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Biomedical subjects

G L Anderson

Publications and source records attributed to G L Anderson.

At least 19 recordsLinked to original sources
PubMed2001

The initiating factors of late preconditioning in skeletal muscle.

PURPOSE: The goal of these studies was to determine the initiating factors for late preconditioning in the microcirculation of skeletal muscle. MATERIALS AND METHODS: The cremaster muscle of male Sprague-Dawley rats underwent 4 h of ischemia and then 60 min of reperfusion. Ischemic preconditioning (IPC) consisted of 45 min of ischemia but was done 24 h before the 4 h of ischemia. To mimic the effects of IPC in the late phase, adenosine (ADO) or sodium nitroprusside (SNP) was given 24 h before the prolonged ischemia via local intraarterial infusion. To block the effects of IPC in the late phase, 8-sulfophenyl-theophylline (a nonspecific ADO receptor blocker) or N(W)-nitro-l-arginine (a nonselective nitric oxide synthase antagonist) was given prior to IPC. Microvascular response to IPC and pharmacological preconditioning were determined by measuring arteriole diameters and capillary perfusion using intravital microscopy. RESULTS: Administration of ADO or SNP on day 1 without IPC produced a similar microvascular protection against prolonged ischemia/reperfusion on day 2 as that induced by IPC alone. In contrast, blocking ADO receptors or nitric oxide synthase on day 1 just prior to IPC eliminated the IPC-induced microvascular protection seen on day 2. In addition, inhibition of nitric oxide synthase on day 1 diminished the protection induced by ADO, but blocking ADO receptors on day 1 did not compromise the protection induced by SNP. CONCLUSION: The results from these studies suggest that up regulation of ADO is the initiating factor with secondary up regulation of nitric oxide in late preconditioning. Both ADO and nitric oxide contribute to initiating microvascular protection in the late phase of IPC.

Adenosine↗
PubMed2001

Assessment of sublethal endpoints for toxicity testing with the nematode Caenorhabditis elegans.

Toxicity tests in invertebrates often use sublethal endpoints, which may exhibit different sensitivity for various toxicants. Our objective was to characterize the sensitivity of movement, feeding, growth, and reproduction as endpoints for heavy metal toxicity testing with Caenorhabditis elegans. Growth and feeding were assessed in the same nematode samples used to assess movement and reproduction. Median effective concentrations (EC50s) for 24-h exposures to Pb, Cu, and Cd were determined for movement, feeding, and growth and a 72-h EC50 was derived for reproduction. The order of toxicity was Cu > Pb > Cd for each endpoint, including lethality and movement. There were no differences in sensitivity among endpoints for any metal. When exposed for 4 h at (sublethal) concentrations that were 14 times the 24-h EC50 value, Pb and Cu reduced feeding to the same extent while movement was reduced significantly more by Pb than by Cu. Thus, a difference in sensitivity of endpoints was apparent at 4 h, which was not evident at 24 h. These observations suggest potentially different mechanisms of toxicity for 24- and 4-h tests.

Animals↗
PubMed2001

Intervention approaches against I/R-induced arterial insufficiency in reconstructive surgery.

Ischemia and reperfusion in skeletal muscle is unavoidable during many reconstructive surgeries. Typical examples include replantation, transplantation, and free muscle transfer. One important complication during or after surgery is arterial insufficiency or a no-reflow phenomenon. The microcirculation is a primary target of ischemia and reperfusion injury. Vasoconstriction, poor blood flow, and capillary no-reflow, are the prominent features in the microcirculation seen during reperfusion. Currently, extensive efforts have focused on the theory that reactive oxygen species induce endothelial dysfunction in the microcirculation during reperfusion. Some intervention approaches, including ischemic preconditioning, are developing to interfere with or modulate the pathophysiological processes that are set in motion during ischemia and reperfusion.

Arterial Occlusive Diseases↗
PubMed2000

Caenorhabditis elegans as an alternative animal species.

