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Biomedical subjects

D S Wilson

Publications and source records attributed to D S Wilson.

At least 37 records · Page 2Linked to original sources
PubMed1995

Left ventricular function after extended hypothermic preservation of the heart is dependent on functional coronary capillarity.

BACKGROUND: A growing body of knowledge has led to the hypothesis that injury to the microcirculation during hypothermic myocardial preservation may result in decreased contractility of hearts upon reperfusion. METHODS AND RESULTS: To test this hypothesis, we examined the relationship between no-reflow and left ventricular function after hypothermic cardiac preservation after reperfusion with solutions containing dilute whole blood (DWB) or washed red blood cells (K2RBC). Rat hearts were arrested with high-potassium cardioplegia, then flushed and stored for 6 hours in low-potassium cardioplegia at 4 degrees C. Hearts were reperfused at a constant flow rate (4 mL/min) with K2RBC for 60 minutes (group 1, n = 5) or DWB for 7 minutes followed by 53 minutes of K2RBC (group 2, n = 5). Left ventricular developed pressure (LVDP) was measured with an intraventricular balloon. Immediately after functional assessment, hearts were perfused with an india ink solution to mark flow, then glutaraldehyde. Morphometric techniques were used to determine the degree of capillary compression [delta d(c)], perfused capillary number per fiber area [QA(0)P], and perfused capillary surface area per fiber volume [Sv(c,f)P]. Capillaries were moderately compressed in both groups after reperfusion (group 1, 19 +/- 1%; group 2, 20 +/- 1%). QA(0)P and Sv(c,f)P were highly correlated with delta d(c) in hearts reperfused with K2RBC (r = .92 and r = .92; P < .01). Although statistically significant, the correlation was not as strong in DWB-reperfused hearts (r = .66 and r = .67; P < .05). LVDP was correlated to QA(0)P and Sv(c,f)P (r = .86 and r = .87, respectively) for groups 1 and 2. CONCLUSIONS: The weaker correlation between capillary perfusion and capillary compression in DWB-reperfused hearts suggests that factors other than compression contribute to no-reflow after hypothermic preservation. Regardless of the composition of the reperfusate, recovery of left ventricular function after hypothermic ischemia is directly related to coronary capillary perfusion upon reperfusion.

Animals↗
PubMed1995

High resolution crystal structure of a paired (Pax) class cooperative homeodomain dimer on DNA.

The crystal structure of the paired homeodomain bound to DNA as a cooperative dimer has been determined to 2.0 A resolution. Direct contacts between each homeodomain and the DNA are similar to those described previously. In addition, an extensive network of water molecules mediates contacts between the recognition helix and the DNA major groove. Several symmetrical contacts between the two homeodomains underlie the cooperative interaction, and deformations in the DNA structure are necessary for the establishment of these contacts. Comparison with structures of homeodomains bound monomerically to DNA suggests that the binding of a single paired homeodomain can introduce these DNA distortions, thus preparing a template for the cooperative interaction with a second homeodomain. This study shows how the paired (Pax) class homeodomains have achieved cooperativity in DNA binding without the assistance of other domains, thereby enabling the recognition of target sequences that are long enough to ensure specificity.

Amino Acid Sequence↗
PubMed1995

Homeodomain proteins. Cooperating to be different.

The product of the Drosophila extradenticle gene interacts cooperatively with homeodomain proteins encoded by homeotic selector genes, and may account in part for their distinct regulatory properties.

Animals↗
PubMed1995

Analysis of explanted silicone implants: a report of 300 patients.

