PubMed Health⌕ Search

Biomedical subjects

Leon C Moore

Publications and source records attributed to Leon C Moore.

10 recordsLinked to original sources
PubMed2006

A robust method for detection of linear and nonlinear interactions: application to renal blood flow dynamics.

We have developed a method that can identify switching dynamics in time series, termed the improved annealed competition of experts (IACE) algorithm. In this paper, we extend the approach and use it for detection of linear and nonlinear interactions, by employing histograms showing the frequency of switching modes obtained from the IACE, then examining time-frequency spectra. This extended approach is termed Histogram of improved annealed competition of experts-time frequency (HIACE-TF). The hypothesis is that frequent switching dynamics in HIACE-TF results are due to interactions between different dynamic components. To validate this assertion, we used both simulation examples as well as application to renal blood flow data. We compared simulation results to a time-phase bispectrum (TPB) approach, which can also be used to detect time-varying quadratic phase coupling between various components. We found that the HIACE-TF approach is more accurate than the TPB in detecting interactions, and remains accurate for signal-to-noise ratios as low as 15 dB. With all 10 data sets, comprised of volumetric renal blood flow data, we also validated the feasibility of the HIACE-TF approach in detecting nonlinear interactions between the two mechanisms responsible for renal autoregulation. Further validation of the HIACE-TF approach was achieved by comparing it to a realistic mathematical model that has the capability to generate either the presence or the absence of nonlinear interactions between two renal autoregulatory mechanisms.

Algorithms↗
PubMed2005

Multistability in tubuloglomerular feedback and spectral complexity in spontaneously hypertensive rats.

Single-nephron proximal tubule pressure in spontaneously hypertensive rats (SHR) can exhibit highly irregular oscillations similar to deterministic chaos. We used a mathematical model of tubuloglomerular feedback (TGF) to investigate potential sources of the irregular oscillations and the corresponding complex power spectra in SHR. A bifurcation analysis of the TGF model equations, for nonzero thick ascending limb (TAL) NaCl permeability, was performed by finding roots of the characteristic equation, and numerical simulations of model solutions were conducted to assist in the interpretation of the analysis. These techniques revealed four parameter regions, consistent with TGF gain and delays in SHR, where multiple stable model solutions are possible: 1) a region having one stable, time-independent steady-state solution; 2) a region having one stable oscillatory solution only, of frequency f1; 3) a region having one stable oscillatory solution only, of frequency f2, which is approximately equal to 2f1; and 4) a region having two possible stable oscillatory solutions, of frequencies f1 and f2. In addition, we conducted simulations in which TAL volume was assumed to vary as a function of time and simulations in which two or three nephrons were assumed to have coupled TGF systems. Four potential sources of spectral complexity in SHR were identified: 1) bifurcations that permit switching between different stable oscillatory modes, leading to multiple spectral peaks and their respective harmonic peaks; 2) sustained lability in delay parameters, leading to broadening of peaks and of their harmonics; 3) episodic, but abrupt, lability in delay parameters, leading to multiple peaks and their harmonics; and 4) coupling of small numbers of nephrons, leading to multiple peaks and their harmonics. We conclude that the TGF system in SHR may exhibit multistability and that the complex power spectra of the irregular TGF fluctuations in this strain may be explained by switching between multiple dynamic modes, temporal variation in TGF parameters, and nephron coupling.

Animals↗
PubMed2005

Fluid secretion and the Na+-K+-2Cl- cotransporter in mouse exorbital lacrimal gland.

We have previously suggested that fluid flow in the mouse exorbital lacrimal gland is driven by the opening of apical Cl- and K+ channels. These ions move into the lumen of the gland and water follows by osmosis. In many tissues, the Na+-K+-2Cl- cotransporter (NKCC1) replaces the Cl- and K+ ions that move into the lumen. We hypothesize that mouse exorbital lacrimal glands would have NKCC1 co-transporters and that they would be important in fluid transport by this gland. We used immunocytochemistry to localize NKCC1-like immunoreactivity to the membranes of the acinar cells as well as to the basolateral membranes of the duct cells. We developed a method to measure tear flow and its composition from mouse glands in situ. Stimulation with the acetylcholine agonist carbachol produced a peak flow followed by a plateau. Ion concentration measurements of this stimulated fluid showed it was high in K+ and Cl-. Treatment of the gland with furosemide, a blocker of the NKCC1 cotransporter, reduced the plateau phase of fluid flow by approximately 30%. Isolated cells exposed to a hypertonic shock shrank by approximately 20% and then showed a regulatory volume increase (RVI). Both the RVI and swelling were blocked by treatment with furosemide. Cells isolated from these glands shrink by approximately 10% in the presence of carbachol. Blocking NKCC1 with furosemide reduced the amount of shrinkage by approximately 50%. These data suggest that NKCC1 plays an important role in fluid secretion by the exorbital gland of mice.

