On the therapeutic potential for insulin-like growth factor use in motor neuron disease.
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Amyotrophic Lateral Sclerosis↗
Biomedical subjects
D J Marsh
Publications and source records attributed to D J Marsh.
Development and testing of a bovine trichomoniasis vaccine.
Eighteen culled dairy cows were randomly allocated into 1 of 5 treatment groups. Six cows were vaccinated twice (2V), 21 days apart, 3 with whole cell (2WC) and 3 with fragmented cell membrane (2FC) containing 1 x 10(9)Trichomonas fetus organisms or protein equivalent in a commercial mineral oil adjuvant vaccine. Six more cows were vaccinated once (1V), 3 with whole cell (1WC) and 3 with fragmented cell vaccine (1FC), using the same vaccine, while 6 cows were used as the unvaccinated controls. All cows were challenged with 1 x 10(5) organisms 4 weeks after the second or the only vaccination. After challenge, cervico-vaginal mucus (CVM) samples were cultured for T . fetus weekly for 9 weeks. Whole cell vaccines were superior to fragmented cell vaccines, and both performed better than no vaccination for apparent elimination of trichomonad infections in dairy cows. In addition, 2V was superior to 1V, which, in turn, was superior to no vaccination. Furthermore, clearance time was reduced most by 2V and whole cell vaccination compared with 1V and fragmented cell vaccination. Clearance time was decreased significantly in all vaccinated cows compared with that in unvaccinated cows.
Journal Article↗
Testing of trichomoniasis vaccine in heifers mated to infected bulls.
This study was conducted to evaluate the effectiveness of a Trichomonas fetus vaccine to protect heifers from infection when bred to infected bulls. The vaccine consisted of a whole cell vaccine of T. fetus organisms stabilized in formaldehyde and adjuvanted in a mineral oil base. In the trial, fewer vaccinated heifers became infected than unvaccinated controls (69.4 vs 93.0%, respectively; P<0.08). The vaccinated heifers tended to clear the infections sooner than the controls (48.9 vs 68.5 days, respectively; P<0.10). The average number of days open was shorter in the vaccinated heifers than in the controls (33.2 vs 56.9 days, respectively; P<0.07). The first service conception rate was higher in the vaccinated heifers than in the controls (66.7 vs 33.3%, respectively; P<0.05). The number of services per conception in conceiving heifers was lower in vaccinated than in control heifers (1.44 vs 1.73, respectively; P<0.16). Cervicovaginal mucus (CVM) samples were collected every 14 days following first challenge (first service). On average, more CVM samples were positive for T. fetus for a longer period of time in the control than in the vaccinated heifers (3.9 vs 1.85 sampling periods, respectively; P<0.08). We concluded that, under the conditions of this trial, some protection to T. fetus was afforded by double vaccination with a whole cell vaccine. However, vaccination does not completely prevent heifers from developing infection.
Journal Article↗
On the efficacy of linear system analysis of renal autoregulation in rats.
In order to assess the linearity of the mechanisms subserving renal blood flow autoregulation, broad-band arterial pressure fluctuations at three different power levels were induced experimentally and the resulting renal blood flow responses were recorded. Linear system analysis methods were applied in both the time and frequency domain. In the frequency domain, spectral estimates employing FFT, autoregressive moving average (ARMA) and moving average (MA) methods were used; only the MA model showed two vascular control mechanisms active at 0.02-0.05 Hz and 0.1-0.18 Hz consistent with previous experimental findings [Holstein-Rathlou et al., Amer. J. Physiol., vol. 258, 1990.]. In the time domain, impulse response functions obtained from the MA model indicated likewise the presence of these two vascular control mechanisms, but the ARMA model failed to show any vascular control mechanism at 0.02-0.05 Hz. The residuals (i.e., model prediction errors) of the MA model were smaller than the ARMA model for all levels of arterial pressure forcings. The observed low coherence values and the significant model residuals in the 0.02-0.05 Hz frequency range suggest that the tubuloglomerular feedback (TGF) active in this frequency range is a nonlinear vascular control mechanism. In addition, experimental results suggest that the operation of the TGF mechanism is more evident at low/moderate pressure fluctuations and becomes overwhelmed when the arterial pressure forcing is too high.
Animals↗
A laser Doppler instrument for in vivo measurements of blood flow in single renal arterioles.