Caenorhabditis elegans has proven useful in toxicity testing of known toxicants, but its potential for assessing the toxicity of new pharmaceuticals is relatively unexplored. In this study the procedures used in aquatic testing of toxicants were modified to permit testing of small amounts (<40 mg) of gadolinium-based magnetic resonance imaging (MRI) compounds. Five blinded compounds were tested. The toxicity of these compounds determined using C. elegans was compared to existing mammalian test system data (minimum lethal dose [MLD] values for mice). Four of five compounds tested had the same relative sensitivity with C. elegans as with the mouse test system. Testing with C. elegans is efficient and could markedly reduce the cost of screening potentially useful compounds.

Animal Testing Alternatives↗
PubMed2000

Platelet-activating factor contributes to postischemic vasospasm.

BACKGROUND: The purpose of the present study was to determine if platelet-activating factor is an important mediator that produces vasospasm during reperfusion after ischemia in skeletal muscle. MATERIALS AND METHODS: A vascular isolated cremaster muscle in male Sprague-Dawley rats was coupled with local intraarterial drug infusion as a model to study microcirculation responses to ischemia/reperfusion injury. Arteriole diameters and capillary perfusion were measured using intravital microscopy. Group 1: platelet-activating factor dose response. Group 2: Effects of a cyclooxygenase inhibitor; indomethacin, and a thromboxane synthetase inhibitor, imidazole, on the response to platelet-activating factor. Group 3: Effects of nitric oxide synthesis inhibitor; N(omega)-nitro-L-arginine methyl ester, on the response to platelet-activating factor. Group 4: Effects of a platelet-activating factor receptor antagonist, CV-3988, indomethacin, and imidazole after 4 h of warm ischemia and reperfusion. RESULTS: Intraarterial infusion of platelet-activating factor produced a dose-related but mild vasoconstriction. Pretreatment with indomethacin or imidazole resulted in significant vasodilation actually emanating from platelet-activating factor infusion. Nitric oxide inhibition (with N(omega)-nitro-L-arginine methyl ester) enhanced the vasoconstriction produced by platelet-activating factor. Pretreatment with CV-3988, indomethacin, or imidazole significantly attenuated ischemia/reperfusion-induced vasospasm and capillary no-reflow in the cremaster muscles. CONCLUSIONS: Ischemia/reperfusion-induced vasoconstriction is at least in part mediated by platelet-activating factor and thromboxane A(2).

Animals↗
PubMed2000

Interaction of angiogenesis inhibitor TNP-470 with basic fibroblast growth factor receptors.

TNP-470 is a synthetic analogue of fumagillin that acts as a potent angiogenesis inhibitor. Recently, our laboratory demonstrated that systemic administration of TNP-470 (5.0 mg/kg) decreased the rate of cutaneous wound healing by greater than 20%. In this study, we tested the hypothesis that TNP-470 interferes with the wound repair-stimulating action of basic fibroblast growth factor (bFGF) by competing with endogenous bFGF for its binding sites on the receptor protein. The influence of TNP-470 was examined in vitro in a ligand competition assay of high- and low-affinity receptor binding to (125)I-bFGF in NIH/3T3 cells. Results demonstrated that recognition of (125)I-bFGF by low-affinity growth factor binding sites was significantly decreased (P < 0.01) in the presence of TNP-470. However, TNP-470 inhibition of radiolabeled bFGF binding to high-affinity sites was not significantly affected (P = 0.07). In view of recent studies demonstrating that the low-affinity receptors of bFGF were heparan sulfate proteoglycans, we suggest that the influence of TNP-470 on diminished wound healing is due to its direct recognition by these molecules.

3T3 Cells↗
PubMed2000

Initiation of microvascular protection by nitric oxide in late preconditioning.