Breast implants from 300 consecutive patients during the 35-month period from February 1, 1991 to January 1, 1994 were examined. Of these, 214 (71.3%) patients had disruption (frank rupture or severe silicone bleed or both) of one or both implants. Of the 592 implants removed, 376 (63.5%) had disruption. We found virtually no difference in disruption rates between those patients relating symptoms to their implants and those who did not (71.8% vs. 70.9%). However, disruption was directly related to time since implantation. We observed 103 of 142 patients relating various symptoms to their silicone implants. About half (52) reported improvement after implant removal. We found no direct correlation between disruption and repeated closed capsulotomy. Of 505 implants, 69 of 92 implants having had one or more closed capsulotomies were disrupted (75%). However, 245 of 413 implants never having had a closed capsulotomy also showed disruption (59.3%). We found mammography to be of very limited value in assessing disruption. Our study showed a low 16.2% sensitivity rate. The same was true with magnetic resonance imaging interpretation, especially in the diagnosis of severe silicone bleed. Although our series was quite small, magnetic resonance imaging interpretation was found to be an unreliable tool in our study. A Kaplan-Meier survival curve for mammary implants based on this study has proven very helpful and effective in communicating with patients and has served as a guideline in predicting the presence or absence of implant disruption.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Implants↗
PubMed1995

The initial response of blood leukocytes to incubation with perfluorocarbon blood substitute emulsions.

Due to their enhanced oxygen carrying characteristics, perfluorocarbon emulsions are valuable adjuncts to coronary revascularization procedures. However, the effects of perfluorocarbon emulsions on white blood cell function are unclear. The purpose of this study was to determine the effects of three perfluorocarbon emulsions on the adhesion characteristics of leukocytes. Heparinized blood from donor rats was mixed with either Phosphate Buffered Saline (PBS), PFB-1, PFB-2 (both non-complement activating perflubron emulsions, Alliance Pharmaceutical Corp.) or Fluosol (20% w/v PFC, Alpha Therapeutic) in a ratio of one part emulsion to six parts blood. The blood-emulsion mixtures were incubated for ten minutes at 37 degrees C, then passed down nylon wool leukocyte adhesion columns. Blood samples were counted for: Leukocytes, Granulocytes and Lymphocytes. % Cell Adherence was calculated as: (1-[WBC-out]/[WBC-in]). We found that, compared to PBS control, the granulocyte adherence to the nylon fiber was significantly increased for both Fluosol-20 and PFB-1 (P < 0.05). In contrast, PFB-2 (designed for reduced cell surface activity) caused no significant change in leukocyte adhesion. In fact, a modest decrease in granulocyte adhesion was observed with PFB-2. These findings suggest a direct effect of some, but not all, PFC emulsions on blood leukocyte function.

Animals↗
PubMed1995

Early in reperfusion following myocardial ischemia, leukocyte activation is necessary for venular adhesion but not capillary retention.

OBJECTIVE: The pathobiology of leukocyte sequestration in the coronary microcirculation following ischemia is unclear. We examined the location(s) and persistence of leukocyte sequestration of unactivated and preactivated blood in the coronary microcirculation early during reperfusion following ischemia. METHODS: Isolated rat hearts were subjected to 30 min of 37 degrees C, no-flow ischemia. Hearts were initially reperfused with diluted whole blood containing fluorescent leukocytes (DWB*). At 5, 20, and 35 min of reperfusion (R), the deposition of leukocytes in the coronary capillaries and venules was observed directly using intravital fluorescence microscopy. Four groups were studied: a nonischemic control group (Gr I), and postischemic groups reperfused with DWB* treated with vehicle (Gr II) or preactivated with 10(-8) M N-formylmethionyl-leucyl-phenylalanine (fMLP) (Gr III) or 10(-6) M fMLP (Gr IV). RESULTS: At R5, postischemic reperfusion with unactivated blood caused a significant trapping of leukocytes in coronary capillaries (Gr I = 2.2 +/- 0.4 versus Gr II = 5.6 +/- 0.6 leukocytes per capillary field, P < 0.05). Hearts in Gr IV exhibited significantly greater leukocyte retention in capillaries compared to all other groups at R5 (R5, Gr IV = 8.8 leukocytes per capillary field, P < 0.05) and at R35. At R5, although more leukocytes were observed adhered to the venules in Gr II compared to Gr I, the difference was not statistically significant (Gr I = 1.7 +/- 0.7 versus Gr II = 3.4 +/- 0.5 leukocytes per 100 microns venule, P = 0.23). DWB* preactivated with the lower concentration of fMLP (10(-8) M) resulted in a significant increase in venular leukocyte adhesion at R5 compared to Gr I and Gr II (Gr III 6.1 +/- 0.5, P < 0.05). After 35 min of reperfusion, a greater percentage of leukocytes remained in the capillaries than in the venules. CONCLUSIONS: These direct observations suggest that early in reperfusion after ischemia, both leukocyte and endothelial activation are necessary for venular adhesion, but that ischemia-induced coronary microvascular alterations are sufficient to promote leukocyte retention in coronary capillaries. These results also indicate that during 35 min of reperfusion, the degree of leukocyte washout is greater in the venules than in the capillaries. These results suggest that the mechanisms contributing to leukocyte retention early in reperfusion following myocardial ischemia are, indeed, different in the capillaries and venules and that the mechanisms affecting retention in capillaries are more persistent than those in the venules.