A laser Doppler instrument has been developed to measure the blood flow in single vessels for the study of the dynamics of local control mechanisms. A commercial blood perfusion monitor, designed to measure blood perfusion in a vascular field containing many randomly oriented blood vessels, was modified to perform measurements of blood flow in a single arteriole. In vitro tests of the instrument revealed that the relationship between blood flow and Doppler shift was not a simple linear function. Causes of nonlinearity are revealed and proper use of the device avoids the problem. The device was applied to efferent arterioles that are visible on the surface of the rat kidney. An angiotensin converting enzyme inhibitor and graded doses of angiotensin II were used to perturb kidney blood flow. The induced changes in whole kidney blood flow, measured with an electromagnetic flow probe, and in single efferent arteriolar blood flow, measured with the new instrument, were correlated. An oscillation at approximately 0.035 Hz, previously described in the tubular pressure and attributed to a local feedback mechanism acting on arteriolar resistance, was found in the arteriolar blood flow. The new instrument is easy to use and provides temporal resolution not available with more conventional methods used for flow measurement in the microcirculation.
Animals↗
Effect of captopril on fluctuations of blood pressure and renal blood flow in rats.
Arterial blood pressure and renal blood flow (RBF) fluctuations in rats were studied by autoregressive (AR) and autoregressive-moving average (ARMA) modeling. These estimation procedures provided greater sensitivity and frequency resolution than classic fast Fourier transform (FFT)-based methods and also require shorter observation periods. We estimated the transfer function of RBF autoregulation to test whether inhibition of angiotensin-converting enzyme impairs whole kidney dynamic autoregulation. The transfer function in control animals measured with the ARMA method was similar to transfer functions obtained previously, using FFT methods. Because of better frequency resolution, we also detected an oscillation in RBF at 50 mHz, the same frequency as an oscillation in tubular pressure and glomerular filtration rate that had been attributed to tubuloglomerular feedback (TGF), but that FFT methods had not previously found in whole kidney blood flow. Captopril increased the amplitude of RBF fluctuations and increased the gain of the transfer function at frequencies below 100 mHz, a frequency bandwidth previously associated with TGF. The increased gain indicates that TGF operates less effectively to mediate dynamic autoregulation when angiotensin conversion is inhibited. Gain at frequencies greater than 100 mHz, previously ascribed to the myogenic mechanism, was not affected by captopril. These results show that angiotensin, by modulating TGF, reduces fluctuations of RBF about the mean value.
Animals↗
Mechanisms of temporal variation in single-nephron blood flow in rats.
Modified laser-Doppler velocimetry was used to determine the number of different mechanisms regulating single-nephron blood flow. Two oscillations were identified in star vessel blood flow, one at 20-50 mHz and another at 100-200 mHz. Tubuloglomerular feedback (TGF) mediates the slower oscillation, and the faster one is probably myogenic in origin. Acute hypertension increased autospectral power in the 20-50 mHz and 100-200 mHz frequency bands to 282 +/- 50 and 248 +/- 64%, respectively, of control even though mean single-nephron blood flow was autoregulated. Mean blood flow increased 24.6 +/- 6.1% when TGF was inhibited by intratubular perfusion with furosemide, and it decreased 42.8 +/- 3.9% when TGF was saturated by tubular perfusion with artificial tubular fluid at high rates. Autospectral power in the low-frequency band decreased 50.5 +/- 9.6% during furosemide and decreased 74.9 +/- 5.9% during TGF saturation, consistent with a TGF origin of the slow oscillation. In contrast, autospectral power of the high-frequency oscillation increased 75.4 +/- 23.9% during TGF inhibition and decreased 35.8 +/- 11% when TGF was saturated, suggesting interactions between the two spontaneously oscillating components in efferent arteriole blood flow.
Animals↗
Blood pressure variability and the renal response.
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Animals↗
Dynamics of TGF-initiated nephron-nephron interactions in normotensive rats and SHR.
Proximal tubular pressure, glomerular filtration rate, and early distal tubule Cl- oscillate at 35 mHz in normotensive rats because of tubuloglomerular feedback (TGF); the oscillation bifurcates to chaos in spontaneously hypertensive rats (SHR). To examine the importance of TGF-initiated vascular interactions between nephrons in these dynamics, we measured tubular pressure simultaneously in two or more nephrons. The oscillations were synchronized in nephrons supplied by a common cortical radial artery. The correlation coefficient of pressure records from coupled nephrons was 0.86 +/- 0.02. Intratubular furosemide perfusion diminished the oscillation in both the perfused and the coupled nephron; total autospectral power in each of the nephrons and cross-spectral power were reduced to 45% of control. The correlation between noncoupled nephrons was not significant, and intratubular furosemide perfused in one nephron had no effect on adjacent but noncoupled nephrons. In SHR, the correlation coefficient of tubular pressure records was high from coupled nephrons only; furosemide diminished the autospectral power of pressure fluctuations to approximately 60-75% of control in both perfused and coupled nephrons, and cross-spectral power was affected by a similar amount. Nephron-nephron interactions, specific to vascular connectivity, persist in SHR and appear to be stronger than in normotensive rats.
