Search PubMed⌕ Search

Biomedical subjects

C S Lin

Publications and source records attributed to C S Lin.

At least 181 records · Page 10Linked to original sources
PubMed1992

Pharmacokinetic data in the evaluation of the safety of food and color additives.

Safety evaluation of food and color additives intended for human use is usually based on toxicity data obtained from animal studies; human data are rarely available. The extrapolation of animal data to humans is often controversial. The important role that pharmacokinetic data could play in the safety evaluation of food and color additives is now widely recognized. This paper reviews the current scientific knowledge concerning the application of properly designed pharmacokinetic studies to the evaluation of the safety of food and color additives. In principle, pharmacokinetic data can be useful not only in designing, interpreting, and extrapolating animal toxicity studies to humans, but also in providing insight into the mechanisms of toxicity. Examples of such applications are provided.

Animals↗
PubMed1992

Cloning of the alpha-adducin gene from the Huntington's disease candidate region of chromosome 4 by exon amplification.

We have applied the technique of exon amplification to the isolation of genes from the chromosome 4p16.3 Huntington's disease (HD) candidate region. Exons recovered from cosmid Y24 identified cDNA clones corresponding to the alpha-subunit of adducin, a calmodulin-binding protein that is thought to promote assembly of spectrin-actin complexes in the formation of the membrane cytoskeleton, alpha-adducin is widely expressed and, at least in brain, is encoded by alternatively spliced mRNAs. The alpha-adducin gene maps immediately telomeric to D4S95, in a region likely to contain the HD defect, and must be scrutinized to establish whether it is the site of the HD mutation.

Alternative Splicing↗
PubMed1992

Evaluating the safety of food and color additives with pharmacokinetic data.

Pharmacokinetic studies are designed to quantify, as a function of time, the processes associated with absorption, distribution, metabolism, and excretion of a chemical in experimental animals or in humans. Such studies have played an important role in drug safety evaluation and could be very useful in the safety evaluation of food and color additives. This presentation provides an overview of the potential use of metabolic and pharmacokinetic data in the design and evaluation of toxicological studies and in the assessment of the potential hazard to humans from exposure to food or color additives.

Animals↗
PubMed1992

The genomic structure of the human skeletal muscle sodium channel gene.

Electrical excitability of neurons and muscle cells reflects the actions of a family of structurally related sodium channels. Mutations in the adult skeletal muscle sodium channel have been associated with the inherited neuromuscular disorders paramyotonia congenita (PMC) and hyperkalemic periodic paralysis (HPP). We have deciphered the entire genomic structure of the human skeletal muscle sodium channel gene and developed a restriction map of the locus. SCN4A consists of 24 exons spanning 35 kb of distance on chromosome 17q. We describe the sequence of all intron/exon boundaries, the presence of several polymorphisms in the coding sequence, and the locations within introns of two dinucleotide repeat polymorphisms. This is the first sodium channel for which the entire genomic structure has been resolved. The organization of the SCN4A exons relative to the proposed protein structure is presented and represents a foundation for functional and evolutionary comparisons of sodium channels. Knowledge of the exon structure and flanking intron sequences for SCN4A will permit a systematic search for mutations in PMC and HPP.

Amino Acid Sequence↗
PubMed1992

Thyrotoxicosis accompanied with periodic seizure attacks a case report and review of literature.

A 58-year-old female was admitted and discovered to be a victim of thyrotoxicosis. She had experience periodic seizure attacks for 14 months. These seizures disappeared when function of the thyroid returned to normal. We performed many studies to search for the cause of the seizures. No epileptic focus could be detected from an EEG or a MRI of the brain. There was no abnormal laboratory data such as: hypoglycemia, hypoxemia, serum electrolyte imbalance, or an acid-base imbalance. No evidence of CNS infection was noted. She had good response to antithyroid treatment. We therefore suggest, that the seizure attacks may be related to thyrotoxicosis. In reviewing the literature, we found that only 13 cases of thyrotoxicosis with seizures have been reported since 1956 [1-9].

Female↗
PubMed1991

FK-506 and cyclosporin A inhibit highly similar signal transduction pathways in human T lymphocytes.

