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K Pettigrew

Publications and source records attributed to K Pettigrew.

At least 19 recordsLinked to original sources
PubMed2001

Regional differences in mechanisms of cerebral circulatory response to neuronal activation.

Vibrissal stimulation raises cerebral blood flow (CBF) in the ipsilateral spinal and principal sensory trigeminal nuclei and contralateral ventroposteromedial (VPM) thalamic nucleus and barrel cortex. To investigate possible roles of adenosine and nitric oxide (NO) in these increases, local CBF was determined during unilateral vibrissal stimulation in unanesthetized rats after adenosine receptor blockade with caffeine or NO synthase inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole (7-NI). Caffeine lowered baseline CBF in all structures but reduced the percent increase during stimulation only in the two trigeminal nuclei. L-NAME and 7-NI lowered baseline CBF but reduced the percent increase during stimulation only in the higher stations of this sensory pathway, i.e., L-NAME in the VPM nucleus and 7-NI in both the VPM nucleus and barrel cortex. Combinations of caffeine with 7-NI or L-NAME did not have additive effects, and none alone or in combination completely eliminated functional activation of CBF. These results suggest that caffeine-sensitive and NO-dependent mechanisms are involved but with different regional distributions, and neither fully accounts for the functional activation of CBF.

Animals↗
PubMed2000

Selection of an adaptive test statistic for use with multiple comparison analyses of neuroimaging data.

Statistical analysis of neuroimages is commonly approached with intergroup comparisons made by repeated application of univariate or multivariate tests performed on the set of the regions of interest sampled in the acquired images. The use of such large numbers of tests requires application of techniques for correction for multiple comparisons. Standard multiple comparison adjustments (such as the Bonferroni) may be overly conservative when data are correlated and/or not normally distributed. Resampling-based step-down procedures that successfully account for unknown correlation structures in the data have recently been introduced. We combined resampling step-down procedures with the Minimum Variance Adaptive method, which allows selection of an optimal test statistic from a predefined class of statistics for the data under analysis. As shown in simulation studies and analysis of autoradiographic data, the combined technique exhibits a significant increase in statistical power, even for small sample sizes (n = 8, 9, 10).

Algorithms↗
PubMed2000

The cost of access to mental health services in managed care.

Managed care has controlled the cost of specialty mental health services, but its impact on access to care is not well described. In a retrospective design, the study used empirical data to demonstrate a direct relationship between managed care plans' claims costs per member per month and the proportion of plan members who use specialty mental health services annually. Each increment of $1 per member per month in spending on claims was associated with a.9 percent increase in the proportion of enrollees receiving specialty mental health treatment. These data raise concerns that plans with low per-member per-month costs may unduly restrict access to specialty treatment.

Cost Control↗
PubMed1995

Benzodiazepine receptors mediate regional blood flow changes in the living human brain.

We studied the effects of a high-affinity gamma-aminobutyric acid (GABA)-benzodiazepine-receptor agonist (lorazepam) and an antagonist (flumazenil) in humans, using H2(15)O positron-emission tomography. Administration of lorazepam to healthy volunteers caused time- and dose-dependent reductions in regional cerebral blood flow and self-reported alterations in behavioral/mood parameters. Flumazenil administration reversed these changes. These observations indicated that benzodiazepine-induced effects on regional cerebral blood flow and mood/behavior are mediated at some level through GABA-benzodiazepine receptors, although the specific mechanism remains unclear. The approach described here provides a method for quantifying GABA-benzodiazepine-receptor-mediated neurotransmission in the living human brain and may be useful for studying the role of these receptors in a variety of neuropsychiatric disorders.

Adult↗
PubMed1995

Conditions that may determine blood vessel phenotype in tissues grafted to brain.

The hypothesis, that a blood vessel's phenotype is determined by the tissue it vascularizes and not by the vessel's source, does not hold for tissue beyond a certain period of development. In mature skeletal muscle grafted to choroid plexus of adult and 2-week-old rats, some vessels were choroidal or fenestrated (FV) rather than, according to the hypothesis, continuous (CV), like those of muscle. In E14 fetal muscle placed on the choroid plexus, approximately 80% of the grafts' capillaries were CV, like those of muscle. Most choroidal FV that entered the grafts were apparently changed to CV. By E16, about 70% of the graft vessels remained as FV rather than being converted. Thus, FV were changed to CV by a hypothetical conversion factor made, apparently, by E14 grafts but not by E16 grafts. In grafts from [3H]thymidine-labeled donors, an appreciable number of CV in E14 grafts were identified as intrinsic to the muscle. When hosts were labeled to verify the origin of FV in their nonlabeled donor grafts, only a few FV, to date, were tagged. The FV must have come from host choroid plexus, the only available source of graft FV. Vascular endothelial growth factor (VEGF) might convert CV into FV, yet VEGF and the mRNA for its receptor were present in choroid plexus but not in the grafts. Therefore, VEGF is not a conversion factor. The purported factor that changes FV to CV may be expressed in E14 muscle grafts but diminishes by fetal age E16 and beyond.