Animals↗
PubMed1993

Single- and multiple-dose pharmacokinetics of clarithromycin, a new macrolide antimicrobial.

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were evaluated after single and multiple oral doses of 250 and 500 mg of clarithromycin. Multiple-dose regimens used 12-hour dosing intervals for 7 doses. Plasma and urine concentrations were measured using high-performance liquid chromatography. Appearance of clarithromycin and its metabolite in plasma were rapid, as reflected by mean times to maximum plasma concentration ranging from 1.8 to 2.6 and 1.8 to 2.9 hours, respectively. The rises in clarithromycin peak plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) were disproportionate to increase in dose, suggesting nonlinearity in parent compound pharmacokinetics. Clarithromycin terminal disposition half-life (t1/2) also exhibited dose dependency, ranging from harmonic means of 2.7 to 4.8 hours. In contrast, based on Cmax AUC, and predicted/observed accumulation ratios, nonlinearity in metabolite pharmacokinetics was not observed. Plasma accumulation of metabolite occurred to a much lesser degree than that of the parent compound despite a substantially longer t1/2 for the metabolite (metabolite accumulation ratios based on AUC dose 7/AUC dose 1:250-mg regimen = 1.03 +/- 0.33, 500-mg regimen = 0.81 +/- 0.29, parent accumulation ratios: 250-mg regimen = 1.64 +/- 0.47, 500-mg regimen = 1.65 +/- 0.69). This would suggest that formation of this metabolite is capacity-limited and that this may in part account for the nonlinearity observed in clarithromycin pharmacokinetics. Urinary excretion constituted a relatively important route of elimination of clarithromycin, with renal clearance accounting for 17 to 31% of apparent total body clearance.

Administration, Oral↗
PubMed1993

Binding of plasma selenoprotein P to cell membranes.

Competitive binding assays were performed to determine the amount of binding of 75Se-labeled plasma selenoprotein P (PSP) to membranes from different rat tissues at physiologic pH. 75Se PSP for use as a ligand in the binding assays was labeled in vivo by injecting rats with 75Se selenious acid. PSP was obtained from plasma by salt precipitation and affinity and ion-exchange chromatography. Membranes for receptor assays were prepared from liver, kidney, testes, and brain of rats fed diets with either 0.01, 0.1, or 2 ppm selenium. At pH 7.4 PSP was bound differentially to tissues in the following order: brain > kidney > testes > liver. Specific binding of PSP to tissue membranes from rats fed the different levels of selenium increased with increasing amounts of dietary selenium. Saturation assays indicated apparent saturation of membrane receptors by the 75Se-labeled PSP. Another significant new finding was a 134-kDa complex of PSP and membrane receptor, identified by gel-filtration chromatography of cross-linked samples from binding assays. This provides evidence for a membrane receptor for PSP in rat tissues.

Animals↗
PubMed1992

Drug-food interaction potential of clarithromycin, a new macrolide antimicrobial.

To evaluate the effect of food on bioavailability, clarithromycin and 14-hydroxyclarithromycin (active metabolite) pharmacokinetics were assessed in 26 healthy adult volunteers after ingestion of a single oral 500-mg dose of clarithromycin in a fasting state (2 hours before breakfast after an overnight fast) and a nonfasting state (0.5 hours after the start of breakfast). Clarithromycin and 14-hydroxy metabolite plasma concentrations were measured using a high-performance liquid chromatographic technique. Food intake immediately before dosing increased the extent of absorption from the 500-mg tablet formulation by approximately 25%. The mean increase in metabolite area under the plasma concentration-time curve was approximately 9%. These results suggest that clarithromycin can be taken without regard to timing in relation to meals.