This report compares the ability of cyclosporin A and FK-506 to inhibit human T cell activation triggered via cell surface molecules that utilize different intracellular processes. We stimulated highly purified peripheral blood T lymphocytes with mitogens (Con A and PHA), ionomycin + PMA, or monoclonal antibodies specific for cell surface antigens involved in activation (CD2, CD3, CD28) either in combination with each other or in conjunction with PMA. Using measurements of the proliferative response, IL-2 production, and changes in intracellular Ca2+ ([Ca2+]i), we demonstrate that FK-506 exerts its inhibitory effect on early events of T-cell activation in a manner indistinguishable from that of CsA. An important finding in this study is the strict correlation between those activation pathways that are inhibited by FK-506 and CsA and the requirement that the sensitive pathways induce a measurable rise in [Ca2+]i. This correlation held even for the CD28/CD2 pathway which was previously shown to be calcium-independent; however by employing FACS analysis of [Ca2+]i within individual cells, a subset of cells activated via CD28/CD2 was found to respond with a measurable rise in [Ca2+]i. We also noted that the proliferative response induced by certain stimuli, such as ionomycin + PMA and PHA + PMA, was partially resistant to FK-506 and CsA, while IL-2 production was completely suppressed. The partial FK-506/CsA-resistance of these responses was shown to be determined by the amount of PMA added to the cultures. We conclude from our investigations that FK-506 and CsA inhibit highly similar signal transduction pathways in human T lymphocytes.

Anti-Bacterial Agents↗
PubMed1991

New DNA markers in the Huntington's disease gene candidate region.

The search for the Huntington's disease (HD) gene has prompted construction of a complete long-range restriction map of a 2.5-Mb candidate region, distal to the DNA marker D4S10. To facilitate the procurement of cloned DNA from this candidate region, we have augmented the existing regional mapping panel of somatic cell hybrids with hybrid HHW1071 containing a t(4p16;12) chromosome from a patient with Wolf-Hirschhorn syndrome. This translocation maps between D4S180 and D4S127, subdividing the HD candidate region and setting a proximal limit to the Wolf-Hirschhorn syndrome region. Using the expanded mapping panel, we have regionally assigned 14 independently cloned cosmids, five proximal to the t(4;12) breakpoint in the same region as D4S10 and nine distal to the breakpoint. By a combination of overlap with previously mapped cosmids and pulsed-field gel analysis, each of these cosmids has been positioned on the long-range restriction map of 4p16.3, increasing the clone coverage of the candidate region to approximately 40%. Single-copy probes from mapped cosmids were used to identify eight new DNA polymorphisms spanning the HD candidate region. These new DNA markers should prove valuable for analysis of recombination and linkage disequilibrium in HD, as well as for preclinical diagnosis of the disorder.

Alleles↗
PubMed1991

The relationship between systolic anterior motion of the mitral valve and the left ventricular outflow tract Doppler in hypertrophic cardiomyopathy.

In an attempt to investigate the role of left ventricular blood outflow in the generation of systolic anterior motion (SAM) of the mitral valve in patients with hypertrophic cardiomyopathy, we precisely analyzed the temporal relation of SAM and the left ventricular outflow tract (LVOT) systolic Doppler events obtained at the maximal mitral-septal apposition or equivalent area in eight patients with severe SAM, in five patients with mild/moderate SAM, and in seven patients with no SAM, using M-mode and pulsed Doppler echocardiography; the results were compared with those in 10 normal subjects. In all 13 patients with SAM, the timing of SAM generation corresponded to the LVOT Doppler events either between the onset of SAM and the onset of Doppler (r = 0.834, p less than 0.0001) or between the peak of SAM and the peak of Doppler (r = 0.836, p less than 0.0001). The excursion rate of the development of SAM showed a correlation with the LVOT blood outflow acceleration (r = 0.828, p less than 0.0001). The timing of SAM resolution also correlated with the Doppler events, either between the offset of SAM and the offset of Doppler (r = 0.795, p less than 0.001) or the end of SAM and the end of Doppler (r = 0.859, p less than 0.0001). The LVOT blood outflow deceleration showed a correlation with the regression rate of SAM (r = 0.668, p less than 0.013). The LVOT blood outflow acceleration was significantly higher in patients with severe SAM than in patients with mild/moderate SAM or no SAM. This study suggests that the high LVOT blood outflow acceleration in early systole possibly plays an important part in the generation of the Bernoulli pressure drop and results in anterior motion of the mitral valve. At mid-systole, a drag force and/or suction effect of pressure drop produced by continuous outflow blood may sustain the anterior motion of the mitral valve. At late systole, as the blood flow decelerates, the regression of SAM then occurs.

Cardiomyopathy, Hypertrophic↗
PubMed1991

Potential diagnosis of hemodynamic abnormalities in patent ductus arteriosus by cine magnetic resonance imaging.