Animals↗
PubMed2005

Identification of transient renal autoregulatory mechanisms using time-frequency spectral techniques.

Identification of the two principal mediators of renal autoregulation from time-series data is difficult, as both the tubuloglomerular feedback (TGF) and myogenic (MYO) mechanisms interact and share a common effector, the afferent arteriole. Moreover, although both mechanisms can exhibit oscillations in well-characterized frequency bands, these systems often operate in nonoscillatory states not detectable by frequency-domain analysis. To overcome these difficulties, we have developed a new approach to the characterization of the TGF and MYO systems. A laser Doppler probe is used to measure fluctuations in local cortical blood flow (CBF) in response to spontaneous changes in blood pressure (BP) and to large imposed perturbations in BP, which elicit strong, simultaneous, transient, oscillatory blood flow responses. These transient responses are identified by high-resolution time-frequency spectral analysis of the time-series data. In this report, we compare four different time-frequency spectral techniques (the short-time Fourier transform (STFT), smoothed pseudo Wigner-Ville, and two recently developed methods: the Hilbert-Huang transform and time varying optimal parameter search (TVOPS)) to determine which of these four methods is best suited for the identification of transient oscillations in renal autoregulatory mechanisms. We found that TVOPS consistently provided the best performance in both simulation examples and identification of the two autoregulatory mechanisms in actual data. While the STFT suffers in time and frequency resolution as compared to the other three methods, it was able to identify the two autoregulatory mechanisms. Taken together, our experience suggests a two level approach to the analysis of renal blood flow (RBF) data: STFT to obtain a low-resolution time-frequency spectrogram, followed by the use of a higher resolution technique, such as the TVOPS, if even higher time-frequency resolution of the transient responses is required.

Algorithms↗
PubMed2004

Feedback-mediated dynamics in two coupled nephrons.

Previously, we developed a dynamic model for the tubuloglomerular feedback (TGF) system in a single, short-looped nephron of the mammalian kidney. In that model, a semi-linear hyperbolic partial differential equation was used to represent two fundamental processes of solute transport in the nephron's thick ascending limb (TAL): chloride advection by fluid flow along the TAL lumen and transepithelial chloride transport from the lumen to the interstitium. An empirical function and a time delay were used to relate glomerular filtration rate to the chloride concentration at the macula densa of the TAL. Analysis of the model equations indicated that stable limit-cycle oscillations (LCO) in nephron fluid flow and chloride concentration can emerge for sufficiently large feedback gain magnitude and time delay. In this study, the single-nephron model was extended to two nephrons, which were coupled through their filtration rates. Explicit analytical conditions were obtained for bifurcation loci corresponding to two special cases: (1) identical time delays but differing feedback gains, and (2) identical gains but differing delays. Similar to the case of a single nephron, our analysis indicates that stable LCO can emerge in coupled nephrons for sufficiently large gains and delays. However, these LCO may emerge at lower values of the feedback gain, relative to a single (i.e., uncoupled) nephron, or at shorter delays, provided the delays are sufficiently close. These results suggest that, in vivo, if two nephrons are sufficiently similar, then coupling will tend to increase the likelihood of LCO.

Animals↗
PubMed2003

Effect of sustained flow perturbations on stability and compensation of tubuloglomerular feedback.

