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Biomedical subjects

G T Shires

Publications and source records attributed to G T Shires.

At least 37 records · Page 2Linked to original sources
PubMed1993

Thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) as a 23Na shift reagent for the in vivo rat liver.

The use of thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate (TmDOTP5-) as an in vivo 23Na NMR shift reagent for rat liver was evaluated by collecting interleaved 23Na and 31P spectra. Infusion of 80 mM TmDOTP5- without added Ca2+ produced baseline-resolved peaks from intra- and extracellular sodium without producing any changes in phosphate metabolite resonances or intracellular pH. Several key physiological parameters measured in parallel groups of animals confirmed that liver physiology is largely unaffected by this shift reagent. A direct comparison of TmDOTP5- versus DyTTHA3- showed that after infusion of 5-8 times more DyTTHA3-, the extracellular sodium peak shifted by the same amount as with TmDOTP5-, but the two 23Na resonances were very broad and not resolved. The baseline-resolved peaks with TmDOTP5- allowed us to measure the in vivo T1 and T2 relaxation characteristics of intra- and extracellular Na+. The measured T1, T2s, and T2f values and the relative contributions from the slow and fast T2 components for intracellular Na+ in liver did not differ significantly from the values reported for perfused frog heart. The T1 and T2 relaxation curves of the extracellular Na+ resonances fit a monoexponential function. Analysis of the relative contribution of the fast- and slow-relaxing T2 components from intracellular Na+ resulted in a calculated visibility factor of 69 +/- 4% and the intracellular Na+ concentration calculated from the NMR peak intensity ratio, the measured visibility factor, and literature values of intra- and extracellular volume was 19 mM. These results indicate that TmDOTP5- promises to be quite useful as an in vivo shift reagent for liver and other organs.

Animals↗
PubMed1993

The effects of isotonic saline volume resuscitation in uncontrolled hemorrhage.

In the present study, the effects of early isotonic fluid resuscitation on uncontrolled hemorrhage in rats under pentobarbital anesthesia were assessed. Forty-five female Sprague-Dawley rats, weighing between 230 and 295 grams, were anesthetized and cannulated. Uncontrolled hemorrhage was initiated by a 75 percent tail resection, and the rats were randomly divided into three groups: group 1, no resuscitation; groups 2 and 3, saline solution administration over a four minute interval (40 and 80 milliliters per kilogram, respectively), 15 minutes after the initial hemorrhage. Changes in blood pressure, blood loss and mortality rates were recorded and the rats were observed for up to 360 minutes. The mortality rates were 73, 40 and 53 percent for groups 1, 2 and 3, respectively. The corresponding average survival times for these groups were 135, 195 and 178 minutes. The difference between groups 1 and 2 were above the 95 percent confidence level using the chi-square test (mortality) and the Student's t test. The average total blood loss in groups 2 and 3 was 31.7 and 41.4 milliliters per kilogram of body weight; when compared with group 1 (24.6 milliliters per kilogram), the difference between the two latter groups (1 and 3) was statistically significant with a p < 0.001. These results suggest that early infusion of isotonic fluid improves survival time and reduces short term mortality in uncontrolled hemorrhage regardless of the associated increases in blood loss.

Animals↗
PubMed1992

Macrophage inflammatory protein 1 modulates macrophage function.

Macrophage inflammatory protein 1 (MIP 1), initially purified from the conditioned medium of endotoxin-stimulated macrophages, is a low m.w. heparin-binding protein doublet comprising two peptides, MIP 1 alpha and MIP 1 beta. Although native doublet MIP 1 has previously been shown to exert pyrogenic, mitogenic, and proinflammatory effects on other cell types, its actions on its cell of origin, the macrophage, have not been well catalogued. Our study reports several aspects of macrophage function that are modulated by MIP 1. MIP 1 was not directly cytotoxic for WEHI tumor cells, but MIP 1-treated macrophage exhibited enhanced antibody-independent macrophage cytotoxicity for tumor targets. MIP 1 treatment stimulated proliferation of mature tissue macrophages, and this effect was enhanced upon costimulations with either CSF-1 or granulocyte-macrophage-CSF. Thioglycollate-elicited peritoneal exudate macrophages incubated with native doublet MIP 1-secreted bioactive TNF and IL-6, as well as immunoreactive IL-1 alpha, and these effects were enhanced significantly when the cells were costimulated with IFN-gamma. Purified preparations of the recombinantly derived MIP 1 alpha peptide alone stimulated the secretion of TNF, IL-1 alpha, and IL-6 by peritoneal macrophages, but MIP 1 beta did not. In fact, as little as eightfold excess MIP 1 beta blocked TNF-induction by MIP 1 alpha to a significant degree. By contrast to these apparent "macrophage activating" properties of MIP 1, the cytokine failed to trigger the macrophage oxidative burst, or to up-regulate the expression of Ia on the macrophage surface. Taken together, these data reveal that MIP 1 peptides act as autocrine modulators of their cells of origin, and raise the possibility that MIP 1 peptides may play a role in modulating macrophage responses to inflammatory stimuli in vivo.

