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PubMed1993

Individual-site binding data and the energetics of protein-DNA interactions.

Individual-site isotherms for the binding of bacteriophage lambda repressor to the left and right lambda operators have been determined [D. F. Senear, M. Brenowitz, M. A. Shea, and G. K. Ackers (1986) Biochemistry, Vol. 25, pp. 7344-7354.] using the DNAse protection technique [footprinting; D. J. Galas and A. Schmitz (1978) Nucleic Acids Research, Vol. 5, pp. 3157-3170]. These extensive data have been interpreted with a quantitative model that emphasized cooperative interactions between adjacently bound ligands [occupied <==> occupied interactions; G. K. Ackers, A. D. Johnson, and M. A. Shea (1982) Proceedings of the National Academy of Science, USA, Vol. 79, pp. 1129-1133]. Overlooked in this model are the effects of cooperative interactions between a site containing a bound ligand and its neighboring unoccupied site (occupied <==> unoccupied interactions). This paper reinterprets the existing data with a model that considers occupied <==> unoccupied as well as occupied <==> occupied interactions. The results yield parameters that differ substantially from those already reported. A discussion on the advisability of ignoring occupied <==> unoccupied interactions is included.

Binding Sites↗
PubMed2001

Assessment of near-infrared spectral information for rapid monitoring of bioprocess quality.

Access to real-time process information is desirable for consistent and efficient operation of bioprocesses. Near-infrared spectroscopy (NIRS) is known to have potential for providing real-time information on the quantitative levels of important bioprocess variables. However, given the fact that a typical NIR spectrum encompasses information regarding almost all the constituents of the sample matrix, there are few case studies that have investigated the spectral details for applications in bioprocess quality assessment or qualitative bioprocess monitoring. Such information would be invaluable in providing operator-level assistance on the progress of a bioprocess in industrial-scale productions. We investigated this aspect and report the results of our investigation. Near-infrared spectral information derived from scanning unprocessed culture fluid (broth) samples from a complex antibiotic production process was assessed for a data set that incorporated bioprocess variations. Principal component analysis was applied to the spectral data and the loadings and scores of the principal components studied. Changes in the spectral information that corresponded to variations in the bioprocess could be deciphered. Despite the complexity of the matrix, near-infrared spectra of the culture broth are shown to have valuable information that can be deconvoluted with the help of factor analysis techniques such as principal component analysis (PCA). Although complex to interpret, the loadings and score plots are shown to offer potential in process diagnosis that could be of value in the rapid assessment of process quality, and in data assessment prior to quantitative model development.

Anti-Bacterial Agents↗
PubMed1988

Ammonia can stimulate or inhibit aggregate density in Dictyostelium mucoroides: a quantitative test of the hypothesis that ammonia is the aggregation-suppressing gas.

Ammonia, at moderate concentrations, stimulates aggregate density of Dictyostelium mucoroides. The range of stimulatory concentrations includes ammonia concentrations established by populations of amebae. At higher concentrations, ammonia inhibits aggregate density. A quantitative test of the hypothesis that ammonia is the aggregation-suppressing gas has been carried out. The concentration of ammonia established over defined populations of amebae is one or two orders of magnitude lower than the concentration of ammonia required to exert the same degree of inhibitory effect as the populations of amebae exert. An additional difference between ammonia and the aggregation-suppressing gas is the fact that increasing concentrations of the aggregation-suppressing gas cause progressively larger aggregation streams, while increasing concentrations of ammonia have no such effect. The stimulatory effect of ammonia at concentrations established by ameba populations indicates that ammonia must be included in the variables affecting the aggregation process and that this ammonia effect must be taken into account in any quantitative modelling of the aggregation process.

Ammonia↗
PubMed2006

Roles of COX-2 and iNOS in the bony repair of the injured growth plate cartilage.

Growth plate injuries often lead to bone growth defects, which primarily occur due to bony repair at injury sites. Bony repair is preceded by an injury-induced inflammatory response, which could play a role in regulating the repair process. Here, roles of two inflammatory mediators, cyclo-oxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), in the injury responses were analysed by examining their gene expression and effects of blocking their activities, respectively, with celecoxib and aminoguanidine during 2 days prior to and until 7 days after injury in a rat tibial growth plate injury model. Quantitative RT-PCR assays revealed upregulated expression of COX-2 on days 1 and 4 and iNOS on day 1. Histological analysis of injury sites revealed significant reductions in inflammatory infiltrate (particularly neutrophils) on day 1 in treated groups compared to saline control. While bony tissue proportions at injury sites were unaffected by either treatment, mesenchymal tissue proportions were larger but cartilaginous tissue proportions were smaller on day 8 (though statistically insignificant), and bone remodelling appeared delayed with a smaller bone marrow proportion on day 14 in both treatment groups. These findings suggest that COX-2 and iNOS mediate injury-induced inflammatory response, and may play a role in enhancing mesenchymal cell differentiation to cartilaginous cells and in promoting bone remodelling during bony repair of growth plate injury sites. Furthermore, increased expression of cartilage-related (collagen-2, collagen-10, SOX-9) and bone-related molecules (osteocalcin, cbfalpha-1) suggest involvement of both endochondral and direct bone formation mechanisms during bony repair.

