Letter to the editor: 1H, 13C and 15N chemical shift assignments of the acidic fibroblast growth factor from Notopthalmus viridescens.
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Animals↗
Biomedical subjects
C Yu
Publications and source records attributed to C Yu.
Surround modulation in human vision unmasked by masking experiments.
The responses of neurons in cat and monkey primary visual cortex are modulated by stimuli outside the classical receptive field. Here we report psychophysical evidence from masking experiments for two distinct types of surround modulation, one narrowly tuned to iso-orientation (stimuli with center and surround at the same orientation) and the other broadly tuned to cross-orientation (center and surround at perpendicular orientations). Surround modulation at iso- and cross-orientations showed distinct contrast dependencies, and high-contrast cross-oriented surrounds were able to completely eliminate masking. Surround modulation was modeled by subtracting divisive inhibition that raised the gain of spatial filters.
Adult↗
Contribution of Are1p and Are2p to steryl ester synthesis in the yeast Saccharomyces cerevisiae.
In the yeast Saccharomyces cerevisiae, two acyl-CoA:sterol acyltransferases (ASATs) that catalyze the synthesis of steryl esters have been identified, namely Are2p (Sat1p) and Are1p (Sat2p). Deletion of either ARE1 or ARE2 has no effect on cell viability, and are1are2 double mutants grow in a similar manner to wild-type despite the complete lack of cellular ASAT activity and steryl ester formation [Yang, H., Bard, M., Bruner, D. A., Gleeson, A., Deckelbaum, R. J., Aljinovic, G., Pohl, T. M., Rothstein, R. & Sturley, S. L. (1996) Science 272, 1353-1356; Yu, C., Kennedy, J., Chang, C. C. Y. & Rothblatt, J. A. (1996) J. Biol. Chem. 271, 24157-24163]. Here we show that both Are2p and Are1p reside in the endoplasmic reticulum as demonstrated by measuring ASAT activity in subcellular fractions of are1 and are2 deletion strains. This localization was confirmed by fluorescence microscopy using hybrid proteins of Are2p and Are1p fused to green fluorescent protein (GFP). Lipid analysis of are1 and are2 deletion strains revealed that Are2p and Are1p utilize sterol substrates in vivo with different efficiency; Are2p has a significant preference for ergosterol as a substrate, whereas Are1p esterifies sterol precursors, mainly lanosterol, as well as ergosterol. The specificity towards fatty acids is similar for both isoenzymes. The lack of steryl esters in are1are2 mutant cells is largely compensated by an increased level of free sterols. Nevertheless, terbinafine, an inhibitor of ergosterol biosynthesis, inhibits growth of are1are2 cells more efficiently than growth of wild-type. In a growth competition experiment are1are2 cells grow more slowly than wild-type after several rounds of cultivation, suggesting that Are1p and Are2p or steryl esters, the product formed by these two enzymes, are more important in the natural environment than under laboratory conditions.
Acyltransferases↗
Radiosurgical salvage therapy for patients presenting with recurrence of metastatic disease to the brain.
OBJECTIVE: Radiosurgery has emerged as an important modality in the management of metastatic disease to the brain. A number of groups have published results suggesting that high local control rates can be achieved, with improvements in overall survival that rival the results of open surgical treatment. Typically, however, whole-brain radiotherapy has been used in the salvage therapy of patients who have undergone previous craniotomy or radiosurgery. We describe our experience with radiosurgical salvage in this group of patients. METHODS: From August 1994 to February 1999, 190 patients with brain metastasis were treated with gamma unit radiosurgery at our institution. A subset of 45 patients, who underwent radiosurgical salvage for new tumors in a region remote from an initially treated tumor, form the population base for this study. The usual criteria for repeat treatment were recurrence with five or fewer discrete lesions outside of the previously treated radiosurgical volume and Karnofsky Performance Scale score of at least 70. Survival and freedom from progression were measured from the time of radiosurgical treatment and were computed by the Kaplan-Meier product-limit method. Two or more curves were compared using the log-rank method. RESULTS: In this subgroup of patients, a total of 176 tumors were treated. The median time from first radiosurgical procedure to first salvage was 17.4 weeks. Median survival from the second radiosurgical intervention was 28 weeks. Of the 45 study patients, 34 patients underwent a single salvage procedure, 10 patients underwent two salvage procedures, and 1 patient had three salvage procedures. The actuarial freedom from progression for treated tumors at 52 weeks was 92.4%. Patients undergoing upfront whole-brain irradiation were less likely to require salvage therapy (P = 0.008). There were 33 deaths after salvage radiosurgery during the reporting period. Central nervous system causes accounted for 13 deaths, whereas 19 deaths resulted from systemic disease. The cause of death in one patient could not be determined. No statistically significant advantage in overall survival could be demonstrated in patients treated with whole-brain irradiation. CONCLUSION: Radiosurgical salvage represents a valuable means of treatment for central nervous system recurrence for patients who have undergone previous treatment for metastatic disease to the brain. Whole-brain irradiation may reduce the need for salvage therapy, but no advantage in overall survival could be demonstrated in this subgroup.
