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Article |
a Trigger for the Initiation of Endometrial Prostaglandin F2 Release at Luteolysis in Cattle?1
a Laboratory of Reproductive Endocrinology, Faculty of Agriculture, Okayama University, Okayama 700–8530, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(TNF) in the regulation of luteolytic prostaglandin (PG) F2 release by the bovine endometrium, the effect of TNF- on PGF2 output by the endometrial tissues in vitro was investigated and compared with the effect of oxytocin (OT). Furthermore, the presence of specific receptors for TNF in the bovine endometrium during the estrous cycle was determined. Endometrial slices (20–30 mg) taken from six stages of the estrous cycle (estrus: Day 0; early I: Days 2–3; early II: Days 5–6; mid-: Days 8–12; late: Days 15–17; and follicular: Days 19–21), as determined by macroscopic examination of the ovaries and uterus, were exposed to TNF (0.06–6 nM) and/or OT (100 nM). OT stimulated PGF2 output at the follicular stage and at estrus (P < 0.001), but not at the late luteal stage. On the other hand, the stimulatory effects of TNF on PGF2 output were observed not only at the follicular stage but also at the late luteal stage (P < 0.001). When the endometrial tissues at late luteal stage were simultaneously exposed to TNF (0.6 nM) and OT (100 nM), the stimulatory effect on PGF2 output was higher than the effect of TNF or OT alone (P < 0.05). Specific binding of TNF to the bovine endometrial membranes was observed throughout the estrous cycle. The concentration of TNF- receptor at the early I luteal stage was less than the concentrations at other luteal stages (P < 0.01). The dissociation constant (Kd) values of the endometrial membranes were constant during the estrous cycle. The overall results lead us to hypothesize that TNF may be a trigger for the output of PGF2 by the endometrium at the initiation of luteolysis in cattle.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(PGF2) is released by the uterus in a pulsatile manner to cause regression of the corpus luteum (CL) in ruminants [1]. The pulsatile release of oxytocin (OT) by the neurohypophysis and/or CL stimulates the production of pulsatile uterine PGF2 [2]. Thus, luteal and/or neurohypophyseal OT and uterine PGF2 comprise a positive feedback loop, and activation of this feedback loop may be responsible for the generation of each pulse of PGF2 [3, 4]. It has been suggested that the initial PGF2 release triggers the release of additional OT from the CL and neurohypophysis [5–7]. However, the stimulus that initiates secretion of PGF2 is not known. Furthermore, although immunization against OT and administration of an OT antagonist block luteolysis in sheep and goats [8–10], the blockade of uterine OT receptors with a specific OT antagonist from Day 15 until Day 22 of the estrous cycle affects neither luteolysis nor the duration of the estrous cycle compared with values in control heifers [11]. Therefore, we hypothesize that PGF2 production by the bovine endometrium is regulated by not only OT but also one or more other factors that initiate PGF2 release.
It has been suggested that tumor necrosis factor (TNF-) induces PGF2 output by rat [12] and human endometrial cells [13]. Moreover, TNF mRNA and immunoreactive TNF protein have been detected in oviducts, placentas, uteri, and embryonic tissues in mice [14, 15], rats [16], and humans [17, 18]. Interestingly, the TNF gene products in the endometrium are most prominent in the late secretory phase of the human menstrual cycle [18] and in diestrus-II of the mouse estrous cycle [15]. These findings imply that TNF plays a role in the termination of the ovarian cycle in primates and rodents.
In the present study, to determine the physiological significance of TNF in the initiation and regulation of luteolytic PGF2 secretion by the bovine uterus, we investigated the stimulatory effect of TNF on PGF2 output by the bovine endometrium during the estrous cycle as well as the specific receptors for TNF in the bovine endometrium through the estrous cycle.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Uteri of Holstein cows were obtained at a local abattoir within 30 min after exsanguination and were transported on ice to the laboratory within 1–1.5 h. The stages of the estrous cycle were determined by macroscopic observation of the ovaries and uterus (Table 1). The endometrial strips were dissected from the myometrial layer with the scalpel. Intercaruncular endometrial tissues from the uterine horn, ipsilateral to the CL, were used for the tissue culture. For studies on the specific binding of TNF, intercaruncular and caruncular endometrial tissues from the uterine horn, ipsilateral to the CL, were frozen rapidly in liquid nitrogen and then stored at -80°C until the analyses.
