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Biomedical subjects

R Christensen

Publications and source records attributed to R Christensen.

At least 37 records · Page 2Linked to original sources
PubMed2000

Bayesian accelerated failure time analysis with application to veterinary epidemiology.

Standard methods for analysing survival data with covariates rely on asymptotic inferences. Bayesian methods can be performed using simple computations and are applicable for any sample size. We propose a practical method for making prior specifications and discuss a complete Bayesian analysis for parametric accelerated failure time regression models. We emphasize inferences for the survival curve rather than regression coefficients. A key feature of the Bayesian framework is that model comparisons for various choices of baseline distribution are easily handled by the calculation of Bayes factors. Such comparisons between non-nested models are difficult in the frequentist setting. We illustrate diagnostic tools and examine the sensitivity of the Bayesian methods.

Abortion, Veterinary↗
PubMed2000

Development of a skin-based metabolic sink for phenylalanine by overexpression of phenylalanine hydroxylase and GTP cyclohydrolase in primary human keratinocytes.

Phenylketonuria, PKU, is caused by deficiency of phenylalanine hydroxylase (PAH) resulting in increased levels of phenylalanine in body fluids. PAH requires the non-protein cofactor BH4 and the rate-limiting step in the synthesis of BH4 is GTP cyclohydrolase I (GTP-CH). Here we show that overexpression of the two enzymes PAH and GTP-CH in primary human keratinocytes leads to high levels of phenylalanine clearance without BH4 supplementation. Integration of multiple PAH and GTP-CH transgenes were achieved after optimized retroviral transduction. Phenylalanine clearance was measured ex vivo in primary human keratinocytes cotransduced with PAH and GTP-CH (more than 370 nmol/24 h/106 cells), a level exceeding that of a human liver cell line (HepG2 cells). Cells overexpressing either one of the enzymes alone did not clear significant amounts of phenylalanine. Transfer of the two genes into the same cell was not necessary, since cocultivation of cells transduced separately with PAH and GTP-CH also resulted in phenylalanine clearance. Thus the experiments indicate metabolic cooperation between cells overexpressing PAH and cells overexpressing GTP-CH, possibly due to intercellular transport of synthesized BH4.

Biopterins↗
PubMed1999

Nodular fasciitis and solitary fibrous tumor of the oral region: tumors of fibroblast heterogeneity.

OBJECTIVE: Fibroblastic proliferations of the oral cavity are extremely varied, yet they share certain features-spindle cell morphology, collagen synthesis, and fasciculation. Nodular fasciitis is a cellular fibroblastic lesion, uncommonly located in the oral submucosa, that shows smooth muscle actin (SMA) immunoreactivity. Solitary fibrous tumor expresses a CD34 fibroblast phenotype. The aim of this study is to report instances of nodular fasciitis and solitary fibrous tumor in the orofacial region and investigate immunohistochemical markers to compare and contrast fibroblastic phenotypic heterogeneity in these tumors. STUDY DESIGN: Seven benign cellular fibrogenic tumors initially diagnosed as nodular fasciitis over a 10-year period were examined. Immunohistochemical markers, including S-100 protein, SMA, CD68, CD34, and vimentin, were used to further characterize these lesions. RESULTS: All tumors occurred in adults, and the buccal mucosa was found to be the favored site. The spindle cells in these tumors showed phenotypic heterogeneity both within and between tumors. All were vimentin-reactive and harbored small populations of CD68-positive macrophage/dendrocytes. Five tumors were SMA-positive and CD34-negative; the tumor in one case was SMA-negative and CD34-positive, and that in another was SMA-positive and CD34-positive. CONCLUSION: Although rare, nodular fasciitis and solitary fibrous tumor arise in oral submucosa, usually in the cheek. The histopathologic features and immunomarkers indicative of myofibroblastic differentiation are seen in nodular fasciitis, whereas solitary fibrous tumor is CD34-positive; however, one instance was found to be positive for both markers. All of these cases harbored subpopulations of CD68-positive cells. Immunomarkers are a valuable adjunct in differentiating nodular fasciitis from solitary fibrous tumor, yet some tumors may harbor heterogeneous fibroblast phenotypes.

Actins↗
PubMed1999

Screening methods for thyroid hormone disruptors.

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.

Animals↗
PubMed1998

Tissue heat content and distribution during and after cardiopulmonary bypass at 31 degrees C and 27 degrees C.