Animals↗
PubMed2006

Quantitative myocardial perfusion analysis with a dual-bolus contrast-enhanced first-pass MRI technique in humans.

PURPOSE: To compare fully quantitative and semiquantitative analysis of rest and stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) using a dual-bolus first-pass perfusion MRI method in humans. MATERIALS AND METHODS: Rest and dipyridamole stress perfusion imaging was performed on 10 healthy humans by administering gadolinium contrast using a dual-bolus protocol. Ventricular and myocardial time-signal intensity curves were generated from a series of T1-weighted images and adjusted for surface-coil intensity variations. Corrected signal intensity curves were then fitted using fully quantitative model constrained deconvolution (MCD) to quantify MBF (mL/min/g) and MPR. The results were compared with semiquantitative contrast enhancement ratio (CER) and upslope index (SLP) measurements. RESULTS: MBF (mL/min/g) estimated with MCD averaged 1.02 +/- 0.22 at rest and 3.39 +/- 0.59 for stress with no overlap in measures. MPR was 3.43 +/- 0.71, 1.91 +/- 0.65, and 1.16 +/- 0.19 using MCD, SLP, and CER. Both semiquantitative parameters (SLP and CER) significantly underestimated MPR (P < 0.001) and failed to completely discriminate rest and stress perfusion. CONCLUSION: Rest and stress MBF (mL/min/g) and MPR estimated by dual-bolus perfusion MRI fit within published ranges. Semiquantitative methods (SLP and CER) significantly underestimated MPR.

Adult↗
PubMed2006

Free-breathing delayed hyperenhanced imaging of the myocardium: a clinical application of real-time navigator echo imaging.

PURPOSE: To compare a free-breathing (FB) acquisition with the current standard of breath-holding (BH) in a clinical setting using identical two-dimensional MR pulse sequences for imaging of myocardial delayed hyperenhancement. MATERIALS AND METHODS: Two-dimensional gadolinium-enhanced images were acquired using FB and BH techniques in 18 subjects to evaluate delayed enhancement of myocardial infarction. The FB acquisition used a navigator echo to monitor the position of the right hemidiaphragm for respiratory gating and correction. Visual analysis using a 16-segment model, quantitative signal difference to noise ratios, and percent left ventricle (LV) viability measurements for the two acquisition types were statistically compared. RESULTS: An excellent agreement between two-dimensional BH and two-dimensional FB acquisitions was found. In one patient, a nontransmural infarct was seen only in the FB images. There were no statistically significant differences in the number of infarcted segments or the measured signal difference to noise ratios (SDNR) between the two methods. Linear regression and Bland Altman analysis of the percentage LV viable myocardium yielded a good fit and narrow limits of agreement. CONCLUSION: An FB navigator echo acquisition can be effectively used in the setting of myocardial delay hyperenhanced imaging. Image quality is similar or superior to that of BH imaging.

Adult↗
PubMed1990

Effects of isolated rheumatoid synovial cells on cartilage degradation in vitro.

Rheumatoid synovium in coculture with cartilage has been shown to release a factor(s) that stimulates the depletion of glycosaminoglycans (GAG) from cartilage matrix. Human rheumatoid synovium was enzymatically disaggregated and the isolated cells were subjected to a variety of mechanical and immunological treatments. Synovial cell conditioned media (SCCM) were prepared and analyzed for their ability to stimulate GAG depletion. SCCM prepared from increasing concentrations of isolated synovial cells demonstrated cartilage degradative activity in a dose-dependent manner. This activity was characterized as interleukin-1 like and was found mostly within the adherent cell population where the synovial macrophages retained significant degradative ability. T cells alone were found to have no direct degradative effect on cartilage, but their presence appeared to augment the response of the adherent cells. The techniques described here provide a quantitative model for examining the degradative factors from synovium as well as the cellular interactions that promote their release.

Animals↗
PubMed1992

Strains and forces in selected carpal ligaments during in vitro flexion and deviation movements of the hand.

