1 Yale University School of Nursing, and 2 Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536
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ABSTRACT |
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Islet responses of two different Mus geni, the laboratory mouse (Mus musculus) and a phylogenetically more ancient species (Mus caroli), were measured and compared with the responses of islets from rats (Rattus norvegicus). A minimal and flat second-phase response to 20 mM glucose was evoked from M. musculus islets, whereas a large rising second-phase response characterized rat islets. M. caroli responses were intermediate between these two extremes; a modest rising second-phase response to 20 mM glucose was observed. Prior, brief stimulation of rat islets with 20 mM glucose results in an amplified insulin secretory response to a subsequent 20 mM glucose challenge. No such potentiation or priming was observed from M. musculus islets. In contrast, M. caroli islets displayed a modest twofold potentiated first-phase response upon subsequent restimulation with 20 mM glucose. Inositol phosphate (IP) accumulation in response to 20 mM glucose stimulation in [3H]inositol-prelabeled rat or mouse islets paralleled the insulin secretory responses. The divergence in 20 mM glucose-induced insulin release between these species may be attributable to differences in phospholipase C-mediated IP accumulation in islets.
islets; insulin secretion; biphasic response; phospholipase C; evolution
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INTRODUCTION |
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A COMMON ANCESTOR, Antemus, is thought to have given rise to the two most common murid species used in biomedical research, rats and mice (11). Approximately 10 million years ago (MYA), the phylogenetic tree connecting the genus Rattus and the future genus Mus diverged. Several levels of quasi-synchronous speciation events ~2 MYA further subdivided the Mus species. One branch led ultimately to Mus musculus, the commonly employed laboratory mouse, whereas another, more ancient lineage culminated in Mus caroli.
Our interest in the phylogeny of mice and rats has been stimulated by the observations that pronounced species differences exist in terms of their islet sensitivity to glucose stimulation. For example, over 30 years ago, Malaisse and Malaisse-Lagae (25) reported that, in response to glucose stimulation, less insulin was released from mouse pancreatic pieces than from similarly stimulated rat pancreatic pieces. The advent of more sophisticated methodology employing the perfused rat or mouse pancreas preparation or perifused islets substantiated these early observations (5, 23, 24, 35, 36, 53). The most dramatic deviation between the two most commonly employed species used to study the biochemical mechanisms that regulate insulin secretion occurs during the sustained second-phase insulin secretory response to glucose stimulation (5). A large, rising second-phase insulin secretory response to stimulatory glucose is characteristic of rat islets (5, 15, 21, 22, 29, 30). In quantitative terms, the increments in release rates above basal control values are on the order of 25- to 50-fold. The robust secretory response from rat islets is duplicated by human islets studied by the hyperglycemic clamp technique (18, 19, 38), supporting the concept that the same biochemical mechanisms regulate the responses of rat and human islets. In contrast to these two species, sustained insulin release rates from mouse islets in response to glucose are flat and only modestly elevated above prestimulatory release rates. This pattern has been observed in studies utilizing both the perfused pancreas preparation and perifused islets (5, 23, 24, 35, 36, 53). Failure of mouse islets to respond to high glucose cannot be attributed to any reduction in insulin content, because both species contain comparable amounts of stored insulin (16, 17, 51). Moreover, when stimulated with the combination of glucose plus a cholinergic agonist, a dramatic enhancement of second-phase release rates is observed from mouse islets (20, 53).
The failure of glucose to evoke a rising second-phase secretory response from perfused or perifused mouse islets is not the only anomaly compared with rat islet responses. It is well documented that brief prior exposure of rat or human islets to stimulatory glucose amplifies the subsequent response to the hexose (6, 13, 14, 22, 45). Termed time-dependent potentiation (TDP) or sensitization, the response to a second stimulation, particularly the first phase of release, is markedly enhanced. Mouse islets also fail to display the induction of TDP to a prior glucose stimulus under conditions in which it can be readily detected in rat islets (6, 51). Finally, sustained exposure of rat islets to high glucose desensitizes them to subsequent restimulation (10, 41, 55), termed time-dependent inhibition (TDI) of release or desensitization. Mouse islets are also immune to this adverse effect of chronic high glucose exposure (41).