BACKGROUND: Afterdrop following cardiopulmonary bypass results from redistribution of body heat to inadequately warmed peripheral tissues. However, the distribution of heat between the thermal compartments and the extent to which core-to-peripheral redistribution contributes to post-bypass hypothermia remains unknown. METHODS: Patients were cooled during cardiopulmonary bypass to nasopharyngeal temperatures near 31 degrees C (n=8) or 27 degrees C (n=8) and subsequently rewarmed by the bypass heat exchanger to approximately 37.5 degrees C. A nasopharyngeal probe evaluated core (trunk and head) temperature and heat content. Peripheral compartment (arm and leg) temperature and heat content were estimated using fourth-order regressions and integration over volume from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. RESULTS: In the 31 degrees C group, the average peripheral tissue temperature decreased to 31.9+/-1.4 degrees C (means+/-SD) and subsequently increased to 34+/-1.4 degrees C at the end of bypass. The core-to-peripheral tissue temperature gradient was 3.5+/-1.8 degrees C at the end of rewarming, and the afterdrop was 1.5+/-0.4 degrees C. Total body heat content decreased 231+/-93 kcal. During pump rewarming, the peripheral heat content increased to 7+/-27 kcal below precooling values, whereas the core heat content increased to 94+/-33 kcal above precooling values. Body heat content at the end of rewarming was thus 87+/-42 kcal more than at the onset of cooling. In the 27 degrees C group, the average peripheral tissue temperature decreased to a minimum of 29.8 +/-1.7 degrees C and subsequently increased to 32.8+/-2.1 degrees C at the end of bypass. The core-to-peripheral tissue temperature gradient was 4.6+/-1.9 degrees C at the end of rewarming, and the afterdrop was 2.3+/-0.9 degrees C. Total body heat content decreased 419+/-49 kcal. During pump rewarming, core heat content increased to 66+/-23 kcal above precooling values, whereas peripheral heat content remained 70+/-42 kcal below precooling values. Body heat content at the end of rewarming was thus 4+/-52 kcal less than at the onset of cooling. CONCLUSIONS: Peripheral tissues failed to fully rewarm by the end of bypass in the patients in the 27 degrees C group, and the afterdrop was 2.3+/-0.9 degrees C. Peripheral tissues rewarmed better in the patients in the 31 degrees C group, and the afterdrop was only 1.5+/-0.4 degrees C.

Adult↗
PubMed1997

Isoflurane produces marked and nonlinear decreases in the vasoconstriction and shivering thresholds.

In summary, we present a new model for evaluating thermoregulatory effects of drug administration, pregnancy, illness, etc. Specifically, we experimentally manipulated both skin and core temperatures, and subsequently compensated for the changes in skin temperature using the relationships between skin and core contributions to thermoregulatory control. We thus were able to report our results for warm- and cold-responses in terms of calculated core-temperature thresholds at a single designated skin temperature. Advantages of this model include its being nearly noninvasive and requiring relatively little core temperature manipulation. Using this technique, we have shown that the shape and magnitude of thermoregulatory impairment produced by various anesthetic drugs differs. Propofol linearly increases the sweating threshold and linearly decreases the vasoconstriction and shivering threshold. In contrast, volatile anesthetics produce a nonlinear reduction in the major cold-response thresholds, reducing the vasoconstriction and shivering thresholds disproportionately at higher anesthetic concentrations. Midazolam not only produces a different magnitude of thermoregulatory impairment, but also a novel pattern of threshold changes. Anesthetic-induced thermoregulatory impairment thus depends both on anesthetic type and dose.

Anesthetics, Inhalation↗
PubMed1997

The effect of opioids on thermoregulatory responses in humans and the special antishivering action of meperidine.

In summary, both mu-receptor and combined mu/kappa-receptor opioids impair thermoregulatory control. Alfentanil, a pure mu-receptor agonist slightly increased the thresholds for sweating and markedly decreased the thresholds for vasoconstriction and shivering. However, the vasoconstriction-to-shivering range remained normal during alfentanil administration as it does during general anesthesia. Meperidine, a combined mu- and kappa-receptor agonist, also slightly increased the threshold for sweating and reduced the thresholds for vasoconstriction. However, meperidine reduced the shivering threshold twice as much as the vasoconstriction threshold, thus significantly increasing the vasoconstriction-to-shivering range. Furthermore, shivering during meperidine administration, once triggered, was of low intensity suggesting that the drug also decreased the gain of shivering. The special antishivering action of meperidine appears to result, at least in part, from its kappa-receptor activity.

Alfentanil↗
PubMed1997

Thermoregulatory vasoconstriction does not impede core warming during cutaneous heating.

