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Biomedical subjects

S McKinney

Publications and source records attributed to S McKinney.

At least 19 recordsLinked to original sources
PubMed2001

Gamma-aminobutyric acid type A receptors modulate cAMP-mediated long-term potentiation and long-term depression at monosynaptic CA3-CA1 synapses.

cAMP induces a protein-synthesis-dependent late phase of long-term potentiation (LTP) at CA3-CA1 synapses in acute hippocampal slices. Herein we report cAMP-mediated LTP and long-term depression (LTD) at monosynaptic CA3-CA1 cell pairs in organotypic hippocampal slice cultures. After bath application of the membrane-permeable cAMP analog adenosine 3',5'-cyclic monophosphorothioate, Sp isomer (Sp-cAMPS), synaptic transmission was enhanced for at least 2 h. Consistent with previous findings, the late phase of LTP requires activation of cAMP-dependent protein kinase A and protein synthesis. There is also an early phase of LTP induced by cAMP; the early phase depends on protein kinase A but, in contrast to the later phase, does not require protein synthesis. In addition, the cAMP-induced LTP is associated with a reduction of paired-pulse facilitation, suggesting that presynaptic modification may be involved. Furthermore, we found that Sp-cAMPS induced LTD in slices pretreated with picrotoxin, a gamma-aminobutyric acid type A (GABA(A)) receptor antagonist. This form of LTD depends on protein synthesis and protein phosphatase(s) and is accompanied by an increased ratio of failed synaptic transmission. These results suggest that GABA(A) receptors can modulate the effect of cAMP on synaptic transmission and thus determine the direction of synaptic plasticity.

Animals↗
PubMed2000

Pulmonary NO synthase inhibition and inspired CO2: effects on V'/Q' and pulmonary blood flow distribution.

Inhaled carbon dioxide decreases ventilation/perfusion ratio (V'/Q') heterogeneity in dogs. The aim of this study was to test whether inhaled CO2 improves the V'/Q' by inhibition of nitric oxide production and whether inhibition of endogenous NO production in the lung alters gas exchange and V'/Q' matching. Eleven healthy dogs were anaesthetized and mechanically ventilated. The multiple inert gas elimination technique (MIGET) was used to measure V'/Q' heterogeneity and regional pulmonary blood flow heterogeneity was assessed in five dogs using fluorescent microspheres. In a separate set of five dogs, exhaled NO levels were measured via chemiluminescence. All dogs were studied before and after 4.8% inspired CO2, and then given the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg x kg(-1)) via nebulization, after which they were studied again with room air and inhaled CO2. CO2 and L-NAME improved arterial and alveolar oxygen tension, but the improvements with L-NAME did not reach statistical significance. Improved V'/Q' matching, as assessed by the MIGET, occurred under all experimental conditions. Exhaled NO levels were reduced by 40% with CO2 and 70% with L-NAME. The standard deviation of regional pulmonary blood flow assessed via microspheres decreased only with inhaled CO2. Fractal analysis of pulmonary blood flow distributions revealed that regional blood flow was highly correlated with flow to neighbouring pieces of lung in all four conditions with no changes in the fractal dimension. Inspired carbon dioxide improves ventilation perfusion ratio matching and is associated with a more homogeneous distribution of pulmonary blood flow. Although inspired carbon dioxide causes a reduction in exhaled nitric oxide, the differences in pulmonary perfusion distributions found between carbon dioxide and N(omega)-nitro-L-arginine methyl ester suggest that the carbon dioxide effect is not mediated by a reduction in nitric oxide production. The improved ventilation perfusion ratio matching with inhibition of nitric oxide synthase suggests the intriguing possibility requiring further study that endogenous production of nitric oxide in the lung does not subserve ventilation perfusion ratio regulation.

Administration, Inhalation↗
PubMed2000

High spatial resolution measurements of organ blood flow in small laboratory animals.