The forces induced in tiny wrist joint ligaments must be estimated in order to understand their role in the mechanism of the joint. We estimated forces in a number of selected ligaments in seven human wrist joint specimens, using a noninvasive method. The method is based on the rationale that the force generated in a ligament depends on its change of length with the joint under load. In vitro length changes of the ligaments were determined during flexion and deviation movements of the hand, using a roentgenstereophotogrammetric analysis technique. Subsequently, bone-ligament-bone (BLB) preparations were dissected from the specimens. From these BLB preparations the zero-force length and the force-elongation relationship were determined in a material testing machine. The forces generated in the ligaments during flexion and deviation were calculated by combining results on the in vitro ligament length changes, the zero-force length, and the force-elongation relationship. Large interspecimen variations of the force patterns were found. Due to this variability, it is not possible to obtain quantitative models for the kinetic behavior of the ligaments. However, qualitative trends could be distilled from the strain and force patterns. It is clear that for most ligaments, the zero-force lengths were not equal to the lengths they possessed in the neutral position of the hand. Furthermore, it could be shown which motions of the hand would most likely strain a particular ligament. It could be shown that the variations in the force patterns originate mainly from variations in the zero-force lengths, and from variations in the force-strain relationship between specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2007

Kinematic changes of the foot and ankle in patients with systemic rheumatoid arthritis and forefoot deformity.

Minimal published data exist characterizing the effect of rheumatoid arthritis of the forefoot (RA) on multi-segmental gait kinematics. The purpose of this study was to examine specific changes in segmental foot motion in patients with RA as compared to persons without foot/ankle pathology. This was a cross-sectional, descriptive study consisting of 22 preoperative adult patients (29 feet) diagnosed with RA and 25 adult patients with no known foot pathology (Control). All RA patients were evaluated by the same orthopaedic surgeon. This group consisted of 20 women and 2 men with a mean age of 54 years (range, 17-76 years). The Control cohort consisted of 13 men and 12 women with a mean age of 41 years (range, 27-73 years). Foot and ankle motion data for the RA population were obtained using a 15-camera Vicon Motion Analysis System (Vicon Motion Systems, Inc., Lake Forest, CA). Anterior-posterior, lateral, and modified coronal radiographic views were obtained to relate marker position to underlying bony anatomy. Temporal and three-dimensional kinematic parameters were obtained via the 4-segment Milwaukee Foot Model. Quantitative comparisons of range of motion values during the seven phases of gait were made between RA and Control ankles using unpaired nonparametric methods. The RA group showed significant differences (p < 0.001) as compared to Controls with prolonged stance time, shortened stride length, increased cadence, and a walking speed that was 80% of Control. Overall, kinematic data in the RA cohort showed significant differences (p < 0.001) in motion for tibial, hindfoot, and forefoot motion as compared to Controls. The effect of RA on segmental foot motion is poorly understood. This study characterized the effect that RA has on motion about the foot and ankle during gait, providing insight into this pathology to improve quantitative assessment, treatment planning, and rehabilitative care.

Adult↗
PubMed2003

Epimer interconversion, isomerization, and hydrolysis of tetrahydrouridine: implications for cytidine deaminase inhibition.

Tetrahydrouridine (THU) is an inhibitor of cytidine deaminase (CDA), the enzyme responsible for the deactivation of ara-C and other cytidine analogues in vivo, and therefore is capable of improving the therapeutic efficacy of these antitumor agents. In aqueous solution formulations, THU exists as a mixture of epimers differing in stereochemistry of the 4-OH substituent. The aims of this study were to investigate the interconversion kinetics of the epimers of THU, the CDA inhibitory effects of these epimers, and the stability and degradation mechanisms of THU epimer mixtures in aqueous solution with the ultimate goal of developing optimal conditions for a parenteral formulation of THU. A stability indicating HPLC assay utilizing a derivatized beta-cyclodextrin column was developed to separate the two epimers of THU and to monitor their reversible isomerization to their beta-ribopyranosyl counterparts and their hydrolysis to form N-glycosidic bond cleavage products. MS and one- and two-dimensional (1)H- and (13)C-NMR measurements were conducted to identify THU epimers and degradation products and to quantitatively model the degradation kinetics. The interconversion reaction between the two THU epimers is acid catalyzed with a first-order rate constant for conversion of epimer 1(1) to epimer 1(2) of (7.4 +/- 0.3) x 10(-3) h(-1) and an equilibrium constant ([1(2)]/[1(1)] of 1.7 +/- 0.1 at pH 7.4 and 25 degrees C. Epimer interconversion was therefore sufficiently slow at pH 7.4 to allow the isolation of each and evaluation of their CDA inhibitory activities utilizing 1% (w/v) mouse kidney homogenates as a source for cytidine deaminase and cytidine as a substrate. Inhibition constants for the two THU epimers (1(1) and 1(2)) were determined to be 8 +/- 1 x 10(-7) M and 6.2 +/- 0.2 x 10(-8) M, respectively. Studies at elevated temperature suggested that THU degradation from epimer mixtures is biphasic with the initial rate of disappearance being acid catalyzed and first order in initial THU concentration, thus ruling out dimerization as a potential reaction mechanism. NMR/MS analyses revealed that the major degradation products included the beta-ribopyranosyl THU isomers (two epimers), the reduced pyrimidinone base (tetrahydrouracil), and various anomers of D-ribose formed through N-glycosidic bond cleavage, and the products of subsequent reactions of the base. Kinetic modeling of the data obtained from both HPLC and NMR measurements indicated that in an acidic solution THU beta-ribofuranosyl --> beta-ribopyranosyl isomerization is a rapid equilibrium reaction, which proceeds through an intermediate observable in 1H-NMR, and is followed by slower N-glycosidic bond hydrolysis. All the reactions between THU, its ribopyranosyl isomers, the intermediate, and the base are acid catalyzed and appear to proceed through the same sugar ring-opened intermediate (carbinolamine), consistent with previous literature.