Cine magnetic resonance imaging was performed in 11 patients with communication between systemic and pulmonary circulation. In five patients with uncomplicated patent ductus arteriosus (PDA), ductus arteriosus was delineated by a persistent band of low signal intensity, whereas in two patients who also had severe pulmonary hypertension the signal intensity was varied. Two separate low signal intensities in the main pulmonary artery and the descending aorta were each uniformly recorded in the five patients with uncomplicated PDA, consistent with continuous left-to-right shunt and turbulent flow acceleration, respectively. In one of the patients with severe pulmonary hypertension but not Eisenmenger's syndrome, the areas of low signal intensity from left-to-right shunt and turbulent flow acceleration diminished. In the patient with Eisenmenger's PDA the right-to-left shunt was also characterized by an area of low signal intensity but with a reversal in direction. Cine MR imaging has the potential to be a noninvasive and supplemental method for evaluating PDA.

Adolescent↗
PubMed1991

DSP4 treatment worsens hippocampal pyramidal cell damage after transient ischemia.

Recent studies in the rat have suggested that hippocampal norepinephrine can regulate the amount of damage seen after transient forebrain ischemia. We used the gerbil to study the role of norepinephrine in ischemic damage. Using tyrosine hydroxylase immunocytochemistry and chemical measurements of norepinephrine, we determined that the gerbil hippocampus has a similar but topographically different norepinephrine innervation than the rat. Brains from gerbils treated with 100 mg/kg of N-(2-chloroethyl)-N-methyl-2-bromobenzylamine (DSP4) had 60% less norepinephrine than saline-treated controls, similar to the effect of the drug in rats. We administered DSP4 to gerbils two weeks before exposing them to 5 min of bilateral carotid artery occlusion. Animals treated with DSP4 and subjected to ischemia had worse pyramidal cell loss in the CA3 and CA4 regions than saline-treated ischemic controls. CA1 pyramidal cell loss (about 90%) was severe in both the saline- and DSP4-treated animals. These data provide further evidence that norepinephrine can regulate the neuronal death in the hippocampal formation after transient forebrain ischemia. Furthermore, this is the first demonstration of that regulation in the gerbil and suggests that noradrenergic input to the hippocampus may be important in ischemia in other species besides the rat.

Animals↗
PubMed1991

Use of the perforated balloon catheter to infuse marker substances into diseased coronary artery walls after experimental postmortem angioplasty.

A perforated balloon catheter was used in human coronary arteries after postmortem angioplasty had been performed. The catheter used has a standard angioplasty balloon with a pattern of laser-produced holes, 25 microns in size, which generate streams of fluid under pressure. Studies of the routes by which marker substances enter diseased arterial tissue when infused by the perforated balloon after experimental angioplasty are described. A colored marker dye entered the new crevices and dissection planes created by the angioplasty, but did not extend greater than 2 cm either proximal or distal to the perfused segment. Horseradish peroxidase entered tissue not only from the lumen and adventitia as occurs with its infusion into normal tissue with the perforated balloon, but also extended from new crevices and dissection planes created by the angioplasty. Platelet aggregation, coagulation and cell proliferation, the likely causes of restenosis after angioplasty, originate in the sites of greatest tissue disruption and blood stasis. These postmortem studies suggest that active drugs are delivered to the arterial wall in a manner likely to be effective in preventing these events.

Aged↗
PubMed1991

Second messenger-mediated actions of norepinephrine on target neurons in central circuits: a new perspective on intracellular mechanisms and functional consequences.

Ever since the initial demonstration of a widespread distribution of noradrenergic fibers to functionally diverse regions of the mammalian forebrain, there has been considerable interest in determining the electrophysiological effects of norepinephrine (NE) on individual neurons within these target areas. While early studies showed that NE could directly inhibit cell firing via increased intracellular levels of cyclic AMP, more recent work has revealed a spectrum of noradrenergic actions, which are more accurately characterized as neuromodulatory. More specifically, numerous experimental conditions have been described where NE at levels subthreshold for producing direct depressant effects on spontaneous firing can facilitate neuronal responses to both excitatory and inhibitory synaptic stimuli. The goal of this report is to review recent evidence which suggests that the various modulatory actions of NE on central neurons result from the activation of different adrenoceptor-linked second messenger systems. In particular, we have focused on the candidate signal transduction mechanisms that may underlie NE's ability to augment cerebellar and cortical neuronal responsiveness to GABAergic synaptic inputs. The consequences of such NE-induced changes in synaptic efficacy are considered not only with respect to their influences on feature extraction properties of individual sensory cortical neurons but also with regard to the potential impact such actions would have on the signal processing capabilities of a network of noradrenergically innervated cortical cells.