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Endometrial Tissue Culture
Endometrial strips described above were washed 3 times in sterile saline containing 100 IU/ml penicillin and 100 µg/ml streptomycin. The tissue was then cut into small pieces (approximately 20–30 mg) with a scalpel and subsequently washed in sterile saline. After hanging the tissues with steel needles (Gamakatsu Co., Hyogo, Japan), the individual endometrial tissues were placed in culture glass tubes (12 x 75 mm) containing 3 ml of culture medium (Dulbecco's Modified Eagle's Medium and Ham's F-12 medium 1:1 [v:v]; Sigma Chemical Co., St. Louis, MO; #D8900) supplemented with 0.1% BSA (Boehringer Mannheim GmbH, Mannheim, Germany; #735078), 100 IU/ml penicillin and 100 µg/ml streptomycin. The tissues were incubated in a shaking water bath at 37°C. The media were continuously gassed with 5% CO2 in air during incubation. After 1 h of preincubation, each sample of endometrial tissue was transferred into a new tube with fresh medium and simultaneously was stimulated with recombinant human TNF (DAINIPPON Pharmaceutical Co., Ltd., Osaka, Japan; lot. no. HF-13) and/or OT (Teikoku Hormone MFG Co., Tokyo, Japan) for the following experiments.
Time- and Dose-Dependent Effects of TNF on PGF2 Output
Endometrial tissues at the follicular stage of the estrous cycle, obtained from 3 cows, were exposed to TNF (0, 0.06, 0.6, and 6 nM) for 0.5, 1, 2, or 4 h; each experiment was performed in triplicate.
Cyclic Changes of PGF2 Output in Response to TNF and/or OT
The endometrial tissues taken from cows at six stages of the estrous cycle—estrus (n = 3), early I luteal (n = 3), early II luteal (n = 4), mid-luteal (n = 3), late luteal (n = 5), and follicular (n = 3)—were exposed to TNF (0.6 nM) and/or OT (100 nM) for 4 h; each experiment was performed in triplicate.
At the end of each experiment, the conditioned media were collected in tubes with 10 µl stabilizer (0.3 M EDTA, 1% aspirin [Sigma; #A2093], pH 7.3), and frozen at -30°C until the PGF2 assay. The tissues were blotted on filter paper and weighed.
PGF2 Determination
The concentrations of PGF2 in the culture media were determined with an enzyme immunoassay described previously [23]. The PGF2 standard curve ranged from 0.016 ng/ml to 4 ng/ml, and the ED50 of the assay was 0.25 ng/ml. The intra- and interassay coefficients of variation were 7.4% and 11.6%, respectively. The output of PGF2 was calculated as nanogram of PGF2 per gram of endometrial tissue and expressed as a percentage of control values.
Membrane Preparation
The endometrial tissues taken from cows at six stages of the estrous cycle—estrus (n = 3), early I luteal (n = 3), early II luteal (n = 3), mid-luteal (n = 3), late luteal (n = 3), and follicular (n = 3)—were thawed and minced with scissors in ice-cold 25 mM Tris-HCl buffer containing 300 mM sucrose, 2 mM EDTA, and Complete-Mini (Boehringer Mannheim GmbH; #1836153), pH 7.4. Then the endometrial tissues were homogenized in the same buffer with a Polytron homogenizer (Kinematica, Lucerne, Switzerland) using three 10-sec bursts separated by 1-min cooling periods in ice.
The homogenate of endometrial tissue was subsequently centrifuged at 800 x g for 10 min to remove tissue debris, and the supernatant was collected and centrifuged at 30 000 x g for 20 min to obtain the plasma membrane pellet. The pellets were resuspended and recentrifuged in the same buffer to dissociate TNF from binding sites. The pellets then were washed three times by centrifugation for 10 min at 30 000 x g, decanted, and resuspended in 25 mM Tris-HCl containing 10 mM MgCl2 (pH 7.4). All steps of the endometrial membrane preparations were conducted at 4°C. The protein concentrations of the membrane preparations were determined by the method of Osnes et al. [24], using BSA as a standard.
