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Biomedical subjects

S Lin

Publications and source records attributed to S Lin.

At least 451 records · Page 25Linked to original sources
PubMed1995

A new bioassay for insulin in conscious rabbits by continuous measurement of glycemic responses.

Because of the substantial variability often observed in the determination of insulin potency by the United States Pharmacopeia (USP) bioassay method, a large number of rabbits are required in order to attain an accuracy of +/- 6% and each bioassay needs 2-3 weeks to be completed. In this report, an improved bioassay method has been developed. This bioassay was conducted in conscious healthy rabbits. The decline in blood glucose levels, following intravenous injection of an insulin preparation, was monitored (in uninterrupted manner) by the continuous glucose monitoring system developed. A glucose response curve was generated, and from this response curve, various pharmacodynamic parameters were easily determined. The whole procedure could be completed in 1 day and also achieved an accuracy where upon only one rabbit is needed to determine accurately the insulin potency. To validate the method, a total of nine healthy rabbits were studied to determine the inter- and intra-animal reproducibility. The values of insulin potency determined from four pharmacodynamic parameters were compared, and the potency calculated from the ABGC (area of the blood glucose response curve under baseline) was found to be the most accurate: a mean (+/- SEM) value of 102.3(+/- 1.2)% was determined by inter-animal study (n = 9) and a value of 100.6(+/- 1.3)% by intra-animal study (n = 4). The inter-bioassay variability among the random-dose bioassays was 1.2% for inter-animal and 1.3% for intra-animal studies. The insulin potency in an insulin sample determined by this bioassay had attained an overall mean (+/- SEM) value of 101.6(+/- 0.8)% (n = 17).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Fracture phenomena in an isotonic salt solution during freezing and their elimination using glycerol.

Thermal stress and consequent fracture in frozen organs or cell suspensions have been proposed to be two causes of cell cryoinjury. A specific device was developed to study the thermal stress and the fracture phenomena during a slow cooling process of isotonic NaCl solutions with different concentrations of glycerol (cryoprotectant) in a cylindrical tube. It was shown from the experimental results that glycerol significantly influenced the solidification process of the ternary solutions and reduced the thermal stress. The higher the initial glycerol concentration, the lower the thermal stress in the frozen solutions. Glycerol concentrations over 0.3 M were sufficient to eliminate the fracture of the frozen solutions under the present experimental conditions. To explain the action of glycerol in reducing the thermal stress and preventing the ice fracture, a further study on ice crystal formation and growth of ice in these solutions was undertaken using cryomicroscopy. It is known from previous studies that an increase of initial glycerol concentration reduced frozen fraction of water in the solution at any given low temperature due to colligative properties of solution, which reduced the total ice volume expansion during water solidification. The present cryomicroscopic investigation showed that under a fixed cooling condition the different initial glycerol concentrations induced the different microstructures of the frozen solutions at not only a given low temperature but also a given frozen fraction of water. It has been known that ice volume expansion during solidification is a major factor causing the thermal stress and the interior microstructure is critical for the mechanical strength of a solid. Therefore, functions of glycerol in reducing the total ice volume expansion during water solidification and in influencing interior microstructure of the ice may contribute to reduce the thermal stress and prevent the fracture in the frozen solutions.

Animals↗
PubMed1995

The Aequorea victoria green fluorescent protein can be used as a reporter in live zebrafish embryos.

The green fluorescent protein (GFP) from the cnidarian Aequorea victoria is capable of producing fluorescence without an exogenously added substrate. Here we demonstrate that a cDNA for GFP driven by a Xenopus elongation factor 1 alpha enhancer-promoter can confer fluorescence upon live zebrafish embryos, either as an injected plasmid or as a transgene after passage through the germline. When injected into zebrafish embryos at the one-cell stage, this construct starts to express detectable GFP after about 4 hr of development at 28 degrees C, about 1 hr after the midblastula transition. Fluorescence can be observed in cells of many tissue types in the embryo for at least 3 weeks after injection. We used three different expression constructs, each employing a modified ef1 alpha enhancer-promoter, to generate 12 transgenic lines. Eight of the 12 lines, including 5 of 5 derived from one construct with an intron, express detectable fluorescence in the F1 and, where tested, in the F2 generation. Most expressing lines showed very similar expression patterns. Generally, fluorescence is not seen in the transgenic embryos before 20 hr postfertilization, at which point it appears uniformly throughout the embryo. Fluorescence is most visible between 24-36 hr, and it becomes less visible after this, except that in many lines strong fluorescence remains visible in the eye for at least 5 days. A single inherited copy of the transgene is sufficient to produce detectable fluorescence in hemizygous F1 and F2 embryos.