Action Potentials↗
PubMed1991

Purification and Characterization of d-Aminoacylase from Alcaligenes faecalis DA1.

A d-aminoacylase from Alcaligenes faecalis DA1 has been purified to homogeneity by a simple purification procedure with two columns, Fractogel DEAE-650 and HW-50. The specific activity of the purified enzyme was found to be 580 U/mg of protein with N-acetyl-dl-methionine as the reaction substrate. The apparent molecular weight and isoelectric point of this enzyme were determined to be 55,000 and 5.4, respectively.

Journal Article↗
PubMed1991

Ontogeny of corticocortical projections of the rat somatosensory cortex.

Rhodamine-coated microspheres (RCMs) were injected into the primary somatosensory cortex (SI) of rats ranging in age from postnatal (PN) day 1 to adulthood. Ipsilateral corticocortical and callosal projections within the SI were identified as early as PN day 1. At the end of the first PN week, ipsilaterally projecting neurons located in sublayer VIb were the first to assume an adult-like pattern of connectivity. Injections at subsequent postnatal ages revealed that an adult pattern of lamination of ipsilateral corticocortical projections within the SI is established between PN weeks 2 and 3, comprising projection neurons from layers II/III, layer V, and sublayer VIb. Therefore, local interactions in the rat SI are mediated not only by pyramidal neurons of layers III and V, derived from the cortical plate, but also by a subpopulation of ontogenetically older neurons located in the sublayer VIb, which may correspond to the subplate neurons of other species. Overall, these results suggest the existence of three independent short-range corticocortical systems of projections within the rat SI, which differ in terms of the laminar distribution and ontogenetic origin of their cells.

Aging↗
PubMed1990

A major direct GABAergic pathway from zona incerta to neocortex.

Retrograde fluorescent tracers were used to demonstrate a previously unknown but sizable direct gamma-aminobutyric acid (GABA)-containing neuronal pathway from the zona incerta to the neocortex in rats. This incertocortical pathway was found to project bilaterally to the entire neocortex and exhibited a rough corticotopic organization. Many of the zona incerta neurons projecting to the parietal and occipital cortices could also be immunohistochemically stained with antibodies to glutamic acid decarboxylase and GABA. Few of these neurons were immunoreactive to tyrosine hydroxylase antibodies, which identify dopamine-containing neurons. Injections in the frontal and entorhinal cortices labeled many neurons near or within the dopaminergic A13 subdivision of the zona incerta. In addition, the incertocortical system was found to be significantly larger during early postnatal (2 to 3 weeks) development. The projection pattern of this newly discovered pathway resembles that of the monoaminergic and cholinergic systems, arising from the brainstem and forebrain, suggesting possible similarities of function.

Animals↗
PubMed1990

Differential control of tropomyosin mRNA levels during myogenesis suggests the existence of an isoform competition-autoregulatory compensation control mechanism.

We have isolated tropomyosin cDNAs from human skeletal muscle and nonmuscle cDNA libraries and constructed gene-specific DNA probes for each of the four functional tropomyosin genes. These DNA probes were used to define the regulation of the corresponding mRNAs during the process of myogenesis. Tropomyosin regulation was compared with that of beta- and gamma-actin. No two striated muscle-specific tropomyosin mRNAs are coordinately accumulated during myogenesis nor in adult striated muscles. Similarly, no two nonmuscle tropomyosins are coordinately repressed during myogenesis. However, mRNAs encoding the 248 amino acid nonmuscle tropomyosins and beta- and gamma-actin are more persistent in adult skeletal muscle than those encoding the 284 amino acid nonmuscle tropomyosins. In particular, the nonmuscle tropomyosin Tm4 is expressed at similar levels in adult rat nonmuscle and striated muscle tissues. We conclude that each tropomyosin mRNA has its own unique determinants of accumulation and that the 248 amino acid nonmuscle tropomyosins may have a role in the architecture of the adult myofiber. The variable regulation of nonmuscle isoforms during myogenesis suggests that the different isoforms compete for inclusion into cellular structures and that compensating autoregulation of mRNA levels bring gene expression into alignment with the competitiveness of each individual gene product. Such an isoform competition-autoregulatory compensation mechanism would readily explain the unique regulation of each gene.

Animals↗