Radioreceptor Assay
TNF was iodinated with carrier-free Na125I (Amersham International plc, Buckinghamshire, England; IMS 30) by the iodogen method as described previously [25]. The specific activity of [125I]-labeled TNF was 324.3 Ci/mmol and the maximum bindability was 20%.
Preliminary studies with the endometrial membranes (the mid-luteal stage of the estrous cycle) were carried out to establish the optimal conditions of incubation time and temperature for maximal binding of [125I]-labeled TNF to the membranes. To reduce nonspecific binding, culture glass tubes were coated overnight with complete calf serum, and then binding assays were initiated. Nonspecific binding was assessed for each level of tracer through co-incubation with a 300-fold excess of unlabeled TNF (120 nM; 10 µl). The incubation mixture consisted of approximately 5 x 104 dpm (0.4 nM) [125I]-labed TNF (50 µl) and 10 µg protein (50 µl). The total volume of the mixture was 110 µl. The specificity of [125I]-labeled TNF binding was determined by incubating increasing amounts of unlabeled recombinant bovine interferon- (IFN; Novartis Pharmaceutical Co., Basel, Switzerland) or recombinant human interleukin-1 (IL1; DAINIPPON Pharmaceutical Co., Ltd.; lot. no. HL-18) with a constant amount of [125I]-labeled TNF (5 x 104 dpm/tube). All reagents were prepared in 10 mM Tris containing 10 mM MgCl2 (pH 7.5), 3.0 mM NaN3, and 0.1% (w:v) BSA.
The incubation was terminated by transferring the tubes into ice-cold water and by adding the same buffer into the assay tube. Bound and free tracers were separated by centrifugation at 3000 x g for 40 min at 4°C. Supernatants were decanted immediately, and the pellets were counted for [125I] in a 
counter (Pharmacia-Wallac 1282; Compugamma CS, Turku, Finland) at an efficiency of 82%. Nonspecific binding accounted for < 35% of total binding.
Statistical Analysis
The data are shown as the mean ± SEM of values obtained in 3–5 separate experiments, each performed in triplicate. The statistical significance of differences in concentration of PGF2 in culture media between the control and treated groups was assessed by one-way analysis of variance followed by Bonferroni's multiple comparison test (GraphPad PRISM; Graphpad Software, Inc., San Diego, CA). For the statistical analyses of differences in PGF2 output, the percentage relative to the control was used. The data on binding of TNF to endometrial membranes were analyzed with the LIGAND program [26] using nonlinear iterative curve-fitting procedures [27]. The initial parameters were calculated by Scatchard analysis [28] and were then iteratively refined until the weighted sum of squares was minimized. The goodness of fit for the selected model was analyzed by a "run's test." Different models (one or two binding sites) were compared using F-test statistics to determine whether a change in the model resulted in a significant reduction in the weighted sum of squares. The criteria for rejecting or accepting a particular model were based on the calculated probability values [26]. The statistical significance of differences in the binding parameters of TNF receptors was assessed by one-way analysis of variance followed by Bonferroni's multiple comparison test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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on PGF2 Output
TNF stimulated PGF2 output by the bovine endometrium (the follicular stage of the estrous cycle) in a time- (Fig. 1) and dose-dependent (Fig. 2) manner (P < 0.05). Although TNF had no effect on PGF2 output after 0.5 or 1 h of incubation (Fig. 1), PGF2 output increased significantly after 2 and 4 h of incubation with TNF to 221% (P < 0.01) and to 425% (P < 0.001) of the basal output, respectively. PGF2 output by the endometrium increased (P < 0.01) in response to TNF at all the doses used (Fig. 2). The highest stimulations (approximately 740% of the basal output; P < 0.001) were observed when the endometrium was incubated with 0.6 or 6 nM TNF.