Animals↗
PubMed1995

Attenuation of esophageal shortening during peristalsis with hiatus hernia.

BACKGROUND & AIMS: Minimal quantitative information exists on esophageal shortening during peristalsis in the human esophagus. The aim of this study was to ascertain the effect of hiatus hernia on longitudinal muscle-mediated peristaltic esophageal shortening. METHODS: Seven volunteers and 11 patients with hiatal hernia had metal clips endoscopically affixed at the squamocolumnar junction and 3-5 cm proximal to it (n = 11). Location of the lower esophageal sphincter and axial clip movement were assessed using concurrent manometry and videofluoroscopy during barium swallows in a supine and upright posture with and without abdominal compression. RESULTS: Three subject groups were defined by the proximity of the squamocolumnar junction to the diaphragmatic hiatus: group 1, < or = 0 cm; group 2, between 0 and 2 cm; and group 3, > or = 2 cm. Peristaltic esophageal shortening was progressively diminished, re-elongation progressively prolonged, and the degree of contraction observed in the distal esophageal segment reduced with progressive degree of hiatus hernia. There was minimal mobility of the squamocolumnar junction relative to the hiatus with posture or abdominal compression. CONCLUSIONS: Longitudinal muscle contraction during peristalsis normally causes transient elevation of the squamocolumnar junction above the diaphragm. Esophageal shortening during primary peristalsis is reduced with increasing degree of hiatus hernia, suggesting that there is diminished opposition of longitudinal muscle contraction from the phrenoesophageal attachments.

Adult↗
PubMed1995

Uterine artery Doppler velocimetry in relation to trophoblast migration into the myometrium of the placental bed.

OBJECTIVE: To test the hypothesis that an abnormally high resistance in the uterine artery indicates impaired trophoblast migration into the myometrium of the placental bed. METHODS: Doppler velocimetry in the uterine artery was carried out in 43 pregnant women within 7 days before cesarean delivery and placental bed biopsy. A pathologist evaluated the placental bed biopsies histologically. Trophoblast migration was absent in 28 cases (impaired migration group) and present in 15 (migration group). Clinical characteristics were compared between these two groups. RESULTS: There was no significant difference in the mean gestational ages at delivery in the two groups, but those with impaired migration included a higher incidence of small for gestational age infants (46.4 versus 6.7%, P < .01) and a lower mean (+/- standard deviation) birth weight (1622 +/- 528 versus 2287 +/- 748 g, P < .01). The systolic-diastolic ratio (S/D) in the uterine artery was higher in the impaired migration group (2.45 +/- 0.81 versus 1.92 +/- 0.34, P < .05). The absence of migration could be deduced from the S/D of the uterine artery, with a predictive value of 92.3% when we set the cutoff value of the ratio at 2.5. CONCLUSION: The results suggest that abnormal uterine artery flow velocity waveforms may indicate impaired trophoblast migration into the myometrium of the placental bed.

Arteries↗
PubMed1995

A scanning tunnelling microscopic study of site-specifically immobilized immunoglobulin G on gold.

A convenient and efficient method for the site-specific incorporation of foreign cysteine residues at the C-termini of immunoglobulin G (IgG) using carboxypeptidase-Y-catalyzed transpeptidation is explored as a means of ensuring oriented immobilization of IgG on gold. A scanning tunnelling microscopic study of the immobilization of the modified IgG molecules on gold surfaces is reported. The results show not only that some globular features are observed to form striking surface patterns with a geometric size close to that of the fragments of IgG but also that the conformation of the bound IgG molecules appears more stable when adsorbed on gold. The effect of the immobilization method on these topographic features is discussed.

Animals↗
PubMed1995

Direct observation of sub-picosecond equilibration of excitation energy in the light-harvesting antenna of Rhodospirillum rubrum.

