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1 Department of Neurology
2 Institute of Laboratory Animal Science, Friedrich Schiller University, Jena, Germany
3Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Sciences Center, San Antonio, TX, USA
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Abstract |
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(Received 18 October 2004;
accepted after revision 11 February 2005;
first published online 17 February 2005)
Corresponding author M. Schwab: Department of Neurology, Friedrich Schiller University, 07740 Jena, Germany. Email: matthias.schwab{at}med.uni-jena.de
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Introduction |
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In the fetal sheep we have demonstrated that an increase in cerebral vascular resistance (CVR) contributes a portion of the overall increase in fetal peripheral vascular resistance following fetal exposure to betamethasone (Schwab et al. 2000). This increase in CVR led to a decreased cerebral blood flow (CBF). The vascular changes were associated with a decline of complex properties of electrocortical activity (Schwab et al. 2001b). Using fetal magnetencephalography we were able to show that cortical brain function in the human fetus was also altered by antenatal glucocorticoid therapy (Schleussner et al. 2004). An increased cerebrovascular resistance might contribute to the altered fetal brain function and could be potentially harmful to the fetus especially in conditions that require maximal vasodilatation. The purpose of our present study was to obtain further information on glucocorticoid effects on CBF at the gestational ages when glucocorticoids are administered clinically. At this time, fetal cardiovascular (Unno et al. 1999; Shinozuka et al. 2000) and cerebrovascular system (Müller et al. 2002) undergo a critical stage of maturation and the fetal hypothalamic–pituitary–adrenal (HPA) axis begins to become responsive (Norman et al. 1985). Our previous study on acute effects of antenatally administered glucocorticoids on CBF was carried out at 0.87 of gestation, a stage of development when the fetal HPA axis has already begun to mature (Schwab et al. 2000). Between 0.73 of gestation and term, endogenous adrenocorticotrophic hormone (ACTH) concentrations in fetal sheep rise about 1 pg ml–1 day–1 eventually resulting in an increase of cortisol plasma concentrations that starts around 0.85 of gestation (Norman et al. 1985). In the present study, we administered betamethasone at the dose used clinically at 0.73 of gestation before this preparturient increase in the activity of the fetal HPA axis to examine if the betamethasone-induced increase of CVR is a general phenomenon across late gestation. This age corresponds to 29 weeks of gestation in human pregnancy and is therefore more likely to reflect the stage of development at which glucocorticoids are administered to induce lung maturation in premature human infants. Moreover, considerable development of the limits of cerebral autoregulation and, thus, of vasoactive mediators in the cerebral vasculature occurs between 0.73 and 0.87 of gestation (Müller et al. 2002). We hypothesized that cerebrovascular maturation and preparturient increase in the activity of the fetal pituitary–adrenal axis may lead to an age-dependent effect of antenatally administered glucocorticoids on fetal CBF.