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Cyclic Change of PGF2 Output in Response to TNF or OT
Basal output of PGF2 by the bovine endometrium varied during the estrous cycle (Table 2). PGF2 output reached the highest value (639 ± 21 ng/g tissue) at estrus (Table 2) and declined at the early II luteal stage (186 ± 12 ng/g tissue). OT increased PGF2 output at the early I luteal, follicular, and estrus stages of the estrous cycle (Fig. 3a; P < 0.01). In contrast to OT, TNF significantly stimulated PGF2 output at all the stages of the estrous cycle (Fig. 3b; P < 0.001). The stimulatory effect of TNF on PGF2 output by the endometrium at the follicular stage (760% of the basal output) was higher than the stimulatory effects in the other stages (from 222% to 405% of the basal output). The stimulatory effect of OT and TNF on the PGF2 output by the endometrial tissues at the late luteal stage (401% of the basal output) was significantly higher than that of OT (140% of the basal output) or TNF (333% of the basal output) alone (Fig. 4; P < 0.05).
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Binding Characteristics
A preliminary assay of the binding of TNF to the bovine endometrial membranes was carried out to test the conditions for the radioreceptor assay described in Materials and Methods. The maximal binding of TNF to the bovine endometrial membranes was reached after 24–48 h at 38°C (Fig. 5a). Specific binding increased with increasing protein concentrations (Fig. 5b). Figure 5c shows the displacement curves of [125I]-labeled TNF with two related cytokines. The binding was highly specific for TNF. There was little or no competition for TNF binding sites by IFN or IL1.
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TNF receptor concentrations varied during the estrous cycle (Table 3; P < 0.01). TNF receptor concentrations initially increased from the early I to early II luteal stages of the estrous cycle and then remained constant during the mid- and late luteal stages of the estrous cycle. Then, TNF- receptor concentrations tended to decrease from the mid-luteal stages to the estrus (Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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stimulates PGF2 output by the bovine endometrium, and that specific binding sites for TNF are present in the bovine endometrium throughout the estrous cycle. Moreover, our results indicated that OT stimulates the PGF2 output by the bovine endometrium only in the follicular, estrus, and early I stages but not in the late luteal stage, as judged by macroscopic examination of the ovaries and uterus (Fig. 3). Moreover, the stimulatory effect of OT on PGF2 output at the follicular stage of the estrous cycle (248% of the basal output) tended to be lower than that at estrus (305% of the basal output). These results support a previous report of an in vitro study that the bovine endometrium was sensitive to OT only during the periovulatory period but not during the late luteal stage of the estrous cycle [29]. Thus, one might speculate that OT plays a role in amplifying the uterine PGF2 secretion only after initiation of luteolysis in cattle. On the other hand, Schams et al. [30] demonstrated in an in vivo study that the response of PGF2 secretion to the injection of OT into the aorta abdominalis was already observed during the late luteal phase. A similar stimulation of endometrial PGF2 output has been reported when OT given into the systemic circulation of cows on cycle Days 17–19, i.e., the late luteal phase [31, 32]. Such a difference in results may be due to the systems used (i.e., in vitro versus in vivo). Therefore, the relative role of OT in the initiation of luteolysis in cattle requires further investigation. In the present study, a simultaneous exposure of OT and TNF additively affected PGF2 output by the endometrium at the late luteal stage, whereas OT showed no significant effect on PGF2 output at this stage (Fig. 4). Although the productions of TNF gene and protein in the uterus have been clearly demonstrated in mice [15], rat [16], and human [18], it has not been determined whether TNF is synthesized in the bovine endometrium. It remains to be determined whether TNF is present in the bovine endometrium, and if it is present, what its source is. Recently, we found the maximal concentration of TNF at the late luteal stage in the bovine CL [33]. Thus, the luteal TNF could stimulate PGF2 output by the endometrium, which would then initiate luteolysis in cattle. However, it has not been demonstrated that TNF is involved in the pulsatile release of PGF2. Further in vivo and in vitro studies are needed to clarify the role of TNF in luteolysis in cattle.
