Biomedical subjects

M Schroeder

Publications and source records attributed to M Schroeder.

At least 19 recordsLinked to original sources

PubMed1997

Nonparametric simulation based linkage statistics for general pedigrees.

A common strategy for testing for linkage without posing a disease model is to test for increased marker similarity among the affected pedigree members. We developed a simulation based statistic, SimIBD, which measures marker similarity in terms of identity-by-descent (IBD) when it can be determined whether or not the alleles are IBD, and in terms of the probability of the alleles being IBD when it cannot be determined. The SimIBD statistic is not only more powerful than its precursor, the affected-pedigree-member (APM) method, but it is also less sensitive to the misspecification of marker allele frequencies.

Alleles↗

PubMed1996

Generation of an integrated transcription map of the BRCA2 region on chromosome 13q12-q13.

An integrated approach involving physical mapping, identification of transcribed sequences, and computational analysis of genomic sequence was used to generate a detailed transcription map of the 1. 0-Mb region containing the breast cancer susceptibility locus BRCA2 on chromosome 13q12-q13. This region is included in the genetic interval bounded by D13S1444 and D13S310. Retrieved sequences from exon amplification or hybrid selection procedures were grouped into physical intervals and subsequently grouped into transcription units by clone overlap. Overlap was established by direct hybridization, cDNA library screening, PCR cDNA linking (island hopping), and/or sequence alignment. Extensive genomic sequencing was performed in an effort to understand transcription unit organization. In total, approximately 500 kb of genomic sequence was completed. The transcription units were further characterized by hybridization to RNA from a series of human tissues. Evidence for seven genes, two putative pseudogenes, and nine additional putative transcription units was obtained. One of the transcription units was recently identified as BRCA2 but all others are novel genes of unknown function as only limited alignment to sequences in public databases was observed. One large gene with a transcript size of 10.7 kb showed significant similarity to a gene predicted by the Caenorhabditis elegans genome and the Saccharomyces cerevisiae genome sequencing efforts, while another contained a motif sequence similar to the human 2',3' cyclic nucleotide 3' phosphodiesterase gene. Several retrieved transcribed sequences were not aligned into transcription units because no corresponding cDNAs were obtained when screening libraries or because of a lack of definitive evidence for splicing signals or putative coding sequence based on computational analysis. However, the presence of additional genes in the BRCA2 interval is suggested as groups of putative exons and hybrid selected clones that were transcribed in consistent orientations could be localized to common physical intervals.

BRCA2 Protein↗

PubMed1996

Surgical management of pleomorphic adenomas of the parotid gland: a follow-up study of three methods.

PURPOSE: This retrospective study evaluated data pertaining to history, symptoms, diagnosis, and mode of therapy of patients treated for pleomorphic adenoma of the parotid gland. PATIENTS AND METHODS: The records of 475 patients were reviewed. Follow-up was done by questionnaires sent to the referring doctor. RESULTS: The total rate of recurrence was 0.9% after 475 operations for pleomorphic adenoma of the parotid gland. One recurrence (0.7%) was reported for the group with superficial parotidectomy and none for the group with total parotidectomy. The rate of postoperative side effects was also low. The facial nerve was affected in 1.4% after superficial parotidectomy, and in 3.3% after total parotidectomy. CONCLUSION: The results of this follow-up study show that superficial parotidectomy for pleomorphic adenoma located in the superficial lobe of the parotid gland provides adequate therapy and generally avoids recurrence and side effects.

Adenoma, Pleomorphic↗

PubMed1996

An accessory protein enhances both DNA binding and activity of DNA polymerase alpha isolated from normal, but not transformed, human fibroblasts.