With the use of a newly developed Imaging Cryomicrotome to determine the spatial location of fluorescent microspheres in organs, we validate and report our processing algorithms for measuring regional blood flow in small laboratory animals. Microspheres (15-microm diameter) of four different fluorescent colors and one radioactive label were simultaneously injected into the left ventricle of a pig. The heart and kidneys were dissected, and the numbers of fluorescent and radioactive microspheres were determined in 10 randomly selected pieces. All microsphere counts fell well within the 95% expected confidence limits as determined from the radioactive counts. Fluorescent microspheres (15-microm diameter) of four different colors were also injected into the tail vein of a rat and the left ventricle of a rabbit. After correction for Poisson noise, correlation coefficients between the colors were 0.99 +/- 0.02 (means +/- SD) for the rabbit heart and 0.99 +/- 0.02 for the rat lung. Mathematical dissection algorithms, statistics to analyze the spatial data, and methods to visualize blood flow distributions in small animal organs are presented.

Animals↗
PubMed2000

Fractal nature of regional ventilation distribution.

High-resolution measurements of pulmonary perfusion reveal substantial spatial heterogeneity that is fractally distributed. This observation led to the hypothesis that the vascular tree is the principal determinant of regional blood flow. Recent studies using aerosol deposition show similar ventilation heterogeneity that is closely correlated with perfusion. We hypothesize that ventilation has fractal characteristics similar to blood flow. We measured regional ventilation and perfusion with aerosolized and injected fluorescent microspheres in six anesthetized, mechanically ventilated pigs in both prone and supine postures. Adjacent regions were clustered into progressively larger groups. Coefficients of variation were calculated for each cluster size to determine fractal dimensions. At the smallest size lung piece, local ventilation and perfusion are highly correlated, with no significant difference between ventilation and perfusion heterogeneity. On average, the fractal dimension of ventilation is 1.16 in the prone posture and 1. 09 in the supine posture. Ventilation has fractal properties similar to perfusion. Efficient gas exchange is preserved, despite ventilation and perfusion heterogeneity, through close correlation. One potential explanation is the similar geometry of bronchial and vascular structures.

Aerosols↗
PubMed2000

Correlation between ventilation and perfusion determines VA/Q heterogeneity in endotoxemia.

Endotoxin increases ventilation-to-perfusion ratio (VA/Q) heterogeneity in the lung, but the precise changes in alveolar ventilation (VA) and perfusion that lead to VA/Q heterogeneity are unknown. The purpose of this study was to determine how endotoxin affects the distributions of ventilation and perfusion and the impact of these changes on VA/Q heterogeneity. Seven anesthetized, mechanically ventilated juvenile pigs were given E. coli endotoxin intravenously, and regional ventilation and perfusion were measured simultaneously by using aerosolized and injected fluorescent microspheres. Endotoxemia significantly decreased the correlation between regional ventilation and perfusion, increased perfusion heterogeneity, and redistributed perfusion between lung regions. In contrast, ventilation heterogeneity did not change, and redistribution of ventilation was modest. The decrease in correlation between regional ventilation and perfusion was responsible for significantly more VA/Q heterogeneity than were changes in ventilation or perfusion heterogeneity. We conclude that VA/Q heterogeneity increases during endotoxemia primarily as a result of the decrease in correlation between regional ventilation and perfusion, which is in turn determined primarily by changes in perfusion.

Animals↗
PubMed2000

Exercise alters fractal dimension and spatial correlation of pulmonary blood flow in the horse.

We determined the changes in fractal dimensions and spatial correlations of regional pulmonary blood flow with increasing exercise in race horses (n = 4) by using 15-microm fluorescent microspheres. Fluorescence was measured to quantitate regional blood to 1.3-cm(3) samples (n = 1,621-2,503). Perfusion distributions were characterized with fractal dimensions (a measure of spatial variability) and spatial correlations. On average, the fractal dimension decreased with exercise (trot 1.216 to gallop 1.173; P < 0. 05) despite a variable fractal dimension at rest. Spatial correlation of flow to neighboring pieces increased with exercise (trot 0.57 +/- 0.074 to gallop 0.73 +/- 0.051) and was inversely correlated with fractal dimension, indicating better spatial correlation as blood flow distribution becomes more uniform. This is the first study to document a change in fractal dimension as a result of increasing pulmonary blood flow. Spatial differences in response to vasoregulatory mediators may play a role in this phenomenon.