Recent studies evaluating perioperative cutaneous-to-core heat transfer indicate that: Thermoregulatory vasoconstriction prevents further core cooling in anesthetized subjects during mild cooling. Thermoregulatory vasoconstriction only slightly decreases core cooling rates in anesthetized subjects during vigorous cooling. Thermoregulatory vasoconstriction does not impair vigorous core rewarming during anesthesia. Vigorous postanesthetic cutaneous warming increases core temperature much faster than passive insulation. Under conditions of mild thermal stress, thermoregulatory vasoconstriction is thus able to protect core temperature by reducing cutaneous heat transfer and functionally isolating the peripheral and core thermal compartment. Consequently, anesthetic-induced alterations in vasomotor tone is one of the major factors influencing core temperature in patients who are not actively cooled or warmed. In contrast, thermoregulatory tone is insufficient to prevent core temperature perturbations in patients undergoing vigorous cutaneous cooling or warming.

Body Temperature Regulation↗
PubMed1997

Postanesthetic vasoconstriction slows peripheral-to-core transfer of cutaneous heat, thereby isolating the core thermal compartment.

UNLABELLED: Forced-air warming during anesthesia increases core temperature comparably with and without thermoregulatory vasoconstriction. In contrast, postoperative forced-air warming may be no more effective than passive insulation. Nonthermoregulatory anesthesia-induced vasodilation may thus influence heat transfer. We compared postanesthetic core rewarming rates in volunteers given cotton blankets or forced air. Additionally, we compared increases in peripheral and core heat contents in the postanesthetic period with data previously acquired during anesthesia to determine how much vasomotion alters intercompartmental heat transfer. Six men were anesthetized and cooled passively until their core temperatures reached 34 degrees C. Anesthesia was then discontinued, and shivering was prevented by giving meperidine. On one day, the volunteers were covered with warmed blankets for 2 h; on the other, volunteers were warmed with forced air. Peripheral tissue heat contents were determined from intramuscular and skin thermocouples. Predicted changes in core temperature were calculated assuming that increases in body heat content were evenly distributed. Predicted changes were thus those that would be expected if vasomotor activity did not impair peripheral-to-core transfer of applied heat. These results were compared with those obtained previously in a similar study of anesthetized volunteers. Body heat content increased 159 +/- 35 kcal (mean +/- SD) more during forced-air than during blanket warming (P < 0.001). Both peripheral and core temperatures increased significantly faster during active warming: 3.3 +/- 0.7 degrees C and 1.1 +/- 0.4 degrees C, respectively. Nonetheless, predicted core temperature increase during forced-air warming exceeded the actual temperature increase by 0.8 +/- 0.3 degree C (P < 0.001). Vasoconstriction thus isolated core tissues from heat applied to the periphery, with the result that core heat content increased 32 +/- 12 kcal less than expected after 2 h of forced-air warming (P < 0.001). In contrast, predicted and actual core temperatures differed only slightly in the anesthetized volunteers previously studied. In contrast to four previous studies, our results indicate that forced-air warming increases core temperature faster than warm blankets. Postanesthetic vasoconstriction nonetheless impeded peripheral-to-core heat transfer, with the result that core temperatures in the two groups differed less than might be expected based on systemic heat balance estimates. IMPLICATIONS: Comparing intercompartmental heat flow in our previous and current studies suggests that anesthetic-induced vasodilation influences intercompartmental heat transfer and distribution of body heat more than thermoregulatory shunt vasomotion.

Adult↗
PubMed1997

Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold.

BACKGROUND: Meperidine administration is a more effective treatment for shivering than equianalgesic doses of other opioids. However, it remains unknown whether meperidine also profoundly impairs other thermoregulatory responses, such as sweating or vasoconstriction. Proportional inhibition of vasoconstriction and shivering suggests that the drug acts much like alfentanil and anesthetics but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition would imply a special antishivering mechanism. Accordingly, the authors tested the hypothesis that meperidine administration produces a far greater concentration-dependent reduction in the shivering than vasoconstriction threshold. METHODS: Nine volunteers were each studied on three days: 1) control (no opioid); 2) a target total plasma meperidine concentration of 0.6 microgram/ml (40 mg/h); and 3) a target concentration of 1.8 micrograms/ml (120 mg/h). Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core-temperature thresholds (at a designated skin temperature of 34 degrees C) were computed using established linear cutaneous contributions to control sweating (10%) and vasoconstriction and shivering (20%). The dose-dependent effects of unbound meperidine on thermoregulatory response thresholds was then determined using linear regression. Results are presented as means +/- SDs. RESULTS: The unbound meperidine fraction was approximately 35%. Meperidine administration slightly increased the sweating threshold (0.5 +/- 0.8 degree C.microgram-1.ml; r2 = 0.51 +/- 0.37) and markedly decreased the vasoconstriction threshold (-3.3 +/- 1.5 degrees C.microgram-1.ml; r2 = 0.92 +/- 0.08). However, meperidine reduced the shivering threshold nearly twice as much as the vasoconstriction threshold (-6.1 +/- 3.0 degrees C.microgram-1.ml; r2 = 0.97 +/- 0.05; P = 0.001). CONCLUSIONS: The special antishivering efficacy of meperidine results at least in part from an uncharacteristically large reduction in the shivering threshold rather than from exaggerated generalized thermoregulatory inhibition. This pattern of thermoregulatory impairment differs from that produced by alfentanil, clonidine, propofol, and the volatile anesthetics, all which reduce the vasoconstriction and shivering thresholds comparably.