As shown in Figure 2, TNF was physiologically active at very low concentrations (0.06–6 nM) compared with OT (100 nM), although in preliminary experiments, lower concentrations of OT were also stimulatory (data not shown). Moreover, the concentrations of TNF that stimulated PGF2 output were comparable to the affinity of the endometrial TNF receptor (Table 3). Consequently, our present results indicate that PGF2 output induced by TNF occurred through ligand binding to the TNF receptors. In the present study, the concentration of TNF receptors fluctuated during the estrous cycle, although the Kd value of TNF receptors in the endometrium was constant. It has been demonstrated that the abundance of mRNA encoding TNF receptors was strongly dependent upon stage of the estrous cycle in mouse, and in situ hybridization signals in uterine cells were much more intense during diestrus II, when the mouse uterus had been primed with estrogens and then exposed to high concentrations of progesterone (P4) [34]. In the present study, the concentrations of TNF receptors in the bovine endometrium were higher during each of the luteal stages except the early I luteal stage. This change in the concentration of endometrial TNF receptors was similar to the changes in luteal P4 secretion [30]. Moreover, it is suggested that expression of the TNF receptor gene is controlled by female steroid hormones [34]. Therefore, we assume that luteal P4 may be involved in the regulation of the TNF receptor concentration in the bovine endometrium as well as in the mouse endometrium.
Although the concentration of TNF receptors in the bovine endometrium at the early I luteal stage was lower than concentrations at the other luteal stages, TNF strongly stimulated endometrial PGF2 output through the entire estrous cycle. This stimulatory effect was greater at the follicular stage (760% of the basal output) than that at the late luteal stage (381% of the basal output), even though the TNF receptor concentrations at these stages were not significantly different (Table 3). These results suggest that the endometrial responsiveness to TNF is not regulated only by changes in the population density of TNF receptor in the bovine endometrium. It is well known that there are two types of TNF receptors (type I and type II) [35]. However, it is not possible to identify which type of receptors was observed in the present binding study. The intracellular domains of these types of receptors are strikingly different, and this is reflected in the transduction of disparate signals [36, 37]. Therefore, one could speculate that the biological activity of TNF is under complex control, and that the effects of TNF depend not only on how much of its receptor is produced, but also on the relative availability of the two membrane-bound receptors. On the other hand, the localization of TNF receptors in bovine endometrium has been demonstrated. Recently, we have found that the target of TNF in stimulating PGF2 production in bovine endometrium is stromal cells, but not epithelial cells, and that the target of OT is epithelial cells, but not stromal cells [38]. Thus, the different responsiveness to TNF or OT during the estrous cycle could be due to the changes of the proportions of stromal and epithelial cells. Further studies are needed to clarify these points.
In conclusion, the present study indicates the presence of functional TNF receptors in the bovine cyclic endometrium and suggests a possible role for TNF in the regulation of endometrial PGF2 production in cattle. Moreover, the overall results of this study lead us to hypothesize that TNF may play a novel role in the control of PGF2 secretion in the initiation of luteolysis in cattle.
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ACKNOWLEDGMENTS |
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antiserum; the DAINIPPON Pharmaceutical Co., Ltd. (Osaka, Japan) for recombinant human TNF and recombinant human IL1; the Teikoku Hormone MFG Co. (Tokyo, Japan) for synthetic OT; and the Novartis Pharmaceutical Co. (Basel, Switzerland) for recombinant bovine IFN. |
FOOTNOTES |
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1 This research was supported by Grants-in-Aid for Scientific Research (No. 11556054 and 11460129) and a Research Fellow (No. 07809) of the Japan Society for the Promotion of Science (JSPS) from the Ministry of Education, Science, Sports and Culture of Japan. D.J.S. was a postdoctoral fellow supported by JSPS. 
2 Correspondence: Kiyoshi Okuda, Laboratory of Reproductive Endocrinology, Division of Animal Science and Technology, Faculty of Agriculture, Okayama University, Okayama 700–8530, Japan. FAX: 81 86 251 8388; kokuda{at}cc.okayama-u.ac.jp
3 Current address: Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10–718 Olsztyn-Kortowo, Poland.
Accepted: December 31, 1999.
Received: June 11, 1999.