We have attributed the anomalous behavior of mouse islets compared with rat islets to a reduction in glucose signaling via the phospholipase C (PLC)/protein kinase C (PKC) signaling pathway. In support of this hypothesis are studies in which the PLC-mediated hydrolysis of islet phosphoinositide pools has been monitored by measuring inositol phosphate (IP) accumulation in [3H]inositol-prelabeled islets. In rat islets, exposure to stimulatory glucose results in 500-800% increases in IP accumulation (8, 9, 44, 48). The comparable response from mouse islets is an ~0.5- to 1.0-fold increase (34, 53). Accounting for this biochemical deviation may be the underexpression of several PLC isozymes in mouse islets compared with rat islets (42, 53).
In the present series of experiments, an alternative approach was used to probe the differences in glucose sensitivity that exist between species and to elucidate the potential biochemical mechanisms involved. Comparative studies were conducted using islets isolated from a phylogenetically ancient Mus species, Mus caroli, and with the evolutionarily more recent Mus musculus species, the laboratory mouse. Our findings underscore the potential involvement of PLC/PKC activation in the regulation of islet responses to glucose stimulation.
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METHODS |
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Islet isolation. The detailed methodologies employed to assess insulin output from collagenase-isolated islets have been described previously (46). Young adult male M. musculus mice (CD-1 strain, body wts at time of study 20-36 g), male M. caroli mice (body wts at time of study 14-22 g), or male Rattus norvegicus (Sprague-Dawley) rats (body wts at time of study 350-450 g) were used. The CD-1 mice and the Sprague-Dawley rats were purchased from Charles River (Wilmington, MA). The M. caroli mice were obtained from the colony maintained by Dr. Rosemary Elliott at Roswell Park Memorial Institute (Buffalo, NY). All animals were treated in a manner that complied with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (NIH publication no. 85-23, revised 1985). The animals were fed ad libitum. After anesthesia induced by pentobarbital sodium (Nembutal, 50 mg/kg; Abbott, North Chicago, IL), islets were isolated by collagenase digestion and handpicked by use of a glass loop pipette under a stereomicroscope. They were free of visual exocrine contamination.
Perifusion studies.
Groups of 14-18 freshly isolated rat or mouse islets were loaded
onto nylon filters (Tetko, Briarcliff Manor, NY) and perifused in a
Krebs-Ringer bicarbonate (KRB) buffer at a flow rate of 1 ml/min for 30 min in the presence of 3 mM glucose to establish basal and stable
insulin secretory rates. After this 30-min stabilization period, they
were then perifused with the appropriate agonist or agonist
combinations, as indicated in the text and Figs. 1-5 of
RESULTS. Perifusate solutions were gassed with 95%
O2-5% CO2 and maintained at 37°C. Insulin
released into the medium was measured by RIA (1).
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Islet labeling for IP studies. After isolation, groups of 18-26 islets were loaded onto nylon filters, placed in a small glass vial, and incubated for 3 h in a myo-[2-3H]inositol-containing KRB solution made up as follows. Ten microcuries of myo-[2-3H]inositol (specific activity 16-23 Ci/mM) were placed in a 10 × 75-mm culture tube. To this aliquot of tracer were added 250 µl of warmed (to 37°C) and oxygenated KRB medium supplemented with 5.0 mM glucose. After mixing, 240 µl of this solution were gently added to the vial with islets. The vial was capped with a rubber stopper, gassed for 10 s with 95% O2-5% CO2, and incubated at 37°C. The vials were again gently oxygenated after 90 min. After the labeling period, the islets still on nylon filters were washed with 5 ml of fresh KRB.
IP measurements. After washing, the islets on nylon filters were placed in small glass vials. Four hundred microliters of KRB, supplemented with 10 mM LiCl to prevent IP degradation, and the appropriate agonists were added gently to the vial. The vials were capped and gently gassed for 5 s with 95% O2-5% CO2. After 30 min, the generation of IPs was stopped by addition of 400 µl of 20% perchloric acid. Total IPs formed were then measured using Dowex columns as described previously (7, 47).