Algorithms↗
PubMed2000

ROMK1 (Kir1.1) causes apoptosis and chronic silencing of hippocampal neurons.

Lentiviral vectors were constructed to express the weakly rectifying kidney K(+) channel ROMK1 (Kir1.1), either fused to enhanced green fluorescent protein (EGFP) or as a bicistronic message (ROMK1-CITE-EGFP). The channel was stably expressed in cultured rat hippocampal neurons. Infected cells were maintained for 2-4 wk without decrease in expression level or evidence of viral toxicity, although 15.4 mM external KCl was required to prevent apoptosis of neurons expressing functional ROMK1. No other trophic agents tested could prevent cell death, which was probably caused by K(+) loss. This cell death did not occur in glia, which were able to support ROMK1 expression indefinitely. Functional ROMK1, quantified as the nonnative inward current at -144 mV in 5.4 mM external K(+) blockable by 500 microM Ba(2+), ranged from 1 to 40 pA/pF. Infected neurons exhibited a Ba(2+)-induced depolarization of 7 +/- 2 mV relative to matched EGFP-infected controls, as well as a 30% decrease in input resistance and a shift in action potential threshold of 2.6 +/- 0.5 mV. This led to a shift in the relation between injected current and firing frequency, without changes in spike shape, size, or timing. This shift, which quantifies silencing as a function of ROMK1 expression, was predicted from Hodgkin-Huxley models. No cellular compensatory mechanisms in response to expression of ROMK1 were identified, making ROMK1 potentially useful for transgenic studies of silencing and neurodegeneration, although its lethality in normal K(+) has implications for the use of K(+) channels in gene therapy.

Action Potentials↗
PubMed1999

Endogenous platelet-activating factor is critically involved in effector functions of eosinophils stimulated with IL-5 or IgG.

Eosinophil activation and subsequent release of inflammatory mediators are implicated in the pathophysiology of allergic diseases. Eosinophils are activated by various classes of secretagogues, such as cytokines (e.g., IL-5), lipid mediators (e.g., platelet-activating factor (PAF)), and Ig (e.g., immobilized IgG). However, do these agonists act directly on eosinophils or indirectly through the generation of intermediate active metabolites? We now report that endogenous PAF produced by activated eosinophils plays a critical role in eosinophil functions. Human eosinophils produced superoxide when stimulated with immobilized IgG, soluble IL-5, or PAF. Pretreating eosinophils with pertussis toxin abolished their responses to these stimuli, suggesting involvement of a metabolite(s) that acts on G proteins. Indeed, PAF was detected in supernatants from eosinophils stimulated with IgG or IL-5. Furthermore, structurally distinct PAF antagonists, including CV6209, hexanolamine PAF, and Y-24180 (israpafant), inhibited IgG- or IL-5-induced superoxide production and degranulation. Previous reports indicated that exogenous PAF stimulates eosinophil eicosanoid production through formation of lipid bodies. We found in this study that IgG or IL-5 also induces lipid body formation and subsequent leukotriene C4 production mediated by endogenous PAF. Finally, inhibition of cytosolic phospholipase A2, one of the key enzymes involved in PAF synthesis, attenuated both PAF production and effector functions of eosinophils. These findings suggest that endogenous PAF plays important roles in eosinophil functional responses to various exogenous stimuli, such as cytokines and Igs. Therefore, inhibition of PAF synthesis or action may be beneficial for the treatment of eosinophilic inflammation.

Eicosanoids↗
PubMed1999

Hemodilution during venous gas embolization improves gas exchange, without altering V(A)/Q or pulmonary blood flow distributions.