Excitation energy transfer in the light-harvesting antenna of Rhodospirillum rubrum was studied at room temperature using sub-picosecond transient absorption measurements. Upon excitation of Rs. rubrum membranes with a 200 fs, 600 nm laser flash in the Qx transition of the bacteriochlorophyll-a (BChl-a) absorption, the induced transient absorption changes in the Qy region were monitored. In Rs. rubrum membranes the observed delta OD spectrum exhibits ground state bleaching, excited state absorption and stimulated emission. Fast Qx --> Qy relaxation occurs in approximately 100-200 fs as reflected by the building up of stimulated emission. An important observation is that the zero-crossing of the transient difference absorption (delta OD) spectrum exhibits a dynamic redshift from 863 to 875 nm that can be described with by a single exponential with 325 fs time constant. The shape of the transient difference spectrum observed in a purified subunit of the core light-harvesting antenna, B820, consisting of only a single interacting pair of BChl-as, is similar to the spectrum observed in Rs. rubrum membranes and clearly different from the spectrum of BChl-a in a protein/detergent mixture. In the B820 and monomeric BChl-a preparations the 100-200 fs Qx --> Qy relaxation is still observed, but the dynamic redshift of the delta OD spectrum is absent. The spectral kinetics observed in the Rs. rubrum membranes are interpreted in terms of the dynamics of excitation equilibration among the antenna subunits that constitute the inhomogeneously broadened antenna. A simulation of this process using a set of reasonable physical parameters is consistent with an average hopping time in the core light harvesting of 220-270 fs, resulting in an average single-site excitation lifetime of 50-70 fs. The observed rate of this equilibration process is in reasonable agreement with earlier estimations for the hopping time from more indirect measurements. The implications of the findings for the process of excitation trapping by reaction centers will be discussed.

Artifacts↗
PubMed1995

Excited state dynamics in photosystem I: effects of detergent and excitation wavelength.

Femtosecond transient absorption spectroscopy has been used to investigate the energy transfer and trapping processes in both intact membranes and purified detergent-isolated particles from a photosystem II deletion mutant of the cyanobacterium Synechocystis sp. PCC 6803, which contains only the photosystem I reaction center. Processes with similar lifetimes and spectra are observed in both the membrane fragments and the detergent-isolated particles, suggesting little disruption of the core antenna resulting from the detergent treatment. For the detergent-isolated particles, three different excitation wavelengths were used to excite different distributions of pigments in the spectrally heterogeneous core antenna. Only two lifetimes of 2.7-4.3 ps and 24-28 ps, and a nondecaying component are required to describe all the data. The 24-28 ps component is associated with trapping. The trapping process gives rise to a nondecaying spectrum that is due to oxidation of the primary electron donor. The lifetimes and spectra associated with trapping and radical pair formation are independent of excitation wavelength, suggesting that trapping proceeds from an equilibrated excited state. The 2.7-4.3 ps component characterizes the evolution from the initially excited distribution of pigments to the equilibrated excited state distribution. The spectrum associated with the 2.7-4.3 ps component is therefore strongly excitation wavelength dependent. Comparison of the difference spectra associated with the spectrally equilibrated state and the radical pair state suggests that the pigments in the photosystem I core antenna display some degree of excitonic coupling.

Biophysical Phenomena↗
PubMed1995

The mechanisms by which hyperbaric oxygen and carbogen improve tumour oxygenation.

Hyperbaric oxygen (HBO) has been proposed to reduce tumour hypoxia by increasing the amount of dissolved oxygen in the plasma. That this actually occurs has not been verified experimentally. This study was performed to explore changes in tumour oxygenation induced by treatment with normobaric and hyperbaric oxygen and carbogen. R3230Ac mammary adenocarcinomas were implanted into Fisher 344 rats. Arterial blood gases, blood pressure and heart rate were monitored. Tumour oxygenation was measured polarographically in five sets of animals. They received either normobaric 100% oxygen, hyperbaric (3 atmospheres; atm) 100% oxygen, normobaric carbogen or hyperbaric (3 atm) carbogen (HBC) +/- bretylium. HBO reduced the mean level of low pO2 values (< 5 mmHg) from 0.49 to 0.07 (P = 0.0003) and increased the average median pO2 from 8 mmHg to 55 mmHg (P = 0.001). HBC reduced the level of low pO2 values from 0.82 to 0.51 (P = 0.002) an increased median pO2 from 2 mmHg to 6 mmHg (P = 0.05). Normobaric oxygen and carbogen did not change tumour oxygenation significantly. Sympathetic blockade with bretylium before HBC exposure improved oxygenation significantly more than HBC alone (low pO2 0.55-0.17, median pO2 4-17 mmHg). HBO and hyperbaric carbogen improved tumour oxygenation in this model, while normobaric oxygen or carbogen had no effect. Sympathetic-mediated vasoconstriction during hyperbaric carbogen caused it to be less effective than HBO. This mechanism also appeared to operate during normobaric carbogen breathing.

Adenocarcinoma↗
PubMed1995

GABAB receptor-mediated effects in synaptosomes of lethargic (lh/lh) mice.