Western blot studies.
Freshly isolated islets from M. caroli and M. musculus
(CD-1) mice were suspended in a 2:1 ratio of islets per microliter of homogenization buffer (1 mM dithiothreitol, 0.1 mM leupeptin, 5 mM
benzamidine, 10 µg/ml soybean trypsin inhibitor, 5 µg/ml aprotinin,
2 µM pepstatin A, and 2 mM phenylmethylsulfonyl fluoride in 12.5 mM
Tris, 1.25 mM EGTA, 1.25 mM EDTA, and 0.25% Triton X-100, pH 7.6).
Islets were then disrupted by sonic oscillation. Duplicate aliquots
were analyzed for protein content with the Lowry assay by use of BSA to
generate the standard curve and a rat liver preparation in
homogenization buffer as an internal standard. Equal amounts of protein
were loaded from both CD-1 and M. caroli samples for Western
blot analysis. For PKC (15-20 µg), PLC
1 (15-20 µg),
PLC
1 (15-25 µg), and PLC
1 (10-25 µg), proteins were
separated by SDS-PAGE with a 4% stacking gel with a 7% separating gel
at 12 and 16 mA, respectively. Separated proteins were
electro-transferred onto a polyvinylidene difluoride transfer membrane
with 15 V for 20 h. Membranes were stained with Ponceau S staining
solution to confirm transfer. Membranes were then washed with distilled
deionized water briefly and then blocked in Tris-buffered saline
containing 5% Carnation nonfat dried milk and 0.05% Tween 20 for
1 h and 50 min.
Reagents.
Hanks' solution was used for the islet isolation. The perifusion
medium consisted of (in mM) 115 NaCl, 5 KCl, 2.2 CaCl2, 1 MgCl2, and 24 NaHCO3, and 0.17 g/dl BSA. Other
compounds were added where indicated, and the solution was gassed with
a mixture of 95% O2-5% CO2. The
125I-labeled insulin used for the insulin assay was
purchased from NEN, and the labeled
myo-[2-3H]inositol was from Amersham
(Arlington Heights, IL). BSA (RIA grade), carbachol, phorbol
12-myristate 13-acetate (PMA), glucose, and the salts used to make the
Hanks' solution and perifusion medium were purchased from Sigma (St.
Louis, MO). Antibodies to PLC1 and PLC
1 were purchased from
Upstate Biotechnology (Lake Placid, NY). Antibodies to PLC
1 and
PKC
were purchased from Santa Cruz Biotechnology (Santa Cruz, CA).
Anti-rabbit IgG and anti-mouse IgG were also obtained from Santa Cruz
Biotechnology. Rat insulin standard (lot no. 615-ZS-157) was the
generous gift of Dr. Gerald Gold, Eli Lilly (Indianapolis, IN).
Collagenase (type P) was obtained from Boehringer Mannheim Biochemicals
(Indianapolis, IN).
Statistics.
Statistical significance was determined using the Student's
t-test for unpaired data or ANOVA in conjunction with the
Newman-Keuls test for unpaired data. A P value 0.05 was
taken as significant. Values presented in the text, Figs. 1-5, and
Table 1 in RESULTS represent means ± SE of at least
three observations.
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RESULTS |
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Species differences in response to 20 mM glucose stimulation.
The first series of experiments confirmed the existence of species
differences in islet responses to sustained 20 mM glucose stimulation.
The response of islets isolated from Sprague-Dawley rats was biphasic
in character, consisting of an initial spike of secretion followed by a
slowly rising second-phase response (Fig.
1, top). Release rates peaked
~30 min after the onset of 20 mM glucose stimulation and averaged
1,063 ± 84 pg · islet1 · min
1
(n = 8) at this time. Release rates declined to ~50%
of peak values as the perifusion with 20 mM glucose progressed, an
observation reported previously by Curry (15) in studies
with the perfused pancreas. Compared with rates of secretion observed
from rat islets maintained for 90 min with 3 mM glucose (24 ± 6 pg · islet
1 · min
1,
n = 4), peak second-phase release rates were increased
>30-fold. This compares favorably with findings made using the
perfused pancreas preparation and indicates that the physiological
integrity of our islet preparation was maintained during the isolation procedures.