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Methods |
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Experimental procedures were approved by the animal welfare commission of Thuringia, Germany. Fifteen Long-Wool Merino x German Blackheaded Mutton cross-bred ewes of known gestational age were brought into the animal facilities at least 5 days before surgery and kept in rooms with controlled light–dark cycles (12 h light–12 h dark: lights off at 18.00 h and lights on at 06.00 h) always in sight of at least one other ewe. Hay, hay cubes and water were provided ad libitum. After food withdrawal for 24 h, surgery was performed at 106 ± 1 dGA (term 150 dGA). Following 1 g of ketamine I.M. (Ketamin 10, Atarost, Germany) and 0.04 mg kg–1 atropine sulphate I.M. (Atropin, Braun, Germany), anaesthesia was induced by 4% halothane (Fluothane, Zeneca, Germany) using a face mask. Ewes were intubated and anaesthesia was maintained with 1.0–1.5% halothane in 100% oxygen. Ewes were instrumented with catheters inserted into the common carotid artery for blood sampling, into the external jugular vein for postoperative administration of drugs and into the trachea to induce hypercapnia by CO2 insufflation. Following hysterotomy, fetuses were instrumented with polyvinyl catheters (Rüschelit, Rüsch, Germany) inserted into the left common carotid artery for arterial blood pressure recordings, blood gas and reference blood sampling of microsphere measurements. Additional catheters were placed into the left external jugular vein for drug application and into the saphenous vein for the injection of fluorescent microspheres (FMSs). Tips of the catheters were advanced into the ascending aorta, and the anterior and posterior vena cava, respectively. FABP was corrected for hydrostatic pressure differences using a catheter placed into the amniotic cavity. Wire electrodes (LIFYY, Metrofunk Kabel-Union, Germany) were implanted into the left and right supra-scapular muscles, into the cartilage of the sternum for electrocardiogram (ECG) recordings and into the uterine wall to record myometrial activity. All ewes and fetuses received 0.5 g ampicillin (Ampicillin, Ratiopharm, Germany) intravenously and into the amniotic sac twice a day during the first three postoperative days. Metamizol (Arthripur, Atarost, Germany) was administered intravenously to the ewe (30–50 mg kg–1) as an analgesic for at least 3 days. All catheters were maintained patent via a continuous infusion of heparin (Heparin-Natrium, Ratiopharm, Germany) at 15 IU ml–1 in 0.9% NaCl solution delivered at 0.5 ml h–1.
Experimental protocol
Continuous 24 h a day baseline recordings of FABP, amniotic pressure, ECG (to determine cardiac side-effects of microsphere injection) and uterine EMG were started at 110 dGA (Fig. 1). To ensure stable physiological conditions, fetal and maternal arterial blood samples were taken daily at 08.00 h for measurement of blood gases and pH values using a blood gas analyser (ABL600, Radiometer, Copenhagen, Denmark; measurements corrected to the ewe's body temperature). To minimize the influence of circadian cardiovascular rhythms on CBF measurements, all experiments were started at 09.00 h.
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CBF measurements were repeated 24 h and 48 h after the start of treatment (Fig. 1). A second hypercapnic challenge was performed subsequent to the CBF measurement at 24 h. At the end of the experiment ewes were anaesthetized with 4% halothane and fetuses were delivered by Caesarean section. Fetuses were killed by exsanguination while under halothane anaesthesia. To facilitate a standardized section of brain tissue samples fetal brains were perfused via the right carotid artery with a 2% formaldehyde solution at a perfusion pressure of 60 mmHg after a 5 min rinse with heparinized physiological saline. Fetal catheter positions were checked and fetal brains were removed after fixation. Ewes were killed by intravenous injection of 16% pentobarbital sodium solution (Narcoren, Aventis, Germany).
Data acquisition
FABP and amniotic pressure were measured continuously using calibrated pressure transducers (Braun, Melsungen, Germany) connected to the fetal carotid and amniotic catheters. Arterial blood and amniotic pressures as well as the uterine electromyogram (EMG) and the ECG were amplified (models 5900 and 6600, Gould, Valley View, OH, USA) and recorded throughout the baseline and infusion period on a multichannel chart recorder (TA11, Gould). In addition, data were digitized using a 16 channel A/D board (DT 2801F, Data Translation, Marlborough, MA, USA) at a sample rate of 1024 s–1 (ECG), 128 s–1 (uterine EMG) or 64 s–1 (FABP and amniotic pressure).
CBF measurements
FMSs were sonicated and vortexed for 5 min and drawn up into a sterile syringe immediately before injection. Approximately 1.5 x 106 FMSs of 10 µm diameter (FluoSpheres, Molecular Probes, Eugene, OR, USA) were injected into the fetal posterior vena cava via the catheter in the saphenous vein. Beginning 25–30 s before FMS injection, a reference blood sample of 6 ml (1.5 ml NaCl solution from dead space of the catheter and 4.5 ml blood) was withdrawn from the ascending aorta into a heparinized glass syringe at a rate of 2 ml min–1 with a syringe pump (sp200i, World Precision Instruments, Berlin, Germany). To define physiological conditions during CBF measurement blood gas values obtained 2 min before and immediately after FMS injection were averaged. The amount of fetal blood withdrawn for FMS reference flows and for blood samples was replaced by maternal arterial blood immediately after withdrawal of each reference blood sample. The number of FMSs injected was large enough to ensure an adequate number of FMSs per brain tissue sample (> 400) in order to meet the requirements of a systematic error of less than 10% (Buckberg et al. 1971). Cardiovascular side-effects were not observed with the FMS number injected in our experiment.