BACKGROUND: Isovolemic anemia results in improved gas exchange in rabbits with normal lungs but in relatively poorer gas exchange in rabbits with whole-lung atelectasis. In the current study, the authors characterized the effects of hemodilution on gas exchange in a distinct model of diffuse lung injury: venous gas embolization. METHODS: Twelve anesthetized rabbits were mechanically ventilated at a fixed rate and volume. Gas embolization was induced by continuous infusion of nitrogen via an internal jugular venous catheter. Serial hemodilution was performed in six rabbits by simultaneous withdrawal of blood and infusion of an equal volume of 6% hetastarch; six rabbits were followed as controls over time. Measurements included hemodynamic parameters and blood gases, ventilation-perfusion (V(A)/Q) distribution (multiple inert gas elimination technique), pulmonary blood flow distribution (fluorescent microspheres), and expired nitric oxide (NO; chemoluminescence). RESULTS: Venous gas embolization resulted in a decrease in partial pressure of arterial oxygen (PaO2) and an increase in partial pressure of arterial carbon dioxide (PaCO2), with markedly abnormal overall V(A)/Q distribution and a predominance of high V(A)/Q areas. Pulmonary blood flow distribution was markedly left-skewed, with low-flow areas predominating. Hematocrit decreased from 30+/-1% to 11+/-1% (mean +/- SE) with hemodilution. The alveolar-arterial PO2 (A-aPO2) difference decreased from 375+/-61 mmHg at 30% hematocrit to 218+/-12.8 mmHg at 15% hematocrit, but increased again (301+/-33 mmHg) at 11% hematocrit. In contrast, the A-aPO2 difference increased over time in the control group (P < 0.05 between groups over time). Changes in PaO2 in both groups could be explained in large part by variations in intrapulmonary shunt and mixed venous oxygen saturation (SvO2); however, the improvement in gas exchange with hemodilution was not fully explained by significant changes in V(A)/Q or pulmonary blood flow distributions, as quantitated by the coefficient of variation (CV), fractal dimension, and spatial correlation of blood flow. Expired NO increased with with gas embolization but did not change significantly with time or hemodilution. CONCLUSIONS: Isovolemic hemodilution results in improved oxygen exchange in rabbits with lung injury induced by gas embolization. The mechanism for this improvement is not clear.

Animals↗
PubMed1999

Mechanisms of improvement in pulmonary gas exchange during isovolemic hemodilution.

Severe anemia is associated with remarkable stability of pulmonary gas exchange (S. Deem, M. K. Alberts, M. J. Bishop, A. Bidani, and E. R. Swenson. J. Appl. Physiol. 83: 240-246, 1997), although the factors that contribute to this stability have not been studied in detail. In the present study, 10 Flemish Giant rabbits were anesthetized, paralyzed, and mechanically ventilated at a fixed minute ventilation. Serial hemodilution was performed in five rabbits by simultaneous withdrawal of blood and infusion of an equal volume of 6% hetastarch; five rabbits were followed over a comparable time. Ventilation-perfusion (VA/Q) relationships were studied by using the multiple inert-gas-elimination technique, and pulmonary blood flow distribution was assessed by using fluorescent microspheres. Expired nitric oxide (NO) was measured by chemiluminescence. Hemodilution resulted in a linear fall in hematocrit over time, from 30 +/- 1.6 to 11 +/- 1%. Anemia was associated with an increase in arterial PO(2) in comparison with controls (P < 0.01 between groups). The improvement in O(2) exchange was associated with reduced VA/Q heterogeneity, a reduction in the fractal dimension of pulmonary blood flow (P = 0.04), and a relative increase in the spatial correlation of pulmonary blood flow (P = 0. 04). Expired NO increased with anemia, whereas it remained stable in control animals (P < 0.0001 between groups). Anemia results in improved gas exchange in the normal lung as a result of an improvement in overall VA/Q matching. In turn, this may be a result of favorable changes in pulmonary blood flow distribution, as assessed by the fractal dimension and spatial correlation of blood flow and as a result of increased NO availability.

Anemia↗
PubMed1998

Pulmonary embolization causes hypoxemia by redistributing regional blood flow without changing ventilation.