DNA polymerase alpha/primase (pol alpha) isolated from fibroblasts established from a 66-year-old human donor (GM3529) exhibited decreased specific activity compared with pol alpha from either fetal-derived fibroblasts (WI38), or pSV3.neo-transformed GM3529 fibroblasts. The pol alpha specific activity decrease was correlated with a decreased proliferative capacity frequently seen in cells from aged donors. Pol alpha isolated from pSV3.neo-transformed GM3529 cells (GM3529T) exhibited a single isoform with about 10-fold higher specific activity than pol alpha from GM3529 cells. GM3529T pol alpha was immunoreactive with both anti-pol alpha and anti-SV40 large tumor antigen. Polymerases from GM3529 and GM3529T cells were treated with a pol alpha accessory protein, alpha AP, isolated from L1210 cells. Pol alpha from GM3529T cells showed no increase in activity in the presence of alpha AP, while pol alpha isolated from GM3529 cells exhibited about an 8-fold increase in activity after treatment with alpha AP. Double stranded SV40 DNA containing multiple ori sequences exhibited a greater decrease in electrophoretic mobility in the presence of GM3529T pol alpha than when treated with GM3529 pol alpha. In the presence of pol alpha from either GM35229 or GM3529T cells SV40 dsDNA exhibited a decrease in electrophoretic mobility, and in each instance addition of alpha AP resulted in an even greater decrease in DNA mobility. These data indicate that alpha AP increased pol alpha binding to SV40 dsDNA, or that alpha AP bound the DNA in addition to previously bound pol alpha. GM3529 pol alpha also bound non-specific, non-SV40, dsDNA, whereas GM3529T pol alpha with associated TAg did not bind the non-viral dsDNA unless alpha AP was added to the preparation. While not all human diploid fibroblast cell lines derived from aged human donors necessarily exhibit decreased proliferative capacity compared with cells from young donors, decreased specific activity associated with a decline in cellular DNA synthesis is typical of pol alpha from cells derived from aged human donors. We suggest that a decrease in endogenous alpha AP interaction with pol alpha may account, in part, for the loss of DNA binding affinity and specific activity of pol alpha from GM3529 cells derived from an aged donor.

Aged↗

PubMed1996

The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.

Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.

BRCA2 Protein↗

PubMed1996

Nonparametric simulation-based statistics for detecting linkage in general pedigrees.

We present here four nonparametric statistics for linkage analysis that test whether pairs of affected relatives share marker alleles more often than expected. These statistics are based on simulating the null distribution of a given statistic conditional on the unaffecteds' marker genotypes. Each statistic uses a different measure of marker sharing: the SimAPM statistic uses the simulation-based affected-pedigree-member measure based on identity-by-state (IBS) sharing. The SimKIN (kinship) measure is 1.0 for identity-by-descent (IBD) sharing, 0.0 for no IBD status sharing, and the kinship coefficient when the IBD status is ambiguous. The simulation-based IBD (SimIBD) statistic uses a recursive algorithm to determine the probability of two affecteds sharing a specific allele IBD. The SimISO statistic is identical to SimIBD, except that it also measures marker similarity between unaffected pairs. We evaluated our statistics on data simulated under different two-locus disease models, comparing our results to those obtained with several other nonparametric statistics. Use of IBD information produces dramatic increases in power over the SimAPM method, which uses only IBS information. The power of our best statistic in most cases meets or exceeds the power of the other nonparametric statistics. Furthermore, our statistics perform comparisons between all affected relative pairs within general pedigrees and are not restricted to sib pairs or nuclear families.

Algorithms↗

PubMed1995

Propofol blood concentration and the Bispectral Index predict suppression of learning during propofol/epidural anesthesia in volunteers.

Propofol is often used for sedation during regional anesthesia. We tested the hypothesis that propofol blood concentration, the Bispectral Index and the 95% spectral edge frequency predict suppression of learning during propofol/epidural anesthesia in volunteers. In addition, we tested the hypothesis that the Bispectral Index is linearly related to propofol blood concentration. Fourteen healthy, male volunteers were studied on three randomly ordered days: no propofol, target propofol blood concentration 1 microgram/mL, and target propofol blood concentration 2 micrograms/mL. Each day, epidural anesthesia (approximately T11 level) was induced using 2% 2-chloroprocaine. Propofol was infused by a computer-controlled pump, and propofol concentration measured in central venous blood. We administered a Trivial Pursuit-type question task on all 3 days. The electroencephalogram was monitored continuously (Fp1, Fp2; reference, Cz; ground, mastoid). Propofol caused concentration-related impairment of learning. The propofol blood concentration suppressing learning by 50% was 0.66 +/- 0.1 microgram/mL. The Bispectral Index value when learning was suppressed by 50% was 91 +/- 1. In contrast, the 95% spectral edge frequency did not correlate well with learning. The Bispectral Index decreased linearly as propofol blood concentration increased (Bispectral Index = -7.4.[propofol] + 90; r2 = 0.47, n = 278). There was no significant correlation between the 95% spectral edge frequency and propofol concentration. In order to suppress learning, propofol blood concentrations reported to produce amnesia may be targeted. Alternatively, the Bispectral Index may be used to predict anesthetic effect during propofol sedation.