Brain Neoplasms↗
Stereotactic radiosurgery in the treatment of metastatic disease to the brain.
OBJECTIVE: In recent years, stereotactic radiosurgery has been growing in popularity as a treatment modality for metastatic disease to the brain. The technique has advantages of reduced cost and low morbidity compared with open surgical treatment. Furthermore, it avoids the potential cognitive side effects of fractionated whole-brain radiotherapy. We undertook this study to determine the usefulness of adjuvant radiation therapy and to determine prognostic factors in patients treated with stereotactic radiosurgery. METHODS: We reviewed our series of patients with metastatic tumors treated using gamma knife stereotactic radiosurgery from August 1994 to February 1999. Nonparametric methods were used to compare treatment subgroups by demographic features including age, Karnofsky Performance Scale score, diagnosis, and systemic disease status. Univariate and multivariate analyses of survival and freedom from progression were performed using Kaplan-Meier and Cox proportional hazards regression techniques. RESULTS: This study included 190 patients harboring 431 lesions who were treated in 263 treatment sessions. The median follow-up after radiosurgery was 36 weeks for all patients. The median actuarial survival from the time of radiosurgery in all patients was 34 weeks. When patients were stratified according to tumor histology, those without melanoma had a median survival of 39 weeks, and those with melanoma had a median survival of 28 weeks. The cause of death could be determined in 122 (92%) of the patients known to have died during the data capture period. For patients harboring melanoma, death was attributable to systemic disease in 31 (47%), to central nervous system-related processes in 29 (44%), and to unknown causes in 6 (9%). For non-melanoma patients, death was attributable to systemic disease in 45 (68%), to central nervous system-related processes in 17 (26%), and to unknown causes in 4 (6%). Significantly improved survival (P = 0.002) was observed in patients with controlled systemic disease. No significant difference in survival could be ascertained for patients presenting with up to four lesions, although patients with a total tumor volume greater than 9 cc had shortened survival. No survival benefit could be demonstrated for whole-brain radiotherapy administered either concomitantly or after radiosurgery. CONCLUSION: Factors correlated with significantly improved survival included controlled systemic disease and non-melanoma histology. We found no significant survival benefit that could be discerned from adjuvant whole-brain radiotherapy in this patient group.
Adult↗
In situ and interrupted-growth studies of the self-assembly of octadecyltrichlorosilane monolayers
We have examined the self-assembly process of octadecyltrichlorosilane on silicon using x-ray reflectivity. By comparing the commonly used "interrupted-growth" characterization technique with results obtained in situ, we have determined that quenching the growth and then rinsing and drying the sample introduces free area into the film, presumably by removal of non-cross-linked (physisorbed) molecules. Reintroduction of a quenched and rinsed film to solvent does not restore the thickness of the film to its previous value. We have also performed in situ growth studies over a range of concentrations. For all concentrations, we observe growth of islands of vertical molecules. The growth follows Langmuir kinetics, except at short times for low concentration solutions.
Journal Article↗
Proline inhibits aggregation during protein refolding.