To explore mechanisms of hypoxemia after acute pulmonary embolism, we measured regional pulmonary blood flow and alveolar ventilation before and after embolization with 780-micrometers beads in five anesthetized, mechanically ventilated pigs. Regional ventilation and perfusion were determined in approximately 2.0-cm3 lung volumes by using 1-micrometers-diameter aerosolized and 15-micrometers-diameter injected fluorescent microspheres. Hypoxemia after embolization resulted from increased perfusion to regions with low ventilation-to-perfusion ratios. Embolization caused an increase in perfusion heterogeneity and a fall in the correlation between ventilation and perfusion. Correlation between regional ventilation pre- and postembolization was greater than correlation between regional perfusion pre- and postembolization. The majority of regional ventilation-to-perfusion ratio heterogeneity was attributable to changes in regional perfusion. Regional perfusion redistribution without compensatory changes in regional ventilation is responsible for hypoxemia after pulmonary vascular embolization in pigs.

Animals↗
PubMed1997

Spatial pattern of pulmonary blood flow distribution is stable over days.

Despite the heterogeneous distribution of regional pulmonary perfusion over space, local perfusion remains stable over short time periods (20-100 min). The purpose of this study was to determine whether the spatial distribution of pulmonary perfusion remains stable over longer time periods (1-5 days). Regional blood flow was measured each day for 5 days in five awake standing dogs. Fluorescent microspheres of different colors were injected into a limb vein over 30 s on each day. After the last microsphere injection, the dogs were killed, and lungs were flushed free of blood, excised, dried at total lung capacity, and diced into approximately 2-cm3 pieces (n = 1,296-1,487 per dog). Relative blood flow to each piece on each day was determined by extracting the fluorescent dyes and determining the concentrations of each color. We established that blood flow is spatially heterogeneous with a coefficient of variation of 29.5 +/- 2%. Blood flow to each piece is highly correlated with flow to the same piece on all days (r = 0.930 +/- 0.006). The temporal heterogeneity of regional perfusion as measured by the coefficient of variation is 6.9 +/- 0.7% over the 5 days and is nonrandom. The magnitude of spatial and temporal variation is significantly less than previously reported in a study in which anesthetized and mechanically ventilated dogs were used. We conclude that spatial distribution of pulmonary blood flow remains stable over days and we speculate that in the normal awake dog regional perfusion is determined primarily by a fixed structure such as the geometry of the pulmonary vascular tree rather than by local vasoactive regulators. Anesthesia and/or mechanical ventilation may increase the temporal variability in regional perfusion.

Animals↗
PubMed1996

Restraint, dieting, and the continuum model of bulimia nervosa.

The authors evaluated the continuity model of bulimia nervosa, which suggests that bulimia results from extreme weight concern and dieting practices. Individuals with bulimia, current dieters, restrained nondieters, and unrestrained nondieters were compared on measures of general psychopathology, eating-disorder-specific psychopathology, and overeating. Multiple methods, including questionnaires, clinical interviews, and food records, were used to collect data. The continuity and discontinuity models were tested with trend and regression analyses. The results of most analyses were consistent with the continuity perspective. However, binge eating behaviour exhibited a clear nonlinear trend, which occurred because binge eating was common in bulimic individuals but virtually non-existent in the other 3 groups. Current dieters scored higher than restrained nondieters on restraint/ weight concern, but not on psychopathology or binge eating. Overall, the results suggest that "normal" dieting is associated with psychological, but not consummatory, symptoms of bulimia.

Adult↗
PubMed1995

Levonorgestrel as a postcoital contraceptive.

Time-release pellets of levonorgestrel (LNG), the progestogenic hormone contained in the contraceptive system Norplant, were implanted subdermally in mice, after the animals had mated and ovulated but before uterine implantation of embryos would have occurred, to examine whether the hormone could reduce the number of embryos that subsequently implanted and, if so, when it had to be administered in the postcoital period to achieve that effect. Hybrid female mice (C57BL x CBA) were paired with breeder males (CD-1) and LNG pellets were implanted on day 0, the day on which copulation plugs were found, or on day 2 or day 3 in the postcoital period. Mice in some groups were sacrificed on day 14 of the gestation period, and numbers of fetuses and/or resorption sites were counted, while mice in other groups were allowed to go to term. When LNG pellets were implanted subdermally on day 0 of the postcoital period, pellets designed to release 1.5 mg of hormone in 21 days failed to exhibit a contraceptive effect, but pellets designed to release 5 mg of hormone in 90 days were totally effective in preventing uterine implantation of embryos. Although the 5 mg pellets did not prevent embryos from implanting in all cases when administered on day 2, they prevented pregnancies from going to term by causing resorption of those embryos that did implant. When the pellets were implanted as late as day 3 in the postcoital period, uterine implantation of embryos occurred and fetuses were carried to term. Results of the study indicate that subdermal implants of LNG inserted postcoitally can prevent uterine implantation of embryos in mice, and thereby prevent pregnancy, despite fertilization of oocytes having occurred, if the hormone implants are inserted before day 3 of the postcoital period.