Absorption↗
PubMed1992

Clarithromycin pharmacokinetics in healthy young and elderly volunteers.

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 +/- 97 versus 476 +/- 112 mL/min, respectively) and renal clearance (CLR) (84 +/- 31 versus 168 +/- 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.

Administration, Oral↗
PubMed1992

Identification of preventable trauma deaths: confounded inquiries?

The published evaluation of methods for identifying preventable trauma deaths contains many unstudied confounding factors. To investigate the reliability of methods for identifying such preventable deaths, we compared three consensus systems using separate five-member general review panels assessing 20 non-central nervous system fatalities: panel A, independent judgments; panel B, discussion of all cases preceding individual judgments; and panel C, independent judgments followed by discussion and equivocal case reassignment. The Kappa concordance index was low for all methods (method A, 0.20; methods B and C, 0.40). Of the 11 deaths judged preventable by at least one panel, only one death was judged preventable by all three panels. Consensus agreement (four of five assessors) was 20% for panel A, 45% for panel B, and 10% for panel C (difference between panels B and C, p less than 0.03). In panel C, discussion affected the rate of equivocal case designation from 30% to 5%. Thus different consensus methods yielded different results. We conclude that individual case review can be severely flawed and therefore should not be used to measure institutional quality of patient care. We recommend that assessment of institutional performance should be based on objective evaluation methods, which require the study of patient population outcomes, rather than on subjective methods in which individual cases are reviewed.

Confounding Factors, Epidemiologic↗
PubMed1992

Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses.

The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean +/- standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67 +/- 0.48 to 3.72 +/- 1.26 mg/liter.h per 100-mg dose over the 100- to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.8% of the administered dose, respectively. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of clarithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.

Administration, Oral↗
PubMed1991

Ubiquinone protects against loss of tocopherol in rat liver microsomes and mitochondrial membranes.

Liver microsomes and submitochondrial particles (SMP) were isolated from rats fed on a vitamin E or coenzyme Q10/vitamin E enriched diet in order to clarify the antioxidant interactions between coenzyme Q10 and vitamin E. Electron spin resonance spectrometry shows that the decay of vitamin E radicals (tocopheroxy radicals) generated by the arachidonic acid/lipoxygenase oxidation system proceeded at a higher rate in vitamin E enriched microsomes and SMP than in those enriched with coenzyme Q10/vitamin E. Vitamin E levels determined by high performance liquid chromatography revealed that when subjected to enzymatic oxidation, membranes enriched with vitamin E alone were depleted of vitamin E earlier than those enriched with both coenzyme Q10 and vitamin E. These results show that coenzyme Q10 conserves vitamin E, which would help prolong membrane resistance against oxidative damage.

Animals↗
PubMed1989

Mitochondrial electron transport-linked tocopheroxyl radical reduction.

alpha-Tocopherol (vitamin E) is a lipophilic chain-breaking antioxidant which inhibits lipid peroxidation in isolated mitochondrial membranes and protects membranes from oxidative damage. The primary oxidation product of vitamin E is the tocopheroxyl radical. Reduction of the tocopheroxyl radical can occur by reactions with water-soluble anti-oxidants such as ascorbate or glutathione, resulting in the recycling of vitamin E. Physiological concentrations of vitamin E are too low to allow detection of tocopheroxyl radical by ESR. After dietary supplementation with vitamin E, a 10-20-fold increase in the rat liver mitochondrial membrane content of vitamin E was achieved and this allowed for direct detection of the tocopheroxyl radical by ESR, after treatment with an oxidizing system composed of lipoxygenase and arachidonic acid. By using submitochondrial particle membranes, it was shown that NADH, succinate, and reduced cytochrome c-linked oxidation reduce the tocopheroxyl radical, preventing both accumulation of the radical and vitamin E consumption. As the electron transport chain can reduce tocopheroxyl radical it may have an important physiological role in recycling vitamin E.

Animals↗
PubMed1989

Reviving the superorganism.