Animals↗
PubMed1992

Effect of cyclosporine on adrenocortical response to injury and infection.

The effects of cyclosporine administration on the adrenocortical response to the severe stress of burn wound sepsis were studied in Wistar rats. Animals were treated with cyclosporine (10 mg/kg/day) or saline by gavage for 10 days, then subjected to 30% scald burns with wound inoculation with Pseudomonas. Animals were sacrificed on Postburn Days (PBDs) 1, 4, and 7 for determination of serum corticosterone and ACTH levels and adrenal weights and histology. Adrenal glands from animals sacrificed on PBD 7 were also analyzed for DNA, RNA, and protein content. Cyclosporine treatment without injury had no significant effect on body weight gain, adrenal mass, or baseline ACTH or corticosterone levels. During sepsis, cyclosporine-treated animals demonstrated a significantly diminished adrenocortical response compared to those given only saline. Serum corticosterone levels in the cyclosporine group were 45, 53, and 62% lower on PBDs 1, 4, and 7, respectively, than in saline-treated controls (P < 0.01 on each day). ACTH levels were 43 and 36% lower in cyclosporine-treated animals on PBDs 4 and 7, respectively, compared to the saline-treated group (P < 0.05 on each day). Adrenal hyperplasia occurred in both groups by PBD 7, but increases in adrenal mass and in histologic changes associated with hyperplasia (lipid depletion, vascular dilation) were less pronounced in cyclosporine-treated animals compared to those receiving saline, while adrenal composition remained similar between the two groups. Thus, cyclosporine administration is associated with an attenuated adrenocortical response to the stress of sepsis due to diminished circulating levels of ACTH.

Adrenal Cortex↗
PubMed1992

Hypothermia relieves oxidative stress in reperfused skeletal muscle following partial ischemia.

The impact of hypothermia on reperfusion-associated oxidative stress in postischemic skeletal muscle was evaluated in a small animal model of high-grade partial ischemia. The infrarenal aorta of heparinized Sprague-Dawley rats was clamped for 90 min, declamped, and then reperfused for 60 min. Previous characterization of this model with 51Cr-tagged microspheres revealed that hindlimb perfusion during aortic clamping continued at 16.6% of baseline values. Resting transmembrane potential difference (Em) and tissue malondialdehyde (MDA), lactate and high-energy phosphate content were determined in hindlimb skeletal muscle at baseline, during ischemia, and upon reperfusion. Four experimental groups (N = 7 in each group) were studied: control animals underwent aortic clamping and declamping; hypothermia animals underwent topical cooling of hindlimbs prior to aortic clamping, with muscle temperatures maintained between 5 and 15 degrees C during ischemia; sham animals underwent midline laparotomy only; and hypothermia-sham animals underwent cooling and midline laparotomy only. During ischemia, resting Em (-mV) was significantly depolarized (P < 0.05 versus baseline) in control (74.9 +/- 0.8 from 91.0 +/- 0.1), hypothermia (64.4 +/- 1.1 from 90.9 +/- 0.3), and hypothermia-sham (67.2 +/- 1.4 from 90.9 +/- 0.4) animals. Upon reperfusion, resting Em remained depolarized in control animals (74.7 +/- 1.6), while repolarization occurred in hypothermia (88.8 +/- 1.1) and hypothermia-sham (90.7 +/- 0.3) animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1992

Differential effects of cyclo-oxygenase and thromboxane synthetase inhibition on ventilation-perfusion relationships in acid aspiration-induced acute lung injury.