The authors hypothesized that nitric oxide is induced by a brief period of ischemia/reperfusion (ischemic preconditioning, IPC) on postoperative day (POD) 1, and that this released nitric oxide is responsible for initiating a delayed microvascular protection against a prolonged period of ischemia in skeletal muscle on POD day 2. The cremaster muscle of male Sprague-Dawley rats underwent 4 hr of ischemia, and then 60 min of reperfusion. IPC consisted of 45 min of ischemia but was done 24 hr before the prolonged ischemia. Local intraarterial infusion of sodium nitroprusside (SNP, a donor of nitric oxide) or Nw-nitro-L-arginine (L-NA, a nonselective nitric oxide synthase antagonist) were also given 24 hr before prolonged ischemia. Arteriole diameters and capillary perfusion were measured using intravital microscopy. Four groups were compared: 1) control; 2) IPC; 3) SNP + sham IPC; and 4) L-NA + IPC. Four hours of ischemia followed by reperfusion created a significant vasoconstriction and capillary no-reflow in the microcirculation of cremaster muscles. These alterations were largely prevented by IPC. Local intraarterial infusion of SNP without IPC created a similar microvascular protection to that induced by IPC alone. In contrast, intraarterial infusion of L-NA prior to IPC eliminated the IPC-induced microvascular protection. In conclusion, in late preconditioning, nitric oxide contributes to the initiation of a delayed microvascular protection against prolonged ischemia in skeletal muscle.

Animals↗
PubMed1999

Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo.

BACKGROUND: Antiphospholipid (aPL) antibodies are associated with thrombosis in patients diagnosed with antiphospholipid syndrome (APS) and enhance thrombus formation in vivo in mice, but the mechanism of thrombosis by aPL is not completely understood. Although aPL antibodies have been shown to inhibit protein C activation and activate endothelial cells (ECs) in vitro, no study has examined whether these antibodies activate ECs in vivo. Therefore, human affinity-purified aPL (ap aPL) antibodies from APS patients were tested in a mouse model of microcirculation using the cremaster muscle that allows direct microscopic examination of thrombus formation and adhesion of white blood cells (WBCs) to ECs as an indication of EC activation in vivo. Adhesion molecule expression on human umbilical vein endothelial cells (HUVECs) after aPL exposure was performed to confirm EC activation in vitro. METHODS AND RESULTS: All 6 ap aPL antibodies significantly increased the expression of VCAM-1 (2.3- to 4.4-fold), with one of the antibodies also increasing the expression of E-selectin (1.6-fold) on HUVECs in vitro. In the in vivo experiments, each ap aPL antibody except for 1 preparation increased WBC sticking (mean number of WBCs ranged from 22.7 to 50.6) compared with control (14.4), which correlated with enhanced thrombus formation (mean thrombus size ranged from 1098 to 6476 versus 594 microm2 for control). CONCLUSIONS: Activation of ECs by aPL antibodies in vivo may create a prothrombotic state on ECs, which may be the first pathophysiological event of thrombosis in APS.

Adult↗
PubMed1999

Microcirculatory changes following different temperature washouts in a free flap model.

In spite of the extensive experimental work on vascular washout in free flap surgery, an optimal temperature for the washout solution has not been established. This study was designed to determine the effect of the washout solution temperature on the degree to which the microcirculation is cleared of blood. The cremaster muscle flap in the rat was used, in which the microcirculation can be directly viewed and the presence of blood and perfusion parameters within various vessels can be measured during and after washout. Washout was started with a single, high-pressure infusion and continued at 130 mmHg for 15 minutes. The temperature of the washout solution was either 2-3, 20-22, or 35 degrees C. In all three groups, washout cleared the microcirculation almost completely within the first minute. However, we observed that a cold or room temperature washout cleared the microcirculation more completely than a warm washout did. The temperature of the washout solution did not effect post washout capillary perfusion and/or arterial diameters.

Animals↗
PubMed1999

Late-preconditioning protection is evident in the microcirculation of denervated skeletal muscle.