Animals↗
PubMed1995

Determination of local rates of 45Ca influx into rat brain by quantitative autoradiography: studies of aging.

Calcium homeostasis in brain is altered in many conditions, but there is no method to assay quantitatively local calcium flux into brain in vivo. 45Ca uptake into gross-dissected brain regions was measured and compared with results obtained with a quantitative autoradiographic procedure developed to assay influx of 45Ca into brain. Regional calcium contents, brain-to-plasma distribution ratios for calcium and 45Ca, apparent plasma-to-brain transfer coefficients, and net uptake of 45Ca into gross-dissected regions varied by as much as 80%. Local rates of net uptake of 45Ca into 34 structures determined by autoradiography varied by 12- to 14-fold, and rates of movement of 45Ca down concentrations gradients varied by a factor of 7. Previous studies with gross-dissected brain regions suggested changes in calcium uptake into brain during aging, but the values of all the variables assayed in the present study were similar in young adult, middle-aged, and old male rats. A quantitative autoradiographic procedure to assay levels of 45Ca in brain provides the anatomical resolution required to investigate local calcium flux in a variety of physiological and pathological conditions.

Aging↗
PubMed1995

Effects of acute and delayed effects of prior chronic cocaine administration on regional rates of cerebral protein synthesis in rats.

Single or repeated treatments with cocaine (15 mg/kg, i.p.) in rats modify rates of local cerebral protein synthesis (ICPSleu) measured with the [1-14C]leucine method. A single dose of cocaine to naive rats reduced ICPSleu by about 10% throughout the brain; the most statistically significant reduction was in the nucleus accumbens, shell portion (P = .0003). A comparable dose of cocaine administered acutely after 1 wk of daily cocaine injections had no effects on ICPSleu. Delayed effects of prior chronic cocaine treatment were studied in experiments in which one rat of each pair received injections with saline for 8 days and the other cocaine, and on the 15th day ICPSleu was measured. In these experiments delayed effects of the chronic cocaine treatment were observed; in the cocaine-treated rats ICPSleu was significantly increased in selective brain regions, i.e., prefrontal and primary olfactory cortex (P < .006). These results suggest that acute effects of a single dose of cocaine and residual effects of chronic cocaine treatment on ICPSleu are distinctly different and occur in different regions of the brain.

Animals↗
PubMed1993

Hypoxia increases velocity of blood flow through parenchymal microvascular systems in rat brain.

The postulation that hypoxia increases local cerebral blood flow (lCBF) mainly by perfusing more capillaries (the capillary recruitment hypothesis) was tested in awake adult male Sprague-Dawley rats exposed to 10% O2 and control rats. The [14C]iodoantipyrine technique was used to measure lCBF. Local cerebral blood volume was determined by measuring plasma and red cell distribution spaces within the brain parenchyma with 125I-labeled serum albumin (RISA) and 55Fe-labeled red cells (RBC), respectively. Tissue radioactivity in 44 brain areas was estimated by quantitative autoradiography. Hypoxia raised lCBF by 25-90% in all brain areas. In about one-quarter of the brain areas, the rise in blood flow was associated with a small increase in microvascular plasma and blood volumes. This change in blood volume, which could be the result of perfusing more parenchymal microvessels and/or increasing parenchymal microvessel diameter, is not sufficient to account for the observed rise in lCBF. In the remaining areas the RISA, RBC, and blood spaces were either unchanged or only marginally increased by hypoxia. For this hypoxic perturbation, the major mechanism of raising blood flow appears to be increased velocity of microvessel perfusion and not perfusion of more capillaries. These findings provide only limited support for the capillary recruitment hypothesis.

Animals↗
PubMed1993

The velocities of red cell and plasma flows through parenchymal microvessels of rat brain are decreased by pentobarbital.

Local cerebral blood flow is lowered in many brain areas of the rat by high-dose pentobarbital (50 mg/kg). In the present study, the mechanism of this flow change was examined by measuring the distribution of radiolabeled red blood cells (RBCs) and albumin (RISA) in small parenchymal microvessels and calculating the microvascular distribution spaces and mean transit times of RBCs, RISA, and blood. In most brain areas, pentobarbital slightly decreased the RISA space, modestly increased the RBC space, and did not alter the blood space. The mean transit times of RBCs, RISA, and blood through the perfused microvessels were considerably greater in treated rats than in controls. These findings indicate that the mechanism by which high-dose pentobarbital diminishes local cerebral blood flow in rat brain is, in the main, a lowered linear velocity of plasma and RBC flow through small parenchymal microvessels and not decreased percentage of perfused capillaries (capillary retirement). This response is probably driven mainly by lowered local metabolism and may well entail a slight increase in the number of small microvessels that are perfused by RBCs.