Animals↗
PubMed1995

Temporal heterogeneity of regional pulmonary perfusion is spatially clustered.

This study investigates temporal changes in regional pulmonary perfusion. Five dogs were studied with five or six different radiolabeled microspheres being injected via a central vein over 30 s every 20 min. The lungs of each animal were cubed into 1.9 cm3 pieces with spatial coordinates noted for each piece. Within individual pieces, the coefficient of variation of regional perfusion over time was 17.2 +/- 6.8% (SD) and across dogs accounted for 7.26 +/- 5.7% of total perfusion heterogeneity. Temporal variability or "twinkling" was not random. When lung pieces with similar temporal flow patterns were grouped together (regardless of spatial location), groups were more tightly clustered in space than expected by chance. Statistical clustering methods revealed regulation of blood flow on a large scale (lobar arteries), and fractal analyses suggested regulation existed on a smaller scale (arterioles). We conclude that regional pulmonary perfusion is heterogeneous over time in a nonrandom pattern and that pieces clustered by temporal patterns of perfusion are neighbors in the spatial domain.

Animals↗
PubMed1993

Breast-feeding reduces maternal lower-body fat.

The effect of breast-feeding on maternal anthropometric measures during the first 6 postpartum months was studied in 24 women. Mothers, who were seen in the hospital shortly after delivery and at monthly intervals thereafter, kept a record of their infant-feeding practices and provided three 24-hour dietary recalls per month. The women were placed in one of three groups according to their infant-feeding practices: breast-feeding exclusively, combination of breast- and formula-feeding, and formula-feeding only. Changes in anthropometric variables at 6 months postpartum were similar in the three groups, but mothers who breast-fed exclusively or partially had significantly larger reductions in hip circumference measurements (3.6% and 3.1%, respectively) and were less above their prepregnancy weights at 1 month postpartum (7.8% and 8.5% above prepregnancy weight, respectively) than mothers who fed formula exclusively (0.68% reduction in hip circumference and 13.7% above prepregnancy weight). Our findings indicate that a woman's choice of infant-feeding practice influences postpartum anthropometric changes, but these effects may be temporary.

Anthropometry↗
PubMed1993

A comparative study of HLA-DRB1 typing by standard serology and hybridization of non-radioactive sequence-specific oligonucleotide probes to PCR-amplified DNA.

A double-blind study was carried out to evaluate the relative performance and reliability of the PCR/SSOP assay compared to conventional serological typing in identifying HLA-DR alleles. A total of 268 consecutive samples were entered into the study. In 14 (5.2%) of the cases, HLA-DR serology could not be performed due to poor cell viability, while in seven (2.6%) of the cases, PCR/SSOP typing could not be performed due to poor amplification or to contamination with exogenous DNA. Among samples that were successfully typed by both methods, serologic typing correctly identified 455/465 (97.9%) DR antigens, while PCR/SSOP correctly identified 464/465 (99.8%) DR alleles (p = 0.0117, McNemar's test). The majority of discrepancies in serologic typing resulted from a lack of discriminative alloantisera to identify DR6 or DR103. For the overall sample set (N = 268), serology provided accurate results in 244 (91.0%) cases, while PCR/SSOP provided accurate results in 260 (97.0%) cases (p = 0.0037). The results of this study demonstrate that PCR/SSOP typing for HLA-DRB1 alleles provides results that are equal to or surpass serological typing for HLA-DR antigens. In addition, the PCR/SSOP approach offers the advantages of better reagent availability, lower cost, more rapid turn-around time, and greater accuracy, all of which would warrant its use as an HLA typing method of choice.

Alleles↗