Animals↗
Medullary thyroid carcinoma: Australian experience with genetic testing.
Linkage analysis has been performed in four pedigrees with multiple endocrine neoplasia type 2A (MEN 2A) or familial medullary thyroid carcinoma (MTC) using pericentromeric chromosome 10 probes. Important information regarding carrier status has been provided in 10 individuals, many of whom would not have been identified by pentagastrin stimulation testing. We have also used pulsed field gel electrophoresis (PFGE) to link the probes H4.IRBP and pMCK2 to a 150 kb fragment. Using PFGE, no evidence was found in DNA from lymphocytes of a major DNA rearrangement in two individuals affected with MEN 2A and an individual with MEN 2B compared with normals. Metastatic MTC from one patient has been used to generate a cDNA library which will be used to screen for candidate MEN 2A and MEN 2B gene(s).
Carcinoma↗
Tubuloglomerular feedback dynamics and renal blood flow autoregulation in rats.
To decide whether tubuloglomerular feedback (TGF) can account for renal autoregulation, we tested predictions of a TGF simulation. Broad-band and single-frequency perturbations were applied to arterial pressure; arterial blood pressure, renal blood flow and proximal tubule pressure were measured. Data were analyzed by linear systems analysis. Broad-band forcings of arterial pressure were also applied to the model to compare experimental results with simulations. With arterial pressure as the input and tubular pressure, renal blood flow, or renal vascular resistance as outputs, the model correctly predicted gain and phase only in the low-frequency range. Experimental results revealed a second component of vascular control active at 100-150 mHz that was not predicted by the simulation. Forcings at single frequencies showed that the system behaves linearly except in the band of 33-50 mHz in which, in addition, there are autonomous oscillations in TGF. Higher amplitude forcings in this band were attenuated by autoregulatory mechanisms, but low-amplitude forcings entrained the autonomous oscillations and provoked amplified oscillations in blood flow, showing an effect of TGF on whole kidney blood flow. We conclude that two components can be detected in the dynamic regulation of renal blood flow, i.e., a slow component that represents TGF and a faster component that most likely represents an intrinsic vascular myogenic mechanism.
Animals↗
Three-dimensional anatomy and renal concentrating mechanism. I. Modeling results.
Simulations were performed to test the hypothesis that the three-dimensional organization of the renal medulla is essential for formation of hypertonic urine. As in previous models, representations of loops of Henle, distal tubules, collecting ducts, and vasa recta and recent estimates of tubule characteristics were included in a simulation of NaCl, urea, and fluid transport. In addition, this model specifies the relative positions of the medullary structures. By assuming that the structure of the minimum functional unit is a vascular bundle surrounded by tubules and ascending vessels, we have represented the three-dimensional organization of the medulla by a cylindrically symmetric two-dimensional model. The resulting set of equations gives rise to a nonlinear boundary value problem with linear boundary conditions, which was solved numerically via quasi linearization. Compared with previous simulations, the concentrations predicted by this model more accurately match measured quantities in two regards. First, papillary tip concentrations of NaCl and urea are significantly higher, and, second, a monotonic increase in osmolarity is observed in the inner medulla. The three-dimensional organization permitted development of local concentration gradients, which are essential to the final result.
Absorption↗
Three-dimensional anatomy and renal concentrating mechanism. II. Sensitivity results.
A mathematical model has been developed to simulate hypertonic urine formation in the renal medulla. The model uses published values of membrane transport parameters, as have other models, but is unique in its representation of the three-dimensional anatomy of the medulla. The model successfully predicts measured fluid flows, osmolarities, and NaCl and urea concentrations. The model results are presented in the companion to this paper [A. S. Wexler, R. E. Kalaba, D. J. Marsh. Am. J. Physiol. 260 (Renal Fluid Electrolyte Physiol. 29): F368-F383, 1991.]. In this paper we provide tests of the sensitivity of model performance to variations in the description of the anatomy and in membrane transport parameters. From these studies we conclude that 1) strict counterflow arrangements are required in the outer stripe to prevent loss of NaCl to the systemic circulation, 2) the radial organization in the inner stripe materially improves performance of the inner medulla, 3) radial organization of the inner medulla is essential to hypertonic urine formation there, 4) the model is most sensitive to variation in collecting duct parameters, and 5) reabsorption of urea in the distal tubule improves system performance. The results support the claim that the three-dimensional structure, as captured in the model, provides a crucial framework for the production of hypertonic urine.