Species differences in the induction of TDP by prior glucose
stimulation.
In addition to the evocation of a rising second-phase insulin secretory
response, a second time-dependent characteristic of rat islet responses
to glucose stimulation is the induction of priming, also referred to as
sensitization or TDP. The induction of TDP in rat islets by glucose was
confirmed. Rat islets were briefly stimulated with 20 mM glucose,
the hexose level decreased to 3 mM for 15 min, and a repeat
stimulation with 20 mM glucose was conducted. As shown in Fig.
3 (left), this protocol
resulted in a marked enhancement of first-phase secretion rates.
Compared with the peak first-phase response achieved during the initial stimulation, 217 ± 18 pg · islet1 · min
1
(n = 4), a dramatic enhancement of the subsequent
first-phase response was evident. Peak first-phase release rates now
averaged 804 ± 30 pg · islet
1 · min
1.
IP accumulation in rat and mouse islets. An analysis of information flow in the PLC/PKC cycle prompted us to suggest previously that the rising second-phase insulin secretory response and the induction of TDP by glucose were both related to information flow in this signaling pathway (48). In an attempt to provide an explanation for the divergence in second-phase response rates and the induction of TDP in the Mus species investigated, we next examined IP accumulation in [3H]inositol-prelabeled islets. After a 3-h labeling period and a 30-min incubation in 3 mM glucose, levels of labeled IPs were significantly greater in rat islets compared with either of the Mus species investigated (Table 1). We next examined the magnitude of rodent islet IP responses to 20 mM glucose stimulation (Table 1). In agreement with previous reports, a marked enhancement of IP accumulation was observed when rat islets were stimulated with 20 mM glucose. In confirmation of what we previously observed with mouse islets (53) and of a response reported by Sato and Henquin (34), who used this species as well, a minimal IP accumulation in response to 20 mM glucose was observed in M. musculus islets. Lying between these two values were the responses of M. caroli islets to 20 mM glucose.
PKC/PLC isozyme expression patterns in rodent islets.
We have proposed previously (42, 53) that the
underexpression of a nutrient-sensitive PLC isozyme in mouse islets vs. rat islets may be a contributory factor to the deviation in glucose responsiveness observed between these two species. Additional studies
examining the expression patterns of PKC and the major PLC isozymes,
1,
1, and
1, were conducted. Compared with M. musculus islets, M. caroli islets exhibited two- to
threefold increases in the expression of both PKC
and PLC
1 (Fig.
4). M. caroli islets
expresssed slightly less PLC
1 (Fig. 4) than M. musculus
islets, whereas neither species expressed any measurable level of
PLC
1 compared with rat islets (Fig.
5).
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DISCUSSION |
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It is often assumed that the responses of rodent islets to glucose stimulation are similar, irrespective of the species from which they were isolated. This and at least seven other studies (5, 6, 23, 24, 36, 50, 53) suggest caution in the extrapolation of data between rat and mouse islets when glucose is used as the stimulant. In the former species, glucose alone evokes time-dependent actions on their islets that cannot be readily duplicated using mouse islets. Failure of mouse islets to develop a rising second-phase insulin secretory response to stimulatory glucose and the failure of glucose to induce TDP and TDI of secretion are distinguishing features between rodent islet responses. These differences cannot be explained by any obvious disparity in glucose metabolism, because both species utilize glucose at comparable rates (3, 42). On the basis of an analysis of information flow in the PLC/PKC cycle, we have suggested that the reduced activation of PLC by glucose may account for this species disparity (48). The underexpression of several PLC isozymes in mouse islets compared with rat islets may provide the biochemical explanation for this divergence in species responses. This is not to suggest that mouse islets are incapable of PLC activation, but only that they rely more exclusively on the activation of a non-nutrient-regulated PLC isozyme for the provision of phosphoinositide-derived second messengers.