Cyclo-oxygenase metabolites are important regulators of pulmonary vascular and airway tone and may act to regulate ventilation-perfusion (VA/Q) relationships. Hypoxemia that follows aspiration of gastric acid is associated with increased venous admixture, and plasma levels of thromboxane (TX) B2 and 6-keto-PGF2 alpha are increased after experimental acid-induced acute lung injury. The present study was designed to determine the effects of cyclo-oxygenase metabolites on VA/Q relationships in canine acid aspiration. Eighteen anesthetized dogs received 0.2 mL/kg 0.1 N HCl intratracheally; six were pretreated with ibuprofen (IBU), a cyclo-oxygenase inhibitor, 12.5 mg/kg IV, and six other dogs received OKY-046 (OKY), a TX synthetase inhibitor, 0.5 mg/kg IV. The remaining six animals (ACID) served as controls. Continuous distributions of ventilation and perfusion were evaluated with the multiple inert gas elimination technique. Within 30 minutes, acid injury resulted in significant (p < 0.05) decreases in PaO2 from baseline values by 44.7 +/- 5.4 and 47.6 +/- 4.8 mm Hg in the ACID and OKY groups, respectively. Although decreased, the change in PaO2 of 21.0 +/- 4.8 mm Hg in IBU animals was significantly (p < 0.05) attenuated in comparison with the other groups. Ibuprofen increased pulmonary vascular resistance, attenuated perfusion to shunt and low VA/Q areas, and reduced ventilation to unperfused areas for the first 2 hours after acid injury (all p < 0.05), whereas OKY exacerbated hypoxemia and VA/Q inequality.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Oxygen free radicals affect cardiac and skeletal cell membrane potential during hemorrhagic shock in rats.

Oxygen free radical (OFR) damage of excitable cell membranes (heart and skeletal muscle) during hemorrhagic shock and after resuscitation was studied in control rats and in rats pretreated with superoxide dismutase (SOD) and catalase (CAT; 6,000 U each) before hemorrhage. Their mean arterial pressure (MAP) was lowered to and maintained at 45 mmHg until 30% of the shed blood was spontaneously reinfused. The remaining blood and twice that volume of lactated Ringer solution were then infused. Cardiac output and organ blood flow were measured by the microsphere technique. The resting membrane potential (Em) and tissue ATP content in the heart and skeletal muscle were determined. There was no significant difference between the control and SOD + CAT groups in shock duration, maximal shed blood, hemodynamics, regional blood flow, or in ATP content in both heart and skeletal muscle, both during shock and after resuscitation. Radical scavenger treatment did not prevent muscle depolarization during shock. After resuscitation, however, significant repolarization in hearts and skeletal muscle of the SOD + CAT group (heart, -70.0 +/- 1.1; muscle, -87.0 +/- 0.6 mV) was noted when compared with the controls (heart, -62.5 +/- 1.2; muscle, -82.7 +/- 1.1 mV; P less than 0.05). This implicates OFRs as mediators of excitable cell membrane injury following resuscitation.

Adaptation, Physiological↗
PubMed1992

Donor leukocyte migration following extremity transplantation in an experimental model.

In an effort to further define the immunologic mechanisms leading to acute composite-tissue allograft rejection, the migratory patterns of donor leukocytes were evaluated. Using a rat model, 52 orthotopic vascularized hindlimb transplants were performed in strains representing major histocompatibility mismatches. In order to evaluate the effect of allogeneic skin on limb rejection, all donor skin was removed in a second group of allografts. Recipient lymphoid organs were examined during the week following transplantation for antigen-presenting cells using a donor-specific class II monoclonal antibody. Donor leukocytes, with dendritic cell morphology, were identified in recipient spleen and lymph nodes draining the allograft. Significantly higher numbers of donor leukocytes were present during postoperative days 1 through 4 for both groups. Association of these important passenger leukocytes with host T-lymphocytes may represent the site of initiation of the immune response.

Animals↗
PubMed1992

Effect of sepsis on intracellular sodium activity, sodium concentration, and water content in thermal injured rat.

The effects of sepsis on intracellular Na+ activity, Na+ concentration, and H2O partition in skeletal muscle were investigated in a burn rat model. Studies were performed on either postburn day 3 or day 7 during evolving burn wound sepsis. Data are compared among 3 groups of rats: burned and infected (BI), burned not infected (B), and sham burn (C). After 3 days postburn both Na+ activity and concentration decreased in the BI group as compared with B and C groups. By postburn day 7, the BI group developed septic shock and had increased intracellular Na+ activity and concentration. The resting membrane potentials of skeletal muscle cells depolarized. The finding of an increased cell membrane relative permeability of Na+ to K+ could account for the increase in Na+ influx into cells. In addition, intracellular and total muscle H2O contents decreased and extracellular H2O increased. Hypernatremia, hyperchloremia, and hyperosmolality were also observed in the BI group. However, the fact that there was no significant difference between B and C groups indicates that the late derangements were due to septic shock rather than simple burn injury. Thus, the deleterious effects of the evolving burn wound sepsis on Na+ homeostasis might be due to the detrimental effect of increased intracellular Na+ activity on mitochondrial respiratory control with subsequent impairment of cellular functions.