Adult↗

PubMed1995

Heat flow and distribution during induction of general anesthesia.

BACKGROUND: Core hypothermia after induction of general anesthesia results from an internal core-to-peripheral redistribution of body heat and a net loss of heat to the environment. However, the relative contributions of each mechanism remain unknown. The authors evaluated regional body heat content and the extent to which core hypothermia after induction of anesthesia resulted from altered heat balance and internal heat redistribution. METHODS: Six minimally clothed male volunteers in an approximately 22 degrees C environment were evaluated for 2.5 control hours before induction of general anesthesia and for 3 subsequent hours. Overall heat balance was determined from the difference between cutaneous heat loss (thermal flux transducers) and metabolic heat production (oxygen consumption). Arm and leg tissue heat contents were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. To separate the effects of redistribution and net heat loss, we multiplied the change in overall heat balance by body weight and the specific heat of humans. The resulting change in mean body temperature was subtracted from the change in distal esophageal (core) temperature, leaving the core hypothermia specifically resulting from redistribution. RESULTS: Core temperature was nearly constant during the control period but decreased 1.6 +/- 0.3 degree C in the first hour of anesthesia. Redistribution contributed 81% to this initial decrease and required transfer of 46 kcal from the trunk to the extremities. During the subsequent 2 h of anesthesia, core temperature decreased an additional 1.1 +/- 0.3 degree C, with redistribution contributing only 43%. Thus, only 17 kcal was redistributed during the second and third hours of anesthesia. Redistribution therefore contributed 65% to the entire 2.8 +/- 0.5 degree C decrease in core temperature during the 3 h of anesthesia. Proximal extremity heat content decreased slightly after induction of anesthesia, but distal heat content increased markedly. The distal extremities thus contributed most to core cooling. Although the arms constituted only a fifth of extremity mass, redistribution increased arm heat content nearly as much as leg heat content. Distal extremity heat content increased approximately 40 kcal during the first hour of anesthesia and remained elevated for the duration of the study. CONCLUSIONS: The arms and legs are both important components of the peripheral thermal compartment, but distal segments contribute most. Core hypothermia during the first hour after induction resulted largely from redistribution of body heat, and redistribution remained the major cause even after 3 h of anesthesia.

Adult↗

PubMed1995

Optimal duration and temperature of prewarming.

BACKGROUND: Core hypothermia developing immediately after induction of anesthesia results largely from an internal core-to-peripheral redistribution of body heat. Although difficult to treat, redistribution can be prevented by prewarming. The benefits of prewarming may be limited by sweating, thermal discomfort, and efficacy of the warming device. Accordingly, the optimal heater temperature and minimum warming duration likely to substantially reduce redistribution hypothermia were evaluated. METHODS: Sweating, thermal comfort, and extremity heat content were evaluated in seven volunteers. They participated on two study days, each consisting of a 2-h control period followed by 2 h of forced-air warming with the heater set on "medium" (approximately 40 degrees C) or "high" (approximately 43 degrees C). Arm and leg tissue heat contents were determined from 19 intramuscular needle thermocouples, ten skin temperatures, and "deep" foot temperature. RESULTS: Half the volunteers started sweating during the second hour of warming. None of the volunteers felt uncomfortably warm during the first hour of heating, but many subsequently did. With the heater set on "high," arm and leg heat content increased 69 kcal during the first 30 min of warming and 136 kcal during the first hour of warming, representing 38% and 75%, respectively, of the values observed after 2 h of warming. The increase was only slightly less when the heater was set to "medium." CONCLUSIONS: Neither sweating nor thermal discomfort limited heat transfer during the first hour of warming. Thirty minutes of forced-air warming increased peripheral tissue heat content by more than the amount normally redistributed during the first hour of anesthesia. The large increase in arm and leg heat content during prewarming thus explains the observed efficacy of prewarming.

Arm↗

PubMed1995

Heat flow and distribution during epidural anesthesia.