Previously, we have shown a significant increase in number of GABAB receptor binding sites in neocortex and thalamus of lethargic (lh/lh) mice, a mutant strain exhibiting absence seizures. This study was performed to test our hypothesis that presynaptic GABAB receptors would inhibit [3H]GABA release to a greater degree in lh/lh mice compared with their nonepileptic littermates (designated +/+). Synaptosomes isolated from neocortex and thalamus of age-matched male lh/lh and +/+ mice were similar in uptake of [3H]GABA. In the neocortical preparation, baclofen dose-dependently inhibited [3H]GABA release evoked by 12 mM KCl, an effect mediated by GABAB receptors. The maximal inhibition (Imax) value was significantly greater (80%) in lh/lh than +/+ mice, whereas the IC50 (3 microM) was unchanged. In the thalamic preparation, the effect of baclofen (50 microM) was 58% less robust in lh/lh mice. Other effects mediated by GABAB receptors (inhibitions in Ca2+ uptake and cyclic AMP formation) were also significantly reduced in thalamic synaptosomes from lh/lh mice. These data suggest a greater presynaptic GABAB receptor-mediated effect in neocortex and a reduced effect in thalamic nuclei of lh/lh mice. It is possible that selective effects of presynaptic GABAB receptors or GABA release in neocortex and thalamic nuclei of lh/lh mice may contribute to mechanisms underlying absence seizures.

Animals↗
PubMed1995

Molecular cloning, expression, and mapping of the high affinity actin-capping domain of chicken cardiac tensin.

Tensin, an actin filament capping protein first purified from chicken gizzard, is localized to various types of adherens junctions in muscle and nonmuscle cells. In this paper, we describe the isolation and sequencing of tensin cDNA from a chicken cardiac library. The 6.3-kb chicken cardiac tensin cDNA encodes an open reading frame of 1,792 amino acids. Mammalian cells transfected with the chicken tensin cDNA expressed a polypeptide of approximately 200 kD recognizable by antibodies to chicken gizzard tensin. The expressed protein was incorporated into focal adhesions and other actin-containing structures in the transfected cells. To map the domain associated with tensin's high affinity, barbed-end F-actin-capping activity, bacterially expressed recombinant fusion proteins containing various segments of tensin were prepared and assayed for activity. The results of these experiments show that the high affinity capping domain (kD = 1.3 nM) lies within amino acid residues R1037-V1169. Additional studies on a shorter construct, S1061-H1145, showed that these 85 residues were sufficient for producing complete inhibition of actin polymerization and depolymerization. While this active domain is located within that of the "insertin" sequence (Weigt, C., A. Gaertner, A. Wegner, H. Korte, and H. E. Meyer. 1992. J. Mol. Biol. 227:593-595), our data showing complete inhibition of polymerization and shift in critical concentration are consistent with a simple barbed-end capping mechanism rather than the "insertin model." Our results also differ from those of a recent report (Lo, S. H., P. A. Janmey, J. H. Hartwig, and L. B. Chen. 1994. J. Cell Biol. 125:1067-1075), which concluded that their recombinant tensin has an "insertin-like" inhibitory effect on barbed-end actin polymerization, and that this activity is attributed to residues T936-R1037 (residues 888-989 in their numbering system). In our study, a fusion construct (N790-K1060) encompassing T936-R1037 had no significant effect on actin polymerization and depolymerization, even at high concentrations.

3T3 Cells↗
PubMed1995

The 200-MeV proton therapy project at the Paul Scherrer Institute: conceptual design and practical realization.

The new proton therapy facility is being assembled at the Paul Scherrer Institute (PSI). The beam delivered by the PSI sector cyclotron can be split and brought into a new hall where it is degraded from 590 MeV down to an energy in the range of 85-270 MeV. A new beam line following the degrader is used to clean the low-energetic beam in phase space and momentum band. The analyzed beam is then injected into a compact isocentric gantry, where it is applied to the patient using a new dynamic treatment modality, the so-called spot-scanning technique. This technique will permit full three-dimensional conformation of the dose to the target volume to be realized in a routine way without the need for individualized patient hardware like collimators and compensators. By combining the scanning of the focused pencil beam within the beam optics of the gantry and by mounting the patient table eccentrically on the gantry, the diameter of the rotating structure has been reduced to only 4 m. In the article the degrees of freedom available on the gantry to apply the beam to the patient (with two rotations for head treatments) are also discussed. The devices for the positioning of the patient on the gantry (x rays and proton radiography) and outside the treatment room (the patient transporter system and the modified mechanics of the computer tomograph unit) are briefly presented. The status of the facility and first experimental results are introduced for later reference.