Animals↗
PubMed1992

Predicting postoperative pulmonary complications. Is it a real problem?

To identify predictors of postoperative pulmonary complications, a population of 278 patients, mainly hypertensive and diabetic patients undergoing elective general surgery was studied; 60% of the patients underwent abdominal surgery. Of the 278 patients, 6% had postoperative pulmonary complications: 3% had radiographic evidence of infiltrates or segmental atelectasis and 3% had clinical evidence of atelectasis. Among the two thirds of patients undergoing abdominal surgery, only patients with underlying asthma or chronic bronchitis were at increased risk. Generally, patients with better exercise tolerance by self-report, walking distance, or cardiovascular classification had lower rates. Pulmonary function tests did not help to delineate patients at higher risk of postoperative pulmonary complications. Simple clinical information provided as much data about the patients' risk as pulmonary function tests. Many of these complications occurred in patients who sustained other types of postoperative morbidity, suggesting that predicting and preventing postoperative cardiac morbidity may be the best approach to reducing postoperative pulmonary morbidity.

Aged↗
PubMed1991

Pathophysiologic glucocorticoid levels and survival of translocating bacteria.

Burn wound sepsis in rats results in sustained corticosterone elevations and the prolonged presence of translocated bacteria in the mesenteric lymph nodes (MLNs). To determine if survival of bacteria in the MLNs may be influenced by pathophysiologic corticosterone levels, MLNs were quantitatively analyzed from rats randomized to the following groups: burn wound sepsis (BI); BI with adrenocortical response attenuated by cyclosporine (cyclosporine/BI); or cyclosporine/BI with corticosterone replacement (cyclosporine/BI + P). Although rates of bacterial translocation were similar, corticosterone levels were significantly different among the three groups and correlated with the number of lymphocytes and the number of enteric bacteria present per gram of MLN. Thus, pathophysiologic elevations of corticosterone levels during sepsis may exert an effect that allows survival of translocated bacteria in the MLNs of rats, perhaps due to glucocorticoid-associated alterations in regional immunity.

Administration, Cutaneous↗
PubMed1991

Bacterial overgrowth and intestinal atrophy in the etiology of gut barrier failure in the rat.

Bacterial translocation occurs in animal models of shock, trauma, sepsis, and parenteral or elemental enteral alimentation. Bowel atrophy and cecal bacterial overgrowth have both been implicated in the pathophysiology of bacterial translocation in many of these models. To further define the etiology of bacterial translocation resulting from dietary manipulations, rats were fed a elemental/defined-formula diet (DFD) for 2 weeks ad libitum and then randomized to either intestinal decontamination with a nonabsorbable antibiotic (neomycin) or no antibiotic treatment. Neomycin treatment significantly (p less than 0.01) reduced the incidence of bacterial translocation after DFD, in association with a significant reduction in the number of cecal gram-negative bacteria. Neither loss of bowel mass after DFD nor bowel composition was affected by oral neomycin. Bacterial translocation after DFD would thus appear to be the result of cecal bacterial overgrowth rather than a loss of a physical intestinal barrier due to atrophy.

Animals↗
PubMed1991

Diabetes impairs the late inflammatory response to wound healing.

Diabetes mellitus is recognized as a risk factor for compromised wound healing. This study examines leukocyte infiltration and the appearance of tumor necrosis factor-alpha (TNF) and IL-6 in wound chambers implanted in normal and streptozotocin-induced diabetic mice. Perforated silicone wound chambers containing a strip of polyvinyl alcohol sponge were implanted along the flanks of normal and diabetic mice. Wound fluid aspirated from the chambers 1, 3, and 7 days following implantation was analyzed for the total number of leukocytes and TNF and IL-6 levels. While the number of leukocytes in the wound fluid was similar on Days 1 and 3 following implantation, there were significantly fewer inflammatory cells in wound fluid from diabetic animals (13.8 X 10(6)/ml) than in wound fluid from normal animals (28.5 Z 10(6)/ml) on Day 7 following implantation. TNF levels in the cell-free exudate fluid were similar between the two groups on all days examined. IL-6 levels were similar on Days 1 and 3 following implantation between the two groups, but there was significantly more IL-6 in wound fluid from normal animals (10,998 U/ml) than in wound fluid from diabetic animals (2096 U/ml) on Day 7 following implantation. Histologic evaluation of chambers 8 days following implantation revealed decreased neovascularization and less organization of granulation tissue. These data suggest that delayed healing in diabetes is associated with altered leukocyte infiltration and wound fluid IL-6 levels during the late inflammatory phase of wound healing.