We investigated whether ischemic preconditioning induces microvascular protection in skeletal muscle at the late phase (after 24 hours) when the same muscles are subjected to prolonged warm global ischemia. The cremaster muscle of the male Sprague-Dawley rat underwent vascular isolation and was subjected to 4 hours of ischemia and 60 minutes of reperfusion. Early preconditioning consisted of 45 minutes of ischemia followed by 15 minutes of reperfusion before prolonged ischemia/reperfusion; late preconditioning also consisted of 45 minutes of ischemia but was done 24 hours (24-hour period of reperfusion) before the prolonged ischemia/reperfusion. Arteriole diameters and capillary perfusion were measured with use of intravital microscopy. Four groups were compared: rats that underwent early preconditioning, their controls, rats that underwent late preconditioning, and their controls. Early and late preconditioning significantly attenuated vasospasm and capillary no-reflow compared with the controls for each. Average arteriole diameter was significantly larger in the rats that underwent late preconditioning than in any other rats; it was also significantly larger in the controls for late preconditioning than in those for early preconditioning. We introduce a model of the rat cremaster muscle that has been isolated from its vascular supply as a useful preparation to study the effects of late preconditioning on microcirculation in skeletal muscle. Late preconditioning provided better microvascular protection than did early preconditioning. The mechanism for this preconditioning protection is being investigated because it should provide a means for therapeutic intervention.

Animals↗
PubMed1999

Angiogenesis inhibitor TNP-470 inhibits murine cutaneous wound healing.

BACKGROUND: TNP-470 (AGM-1470) is a potent inhibitor of angiogenesis with potential therapeutic applications in neoplastic and angio-proliferative diseases. This study evaluated its effect on cutaneous wound healing in a murine dorsal excisional wound model. MATERIALS AND METHODS: Full-thickness wounds (1.60 cm2) were created on the dorsum of homozygous/hairless mice (7 to 9 weeks). Wound areas were measured on alternate days for 16 days. Experimental groups consisted of (1) TNP-470 administered in doses of 0.05, 0.5, and 5.0 mg/kg on Days 0, 2, and 4 or Days 0 through 6; (2) TNP-470 (5.0 mg/kg) coadministered with minocycline (4.0 and 10 mg/kg) on Days 0, 2, and 4; and (3) TNP-470 (5.0 mg/kg on Days 0, 2, and 4) coadministered with topical basic fibroblast growth factor (bFGF) 1. 0 microg/wound on Days 0, 1, and 2. Hematoxylin and eosin staining was used to compare experimental and control wounds. RESULTS: TNP-470 administration significantly decreased wound healing in a dose-dependent manner versus controls (P <.05). The 5.0 mg/kg concentration yielded the greatest effect by maintaining an average wound area 20.4% greater than controls and a marked delay in wound healing on H&E staining. Alternate-day dosing was as effective as consecutive day administration. Minocycline did not augment the wound healing inhibition of TNP-470. Coadministration of TNP-470 and bFGF eliminated any rate-altering effect of TNP-470 upon wound healing and resulted in wound areas similar to controls. CONCLUSION: Therapy with TNP-470 induces a significant delay in murine cutaneous wound healing. This effect may be exploited for use in situations where wound healing is excessive and debilitating. Topical application of bFGF can overcome TNP-470-induced wound healing inhibition.

Angiogenesis Inhibitors↗
PubMed1999

Leukocyte-endothelium interaction in arterioles after ischemia and reperfusion.