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D. J. Skarzynski, M. M. Bah, K. M. Deptula, I. Woclawek-Potocka, A. Korzekwa, M. Shibaya, W. Pilawski, and K. Okuda Roles of Tumor Necrosis Factor-{alpha} of the Estrous Cycle in Cattle: An In Vivo Study Biol Reprod, December 1, 2003; 69(6): 1907 - 1913. [Abstract] [Full Text] [PDF]
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M. P.B. Wijayagunawardane, C. Gabler, G. Killian, and A. Miyamoto Tumor Necrosis Factor {alpha} in the Bovine Oviduct During the Estrous Cycle: Messenger RNA Expression and Effect on Secretion of Prostaglandins, Endothelin-1, and Angiotensin II Biol Reprod, October 1, 2003; 69(4): 1341 - 1346. [Abstract] [Full Text] [PDF]
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 S. K. Banu, J. A. Arosh, P. Chapdelaine, and M. A. Fortier Molecular cloning and spatio-temporal expression of the prostaglandin transporter: A basis for the action of prostaglandins in the bovine reproductive system PNAS, September 30, 2003; 100(20): 11747 - 11752. [Abstract] [Full Text] [PDF]
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J. A. Arosh, S. K. Banu, P. Chapdelaine, V. Emond, J. J. Kim, L. A. MacLaren, and M. A. Fortier Molecular Cloning and Characterization of Bovine Prostaglandin E2 Receptors EP2 and EP4: Expression and Regulation in Endometrium and Myometrium during the Estrous Cycle and Early Pregnancy Endocrinology, July 1, 2003; 144(7): 3076 - 3091. [Abstract] [Full Text] [PDF]
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D. J. Skarzynski, J. J. Jaroszewski, M. M. Bah, K. M. Deptula, B. Barszczewska, B. Gawronska, and W. Hansel Administration of a Nitric Oxide Synthase Inhibitor Counteracts Prostaglandin F2-Induced Luteolysis in Cattle Biol Reprod, May 1, 2003; 68(5): 1674 - 1681. [Abstract] [Full Text] [PDF]
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J. Parent, P. Chapdelaine, J. Sirois, and M. A. Fortier Expression of Microsomal Prostaglandin E Synthase in Bovine Endometrium: Coexpression with Cyclooxygenase Type 2 and Regulation by Interferon-{tau} Endocrinology, August 1, 2002; 143(8): 2936 - 2943. [Abstract] [Full Text] [PDF]
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J. A. Arosh, J. Parent, P. Chapdelaine, J. Sirois, and M. A. Fortier Expression of Cyclooxygenases 1 and 2 and Prostaglandin E Synthase in Bovine Endometrial Tissue During the Estrous Cycle Biol Reprod, July 1, 2002; 67(1): 161 - 169. [Abstract] [Full Text] [PDF]
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M. Bogacki, W.J. Silvia, R. Rekawiecki, and J. Kotwica Direct Inhibitory Effect of Progesterone on Oxytocin-Induced Secretion of Prostaglandin F2{alpha} from Bovine Endometrial Tissue Biol Reprod, July 1, 2002; 67(1): 184 - 188. [Abstract] [Full Text] [PDF]
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H. Taniguchi, Y. Yokomizo, and K. Okuda Fas-Fas Ligand System Mediates Luteal Cell Death in Bovine Corpus Luteum Biol Reprod, March 1, 2002; 66(3): 754 - 759. [Abstract] [Full Text] [PDF]
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K. Okuda, Y. Uenoyama, B. Berisha, I. G. Lange, H. Taniguchi, S. Kobayashi, S.-i. Kobayashi, A. Miyamoto, and D. Schams Estradiol-17{beta} Is Produced in Bovine Corpus Luteum Biol Reprod, December 1, 2001; 65(6): 1634 - 1639. [Abstract] [Full Text] [PDF]
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D. J. Skarzynski, S. Kobayashi, and K. Okuda Influence of Nitric Oxide and Noradrenaline on Prostaglandin F2{alpha}-Induced Oxytocin Secretion and Intracellular Calcium Mobilization in Cultured Bovine Luteal Cells Biol Reprod, October 1, 2000; 63(4): 1000 - 1005. [Abstract] [Full Text]
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D. J. Skarzynski, Y. Miyamoto, and K. Okuda Production of Prostaglandin F2{alpha} by Cultured Bovine Endometrial Cells in Response to Tumor Necrosis Factor {alpha}: Cell Type Specificity and Intracellular Mechanisms Biol Reprod, May 1, 2000; 62(5): 1116 - 1120. [Abstract] [Full Text]
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