Animals↗
PubMed1991

Differential pathophysiology of bacterial translocation after thermal injury and sepsis.

Bacterial translocation (BT) occurs transiently after thermal injury and may result from an ischemic intestinal insult. To evaluate continued intestinal ischemia in the ongoing BT associated with sepsis after injury, rats were randomized to (1) 30% burn injury with Pseudomonas wound infection (BI), (2) BI + fluid resuscitation (BI + Fluid), (3) BI after allopurinol pretreatment to inhibit xanthine oxidase (BI + Allo), or (4) BI after azapropazone pretreatment to inhibit neutrophil degranulation (BI + Aza). On postburn days (PBD) 1, 4, and 7, animals were studied for evidence of BT and intestinal lipid peroxidation. BI + Fluid, BI + Allo, and BI + Aza significantly (p less than 0.05) reduced rates of BT and ileal lipid peroxidation acutely after thermal injury (PBD 1) compared to BI. All four groups had equally high rates of BT associated with the onset of sepsis (PBDs 4 and 7), without evidence of further intestinal lipid peroxidation. These data indicate that the chronic gut barrier failure associated with sepsis after injury occurs independently of continued intestinal ischemia.

Animals↗
PubMed1991

Splanchnic vasoconstriction and bacterial translocation after thermal injury.

Gut barrier failure and bacterial translocation (BT) after thermal injury may result from splanchnic vasoconstriction and intestinal ischemia. The role of the renin-angiotensin system in intestinal blood flow and BT after thermal injury was studied by pretreatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in Wistar rats before sham or 30% scald burn. Adequacy of ACE inhibition was documented by the absence of a hypertensive response to angiotensin I, and intestinal blood flow was determined using 51Cr-labeled microspheres. Small bowel blood flow was decreased by 46% at 4-h postburn (P less than 0.05) in untreated burned animals despite maintenance of normal cardiac index but returned to baseline levels by 24 h after injury. Enalapril pretreatment resulted in maintenance of small bowel blood flow after thermal injury and was associated with a significantly reduced incidence of BT (20% vs. 75% in untreated burned animals, P less than 0.01). These findings further implicate intestinal ischemia in the etiology of gut barrier dysfunction after thermal injury, mediated in part by activation of the renin-angiotensin system.

Animals↗
PubMed1991

Skeletal muscle amino acid and myofibrillar protein mRNA response to thermal injury and infection.

Skeletal muscle changes associated with severe injury were investigated in male Wistar rats subjected to 30% full thickness scald injury (burn) and thermal injury followed by immediate colonization with 10(8) colony-forming units of Pseudomonas aeruginosa (BI). Freely fed animals (FF) and animals pair fed to the BI animals (PF) served as controls. Thermal injury in conjunction with infection produced a rapid and sustained muscle cellular membrane depolarization (transmembrane potential difference at 12 h after injury: FF 92.1 +/- 0.3 and BI 85.2 +/- 2.3 mV; P less than 0.05). This was followed by body weight loss and skeletal muscle protein wasting (gastrocnemius protein at 7 days: FF 0.35 +/- 0.01 and BI 0.16 +/- 0.03 g; P less than 0.05) and intracellular high-energy phosphate depletion (ATP at 10 days: FF 6.6 +/- 0.4 and BI 4.5 +/- 0.4 mumol/g tissue; P less than 0.05). These body and cellular changes were not accounted for by the anorexia alone. Marked alterations in intracellular free amino acids were also noted in the BI group characterized by increases in levels of all amino acids (total intracellular free amino acids at 7 days: FF 51 +/- 7 and BI 91 +/- 12 mM; P less than 0.05) except intracellular glutamine (at 7 days: FF 6.0 +/- 0.2 and BI 2.4 +/- 0.6 mM; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