Microsphere processing
Following necropsy, 11 brain tissue samples weighing 0.3–2.0 g were dissected in a standardized manner from the right hemisphere of the fetal brain whereas the left hemisphere was kept for future histological examination. Preparation included cortical structures (samples of frontal, median, parietotemporal, parietooccipital and occipital cortex), subcortical structures (samples of striatum, thalamus and hippocampus), structures of the hindbrain (samples of mesencephalon, pons and medulla) and the cerebellum. After weighing, brain tissue samples and the reference blood samples were put into glass containers and exposed to 4 M KOH solution containing 1% Tween 80 (Sigma-Aldrich, Deisenhofen, Germany) for digestion. To optimize the digestion process the glass containers were warmed twice to 50°C for 4 h. Great care was taken to avoid higher temperatures during the warming period since this would have endangered the stability of the microsphere beads. Reference blood samples were not warmed because of their tendency to coagulate. After filtration of the digested tissue samples through a 7 µm pore sized membrane (Bekipor ST7 AL3, Bekaert, Belgium) microsphere dyes were extracted with 500 µl o-Xylol (Sigma-Aldrich, Deisenhofen, Germany) and stored in a freezer to avoid evaporation of the solvent.
Fluorescence measurement was performed with a fluorescence spectrometer (LS 50B Luminescence Spectrometer, Perkin Elmer, Shelton, CT, USA) using quartz glass cuvettes (Suprasil QS 105.200, Hellma, Müllheim, Germany). Fluorescence intensity was read at constant emission wavelengths (393 nm for blue, 452 nm for blue-green, 512 nm for yellow-green, 559.5 nm for orange and 641 nm for crimson). In preliminary trials, these wavelengths had provided the highest degree of linearity between the number of FMS and fluorescence intensity. According to the reference sample method of Rudolph & Heymann (1967) absolute flows were calculated by the formula:
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Data and statistical analysis
Data from an earlier study with a very similar protocol performed at 128 dGA (Schwab et al. 2000) allowed us to compare the effects of betamethasone on fetal CBF and CVR at 0.73 and 0.87 of gestation. Non-parametric tests were used for comparison since data were not normally distributed (Kolmogorov-Smirnov test). Changes in CBF, CVR and blood gases within the experimental groups were tested for significance by Wilcoxon's sign rank test. The Mann-Whitney rank sum test was used for comparison between the experimental groups and between the two gestational ages. All results are given as the mean ± S.E.M. P-values < 0.05 were considered to be significant.
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Results |
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All animals studied had normal arterial blood gas values throughout the protocol and did not show any signs of labour in the uterine electromyogram. Arterial blood gases did not change throughout the baseline period and did not differ between the vehicle and the betamethasone treated group (Table 1). There were no significant differences in fetal weights between the vehicle (1.9 ± 0.14 kg) and the betamethasone treated group (1.7 ± 0.37 kg). Baseline FABP was not different between both groups. In the vehicle treated fetuses, FABP remained unchanged throughout the experiment (41 ± 1 mmHg during baseline recordings versus 41 ± 1 mmHg after 24 h infusion). FABP of betamethasone treated fetuses showed a marked increase of approximately 25% from 40 ± 1 mmHg to 50 ± 2 mmHg within 24 h of infusion (P < 0.01). FABP remained elevated over the entire treatment period.