Leukocyte-endothelium interaction in postcapillary venules plays an important role in reperfusion injury, inflammation, shock, and sepsis. This phenomenon is poorly described in precapillary arterioles. In fact, many researchers have reported no evidence of leukocyte adherence in arterioles whatsoever. Most research has focused on venules of larger rodents, in which observation of the microcirculation, especially arterioles, is limited. We have developed a model which provides a clearer view of these microvessels using the mouse cremaster muscle. This muscle has an approximate thickness of 100 microm allowing images produced by transillumination to be very clear. After vascular isolation, the right cremaster muscle was subjected to 4 h of ischemia, followed by 2 h of reperfusion. The left muscle was not rendered ischemic, thereby allowing it to serve as the animal's own internal control. We observed leukocyte rolling in arterioles in both the ischemic and the nonischemic muscles. Leukocyte sticking was seen in arterioles and venules on both sides, except in control arterioles. The number of rolling and sticking leukocytes on the ischemic side was significantly higher than in controls (P < 0.05) for both arterioles and venules. During the reperfusion period, this number did not change significantly. Transmigration of leukocytes was observed only in venules, but not in arterioles. The number of perfused capillaries was reduced on the ischemic side compared to controls and did not change significantly during the 2 h of reperfusion. Our results demonstrate that leukocyte-endothelium interaction occurs in muscle arterioles of mice. This phenomenon is more pronounced after ischemia and reperfusion, i.e., depends on the extent of tissue insult.

Animals↗
PubMed1999

An animal model to study microcirculatory changes associated with vascular delay.

Vascular delay is a surgical procedure that renders a flap partially ischaemic several days prior to its transfer in order to increase its viability after its transfer. Though much debate exists regarding the actual mechanism of vascular delay, most theories agree that changes in the microcirculation play a key role. In this paper, we describe four experiments that establish the ear of the homozygous (hr/hr) hairless mouse as an effective model for directly viewing and measuring delay-induced changes in microcirculation. In our first experiment, we compared mouse ears that were delayed (n = 18) with ones that were not (control) (n = 13) and showed that vascular delay significantly (P < 0.05) reduced ear flap necrosis. In a second experiment, we delayed mouse ears for 2 (n = 9), 4 (n = 14), 6 (n = 10), 8 (n = 10), 10 (n = 10), 20 (n = 18), 40 (n = 10) and 80 (n = 11) days and found that the reduction in necrosis becomes statistically significant (P < 0.05) over non-delayed controls (n = 12) after a minimum delay period of 6 days. In a third experiment, we delayed mouse ears by ligating only the vein (n = 14), only the artery (n = 11), only the nerve (sympathectomy) (n = 14), and vein, artery and nerve (n = 14) of the main neurovascular pedicle and found significant (P < 0.05) reductions in flap necrosis in all groups compared to nondelayed controls (n = 12). Finally, in a fourth experiment, we measured vessel directionality changes in mouse ears that were delayed for 6 (n = 4), 10 (n = 4), 20 (n = 4), 40 (n = 4) and 80 (n = 4) days, and found that directionality changes became significant (P < 0.05) at 6 days of delay and remained so for all the days studied when compared with non-delayed controls (n = 4).

Animals↗
PubMed1999

Estimation of the correlation between nutrient intake measures under restricted sampling.

Food frequency questionnaires (FFQs) are commonly used to assess dietary intake in epidemiologic research. To evaluate the FFQ reliability, the commonly used approach is to estimate the correlation coefficient between the data given in FFQ and those in food records (for example, 4-day food records [4DFR]) for nutrients of interest. However, in a dietary intervention study, a criterion for eligibility may be to select participants who have baseline FFQ-measured dietary intake of percent energy from fat above a prespecified quantity. Other instruments, such as the 4DFR, may be subsequently administrated only to eligible participants. Under these circumstances, analysis without adjusting for the restricted population will usually lead to biased estimation of correlation coefficients and other parameters of interest. In this paper, we apply likelihood-based and multiple imputation (MI) methods to accommodate such incomplete data obtained as a result of the study design. A simulation study is conducted to examine finite sample performance of various estimators. We note that both the MI estimate and the maximum likelihood (ML) estimate based on a bivariate-normal model are not sensitive to departures from this normality assumption. This led us to investigate robustness properties of the ML estimator analytically. We present some data analyses from a dietary assessment study from the Women's Health Initiative to illustrate the methods.