Animals↗
PubMed1993

Reproducibility of resting cerebral blood flow measurements with H2(15)O positron emission tomography in humans.

Two consecutive measurements of resting CBF were carried out in normal volunteers (n = 25) using H2(15)O positron emission tomography. Absolute whole-brain blood flow (WBBF; ml 100 g-1 min-1, mean +/- SD) for the first (40.3 +/- 6.4) and second (39.3 +/- 6.5) measurements was not significantly different (mean % difference 2.3 +/- 8.7). Analysis of regions of interest showed no significant differences in absolute regional CBF (rCBF) and normalized (rCBF/WBBF) rCBF. Left-right differences were also not significant. These data demonstrate the reproducibility of resting CBF measurements in normal humans.

Adult↗
PubMed1992

EMSA: a SAAM service for the estimation of population parameters based on model fits to identically replicated experiments.

This paper presents a new technique for the aggregation of models to produce population parameter estimates based on a set of identically replicated experiments. After describing the theoretical basis for the technique we discuss tactical and strategic issues associated with its implementation in the SAAM software. Finally, we demonstrate its utility in the aggregation of models fitted to four simulated experiments.

Algorithms↗
PubMed1992

Cerebral glucose utilization and blood flow in adult spontaneously hypertensive rats.

Not only blood pressure but also behavioral activity, brain morphology, and cerebral ventricular size differ between young spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. This suggests that cerebral blood flow and cerebral metabolism may vary between these two rat strains. To test this hypothesis, we measured local cerebral glucose utilization in 31 brain areas of 26-30-week-old rats. Local cerebral blood flow was also assessed in these same areas. Cerebral glucose utilization was measured by the 2-deoxyglucose method; cerebral blood flow was determined by the iodoantipyrene method. In virtually all gray matter structures, the apparent rate of glucose utilization was lower in SHR than in normotensive WKY rats; the interstrain differences varied significantly among structures and were statistically significant (uncorrected t tests) in 14 of 28 gray matter areas. Local cerebral blood flow was fairly similar in the two rat strains. The coupling of blood flow to glucose utilization varied significantly among brain areas in normotensive WKY rats as well as in SHR. In a number of gray matter structures, the coupling of flow to metabolism differed between hypertensive and normotensive animals. These data suggest that for many brain areas, either glucose utilization or glucose partitioning differs between WKY rats and SHR.

Analysis of Variance↗
PubMed1991

Intravascular streaming during carotid artery infusions. Demonstration in humans and reduction using diastole-phased pulsatile administration.

Intra-arterial carotid artery chemotherapy for malignant gliomas is limited by focal injuries to the eye and brain which may be caused by poor mixing of the drug with blood at the infusion site. This inadequate mixing can be eliminated in animal models with diastole-phased pulsatile infusion (DPPI) which creates 1-ml/sec spurts during the slow blood flow phase of diastole. Before treatment with intracarotid cisplatin, 10 patients with malignant gliomas were studied to determine whether intravascular streaming occurs after intracarotid infusion in humans, and if so, if it is reduced with DPPI. Regional cerebral blood flow (rCBF) studies were performed by intravenous injection of H2(15)O and positron emission tomography. This was followed by supra- or infraophthalmic internal carotid artery (ICA) injections of H2(15)O with either continuous infusion or DPPI. Local H2(15)O concentration in the brain was determined and the images of radiotracer distribution in the continuous infusion and DPPI studies were compared to the rCBF images. Intravascular streaming of the infusate was identified by a heterogeneous distribution of the infused H2(15)O in brain compared to rCBF. Extensive and variable intravascular streaming occurred in three patients who received infusions into the supraophthalmic segment of the ICA. Some brain areas received up to 11 times the expected radiotracer delivery, while other regions received as little as one-tenth. This streaming pattern was markedly reduced or eliminated by DPPI. In the five patients who received infraophthalmic infusions, a minimally heterogeneous distribution of the infusate was detected. The authors conclude that extensive intravascular streaming accompanies supraophthalmic ICA infusions in patients. The magnitude of streaming can be substantially reduced or eliminated with DPPI. Those who perform intra-arterial infusion should consider using DPPI to assure uniform drug delivery to brain.

Analysis of Variance↗
PubMed1990

Cerebral capillary bed structure of normotensive and chronically hypertensive rats.