Cyclotrons↗
PubMed1995

Three-dimensional modeling of the oropharynx during swallowing.

The mechanical actions of swallowing in one volunteer were modeled in three dimensions. Biplane fluoroscopy and dynamic ultrafast computed tomography of adjacent levels of the pharynx were performed during swallows of liquid. Synchronized posteroanterior, lateral, and cross-sectional images were scanned and aligned in three dimensions with graphics-animation software. Modeling the oropharyngeal swallow helps analysis and visualization of the mechanics of swallowing, dysphagia, and compensatory therapeutic strategies.

Adult↗
PubMed1995

The phrenic ampulla: distal esophagus or potential hiatal hernia?

The mechanics of phrenic ampullary emptying were analyzed to determine whether this structure functions in a manner similar to the tubular esophagus or a hiatal hernia. Simultaneous videofluoroscopy and intraluminal manometry of the gastroesophageal junction were done during barium swallows in 18 normal volunteers. Esophageal emptying was studied without any external influences, during abdominal compression with a cuff inflated to 100 mmHg, during a Müller maneuver, and after medication with atropine. The key finding of the study was that ampullary emptying was distinct from esophageal bolus transport in several ways: the propagation velocity of the clearing wave was slower, the maximal contact pressures achieved after luminal closure were lower and unaffected by atropine or outflow obstruction, and ampulary emptying was driven by a hydrostatic pressure difference between the ampulla and stomach rather than by a peristaltic contraction. Increased bolus volume slightly enlarged the ampulla. Taken together, these findings suggest that ampullary emptying occurs, in part, as a result of the restoration of esophageal length (presumably by tension from the phrenoesophageal membrane) rather than as a result of an aborally propagated contraction. As such, a normal phrenic ampulla is analogous to a small reducing hiatal hernia. We speculate that overt hernia formation occurs as a result of progressive degeneration of the phrenoesophageal membrane.

Adult↗
PubMed1995

Phase I trial of high-dose tamoxifen as a modulator of drug resistance in combination with daunorubicin in patients with relapsed or refractory acute leukemia.

Tamoxifen and its main metabolite N-desmethyltamoxifen (NDMTmx) have been shown to increase intracellular daunorubicin (DNR) levels in human leukemia cell lines that display the multidrug resistant (MDR) phenotype. We designed a phase I dose escalation study of Tmx (200-700 mg/day p.o. for 7 days) in combination with a fixed dose of DNR (50 mg/m2 intravenously on days 5, 6 and 7) in patients with advanced leukemia to determine whether this combination could be given safely and whether plasma levels of 10 microM, the effective in vitro MDR modulator concentration, could be achieved. Pharmacologic studies of Tmx, NDMTmx and DNR, and its main metabolite daunorubicin-ol (DNR-ol) were performed as was determination of P-glycoprotein (Pgp) using a monoclonal antibody that recognizes an external epitope of the molecule. A total of 14 patients (median age 50, range 22-67) were treated at the following dose levels: 200 mg/day: three patients; 400 mg/day: four patients; 550 mg/day: three patients; and 700 mg/day: four patients. Two patients with relapsed AML achieved remission. Toxicity of the combination was similar to that seen with DNR alone and no severe hepatic, cardiac or retinal toxicity was noted. Plasma Tmx levels approached 7 microM at the two highest dose levels studied; plasma levels of NDMTmx were slightly less. The area under the curve for DNR and its main metabolite daunorubicin-ol (DNR-ol) did not show significant changes with escalation of Tmx dose. This phase I study suggests that concentrations of Tmx high enough to reverse the MDR phenotype can be approached and that the combination of high-dose Tmx with a standard dose of DNR has an acceptable toxicity profile. More evaluation in phase II studies is necessary to define further its role as an MDR modulator.

Adult↗
PubMed1995

A scheme for constructing an irreducible Markov chain for pedigree data.

Estimating probabilities on a pedigree by dependent samples, namely realizations of a Markov chain, has been explored as an alternative method when exact computation is not feasible. If the transition kernel of the Markov chain is aperiodic and irreducible, convergence of the estimates to the true probabilities is guaranteed by the ergodic theorem. However, reducibility is a potential problem for genetic pedigree analysis unless the Markov chain is constructed appropriately. In the present paper, we propose a scheme for constructing an irreducible Markov chain for pedigree data. Transitions between communicating classes, which can be found explicitly, are made by using a Metropolis jumping kernel. The method has been demonstrated to be much more efficient than other currently existing methods.

ABO Blood-Group System↗