The in vitro refolding of hen egg-white lysozyme is studied in the presence of various osmolytes. Proline is found to prevent aggregation during protein refolding. However, other osmolytes used in this study fail to exhibit a similar property. Experimental evidence suggests that proline inhibits protein aggregation by binding to folding intermediate(s) and trapping the folding intermediate(s) into enzymatically inactive, "aggregation-insensitive" state(s). However, elimination of proline from the refolded protein mixture results in significant recovery of the bacteriolytic activity. At higher concentrations (>1.5 M), proline is shown to form loose, higher-order molecular aggregate(s). The supramolecular assembly of proline is found to possess an amphipathic character. Formation of higher-order aggregates is believed to be crucial for proline to function as a protein folding aid. In addition to its role in osmoregulation under water stress conditions, the results of this study hint at the possibility of proline behaving as a protein folding chaperone.
Animals↗
Elucidation of the solution structure of cardiotoxin analogue V from the Taiwan cobra (Naja naja atra)--identification of structural features important for the lethal action of snake venom cardiotoxins.
The aim of the present study is to understand the structural features responsible for the lethal activity of snake venom cardiotoxins. Comparison of the lethal potency of the five cardiotoxin isoforms isolated from the venom of Taiwan cobra (Naja naja atra) reveals that the lethal potency of CTX I and CTX V are about twice of that exhibited by CTX II, CTX III, and CTX IV. In the present study, the solution structure of CTX V has been determined at high resolution using multidimensional proton NMR spectroscopy and dynamical simulated annealing techniques. Comparison of the high resolution solution structures of CTX V with that of CTX IV reveals that the secondary structural elements in both the toxin isoforms consist of a triple and double-stranded antiparallel beta-sheet domains. Critical examination of the three-dimensional structure of CTX V shows that the residues at the tip of Loop III form a distinct "finger-shaped" projection comprising of nonpolar residues. The occurrence of the nonpolar "finger-shaped" projection leads to the formation of a prominent cleft between the residues located at the tip of Loops II and III. Interestingly, the occurrence of a backbone hydrogen bonding (Val27CO to Leu48NH) in CTX IV is found to distort the "finger-shaped" projection and consequently diminish the cleft formation at the tip of Loops II and III. Comparison of the solution structures and lethal potencies of other cardiotoxin isoforms isolated from the Taiwan cobra (Naja naja atra) venom shows that a strong correlation exists between the lethal potency and occurrence of the nonpolar "finger-shaped" projection at the tip of Loop III. Critical analysis of the structures of the various CTX isoforms from the Taiwan cobra suggest that the degree of exposure of the cationic charge (to the solvent) contributed by the invariant lysine residue at position 44 on the convex side of the CTX molecules could be another crucial factor governing their lethal potency.
Amino Acid Sequence↗
Initial clinical experience with a new self-retaining left ventricular lead for permanent left ventricular pacing.
This study evaluated the performance of a new lead for permanent left ventricular (LV) pacing via the coronary sinus (CS) in four men and nine women (mean age = 71 +/- 13 years) with sick sinus syndrome. It consists of a 75-cm-long, 4.8-Fr, unipolar ventricular lead with a distal portion preshaped in an S curve to provide steerability and stability within the CS. Its efficacy and stability for permanent LV pacing were tested at implant, predischarge, and at 1, 3 and 6 months of follow-up. The lead was successfully implanted in 11/13 patients (85%) within a mean fluoroscopy time of 35 +/- 22 minutes. The final positions of the electrodes at the tip of the lead within venous tributaries of the CS were: (1) anterior (n = 2, 18%); (2) posterolateral (n = 5, 45%); and (3) the lateral (n = 4, 36%). Unsuccessful implants were due to unstable lead position (n = 1), or high pacing threshold (n = 1). There was no postprocedural lead dislodgment or significant changes in the R wave amplitude, LV pacing threshold and lead impedance up to 6 months of follow-up. In summary, this initial experience suggests that this new lead offers safe and reliable permanent LV pacing via the CS in the majority of patients and may be used in isolation or in conjunction with right ventricular pacing for biventricular synchronization.
Aged↗
A dosimetric leaf-setting strategy for shaping radiation fields using a multileaf collimator.