Biometry↗
PubMed1999

Individually randomized intervention trials for disease prevention and control.

It is argued that randomized, controlled trials should fulfil a critical role in the identification of practical approaches to the prevention and control of chronic diseases. Because of the great public health potential of chemopreventive and behavioural approaches to chronic disease prevention there is need for a major interdisciplinary scientific effort aimed at intervention development. Because of the cost and duration of controlled trials to evaluate specific interventions there is a need for well-conducted feasibility, pilot and intermediate outcome trials, to inform and to justify corresponding full-scale trials having clinical disease outcomes. Compared to therapeutic trials, prevention trials need to have a greater emphasis on overall benefit versus risk assessment. Such trials need to be large enough, and of sufficient duration, to yield powerful tests of key hypotheses, and informative benefit versus risk summary statements. These requirements have a range of implications for intervention trial design, conduct, monitoring and reporting, which are reviewed and discussed. The clinical trial component of the ongoing Women's Health Initiative provides illustration throughout this discussion.

Aged↗
PubMed1999

Traditional criteria for observation of splenic trauma should be challenged.

Age less than 55 years, normal Glasgow Coma Score (GCS), and absence of hypotension are traditional criteria for the selection of adult patients with blunt splenic trauma for observation. The objective of this study is to challenge these criteria. Two hundred twelve patients who presented with blunt splenic injury between 1992 and 1997 were identified from the Trauma Registry at our Level I trauma center. The patients were divided into three groups: 100 patients (47%) were observed, 108 (51%) underwent immediate splenorrhaphy or splenectomy, and 4 (2%) failed observation. The three groups were compared by participants' ages, GCSs, and histories of hypotension. No statistical differences were noted between the successfully observed patients and those requiring immediate surgery with respect to these criteria. Of the 4 patients who failed observation, all were younger than 55 years, all had a GCS >12, and all were normotensive. Our findings suggest that traditional criteria used to select patients for splenic trauma observation are not absolute indicators and should be liberalized: patients can be successfully observed despite having criteria that, in the past, would have led to immediate operative intervention.

Blood Pressure↗
PubMed1998

Activation of K-Cl cotransport by mild warming in guinea pig red cells.

Unidirectional, ouabain-insensitive K+ influx rose steeply with warming at temperatures above 37 degreesC in guinea pig erythrocytes incubated in isotonic medium. The only component of ouabain-insensitive K+ influx to show the same steep rise was K-Cl cotransport (Q10 of 10 between 37 and 41 degrees C); Na-K-Cl cotransport remained constant or declined and residual K+ influx in hypertonic medium with ouabain and bumetanide rose only gradually. Similar results were obtained for unidirectional K+ efflux. Thermal activation of K-Cl cotransport-mediated K+ influx was fully dependent on the presence of chloride in the medium; none occurred with nitrate replacing chloride. The increase of K+ influx through K-Cl cotransport from 37 to 41 degrees C was blocked by calyculin A, a phosphatase inhibitor. The Q10 of K-Cl cotransport fully activated by hydroxylamine and hypotonicity was about 2. The time course of K+ entry showed an immediate transition to a higher rate when cells were instantly warmed from 37 to 41 degrees C, but there was a 7-min time lag in returning to a lower rate when cells were cooled from 41 to 37 degrees C. These results indicate that the steepness of the response of K-Cl cotransport to mild warming is due to altered regulation of the transporter. Total unidirectional K+ influx was equal to total unidirectional K+ efflux at 37-45 degrees C, but K+ influx exceeded K+ efflux at 41 degrees C when K-Cl cotransport was inhibited by calyculin or prevented by hypertonic incubation. The net loss of K+ that results from the thermal activation of isosomotic K-Cl cotransport reported here would offset a tendency for cell swelling that could arise with warming through an imbalance of pump and leak for Na+ or for K+.

Animals↗