BACKGROUND: Core hypothermia after induction of epidural anesthesia results from both an internal core-to-peripheral redistribution of body heat and a net loss of heat to the environment. However, the relative contributions of each mechanism remain unknown. The authors thus evaluated regional body heat content and the extent to which core hypothermia after induction of anesthesia resulted from altered heat balance and internal heat redistribution. METHODS: Twelve minimally clothed male volunteers were evaluated in a approximately 22 degrees C environment for 2.5 control hours before induction of epidural anesthesia and for 3 subsequent hours. Epidural anesthesia produced a bilateral sympathetic block in only six volunteers, and only their results are reported. Shivering, when observed, was treated with intravenous meperidine. Overall heat balance was determined from the difference between cutaneous heat loss (thermal flux transducers) and metabolic heat production (oxygen consumption). Arm and leg tissue heat contents were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. To separate the effects of redistribution and net heat loss, we multiplied the change in overall heat balance by body weight and the specific heat of humans. The resulting change in mean body temperature was subtracted from the change in esophageal or tympanic membrane (core) temperatures, leaving the core hypothermia specifically resulting from redistribution. RESULTS: Arm heat content decreased approximately 5 kcal/h after induction of anesthesia, but leg heat content increased markedly. Most of the increase in leg heat content was in the lower legs and feet. Core temperature increased slightly during the control period but decreased 0.8 +/- 0.3 degrees C in the 1st hour of anesthesia. Redistribution, contributing 89% to this initial decrease, required a net transfer of 20 kcal from the trunk to the extremities. During the subsequent 2 h of anesthesia, core temperature decreased an additional 0.4 +/- 0.3 degrees C, with redistribution contributing 62%. Thus, only 7 kcal were redistributed during the 2nd and 3rd hours of anesthesia. Redistribution therefore contributed 80% to the entire 1.2 +/- 0.3 degrees C decrease in core temperature during the 3 h of anesthesia. CONCLUSIONS: Core hypothermia during the 1st hour after induction of epidural anesthesia resulted largely from redistribution of body heat from the core thermal compartment to the distal legs. Even after 3 h of anesthesia, redistribution remained the major cause of core hypothermia. Despite the greater fractional contribution of redistribution during epidural anesthesia, core temperature decreased only half as much as during general anesthesia because metabolic rate was maintained and the arms remained vasoconstricted.

Adjuvants, Anesthesia↗

PubMed1994

[Cyclosporin in autoimmune diseases].

At a symposium held in Zurich in November 1993, a series of presentations covered the optimal use of cyclosporin A (CsA) in autoimmune diseases. Besides its immunosuppressive effects in organ transplantation, CsA appears to be active in a variety of autoimmune disorders. Its most pronounced and beneficial clinical effects are seen in patients with severe rheumatoid arthritis. New clinical studies include the nephrotic syndrome in children and patients with systemic lupus erythematodes. The main concern remains CsA induced nephrotoxicity. For the treatment of autoimmune disorders CsA can be used at lower doses (< or = 5 mg/kg per day) than in transplantation medicine. Thus, monitoring of CsA blood concentrations is not usually necessary. The galenics of CsA has been optimized recently, an achievement which will further improve the clinical use of CsA. Due to increased knowledge of intracellular CsA binding proteins and of effects of CsA on T-lymphocytes and cytokine production, it can be expected that novel immunosuppressive compounds will be developed.

Adult↗

PubMed1994

Improved programs for the affected-pedigree-member method of linkage analysis.

The affected-pedigree-member (APM) method is a non-parametric method of linkage analysis, which requires no assumptions about how the trait of interest is inherited [Weeks and Lange, 1988, 1991, 1992; Lange and Weeks, 1990; Weeks et al., 1992]. The APM method uses only the affected members of each pedigree who are typed for the marker(s). Based on the affected members' marker genotypes and the relationships of the affecteds to each other, the APM method computes a statistic which provides a measure of marker similarity. If the affected members are significantly more similar at the marker locus than expected by chance, then one may conclude that the marker is not segregating independently of the disease. Since the APM method tests a hypothesis about marker similarity, and not about recombination between the marker and disease, it makes and requires no assumptions about the mode of inheritance of the disease. For this reason, the APM method has been used for complex diseases such as Alzheimer's, breast cancer, and melanoma [Pericak-Vance et al., 1989, 1990; Haile et al., 1990; Hall et al., 1990; St George-Hyslop et al., 1990; Cannon-Albright et al., 1992]. We would like to announce the availability of a much improved version of the APM program package. This version has been improved in several ways, as outlined below.

Bias↗

PubMed1994

From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe?