A dosimetric leaf-setting strategy of using multileaf collimators (MLC) for shaping radiation fields has been developed. Existing MLC leaf-setting strategies are all based upon geometric criteria. This new approach, however, matches a prescribed field contour with a MLC using clinically consistent dosimetric criteria. The leaf positions are determined using an iterative optimization algorithm. An empirical dose model was developed to compare the dosimetric-based leaf-setting strategy with the geometric-based leaf-setting strategies. Differences up to half a centimeter in the leaf positions and isodose lines were found between setting the MLC geometrically and setting the MLC dosimetrically. The dosimetric leaf-setting strategy provides the ability to achieve better dose conformation for a clinically desired isodose line. Since the desired isodose line that covers a treatment volume is typically higher than 50% of the maximum dose, the scalloping effects due to the finite leaf width at the leaf edge or 50% isodose lines are much reduced. Another benefit of the dosimetric leaf-setting is that it separates the leaf-setting process from the treatment planning process, and this frees the treatment planning vendors from developing detailed dose models for various existing types and future upgrades of MLC systems.
Algorithms↗
A systematic evaluation of air cavity dose perturbation in megavoltage x-ray beams.
The EGS4 Monte Carlo radiation transport code was used to systematically study the dose perturbation near planar and cylindrical air cavities in a water medium irradiated by megavoltage x-ray beams. The variables of the problem included x-ray energy, cavity shape and dimension, and depth of the cavity in water. The Monte Carlo code was initially validated against published measurements and its results were found to agree within 2% with the published measurements. The study results indicate that the dose perturbation is strongly dependent on x-ray energy, field size, depth, and size of cavity in water. For example, the Monte Carlo calculations show dose reductions of 42% and 18% at 0.05 and 2 mm, respectively, beyond the air-water interface distal to the radiation source for a 3 cm thick air slab irradiated by a single 5x5 cm2 15 MV beam. The dose reductions are smaller for a parallel-opposed pair of 5x5 cm2 15 MV x-ray beams, being 21% and 11% for the same depths. The combined set of Monte Carlo calculations showed that the dose reduction near an air cavity is greater for: (a) Smaller x-ray field size, (b) higher x-ray energy, (c) larger air-cavity size, and (d) smaller depth in water where the air cavity is situated. A potential clinical application of these results to the treatment of prostate cancer is discussed.
Air↗
Quality assurance of beam accuracy for Leksell Gamma Unit.
For the acceptance test and annual quality assurance of the Leksell Gamma Unit, measurement of the beam accuracy, defined as a distance between mechanical and radiological isocenters, poses a challenge to medical physicists. The specification for the beam accuracy is within 0.5 mm for the 4-mm collimator helmet. In this report, we introduce a simple technique to analyze the beam accuracy by using a conventional film densitometer plus mathematical modeling. A small piece of film was placed inside the film cassette containing a sharp needle. The needle is located such that its tip is exactly positioned at the mechanical isocenter. Before exposure, the film was pierced by the needle. Density profile was measured by using a densitometer with a spatial resolution of 0.8 mm. The profile was then fitted to a model of the two Gaussian functions. One is for the radiation field profile, the other for a dip caused by the narrow hole. The difference between the centers of the two Gaussian functions defines the deviation of the beam accuracy from the mechanical center of the unit. The deviations for x, y, and z directions from one of our annual measurements are 0.032, 0.054, and 0.195 mm, respectively. The combined deviation is 0.20 mm, which is well within the specification and in excellent agreement with the results from the manufacture's laser measurement. This technique provides a simple, accurate and practical tool for measurement of the beam accuracy in the acceptance test and annual quality assurance of the Leksell Gamma Unit.
Film Dosimetry↗
An investigation of eye lens dose for gamma knife treatments of trigeminal neuralgia.
Stereotactic Gamma Knife radiosurgery has been widely used for treating trigeminal neuralgia (TN). A single large fractional dose of 7000 to 9000 cGy is commonly prescribed as the maximum dose for these treatments. For this reason, if a small percentage of the prescribed dose such as 2-3% scattered to the eye, it could reach or even exceed the tolerance dose of the lens. For several TN cases, we found that the Leksell Gamma Plan system calculates the lens dose about 0.5-2% of the maximum dose independent of the use of eye shielding. These dose values are significantly high and it motivated us to investigate the lens dose for the TN patients treated with stereotactic Gamma Knife radiosurgery. Phantom studies and in vivo dosimetry measurements were carried out for six patients treated at our institution. The average dose to the lens ipsilateral to the treated nerve was measured to be 7.7+/-0.6 cGy. Based on the biological model of Lyman and Emami [Int. J. Radiat. Oncol. Biol. Phys. 21, 109-122 (1991)], the probability of the lens complication (cataract) was determined to be 0.1%. Our findings suggest that few TN patients would develop cataracts after receiving Gamma Knife radiosurgery.