In the present experiments we used a phylogenetic approach to address
how glucose's action on pancreatic -cells has been retained or lost
in different species of mice over time and compared the
-cells with rat islet responses. In addition, we stimulated islets with an alternate fuel agonist in an attempt to ascertain whether the established deviation in glucose sensitivity that exists
extends to another agonist and species as well. Finally, the expression
patterns of the major PLC isozymes and PKC
were measured. For these
studies we employed M. musculus, the common laboratory
mouse, a species that diverged from M. caroli about 1.5 MYA
(11). Phylogenetically, this latter species is closer evolutionarily to the rat, but all of these species are thought to
share a common historical ancestor, Antemus.
In agreement with numerous studies using the perfused rat pancreas preparation or islets isolated from this species, a robust biphasic insulin secretory response was evoked from perifused rat islets stimulated with 20 mM glucose. Most dramatic is the enhancement of insulin release as the perifusion progressed. Compared with release rates observed in the presence of 3 mM glucose, the increment amounts to an ~30-fold increase. When islets from M. musculus, in this case CD-1 mice, were similarly stimulated, a spike of first-phase secretion was noted. However, these islets failed to develop a rising second-phase response that is characteristic of R. norvegicus islets studied using perfusion or perifusion techniques or Homo sapiens islets studied with the hyperglycemic clamp technique (18, 19, 38). Lying between these responses of two species, but much closer in similarity to the rat than the mouse, were the responses evoked from 20 mM glucose-stimulated M. caroli islets. A rising second-phase response to 20 mM glucose was noted. The failure of M. musculus islets to respond in a manner comparable to R. norvegicus or M. caroli islets cannot be attributable to insufficient insulin stores or damage to the islets during isolation. Comparable amounts of insulin were measured in the two Mus species; furthermore, when M. musculus islets were stimulated with 20 mM glucose plus 10 µM carbachol, a dramatic enhancement of sustained insulin secretion was noted.
Two additional stimulants were used to probe the specificity of mouse
islet responses. Unlike rat islets (26, 52), neither Mus species responded to stimulation with 500 nM of the PKC
activator PMA in the presence of low (3 mM) glucose, a finding
previously reported when islets isolated from lean C57BL mice were used
(49). Although islets from both species responded to KIC,
the secretory responses from M. caroli islets again exceeded
those from M. musculus islets. This latter observation would
appear to eliminate the early steps in glucose metabolism, such as
glycolysis and the pentose cycle, as potential explanations for these
deviations. Rather, a common distal response element sensitive to a
mitochondrial signal appears to be involved.
The ability of prior 20 mM glucose stimulation to induce TDP in rat islets and the failure of islets isolated from M. musculus to demonstrate a similar response pattern (6, 50) were also confirmed in this report. Like their second-phase responses to 20 mM glucose stimulation, M. caroli islets demonstrated a response to prior glucose stimulation that was similar to the response from rat islets, although of a smaller amplitude. For example, after a brief priming period with 20 mM glucose, peak first-phase responses to 20 mM glucose restimulation were increased about fourfold from rat islets. A twofold amplification was observed from M. caroli islets. M. musculus islet responses to a second 20 mM glucose stimulation fell ~30%.
We measured IP accumulation, a surrogate marker for PLC activation (4, 7, 31, 32), in rat and mouse islets. The results of these studies confirm the minimal stimulatory effect of 20 mM glucose on this parameter of PLC activation in CD-1 mouse islets compared with the response of rat islets (48). Of particular significance, a finding that reinforces the concept that PLC activation may play a pivotal role in the evocation of the time-dependent effects that glucose exerts upon islets is the observation made with M. caroli islets. Paralleling the capacity of glucose to evoke a modest rising second-phase response and to induce TDP of secretion, an effect on IP accumulation intermediate between R. norvegicus and M. musculus was observed in studies with M. caroli islets.
