for antagonist and agonist binding were [3H]idazoxan and [3H]p-aminoclonidine, respectively. Radioligand binding to membranes isolated from eight brain regions disclosed a small (14%) but statistically significant reduction in [3H]idazoxan binding in a single area, amygdala-pyriform-entorhinal cortex. This was confirmed by a larger (25%) reduction (P less than .02) in agonist binding in the same region. These reductions were present in animals sacrificed 1 day, but not 2 weeks, after the last kindled seizure. Quantitative radiohistochemical studies identified a bilaterally symmetric reduction of approximately 20% of [3H]p-aminoclonidine binding in the pyriform cortex and the central, medial and lateral amygdaloid nuclei. No significant differences were detected in nine other structures. We propose that the reduction in alpha-2 receptor binding contributes in part to the reduced sensitivity of pyriform cortex neurons of kindled animals to the inhibitory effects of alpha 2 agonists. The reduced alpha-2-receptor binding may also underlie a transient attenuation of alpha-2 receptor-mediated neuro-transmission and thereby constitute one mechanism contributing to kindling development.

Adrenergic alpha-Agonists↗
PubMed1989

Effects of intranigral application of clinically-effective anticonvulsants on electroshock-induced seizures.

The authors sought to determine whether focal application of clinically-effective anticonvulsants to the substantia nigra produced anticonvulsant effects. To this end, the effects of phenobarbital, carbamazepine and phenytoin were examined on the electroshock seizure model in rats. Anticonvulsant efficacy was assessed by measuring the duration of tonic hindlimb extension before and after injection. It was found that application of phenobarbital into the nigra produced behavioral stereotypy and suppressed tonic hindlimb extension in a dose-dependent manner. These effects were spatially specific to the substantia nigra. By contrast, application of phenytoin or carbamazepine to the nigra produced neither anticonvulsant effects nor behavioral changes. Direct measurement of phenobarbital and carbamazepine in the substantia nigra showed that differences in concentration in the substantia nigra did not account for the lack of efficacy of carbamazepine. Moreover, concentrations of phenobarbital in the nigra after effective injection into the nigra exceeded concentrations in the nigra after effective systemic injections, by tenfold. Taken together, these data provide no compelling evidence that an action of the substantia nigra alone is sufficient to explain the therapeutic action of clinically-useful anticonvulsants.

Animals↗
PubMed1989

[Human pharmacologic studies on transdermal administration of mepindolol. Pharmacodynamic and orienting pharmacokinetics].

The pharmacodynamic effects of acute and repeated application of a transdermal patch (BIO TSD) containing 20 mg of the beta-receptor blocking agent mepindolol were assessed in 13 normotensive male volunteers. Orienting measurements of mepindolol serum levels were performed additionally. At rest, the effects on blood pressure and heart rate were very limited. However, during submaximum ergometer exercise, significant systemic beta-blocking effects were observed, especially after 5 days treatment. Repeated administration did not induce tachyphylaxis but resulted in an enhanced efficacy. The mepindolol serum concentrations were markedly lower than those measured after oral application of the drug. No systemic or local adverse reactions nor any relevant changes in laboratory parameters were observed.

Administration, Cutaneous↗
PubMed1989

[Determination of the release of drugs from transdermal therapeutic systems. Presentation of a new release system].

A relatively simple release model for transdermal therapeutic systems (TTS) is described. The TTS is separated from the elution solvent by a semipermeable membrane. The elution solvent passes an elution channel with a flow rate of 3-9 ml/h. For the quantitative determination of the drug HPLC or UV spectrometry are used. Depending on the active drug and the design of the TTS, different releasing kinetics are observed. While diclofenac follows approximately a zero order kinetic, the respective kinetic for mepindolol roughly follows a diffusion controlled square root of t-order.

Administration, Cutaneous↗