Brain Stem↗
Development of mouse dendritic cells from lineage-negative c-kit(low) pluripotent hemopoietic stem cells in vitro.
Dendritic cells (DCs) are essential for the presentation of antigens in the primary immune response. To examine the generation of DCs from hemopoietic stem cells in the bone marrow (BM), lineage-negative (Lin-)/CD71- bone marrow cells (BMCs) from C57BL/6 mice were separated into major histocompatibility complex (MHC) class Ihigh/ c-kit(low) and MHC class Ihigh/c-kit(low)(phenotypically c-kit-negative, but c-kit message only detected by reverse transcriptase-polymerase chain reaction) populations. A large number of cells with the morphological, phenotypical, and functional characteristics of DCs was generated from both c-kit(low) and c-kit(low) populations when cultured with a combination of cytokines (GM-CSF, tumor necrosis factor-a [TNF-a], interleukin 7 [IL-7], IL-3, stem cell factor [SCF], and flt3 ligand); the cytokine combination studies revealed that SCF and IL-3 in addition to GM-CSF and TNF-a are essential for DCs to be generated from these primitive populations. To our surprise most (>80%) generated cells expressed high levels of DC surface markers such as DEC205 and MHC class II, and they were potent stimulators in the primary allogeneic T cell activation. The development of DCs from c-kit(<low) cells was slower than that from c-kit(low) cells. These results indicate that c-kit(<low) cells are more primitive than c-kit(low) cells, although both c-kit*(low) cells and c-kit(<low) cells can differentiate into DCs. It should be noted that the combination of these cytokines selectively induces DCs from both c-kit(<low) and c-kit(low) cells in vitro, suggesting that the ex vivo expansion of DCs using these primitive cells would be applicable to immunotherapy.
Animals↗
Nonmyeloablative transplants: preclinical and clinical results.
Conditioning regimens have been intensified to a level at which organ toxicties are dose-limiting, which restricts the application of hematopoietic stem cell transplants to relatively young patients in otherwise good clinical condition. Studies done in a canine model have demonstrated that stable allogeneic mixed donor/host hematopoietic chimerism can be established by the administration of a sublethal dose of 2.0 Gy total body irradiation followed by immunosuppression with mycophenolate mofetil and cyclosporine after major histocompatibility complex-identical marrow transplantation. Both host-versus-graft and graft-versus-host reactions are controlled with mycophenolate mofetil and cyclosporine, which results in a stable state of graft/host tolerance manifested by stable mixed donor/ host hematopoietic chimerism. Current efforts are directed at replacing pretransplant radiation by anti-T-cell reagents, such as antibodies to T cells, or by purine antagonists, such as pentostatin (Nipent; SuperGen, San Ramon, CA). Given the minimal toxicity of this approach in dogs, a clinical study was initiated that uses an almost identical conditioning regimen. Thus far, 26 patients have been treated. Results to date indicate that this is a well-tolerated procedure that can be performed entirely in an outpatient setting. All patients have shown primary engraftment with persistence of mixed or full donor chimerism present through at least 2 months after transplant. Three patients experienced nonfatal graft rejection between 2 and 3 months after transplant, with a return to baseline peripheral counts over the subsequent 1 to 2 months. Acute graft-versus-host disease developed in 10 of 24 evaluable patients, occurring only after discontinuation of mycophenolate mofetil, and was controlled with additional immunosuppression in all cases. Overall, this novel nonmyeloablative conditioning regimen has been well tolerated and has encouraged us to investigate these transplants in other clinical settings, including using HLA-matched unrelated donors.
Animals↗
Effects of fetal ethanol exposure on pituitary-adrenal sensitivity to secretagogues.