There is an obvious discrepancy between the popularity of mistletoe extracts and their classification as a non-conventional treatment modality with unproven efficacy in oncology. The commercial preparations suffer from several major drawbacks: lack of precise declarations for the molecular characteristics and the concentrations of diverse extract constituents; the composition of extracts can even be influenced by the different methods of preparation, the time of harvest, and the type of host tree; lack of experimentally substantiated instructions for the dose of supposedly effective substance(s) and the schedule of applications to clinically trigger an undisputably documented antitumoral activity; lack of thorough clinical studies according to the generally accepted criteria as the measure for responsible recommendations. To provide the indispensable set of data for a rational decision, the immunomodulatory galactoside-specific lectin was biochemically characterized and its antitumoral/antimetastatic activity was documented in three murine tumor model systems, occurring within a narrow dose range. Biweekly treatment with s.c. injections of a lectin dose of 1 ng/kg caused no notable harmful side-effects in patients, who showed modulation of selected immune parameters. In a group of 23 patients with advanced cancer no at least partial remission was seen. In principle, enhancement of factors like cytokine availability or NK-cell activity is not necessarily linked to therapeutic benefit. Factors such as growth promotion of certain tumor cell lines by cytokines, occurrence of respective insensitivity in advanced stages or varying levels of target sensitivity to cell-mediated cytotoxicity with significant interindividual differences deserve attention. Each tumor class has to be considered separately for its responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗

PubMed1994

Epidural anesthesia impairs both central and peripheral thermoregulatory control during general anesthesia.

BACKGROUND: The authors tested the hypotheses that: (1) the vasoconstriction threshold during combined epidural/general anesthesia is less than that during general anesthesia alone; and (2) after vasoconstriction, core cooling rates during combined epidural/general anesthesia are greater than those during general anesthesia alone. Vasoconstriction thresholds and heat balance were evaluated under controlled circumstances in volunteers, whereas the clinical importance of intraoperative thermoregulatory vasoconstriction was evaluated in patients. METHODS: Five volunteers were each evaluated twice. On one of the randomly ordered days, epidural anesthesia (approximately T9 dermatomal level) was induced and maintained with 2-chloroprocaine. On both study days, general anesthesia was induced and maintained with isoflurane (0.7% end-tidal concentration), and core hypothermia was induced by surface cooling and continued for at least 1 h after fingertip vasoconstriction was observed. Patients undergoing colorectal surgery were randomly assigned to combined epidural/enflurane anesthesia (n = 13) or enflurane alone (n = 13). In appropriate patients, epidural anesthesia was maintained by an infusion of bupivacaine. The core temperature that triggered fingertip vasoconstriction identified the threshold. RESULTS: In the volunteers, the vasoconstriction threshold was 36.0 +/- 0.2 degrees C during isoflurane anesthesia alone, but significantly less, 35.1 +/- 0.7 degrees C, during combined epidural/isoflurane anesthesia. Cutaneous heat loss and the rates of core cooling were similar 30 min before vasoconstriction with and without epidural anesthesia. In the 30 min after vasoconstriction, heat loss decreased 33 +/- 13 W when the volunteers were given isoflurane alone, but only 8 +/- 16 W during combined epidural/isoflurane anesthesia. Similarly, the core cooling rates in the 30 min after vasoconstriction were significantly greater during combined epidural/isoflurane anesthesia (0.8 +/- 0.2 degrees C/h) than during isoflurane alone (0.2 +/- 0.1 degrees C/h). In the patients, end-tidal enflurane concentrations were slightly, but significantly, less in the patients given combined epidural/enflurane anesthesia (0.6 +/- 0.2% vs. 0.8 +/- 0.2%). Nonetheless, the vasoconstriction threshold was 34.5 +/- 0.6 degrees C in the epidural/enflurane group, which was significantly less than that in the other patients, 35.6 +/- 0.8 degrees C. When the study ended after 3 h of anesthesia, patients given combined epidural/enflurane anesthesia were 1.2 degrees C more hypothermic than those given general anesthesia alone. The rate of core cooling during the last hour of the study was 0.4 +/- 0.2 degrees C/h during combined epidural/enflurane anesthesia, but only 0.1 +/- 0.3 degrees C/h during enflurane alone. CONCLUSIONS: These data indicate that epidural anesthesia reduces the vasoconstriction threshold during general anesthesia. Furthermore, the markedly reduced rate of core cooling during general anesthesia alone illustrates the importance of leg vasoconstriction in maintaining core temperature.

Adolescent↗

PubMed1994

Thermoregulatory thresholds during epidural and spinal anesthesia.