Animals↗
PubMed1991

Plasma-mediated ablation of corneal tissue at 1053 nm using a Nd:YLF oscillator/regenerative amplifier laser.

Plasma-mediated ablations were performed on human donor corneas with a short pulsed Nd:YLF laser system at 1053 nm. The pulses were 60 psec in duration at a repetition rate of 1.0 kHz. The laser beam was oriented perpendicular to the cornea surface. The threshold energy densities for ablation of epithelium, Bowman's membrane and stroma were measured. They were 6.1 +/- 1.8 J/cm2, 21.0 +/- 5.1 J/cm2 and 10.4 +/- 1.8 J/cm2, respectively. The mean rate of tissue removal at the stromal energy density threshold was about 1 micron per pulse. The walls of the laser excisions were smooth with distortions of less than 1 micron. A new quantitative model of plasma-mediated ablation is introduced and found to closely predict the observed results. Based on the promising nature of the experimental data further investigations are planned in the use of a mode locked Nd:YLF laser as an alternative to excimer lasers for refractive corneal surgery.

Cornea↗
PubMed2002

Quantitative description of loss of clinical benefit following withdrawal of levodopa-carbidopa and bromocriptine in early Parkinson's disease.

In Parkinson's disease, effects of medications on the progression of the underlying disease can be assessed clinically by evaluating patients at baseline prior to treatment and at endpoint following medication washout. With this design, it is critical to employ a washout of sufficient duration to ensure elimination of all symptomatic effects. To assess the time course of resolution of symptomatic effects, we evaluated 31 patients with early Parkinson's disease for 2 weeks following discontinuation of levodopa-carbidopa and bromocriptine after 14 months of treatment. Patients had previously been randomly assigned to treatment with selegiline or placebo, and these had been discontinued 2 months earlier. Data from 20 patients with a clear washout of clinical benefit were used to investigate quantitative models describing the time course of total (Activities of Daily Living + motor) Unified Parkinson's Disease Rating Scale score change. The mean half-life of loss of clinical benefit was 7.9 days (95% confidence interval, 2.2-30.4 days). This indicates that a washout period of 32 days (4 half-lives) may be required to eliminate approximately 90% of the long-term symptomatic effects of levodopa-carbidopa and bromocriptine following their withdrawal from patients with early Parkinson's disease.

Activities of Daily Living↗
PubMed1990

Relaxometry of brain: why white matter appears bright in MRI.

The remarkable success of magnetic resonance imaging of adult brain relates to the unusually large ratio of the longitudinal relaxation rates 1/T1 of white and gray matter, approximately 2:1 at physiological temperature and traditional imaging fields. Several investigators have conjectured that myelin is the source of the greater 1/T1 of white matter without, however, suggesting details of the molecular mechanisms responsible. From measurements of the magnetic field dependence of 1/T1 (NMRD profiles) of adult and neonatal gray and white matter at 5 and 35 degrees C, we find a thermally activated contribution to the NMRD profile of adult white matter that is not present in the profiles of either adult gray or neonatal gray and white matter. We attribute this contribution to myelin and develop a quantitative model that accounts for the unique relaxation behavior of myelinated white matter. We find that myelin water, 15% of the total, has a relatively short T1 that arises from an unexpectedly large interaction with myelin lipid; when cast in terms of an interaction over the entire myelin bilipid-water interface, it is sevenfold greater than the analogous protein-water interfacial interaction. Its magnitude remains to be accounted for, but cholesterol, known to alter the relaxation rates of lipid protons, may play an important role. The contribution of myelin to 1/T1 at physiological temperatures is attributed to thermally activated transmembrane diffusion of water and, hence, more rapid mixing of axonal and the rapidly relaxing myelin water molecules.