A mathematical model previously formulated by us predicts that limit-cycle oscillations (LCO) in nephron flow are mediated by tubuloglomerular feedback (TGF) and that the LCO arise from a bifurcation that depends heavily on the feedback gain magnitude, gamma, and on its relationship to a theoretically determined critical value of gain, gammac. In this study, we used that model to show how sustained perturbations in proximal tubule flow, a common experimental maneuver, can initiate or terminate LCO by changing the values of gamma and gammac, thus changing the sign of gamma - gammac. This result may help explain experiments in which intratubular pressure oscillations were initiated by the sustained introduction or removal of fluid from the proximal tubule (Leyssac PP and Baumbach L. Acta Physiol Scand 117: 415-419, 1983). In addition, our model predicts that, for a range of TGF sensitivities, sustained perturbations that initiate or terminate LCO can yield substantial and abrupt changes in both distal NaCl delivery and NaCl delivery compensation, changes that may play an important role in the response to physiological challenge.

Adaptation, Physiological↗
PubMed2003

Differential gene expression following early renal ischemia/reperfusion.

BACKGROUND: Acute renal failure from ischemia/reperfusion injury is associated with tubule cell apoptosis, the molecular mechanisms of which remain under active investigation. The purpose of this study was to identify apoptosis-related genes that are differentially expressed in the early periods following renal ischemia. METHODS: Mice underwent unilateral renal artery clamping for 45 minutes and were sacrificed at 0, 3, 12, or 24 hours of reperfusion. Tubule cell apoptosis was confirmed by DNA laddering and terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay. We employed cDNA microarrays to define global changes in renal gene expression. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used as confirmatory tools. RESULTS: By microarray analysis, we identified consistent patterns of altered gene expression, including transcription factors, growth factors, signal transduction molecules, and apoptotic factors. Prominent among the last category included FADD, DAXX, BAD, BAK, and p53. Up-regulation of these proapoptotic genes was confirmed by semiquantitative RT-PCR and immunohistochemistry. CONCLUSION: The results indicate that apoptosis may represent an important mechanism for the early loss of tubule cells following ischemia/reperfusion injury. Both the death receptor-dependent (FADD-DAXX) and mitochondrial (BAD-BAK) pathways are activated. The results also provide a molecular basis for the previous findings that significant intrarenal mechanisms exist to enable tubule cell repair and regeneration, as evidenced by the up-regulation of genes such as growth, proliferation, transcription, and cytoskeletal factors.

Animals↗
PubMed2003

Advective transport of nitric oxide in a mathematical model of the afferent arteriole.

Endothelium-derived nitric oxide (NO) is thought to be short-lived in blood because of rapid removal from plasma, mainly by binding to Hb. The extent to which removal limits NO advection is unclear, especially for blood flow in the renal afferent arteriole (AA), which has a transit time of 3-30 ms. A mathematical model of AA fluid dynamics and myogenic response that includes NO diffusion, advection, degradation, and vasorelaxant action was used to estimate NO advective transport. Model simulations indicate that advective transport of locally produced NO is sufficient to yield physiologically significant NO concentrations along much of the AA. Advective transport is insensitive to NO scavenging by Hb because the NO-Hb binding rate is slow relative to AA transit time. Hence, plasma NO concentration near the vessel wall is influenced by both diffusion from endothelial cells and advection from upstream sites. Simulations also suggest that NO advection may constitute a mechanism to stabilize arteriolar flow in response to a localized vasoconstriction accompanied by enhanced NO release.

Animals↗
PubMed2002

Role of gap junctions in fluid secretion of lacrimal glands.

In glands such as the liver and pancreas, gap junctions containing connexin 26 and 32 (Cx26 and Cx32, respectively) couple the secretory cells. Uncoupling these junctions compromises the secretory function of these glands. Lacrimal glands also contain extensive arrays of gap junctions consisting of Cx26 and Cx32. We wanted to determine the role of these junctions in fluid secretion. In Cx32-deficient mice, immunocytochemistry showed that, in the male lacrimal gland, the remaining Cx26 was found evenly distributed in the membrane whereas there was little in the membranes of female glands. Western blot analysis of Cx26 showed that female Cx32-deficient mice expressed Cx26. Patch-clamp analyses of acinar cell coupling showed that the cell pairs from male glands were coupled whereas those from female glands were not. Stimulated fluid production by the glands from Cx32-deficient mice was abnormally low in female glands compared with controls at low topical doses of carbachol. The protein secretory response to different doses of carbachol was the same in all animals. These data suggest that gap junctions are essential for optimal fluid secretion in lacrimal glands.

Analysis of Variance↗