BACKGROUND: Rodents prenatally exposed to ethanol demonstrate hormonal hyper-responsiveness to stressors in adulthood. The present study examined the hypothesis that an increased sensitivity of the adrenal to ACTH and/or the pituitary to corticotropin releasing hormone (CRH) after dexamethasone suppression, may play a role in the hormonal hyper-responsiveness seen in fetal ethanol-exposed rats. METHODS: Sprague-Dawley males and females from prenatal ethanol-exposed (E), pair-fed (PF), and ad libitum-fed control (C) groups were tested in adulthood (90-120 days). Testing was done in a series of two experiments carried out during the trough of the corticosterone rhythm, the time of greatest sensitivity to feedback inhibition. Twenty-four to 48 hr before testing, jugular cannulae were implanted for hormone infusion and blood sample collection. In both experiments, animals were injected intraperitoneally with dexamethasone-21-phosphate (DEX) (15 microg/100 g body weight for males or 30 microg/100 g body weight for females) 3 hr before testing to suppress endogenous hypothalamic-pituitary-adrenal (HPA) activity. Animals were given a bolus infusion of ACTH (0-0.10 mg/rat) and blood samples (0.2 cc) were drawn at 60-min intervals over 240 min for determination of plasma corticosterone (CORT) levels (Experiment 1), or were given a bolus infusion of CRH (0-20 microg/kg body wt) and samples drawn at 0, 5, 15, and 30 min for determination of plasma ACTH and CORT levels (Experiment 2). RESULTS: As expected, sex differences in adrenal response to ACTH and pituitary response to CRH were observed; females had higher CORT and ACTH levels than males at all concentrations of ACTH and CRH. In addition, dose-response relationships between exogenously administered ACTH or CRH and plasma CORT were demonstrated; increasing concentrations of secretagogues resulted in higher and/or more prolonged CORT responses in both males and females. There were no significant differences among E, PF, and C males or females in adrenal sensitivity to ACTH. However, prenatal ethanol exposure altered pituitary sensitivity to CRH in both males and females. E and PF males demonstrated increased plasma ACTH but not CORT compared with C males, whereas E females demonstrated increased plasma ACTH and CORT levels compared with PF and C females after CRH infusion. CONCLUSIONS: Together these data suggest that (1) E animals do not show increased adrenal sensitivity to ACTH compared with controls; (2) the insult of prenatal ethanol exposure may result in altered pituitary sensitivity to CRH after DEX suppression; and (3) there may be a sex-specific difference in sensitivity of the mechanism(s) underlying HPA hyper-responsiveness.
Adrenocorticotropic Hormone↗
[Expression of leukemia inhibitory factor in human decidua].
OBJECTIVE: To study the expression and localization of leukemia inhibitory factor (LIF) in human first trimester decidual. METHOD: By immunohistochemical analysis and in situ hybridization, the LIF mRNA and protein expression were observed in 16 cases of human decidua. RESULTS: LIF mRNA and protein expressions were observed in all decidual specimens, the glanduar epithelium showed higher LIF expression than in stromal cells. CONCLUSION: Expression of LIF in human decidua may contribute to embryo implantation, maintenance of placental functions and embryonic growth promation.
Adult↗
[IL-8 and IL-10 levels in endometriosis and regulated role of neiyifang on them].
OBJECTIVE: To investigate the IL-8 and IL-10 levels in endometriosis and the regulated role of Neiyifang (NYF) on them. METHODS: Animal models with endometriosis after Cummings method was established. IL-8 and IL-10 levels were determined in using double antibody sandwich ELISA. RESULTS: The IL-8 levels of serum and peritoneal fluid, and peritoneal macrophage amounts were markedly higher in the untreated group than those in the control group. The weights of endometriotic tissue and peritoneal macrophage amounts were markedly lower in the treated group of NYF, compared with the untreated group. The lipopolysaccharide stimulated IL-10 secretion in peritoneal macrophages from the untreated group were significantly lower compared with the control group and the treated group of NYF. CONCLUSION: The abnormality of IL-8 and IL-10 levels in endometriosis may be related to the pathogenesis of the disease. The therapeutical mechanism of NYF was mediated by promotion of IL-10 secretion, and further restrained the composition of inflammatory media and the growth of endometriotic tissue.
Animals↗