BACKGROUND: There are significant physiologic differences between spinal and epidural anesthesia. Consequently, these two types of regional anesthesia may influence thermoregulatory processing differently. Accordingly, in volunteers and in patients, we tested the null hypothesis that the core-temperature thresholds triggering thermoregulatory sweating, vasoconstriction, and shivering are similar during epidural and spinal anesthesia. METHODS: Six male volunteers participated on three consecutive study days: epidural or spinal anesthesia were randomly assigned on the 1st and 3rd days (approximately T10 level); no anesthesia was given on the 2nd day. On each day, the volunteers were initially warmed until they started to sweat, and subsequently cooled by central venous infusion of cold fluid until they shivered. Mean skin temperature was kept constant near 36 degrees C throughout each study. The tympanic membrane temperatures triggering a sweating rate of 40 g.m-2.h-1, a finger flow less than 0.1 ml/min, and a marked and sustained increase in oxygen consumption (approximately 30%) were considered the thermoregulatory thresholds for sweating, vasoconstriction, and shivering, respectively. Twenty-one patients were randomly assigned to receive epidural (n = 10) or spinal (n = 11) anesthesia for knee and calf surgery (approximately T10 level). As in the volunteers, the shivering threshold was defined as the tympanic membrane temperature triggering a sustained increase in oxygen consumption. RESULTS: The thresholds and ranges were similar during epidural and spinal anesthesia in the volunteers. However, the sweating-to-vasoconstriction (inter-threshold) range, the vasoconstriction-to-shivering range, and the sweating-to-shivering range all were significantly increased by regional anesthesia. The shivering thresholds in patients assigned to epidural and spinal anesthesia were virtually identical. CONCLUSIONS: Comparable sweating, vasoconstriction, and shivering thresholds during epidural and spinal anesthesia suggest that thermoregulatory processing is similar during each type of regional anesthesia. However, thermoregulatory control was impaired during regional anesthesia, as indicated by the significantly enlarged inter-threshold and sweating-to-shivering ranges.

Adult↗

PubMed1994

Epidural anesthesia increases apparent leg temperature and decreases the shivering threshold.

BACKGROUND: Lower core temperatures than usual are required to trigger shivering during epidural and spinal anesthesia, but the etiology of this impairment remains unknown. In this investigation, we propose and test a specific mechanism by which a peripheral action of regional anesthesia might alter centrally mediated thermoregulatory responses. Conduction anesthesia blocks all thermal sensations; however, cold signals are disproportionately affected because at typical leg temperatures mostly cold receptors fire tonically. It thus seems likely that epidural and spinal anesthesia increase the leg temperature perceived by the thermoregulatory system. Because skin temperature reportedly contributes 5-20% to thermoregulatory control, increased apparent (as distinguished from actual) leg temperature would produce a complimentary decrease in the core temperature triggering thermoregulatory shivering. Accordingly, we tested the hypothesis that abnormal tolerance for hypothermia during epidural anesthesia coincides with an increase in apparent leg temperature. We defined apparent temperature as the leg-skin temperature required to induce a reduction in the shivering threshold comparable to that produced by epidural anesthesia. METHODS: Six women were studied on 4 randomly ordered days: (1) leg-skin temperature near 32 degrees C; (2) leg-skin temperature near 36 degrees C; (3) leg-skin temperature near 38 degrees C; and (4) epidural anesthesia without leg-warming (leg-skin temperature approximately 34 degrees C). At each designated leg temperature, core hypothermia sufficient to evoke shivering was induced by central venous infusion of cold fluid. Upper-body skin temperature was kept constant throughout. In each volunteer, linear regression was used to calculate the correlation between the shivering thresholds on the 3 non-epidural days and concurrent leg temperatures. The slope of these regression equations thus indicated the extent to which leg-warming increased thermoregulatory tolerance for core hypothermia, and was expressed as a percentage leg-skin and leg-tissue contribution to total thermal afferent input. The skin and tissue temperatures that would have been required to produce the observed shivering threshold during epidural anesthesia, the apparent temperatures, were then interpolated from the regression. RESULTS: There was a good linear relation between the shivering threshold and leg-skin temperature (r2 = 0.94 +/- 0.06). The contribution of leg-skin temperature to the shivering threshold was 11 +/- 3% of the total thermal input. Apparent leg-skin temperature during epidural anesthesia was 37.8 +/- 0.5 degrees C, which exceeded actual leg-skin temperature by approximately 4 degrees C. The contribution of leg-tissue temperature to the shivering threshold was 19 +/- 7% of the total. Apparent leg-tissue temperature during epidural anesthesia was 37.1 +/- 0.4 degrees C, which exceeded actual leg-skin temperature by approximately 2 degrees C. CONCLUSIONS: Because leg-skin contributed approximately 11% to the shivering threshold, it is unlikely that the entire skin surface contributes at much less than 20%. These data suggest that the shivering threshold during epidural anesthesia is reduced by a specific mechanism, namely that conduction block significantly increases apparent (as distinguished from actual) leg temperature.