Individuals become functionally organized to survive and reproduce in their environments by the process of natural selection. The question of whether larger units such as groups and communities can possess similar properties of functional organization, and therefore be regarded as "superorganisms", has a long history in biological thought. Modern evolutionary biology has rejected the concept of superorganisms, explaining virtually all adaptations at the individual or gene level. We criticize the modern literature on three counts. First, individual selection in its strong form is founded on a logical contradiction, in which genes-in-individuals are treated differently than individuals-in-groups or species-in-communities. Imposing consistency clearly shows that groups and communities can be organisms in the same sense that individuals are. Furthermore, superorganisms are more than just a theoretical possibility and actually exist in nature. Second, the view that genes are the "ultimate" unit of selection is irrelevant to the question of functional organization. Third, modern evolutionary biology includes numerous conceptual frameworks for analyzing evolution in structured populations. These frameworks should be regarded as different ways of analyzing a common process which, to be correct, must converge on the same conclusions. Unfortunately, evolutionists frequently regard them as competing theories that invoke different mechanisms, such that if one is "right" the others must be "wrong". The problem of multiple frameworks is aggravated by the fact that major terms, such as "units of selection", are defined differently within each framework, yet many evolutionists who use one framework to argue against another assume shared meanings. We suggest that focusing on the concept of organism will help dispell this fog of semantic confusion, allowing all frameworks to converge on the same conclusions regarding units of functional organization.

Animals↗
PubMed1989

Repletion of folate-depleted rats with an amino acid-based diet supplemented with folic acid.

Folate depletion and repletion protocols are not well standardized. Weanling rats were moderately depleted of folate in 28 d with a folate-free purified diet based on 17% amino acids as the nitrogen source. They were then folate repleted for 23 d with the amino acid diet supplemented with either 125, 250, 500, 1000 or 2000 micrograms folic acid/kg. Hematology, growth and tissue folate levels were measured in subsets of the rats when they were 24 (baseline), 52 (depleted) and 75 d old (repleted). The same measurements were made in control rats that had been fed 2 mg folic acid/kg of the amino acid diet for the same period of time. Our findings show that with repletion, growth of previously depleted rats is in direct proportion with the level of supplementation up to 1000 micrograms folic acid/kg diet. Serum folate levels of repleted rats also increased in proportion to supplementation between 500 to 2000 micrograms/kg diet, and liver folate levels increased proportionally with the level of supplement within the range of 125 to 2000 micrograms/kg diet. The 2000 micrograms/kg supplement was sufficient to restore liver folate levels equivalent to that of controls, but body weight and serum folate levels failed to catch up with that of controls in the 23-d repletion period. There was a nonlinear relationship between serum and liver folate levels: serum folate remained constant at about 6 micrograms/l as liver folate increased to about 7 micrograms/g, then serum folate diverged by increasing to 120 micrograms/l with only minor increases in liver folate.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1989

Impairment of enzymic and nonenzymic antioxidants in skin by UVB irradiation.

Antioxidants may play a significant role in ameliorating or preventing photobiologic damage in skin that could lead to cutaneous disorders such as cancer and premature aging. The objective of this study was to assess the acute cutaneous enzymic and nonenzymic antioxidant response to a single exposure of large fluence (300 mJ/cm2) ultraviolet radiation (greater than 280 nm) in hairless mice. This treatment caused an immediate and statistically significant inhibition of glutathione reductase and catalase activity. Glutathione peroxidase and superoxide dismutase were not affected. Glutathione levels decreased and, conversely glutathione disulfide concentrations increased. A slight depletion of the total glutathione was observed, while the content of total ascorbic acid did not change. The lipophilic antioxidants alpha-tocopherol, ubiquinol 9 and ubiquinone 9 also decreased significantly, and the concentration of malondialdehyde remained constant. The free radical scavenging activity of epidermis, as assessed by reduction of the stable, cationic nitroxide radical [2,2,6,6-tetramethyl-1-piperidinoxy-4-(2',4',6'-trimethyl) methylpyridinium perchlorate] was considerably inhibited. The study indicates that immediately after exposure to a large fluence of ultraviolet radiation the enzymic and nonenzymic antioxidant capacity of skin decreases significantly.

Animals↗