When quantitative Western blotting techniques and analysis were used,
the expression of PKC was found to be greater in M. caroli islets than in M. musculus islets. Of the PLC
isozymes analyzed, neither species expressed PLC
1 to any measurable
degree. PLC
1 was slightly underexpressed in M. caroli
islets compared with M. musculus islets. However, a
potential candidate for the amplified IP responses to glucose observed
from M. caroli islets compared with M. musculus
islets is PLC
1, an enzyme expressed in greater amounts in the islets
of the former species. This PLC isozyme's activation, although
complex, is dependent not only on calcium availability but also on
GTP-binding proteins (32, 33). Previous studies with rat
islets have proposed that an adequate supply of GTP, dependent on ATP
generation by metabolic fuels, is necessary for PLC activation
(37).
Our working hypothesis is that the robust activation of PLC by high
glucose is in part responsible for the large rising second-phase secretory response in rat islets. When rat islets are stimulated by 20 mM glucose, the multiple cellular effects of PLC-derived second
messengers induce cumulative changes in islets that only slowly return
to the prestimulatory state. Restimulation during this period results
in a potentiated secretory response (45). The fact that
the PMA (12) evokes a response reminiscent of the rising
second phase of secretion (27, 39) and is an effective inducer of priming in rat islets (28, 52) supports the
concept that PKC activation may be involved in both processes. This
idea is also supported by results in which other agonists that increase information flow in the PLC/PKC system are used to induce priming (43, 45, 54). In the case of M. musculus
islets, the minimal increase in PLC/PKC activation by 20 mM glucose
induces minimal changes in islet sensitivity that are poorly maintained
and incapable of evoking a large second-phase response or to induce
priming. On the other hand, the more significant PLC responses of
M. caroli islets, coupled to the increased expression of
PKC, may be responsible for a modest (when compared with rat islets)
increase in second-phase secretion and the induction of priming.
Several additional issues deserve final comment. First, on the basis of
PLC1's sensitivity to calcium (2) and the obligatory role of calcium in glucose-induced PLC activation (44), we
initially speculated that this PLC isozyme might be the one activated
by various nutrient secretagogues (40). Unlike in rat
islets, we could not detect a significant PLC
1 signal despite the
analysis of similar amounts of islet protein. Although this type of
analysis might appear to exclude PLC
1 as a nutrient-activated
isozyme, it should be remembered that, even though the M. caroli response to glucose was improved compared with M. musculus islets, it was still modest compared with rat islet
responses. It is possible that the activation of this enzyme in rat
islets contributes to the robust glucose-induced secretory response
from this species. Finally, this type of analysis suggests caution in
the extrapolation of findings made by use of transgenic mice to probe
the regulation of glucose homeostasis. If the phenotypic expression of
any observed alteration is a function of glucose-induced insulin
release, the species-dependent contribution of the
-cell should be considered.
In summary, we have confirmed that significant species differences to
glucose stimulation exist between R. norvegicus and M. musculus islets, differences possibly due to genetic divergence occurring over 10 million years of evolution (11). A
phylogenetic Mus species more closely related evolutionarily
to the rat demonstrates responses to glucose stimulation intermediate
between R. norvegicus and M. musculus. This
difference may be attributable to the retained capacity of glucose to
more effectively activate a nutrient-regulated PLC isozyme in the
caroli compared with the musculus species. Our
findings also suggest that the increased expression of PLC1 and
PKC
may be involved in these species-dependent responses of
Mus islets to nutrient stimulation. Finally, when we
consider that attempts are being made to genetically engineer
-cells
for therapeutic purposes, the elucidation of the enzymes that regulate the magnitude of glucose-induced insulin secretion is of more than
passing academic interest.
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ACKNOWLEDGEMENTS |
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These studies were supported by National Institutes of Health Grant no. 41230 (to W. S. Zawalich) and Diabetes and Endocrinology Research Center Grant DK-45735, and a grant from the American Diabetes Association.
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FOOTNOTES |
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Address for reprint requests and other correspondence: W. S. Zawalich, Yale Univ. School of Nursing, 100 Church St. So., New Haven, CT 06536-0740 (E-mail: Walter.Zawalich{at}Yale.Edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 7 July 2000; accepted in final form 15 January 2001.
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