Adult↗

PubMed1994

Propofol causes a dose-dependent decrease in the thermoregulatory threshold for vasoconstriction but has little effect on sweating.

BACKGROUND: Volatile anesthetics increase the core temperature required to trigger sweating and decrease the core temperature required to trigger vasoconstriction. However, little is known about the effects of intravenous anesthetics on thermoregulation. We therefore tested the hypothesis that propofol increases the sweating threshold and decreases the vasoconstriction threshold, thereby increasing the inter-threshold range (core temperatures not triggering autonomic thermoregulatory responses). The study was conducted using a new model in which thermal manipulations were restricted to insensate skin, and sensate skin temperature was controlled. METHODS: Six healthy, male volunteers were studied on 3 randomly ordered days: no propofol, target propofol blood concentration 2 micrograms/ml, and target blood propofol concentration 4 micrograms/ml. Each day, epidural anesthesia (approximately T11 level) was induced, using 2% 2-chloroprocaine (one volunteer received bupivacaine). Thermal manipulations were confined to the legs, and we attempted to maintain upper-body (sensate) skin temperature constant. Propofol was infused by a computer-controlled infusion pump. Volunteers were heated until sweating was observed, then cooled until fingertip vasoconstriction was observed. The sweating threshold was defined as the tympanic membrane temperature triggering sustained evaporative heat loss > 40 g.m-2.h-1. Similarly, the vasoconstriction threshold was defined as the tympanic membrane temperature triggering a sustained reduction in fingertip blood flow to < 0.25 ml/min. Central venous blood was assayed for propofol blood concentration. RESULTS: Increasing propofol concentration produced a linear decrease the vasoconstriction threshold (slope = -0.53 +/- 0.34 degrees C.microgram-1.ml-1; R2 = 0.98 +/- 0.04 [mean +/- SD]), but had little effect on the sweating threshold. The inter-threshold range was 0.51 +/- 0.46 degrees C during epidural anesthesia alone, and increased significantly, by 0.49 +/- 0.31 degrees C.microgram-1.ml-1 during propofol administration. CONCLUSIONS: Like volatile anesthetics, propofol reduces the vasoconstriction threshold and increases the inter-threshold range. However, propofol differs in leaving the sweating threshold unchanged.

Adult↗

PubMed1994

A small GTP-binding protein from Arabidopsis thaliana functionally complements the yeast YPT6 null mutant.

A clone designated A.t.RAB6 encoding a small GTP-binding protein was isolated from a cDNA library of Arabidopsis thaliana leaf tissue. The predicted amino acid sequence was highly homologous to the mammalian and yeast counterparts, H.Rab6 and Ryh1/Ypt6, respectively. Lesser homology was found between the predicted Arabidopsis protein sequence and two small GTP-binding proteins isolated from plant species (44% homology to Zea mays Ypt1 and 43% homology to Nicotiana tabacum Rab5). Conserved stretches in the deduced amino acid sequence of A.t.Rab6 include four regions involved in GTP-binding, an effector region, and C-terminal cysteine residues required for prenylation and subsequent membrane attachment. Northern blot analysis demonstrated that A.t.Rab6 mRNA was expressed in root, leaf, stem, and flower tissues from A. thaliana with the highest levels present in roots. Escherichia coli produced histidine-tagged A.t.Rab6 protein-bound GTP, whereas a mutation in one of the guanine nucleotide-binding sites (asparagine122 to isoleucine) rendered it incapable of binding GTP. Functionally, the A.t.RAB6 gene was able to complement the temperature-sensitive phenotype of the YPT6 null mutant in yeast. The isolation of this gene will aid in the dissection of the machinery involved in soluble protein sorting at the trans-Golgi network of plants.

Amino Acid Sequence↗