Alfentanil↗
PubMed1997

Efficacy of intraoperative cooling methods.

BACKGROUND: Patients may require perioperative cooling for a variety of reasons including treatment of a malignant hyperthermia crisis and induction of therapeutic hypothermia for neurosurgery. The authors compared heat transfer and core cooling rates with five cooling methods. METHODS: Six healthy volunteers were anesthetized with desflurane and nitrous oxide. The cooling methods were 1) circulating water (5 degrees C, full-length mattress and cover), 2) forced air (10 degrees C, full-length cover), 3) gastric lavage (500 ml iced water every 10 min), 4) bladder lavage (300 ml iced Ringer's solution every 10 min), and 5) ice-water immersion. Each method was applied for 40 min or until the volunteers' core temperatures approached 34 degrees C. The volunteers were rewarmed to normothermia between treatments. Core cooling rates were evaluated using linear regression. RESULTS: The first volunteer developed abdominal cramping and diarrhea after gastric lavage. Consequently, the technique was not again attempted. Bladder lavage increased heat loss approximately 10 W and decreased core temperature 0.8 +/- 0.3 degrees C/h (r2 = 0.99 +/- 0.002; means +/- SD). Forced-air and circulating-water cooling comparably increased heat flux, approximately 170 W. Consequently, core cooling rates were similar during the two treatments at 1.7 +/- 0.5 degrees C/h (r2 = 0.99 +/- 0.001) and 1.6 +/- 1.1 degrees C/h (r2 = 0.98 +/- 0.02), respectively. Immersion in an ice water slurry increased heat loss approximately 600-800 W and decreased core temperature 9.7 +/- 4.4 degrees C/h (r2 = 0.98 +/- 0.01). Immersion cooling was associated with an afterdrop of approximately 2 degrees C. CONCLUSIONS: Bladder lavage provided only trivial cooling and gastric lavage provoked complications. Forced-air and circulating-water cooling transferred relatively little heat but are noninvasive and easy to implement. Forced-air or circulating-water cooling, perhaps combined with intravenous administration of refrigerated fluids, may be sufficient in some patients. When noninvasive methods prove insufficient for rapid cooling, ice-water immersion or peritoneal lavage probably should be the next lines of defense.

Adult↗
PubMed1996

Rapid core-to-peripheral tissue heat transfer during cutaneous cooling.

Perioperative thermal manipulations are usually directed at the skin surface because methods of directly warming the core are invasive or ineffective. However, inadequate heat flow between peripheral and core compartments will decrease the rate at which core temperature changes. We therefore determined whether core hypothermia is delayed after initiation of surface cooling. Six volunteers were anesthetized with propofol and midazolam, and maintained under three layers of passive insulation for 2.5-4 h. Subsequently, the skin surface was cooled using forced air, 1000 L/min, at 10 degrees C. Isoflurane was added as necessary to maintain arteriovenous shunt vasodilation. Overall heat balance was determined from the difference between cutaneous heat loss (thermal flux transducers) and metabolic heat production (oxygen consumption). Average arm and leg (peripheral) tissue temperatures were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. Overall body heat content decreased approximately 234 kcal during 2.5 h of active cooling. Core temperature, which was nearly constant before active cooling, decreased approximately 1.3 degrees C/h. There was no delay between initiation of active cooling and the decrease in core temperature. Furthermore, peripheral (arm and leg) and core (trunk and head) tissue heat contents decreased at virtually the same rates: approximately 50 kcal/h and approximately 47 kcal/h, respectively. These data indicate that there is little restriction of heat flow between peripheral and core tissues in vasodilated, anesthetized subjects.

Adult↗
PubMed1996

Isoflurane produces marked and nonlinear decreases in the vasoconstriction and shivering thresholds.