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Under baseline conditions, CBF to the hindbrain was about 50% higher than to subcortical regions and about 100% higher than to the cerebral cortex (Fig. 2). These differences show the heterogeneous distribution of fetal CBF. In conjunction, CVR was highest in the cerebral cortex and lowest in the hindbrain (Fig. 2). CBF values in the cerebral cortex were only about 50% (P < 0.01), in subcortical regions about 60% (P < 0.05) and in the hindbrain about 65% (P < 0.05) of those found at 0.87 of gestation. Corresponding to the rise of CBF between 0.73 and 0.87 of gestation, CVR in the cerebral cortex at 0.73 of gestation was about 45% higher than at 0.87 of gestation (P < 0.05, Fig. 2).
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In vehicle treated fetuses, CBF and CVR remained unchanged throughout the infusion period in all brain regions investigated (Figs 3 and 4). In betamethasone treated fetuses, 24 h of infusion led to a pronounced decrease of CBF (P < 0.05, Fig. 3). In comparison to the vehicle treated group, this decrease was significant in the cerebral cortex (P < 0.01) and the hindbrain (P < 0.05; Fig. 3). In comparison to baseline, CBF decreased following 24 h of betamethasone infusion by 38 ± 4% in the hindbrain, 39 ± 6% in the subcortical regions and 38 ± 3% in the cerebral cortex (P < 0.05, Fig. 3). The CBF decrease at 24 h of betamethasone infusion was mediated by a significant rise of CVR in the cerebral cortex (P < 0.01) and the subcortical regions (P < 0.05; Fig. 4) in comparison to the vehicle treated group. In comparison to baseline, the increase in CVR after 24 h of betamethasone exposure was significant for all brain regions investigated ranging from 111 ± 16% in the cortical to 129 ± 29% in the subcortical regions (P < 0.05; Fig. 4).
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Effects of betamethasone on cerebral hypercapnic vasodilatation
CO2 insufflation increased the Pa,CO2 and decreased the pH values significantly independent of the treatment (P < 0.05, Table 2) while Pa,CO2 increased due to maternal hyperventilation (P < 0.05, Table 2). Under baseline conditions, hypercapnic challenge induced a significant increase in CBF in all brain regions except the hippocampus that was not different between the groups (P < 0.05, Fig. 5). The CBF increase was most pronounced in the hindbrain in which CBF rose by 95 ± 14% whereas the CBF increase in the subcortical and cortical regions was about 87 ± 18% and 80 ± 14%, respectively. The CBF increase was mediated by a decrease in CVR that ranged from 34 ± 9% in the subcortical regions to 42 ± 12% in the hindbrain (P < 0.05, Fig. 6). While regional CBF and CVR responses to hypercapnia at 24 h of vehicle infusion were statistically not different from baseline values in vehicle infused controls, CBF of the betamethasone treated fetuses showed an attenuated response to hypercapnia after 24 h of betamethasone exposure (Figs 5 and 6). Although a significant hypercapnic increase in CBF occurred in all brain regions, this CBF increase did not reach the level of that during the hypercapnic challenge at baseline (P < 0.05, Fig. 5). Thus, hypercapnic CBF to three of the five cortical regions was significantly lower in betamethasone than in vehicle treated fetuses (P < 0.05, Fig. 5). The diminished CBF response to hypercapnia 24 h after onset of betamethasone exposure was mediated by an attenuated vasodilatation in response to the CO2 exposure. Although the CVR decrease was still significant in all brain regions, it was significantly lower in the hindbrain and in the cerebral cortex than during the hypercapnic challenge at baseline (P < 0.05, Fig. 6).
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The relative CBF decrease following 24 h of betamethasone infusion was similar to that previously shown at 0.87 of gestation (P < 0.05, Fig. 7) despite the lower absolute CBF at the younger age (P < 0.05, Fig. 2). CBF to the cerebral cortex decreased to 62 ± 3% compared to 63 ± 14% at 0.87 of gestation, to the subcortical regions to 61 ± 6% compared to 57 ± 8% and to the hindbrain to 62 ± 4% compared to 52 ± 9%. At both gestational ages fetal CBF recovered after 48 h of betamethasone treatment. At this time, CBF to the cerebral cortex had decreased to 67 ± 15% compared to 72 ± 23% at 0.87 of gestation, to the subcortical regions to 68 ± 18% compared to 65 ± 21% and to the hindbrain to 63 ± 23% compared to 72 ± 22%.