Adult↗
PubMed2005

Rapid quantitation of magnetization transfer using pulsed off-resonance irradiation and echo planar imaging.

A technique for producing a quantitative measure of magnetization transfer parameters in a clinically feasible time scale is proposed. The combination of pulsed off-resonance irradiation and echo planar imaging has produced an imaging sequence that negates the need for continuous wave irradiation and allows the approach to steady-state conditions to be studied. Data analysis involves the step-by-step numerical solution of the modified Bloch equations to generate a quantitative model of the measured signal intensity based on the relative size of the bound proton pool and the bound proton pool transverse relaxation time. The sequence and model are applied to the study of a series of agar gels of varying concentrations and the results are compared to those from the literature.

Computer Simulation↗
PubMed2001

Magnetization transfer in MRI: a review.

This review describes magnetization transfer (MT) contrast in magnetic resonance imaging. A qualitative description of how MT works is provided along with experimental evidence that leads to a quantitative model for MT in tissues. The implementation of MT saturation in imaging sequences and the interpretation of the MT-induced signal change in terms of exchange processes and direct effects are presented. Finally, highlights of clinical uses of MT are outlined and future directions for investigation proposed.

Biophysical Phenomena↗
PubMed1995

Computer-assisted mapping of infarcted and viable regions of gross cardiac sections following experimental myocardial infarction.

We have developed a computer-assisted method that creates digital maps of the viable and infarcted regions of tetrazolium-stained gross cardiac sections. Here we describe and test the method, using a canine occlusion-reperfusion infarction model. Quantitative image analysis showed that the method accurately recorded differences between infarcted and viable regions at a spatial resolution of 5-20 pixels per mm2. Microscopic analysis of tissue samples taken from the sections showed that the maps were accurate. In 15 of 15 cases the histology of the samples matched that predicted by the maps. A comparison of infarct area measurements derived from the maps showed that the method was reproducible. The average intraoperator standard deviation was +/- 8% of a slice's infarcted area and the average interoperator standard deviation was +/- 20%. We conclude that the method creates accurate, detailed, and reproducible maps of the infarcted and viable regions of tetrazolium-stained cardiac sections.

Animals↗
PubMed1996

Regulatory interactions between virgin and memory CD4 T lymphocytes.

Naive and memory CD4 T cells from mouse spleen, alone or in a 1:1 mixture, were tested for Con A-induced proliferation in limiting dilution cultures. Dose-response curves for naive cells were linear, but curves for memory cells were hyperbolic, suggesting that positive responses required the activation of several cells of the memory type. Mixtures (1:1) gave zig-zag curves, consistent with a previously described quantitative model in which memory cells block naive cell proliferation at low multiplicities and generate their own positive responses at higher multiplicities. Inhibition of naive cell proliferation by memory cells could be mimicked by IL-10 and blocked by anti-IL-10 antibody. IL-2 addition converted the multihit dose curves of memory T cells to single-hit curves, suggesting that poor IL-2 production limits growth in memory cell cultures. Surprisingly, IL-2 addition to cultures of naive cells led to a decrease in proliferation at high cell input doses. This inhibitory effect of IL-2 could be blocked by antibody to IL-10, and may reflect the presence of contaminating memory cells in the naive cell preparations. These models for analysis of interaction between naive and memory T cells in limiting dilution conditions point to a series of reciprocal interactions between IL-10 and IL-2 producing cells.

Animals↗
PubMed1994

Beyond visible persistence: an alternative account of temporal integration and segregation in visual processing.

When processing sequences of rapidly varying stimuli, the visual system must satisfy two conflicting requirements. To maintain perceptual continuity, sequential stimuli must be integrated into a single, unified percept. On the other hand, to detect rapid changes, sequential stimuli must be segregated from each other. We propose that these conflicting demands are reconciled by a process that codes the temporal relationship between contiguous stimuli: Stimuli that are coded as co-extensive are integrated and those that are coded as disjoint are segregated. This approach represents a conceptual departure from the more traditional "intrinsic persistence" view of temporal integration. The approach provides a parsimonious account of the results of two temporal-integration tasks in which the durations of the leading and trailing displays were varied over a broad range. The data were accurately fit by a quantitative model in which temporal codes were determined by the correlation in time between the visual responses to the leading and trailing displays.

Adult↗