Absorption↗
Chaos in blood flow control in genetic and renovascular hypertensive rats.
Hydrostatic pressure and flow in renal proximal tubules oscillate at 30-40 mHz in normotensive rats anesthetized with halothane. The oscillations originate in tubuloglomerular feedback, a mechanism that provides local blood flow regulation. Instead of oscillations, spontaneously hypertensive rats (SHR) have aperiodic tubular pressure fluctuations; the pattern is suggestive of deterministic chaos. Normal rats made hypertensive by clipping one renal artery had similar aperiodic tubular pressure fluctuations in the unclipped kidney, and the fraction of rats with irregular fluctuations increased with time after the application of the renal artery clip. Statistical measures of deterministic chaos were applied to tubular pressure data. The correlation dimension, a measure of the dimension of the phase space attractor generating the time series, indicated the presence of a low-dimension strange attractor, and the largest Lyapunov exponent, a measure of the rate of divergence in phase space, was positive, indicating sensitivity to initial conditions. These time series therefore satisfy two criteria of deterministic chaos. The measures were the same in SHR as in rats with renovascular hypertension. Since two different models of hypertension displayed similar dynamics, we suggest that chaotic behavior is a common feature of renal vascular control in the natural history of the disease.
Animals↗
Glucose tolerance and insulin action in rats with renovascular hypertension.
To test whether hypertension can cause hyperinsulinemia or insulin resistance, we performed intravenous glucose tolerance tests at 1 month and euglycemic clamps at 3 months after induction of two-kidney, one clip renovascular hypertension in rats. At 1 month, systolic pressure was higher in 21 clipped than in 12 control animals (161 +/- 5 mm Hg, range 134-187 mm Hg versus 119 +/- 3 mm Hg, range 108-146 mm Hg; p less than 0.001). Glucose tolerance, assessed as the glucose fractional disappearance rate between 3 and 11 minutes after the glucose injection, was similar in the clipped and sham groups (0.059 +/- 0.002 versus 0.056 +/- 0.002 min-1, respectively; p greater than 0.4). The total area under the insulin curve during glucose tolerance tests was also similar in the clipped and sham groups (926 +/- 95 versus 869 +/- 126 microunits/ml x min; p greater than 0.4). There was no significant relation between systolic blood pressure and insulin area during glucose tolerance tests in the clipped group, but there was a positive rectilinear relation in the control group (r = 0.66; p = 0.01). Fourteen animals had euglycemic clamps 2 months after glucose tolerance tests. At that time, systolic pressure (direct femoral measurement) was higher in the seven clipped animals (189 +/- 13 mm Hg versus 122 +/- 5 mm Hg in controls; p less than 0.001). Insulin infusions of 1 and 4 milliunits/min/kg body wt effected similar plasma insulin levels in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Oscillations and more complex dynamics in tubuloglomerular feedback.
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Animals↗
Dynamics of renal blood flow autoregulation in rats.
Two separate components could be resolved in tests of the dynamic autoregulation of renal blood flow. The slow component corresponds to the frequency at which spontaneous proximal tubular pressure oscillations are found, and are most likely due to the operation of the TGF. The high frequency component most likely represents an intrinsic vascular, myogenic, mechanism. The gain maximum of the admittance in the frequency range corresponding to the autonomous tubular oscillations indicates that the dynamic characteristics responsible for the occurrence of the spontaneous tubular oscillations must be common to a significant fraction of the total nephron population.
Animals↗
1/f fluctuations in arterial pressure and regulation of renal blood flow in dogs.
To determine whether renal blood flow is regulated against spontaneous fluctuations in arterial pressure and to estimate the frequency band of the regulation, we measured arterial pressure and renal blood flow continuously over several days in conscious dogs. Mean arterial blood pressure showed broad band fluctuations and behaved as a 1/f process, indicating that the blood pressure record is a fractal curve and therefore scale invariant. The fluctuations in arterial pressure caused attenuated fluctuations in renal blood flow; the gain was about -6.5 +/- 0.5 dB through all sampled frequencies greater than or equal to 4 cycle/day. The kidney did not attenuate the blood pressure signal at the lowest frequencies. The results show that renal blood flow is better regulated against fluctuations in pressure at frequencies greater than or equal to 4 cycle/day than it is at lower frequencies. Although there are no direct tests of the underlying regulatory mechanisms, we argue that the responses are generated locally and can be identified with renal autoregulation.
Activity Cycles↗