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Discussion |
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In the last trimester fetal cardiovascular maturation is apparent by a decrease of fetal heart rate and an increase of FABP (Shinozuka et al. 2000). Maturation of the cardiovascular system may have contributed to the different absolute CBF values measured at both gestational ages. At 0.73 of gestation, cerebral autoregulatory capacity is still immature (Müller et al. 2002). The similar glucocorticoid effects on CVR and CBF at both gestational ages, however, are highly indicative that the mediator systems responsible for maintaining fetal CBF are already mature at 0.73 of gestation and are targeted by glucocorticoids largely independent of gestational age during the last trimester. Although fetal adrenals are still hyporesponsive and cortisol levels are low at 0.73 of gestation (Challis & Brooks, 1989), the number of glucocorticoid receptors does not differ between between 0.73 and 0.87 of gestation (Brodhun et al. 2003). This observation may explain similar betamethasone effects at both gestational ages although definitive statements about the activity of glucocorticoid receptors cannot be made with the present knowledge. The pronounced vasoconstrictor glucocorticoid effects seem to be specific for fetal development as they could not be shown in the peripheral and uterine circulation of the ewe (Schwab et al. 2002).
Previous studies using ultrasound Doppler flowmetry to examine glucocorticoid effects on CBF in human fetuses have yielded controversial results. Initial studies reported that the pulsatility index in the middle cerebral artery remained unchanged 48 h and 96 h after dexamethasone administration (Rotmensch et al. 1999) as well as 24 and 72 h after a second dose of betamethasone (Cohlen et al. 1996). Conversely, a recent study found a significant decrease in the pulsatility index in the middle cerebral artery 24 h after betamethasone treatment (Edwards et al. 2002). However, the use of Doppler flowmetry to estimate CBF involves several limitations since flow velocities tend to be variable and global and regional CBF cannot be estimated directly.
We took several precautions to reduce the impact of confounding variables. All experiments were performed at the same time of the day to minimize the potential impact of circadian rhythms on CBF measurements (Endo et al. 1990). We carefully avoided microsphere injections during uterine contractures which are known to affect FABP and heart rate (Brace & Brittingham, 1986) and are associated with a fall of fetal Pa,O2, changes in electrocortical activity and sleep state (Nathanielsz et al. 1980).
Mechanisms of glucocorticoid-induced cerebral vasoconstriction remain to be elucidated. They are likely to involve a gestational age-independent depletion of vasoactive mediators which are crucial for maintaining a stable CBF in the fetal brain, such as prostaglandins and nitric oxide (NO) (Leffler & Busija, 1987; Northington et al. 1997). Glucocorticoids inhibit the synthesis of prostaglandins that are important vasodilatative mediators in the cerebral circulation during the perinatal period (Wagerle & Mishra, 1988; Leffler et al. 1994) by diminishing the expression of cyclooxygenase 2 (Figueroa et al. 1999; Wood et al. 2003). Furthermore, glucocorticoids are able to influence the NO system at various sites in the nitric oxide synthase pathway either directly (Wallerath et al. 1999; Whitworth et al. 2002) or indirectly (Dumont et al. 1998, 1999). Indirect glucocorticoid effects on the NO system may be mediated via the prostaglandin system since the activity of endo-thelial (eNOS) and neuronal nitric oxide synthase (nNOS) in the cerebral vascular bed is positively regulated by prostaglandin E2 via EP3 receptors (Dumont et al. 1998, 1999). The impact of glucocorticoids on the prostaglandin and NO system could also explain the diminished vasodilator response to hypercapnia after betamethasone since both mediators play a major role in mediating vasodilatation during hypercapnia (Leffler et al. 1994; Faraci & Heistad, 1998). Compensatory up-regulation in these two target systems as well as the rise in FABP during betamethasone exposure may diminish glucocorticoid effects on fetal CBF eventually resulting in a recovery of fetal CBF as observed after 48 h of betamethasone infusion.