BACKGROUND: Desflurane decreases the vasoconstriction and shivering thresholds disproportionately at high anesthetic concentrations. This result contrasts with the authors' previous report that isoflurane decreases the vasoconstriction threshold linearly. It is surprising that the basic shape of the concentration-response curve should differ with these two otherwise similar anesthetics. Therefore, the hypothesis that isoflurane produces a nonlinear reduction in the vasoconstriction threshold was tested. Because the effect of isoflurane on shivering remains unknown, the extent to which isoflurane reduces the shivering threshold also was determined. METHODS: Eight men volunteered to be studied on four randomly ordered days: (1) a target end-tidal isoflurane concentration of 0.55%, (2) a target concentration of 0.7%, (3) control (no anesthesia) and a target end-tidal concentration of 0.85%, and (4) a target end-tidal concentration of 1.0%. Volunteers were surface-cooled until peripheral vasoconstriction and shivering were observed. We arithmetically compensated for changes in skin temperature using the established linear cutaneous contributions to control for each response. From the calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C), the concentration-response relation was determined. RESULTS: Isoflurane administration produced a dose-dependent reduction in the vasoconstriction and shivering thresholds, decreasing each approximately 4.6 degrees C at an end-tidal concentration of 1%. Residual analysis indicated that the vasoconstriction and shivering thresholds were decreased in a nonlinear fashion during isoflurane administration. The vasoconstriction-to-shivering range was 1.5 +/- 0.8 degree C without isoflurane, and did not change significantly during isoflurane administration. CONCLUSIONS: The vasoconstriction-to-shivering range remained unchanged by isoflurane administration. In this regard, the effects of isoflurane are similar to those of desflurane, propofol, and alfentanil. The current data differ from the authors' previous report, in that the dose-dependence for vasoconstriction was nonlinear, with isoflurane reducing the threshold disproportionately at higher anesthetic concentrations. Differing dose-dependence in the two studies may result either because the current study's volunteers were not exposed to surgical stimulation and were given less isoflurane, or because of design limitations in the previous protocol.

Adult↗
PubMed1996

Thermoregulatory vasoconstriction does not impede core warming during cutaneous heating.

BACKGROUND: Although forced-air warming rapidly increases intraoperative core temperatures, it is reportedly ineffective postoperatively. A major difference between these two periods is that arteriovenous shunts are usually dilated during surgery, whereas vasoconstriction is uniform in hypothermic postoperative patients. Vasoconstriction may decrease efficacy of warming because its major physiologic purposes are to reduce cutaneous heat transfer and restrict heat transfer between the two thermal compartments. Accordingly, we tested the hypothesis that thermoregulatory vasoconstriction decreases cutaneous transfer of applied heat and restricts peripheral-to-core flow of heat, thereby delaying and reducing the increase in core temperature. METHODS: Eight healthy male volunteers anesthetized with propofol and isoflurane were studied. Volunteers were allowed to cool passively until core temperature reached 33 degrees C. On one randomly assigned day, the isoflurane concentration was reduced, to provoke thermoregulatory arteriovenous shunt vasoconstriction; on the other study day, a sufficient amount of isoflurane was administered to prevent vasoconstriction. On each day, forced-air warming was then applied for 2 h. Peripheral (arm and leg) tissue heat contents were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. Core (trunk and head) heat content was determined from core temperature, assuming a uniform compartmental distribution. Time-dependent changes in peripheral and core tissue heat contents were evaluated using linear regression. Differences between the vasoconstriction and vasodilation study days, and between the peripheral and core compartments, were evaluated using two-tailed, paired t tests. Data are presented as means +/-SD; P < 0.01 was considered statistically significant. RESULTS: Cutaneous heat transfer was similar during vasoconstriction and vasodilation. Forced-air warming increased peripheral tissue heat content comparably when the volunteers were vasodilated and vasoconstricted: 48 +/- 7 versus 53 +/- 10 kcal/h. Core compartment tissue heat content increased similarly when the volunteers were vasodilated and vasoconstricted: 51 +/- 8 versus 44 +/- 11 kcal/h. Combining the two study days, the increase in peripheral and core heat contents did not differ significantly: 51 +/- 8 versus 48 +/- 10 kcal/h, respectively. Core temperature increased at essentially the same rate when the volunteers remained vasodilated (1.3 degrees C/h) as when they were vasoconstricted (1.2 degrees C/h). CONCLUSIONS: The authors failed to confirm their hypothesis that thermoregulatory vasoconstriction decreases cutaneous transfer of applied heat and restricts peripheral-to-core flow of heat in anesthetized subjects. The reported difference between intraoperative and postoperative rewarming efficacy may result from nonthermoregulatory anesthetic-induced vasodilation.

Adult↗