In this study cerebral capillary bed structure and the effects of chronic hypertension on these systems have been assessed in 6- to 7-month-old spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Capillary diameter (D), profile frequency (Na), volume fraction (Vv), and surface area (Sv) were quantitated by light microscopic morphometry of eight brain areas including the sensorimotor cortex and subfornical organ. Previously presented data from normotensive Sprague-Dawley rats (SpD) of similar age were also compared. Within each of the three rat strains, D, Na, Vv, and Sv varied among brain areas. For the sensorimotor cortex and subfornical organ, capillary profile frequency differed significantly among the three rat strains. In SHR and WKY, there was an inverse correlation between profile frequency and diameter, i.e., as Na increased among brain areas, D decreased. In six brain areas capillary volume fraction and surface area were identical in SHR and WKY, but were lower in SpD. Consistent differences between SHR and WKY were found only for the subfornical organ, which suggests some involvement of this structure in hypertension. Since there were few statistically significant differences between SHR and WKY and many statistically significant differences between the two normotensive strains, cerebral capillary bed structure seems to be independent of arterial blood pressure in most brain areas of these rats.

Animals↗
PubMed1990

Kinetic analysis of 3-quinuclidinyl 4-[125I]iodobenzilate transport and specific binding to muscarinic acetylcholine receptor in rat brain in vivo: implications for human studies.

Radioiodinated R- and S-Quinuclidinyl derivatives of RS-benzilate (R- and S-125IQNB) have been synthesized for quantitative evaluation of muscarinic acetylcholine receptor binding in vivo. Two sets of experiments were performed in rats. The first involved determining the metabolite-corrected blood concentration and tissue distribution of tracer R-IQNB (active enantiomer) and S-IQNB (inactive enantiomer) in brain 1 min to 26 h after intravenous injection. The second involved the measurement of brain tissue washout over a 2-min period after loading the brain by an intracarotid artery injection of the ligands. Various pharmacokinetic models were tested, which included transport across the blood-brain barrier (BBB), nonspecific binding, low-affinity binding, and high-affinity binding. Our analysis demonstrated that the assumptions of rapid equilibrium across the BBB and rapid nonspecific binding are incorrect and result in erroneous estimates of the forward rate constant for binding at the high-affinity receptor sites (k3). The estimated values for influx across the BBB (K1), the steady-state accumulation rate in cerebrum (K), and the dissociation rate constant at the high-affinity site (k4) of R-IQNB were independent of the specific compartmental model used to analyze these data (K1 approximately 0.23 ml/min/g, K approximately 0.13 ml/min/g, and k4 approximately 0.0019 min-1 for caudate). In contrast, the estimated values of k3 and the efflux rate constant (k2) varied over a 10-fold range between different compartmental models (k3 approximately 2.3-22 min-1 and k2 approximately 1.6-16 min-1 in caudate), but their ratios were constant (k3/k2 approximately 1.4). Our analysis demonstrates that the estimates of k3 (and derived values such as the binding potential) are model dependent, that the rate of R-IQNB accumulation in cerebrum depends on transport across the BBB as well as the rate of binding, and that uptake in cerebrum is essentially irreversible during the first 360 min after intravenous administration. Graphical analysis was consistent with compartmental analysis of the data and indicated that steady-state uptake of R-IQNB in cerebrum is established within 1-5 min after intravenous injection. We propose a new approach to the analysis of R-IQNB time-activity data that yields reliable quantitative estimates of k3, k4, and the nonspecific binding equilibrium constant (Keq) by either compartmental or graphical analysis. The approach is based on determining the free unbound fraction of radiolabeled ligand in blood and an estimate of K1.(ABSTRACT TRUNCATED AT 400 WORDS)

Algorithms↗
PubMed1990

Optimal duration of experimental period in measurement of local cerebral glucose utilization with the deoxyglucose method.

The time course and magnitude of the effects of product loss on the measurement of local cerebral glucose utilization (LCGU) by the 2-[14C]deoxyglucose (DG) method were studied by determination of LCGU in 38 rats with 25-120 min experimental periods after a [14C]DG pulse and in 45 rats with experimental periods of 2.5-120 min during which arterial plasma [14C]DG concentrations (C*P) were maintained constant. LCGU was calculated by the operational equation, which assumes no product loss, with the original set of rate constants and with a new set redetermined in the rats used in the present study; in each case the rate constants were those specific to the structure. Data on local tissue 14C concentrations and C*P were also plotted according to the multiple time/graphic evaluation technique ("Patlak Plot"). The results show that with both pulse and constant arterial inputs of [14C]DG the influence of the rate constants is critical early after onset of tracer administration but diminishes with time and becomes relatively minor by 30 min. After a [14C]DG pulse calculated LCGU remains constant between 25 and 45 min, indicating a negligible effect of product loss during that period; at 60 min it begins to fall and declines progressively with increasing time, indicating that product loss has become significant. When C*P is maintained constant, calculated LCGU does not change significantly over the full 120 min. The "Patlak Plots" reinforced the conclusions drawn from the time courses of calculated LCGU; evidence for loss of product was undetectable for at least 45 min after a pulse of [14C]DG and for at least 60 min after onset of a constant arterial input of [14C]DG.

Animals↗