Other vasoactive mediators involved in direct vasoconstrictor glucocorticoid effects on peripheral resistance vessels may also contribute to the increased CVR. Femoral arteries from betamethasone exposed sheep fetuses are more sensitive to depolarizing potassium ions and less sensitive to the vasodilators bradykinin and forskolin than resistance vessels from control fetuses (Anwar et al. 1999). Femoral arteries of dexamethasone treated fetuses also exhibit higher sensitivity to endothelin-1 that coincides with an increased ETA-receptor binding measured by autoradiography (Docherty et al. 2001). The effects of betamethasone on CBF and CVR may have implications for the brain of preterm infants in addition to the effects described above on peripheral vasoconstriction. The glucocorticoid-induced FABP increase possibly prevents circulatory shock during birth and enables the preterm infant to reach higher Apgar scores, which are known to be associated with a lower incidence and severity of periventricular and intraventricular haemorrhages (Berger et al. 2002). The rise of CVR during the treatment probably represents a protective mechanism against intraventricular haemorrhage (IVH) by restricting CBF increases following hypoxic events (Chihara et al. 2003). Thus, the changes in CBF and CVR may explain positive results of clinical trials that report a lower incidence of IVH in betamethasone treated fetuses (Leviton et al. 1993; Elimian et al. 1999). Beneficial effects of antenatal glucocorticoids on the incidence of cerebral haemorrhage are of great importance since IVH occurs in approximately 3% of all prematurely born babies (Larroque et al. 2003), increases perinatal mortality considerably and leads to neurological sequelae in 35% of infants affected by high-grade IVH (Whitelaw, 2001).
In contrast to the potential beneficial effects of fetal exposure to glucocorticoids, the decreased cerebral vasodilator response to hypercapnia observed during betamethasone treatment may have potentially disadvantageous effects by impairing the neuroprotective effect of CO2 during hypoxia (Vannucci et al. 1995) thereby increasing the vulnerability of the fetal brain to hypoxic–ischaemic brain damage. Indeed, we have shown increased neuronal necrosis after repeated umbilical cord occlusions in betamethasone treated sheep fetuses (Schwab et al. 2004b). Due a loss of functional CBF reserve chances for a normal neurological outcome may deteriorate, especially if the baby is born during the treatment. Parallel to the glucocorticoid effects on CBF shown here, we found betamethasone-related acute alterations of the neuronal function (Schwab et al. 2001b) and of the neuronal cytoskeleton and synaptic structure (Antonow-Schlorke et al. 2001; Schwab et al. 2001a). Apparently, these changes also occur independent of the gestational age during the last trimester (Antonow-Schlorke et al. 2002; Schmidt et al. 2002; Colberg et al. 2004).
In conclusion, exposure of the fetus to synthetic glucocorticoids has similar effects on both neuronal structure and function as well as on CBF and CVR at the two stages of fetal development studied. These stages represent two phases during the preparturient increase in activity of the fetal pituitary–adrenal axis that orchestrates the maturation of a variety of fetal organ systems in preparation for postnatal life (Thomas et al. 1978; Magyar et al. 1980; Liggins, 1994). The potential cerebrovascular side-effects of the treatment should be considered if glucocorticoids are administered to enhance fetal lung maturation, especially as the fetal betamethasone plasma concentration reached with the dose regime used in the present study is less than half of the fetal betamethasone peak concentration after the standard clinical dose of 12 mg betamethasone I.M. to the mother (Schwab et al. 2004a). Of importance in relation to human therapeutic regimens, we have been able to show that the glucocorticoid effects on synaptic density and cytoskeletal proteins can be reproduced in the primate brain at the dose and via the route of administration used clinically (Antonow-Schlorke et al. 2003). The significance of the observations reported for the neurodevelopmental outcome of the fetus and the newborn remains to be determined.
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P < 0.01, 
P < 0.05 in comparison of both groups.
