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Right arrow Cerebral protection

Ann Thorac Surg 2005;80:2242-2249
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

Resveratrol, a Natural Red Wine Polyphenol, Reduces Ischemia-Reperfusion–Induced Spinal Cord Injury

Sadi Kaplan, MD * , Gianluigi Bisleri, MD, Jeffrey A. Morgan, MD, Faisal H. Cheema, MD, Mehmet C. Oz, MD

Department of Surgery, Division of Cardiothoracic Surgery, College of Physicians and Surgeons, Columbia University, New York, New York

Accepted for publication May 9, 2005.

* Address correspondence to Dr Kaplan, 2 Dedeefendi Altay Sokak 4/11, Kurtulus, Ankara 06600, Turkey (Email: skaplan{at}bir.net.tr).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Severe neurologic injury still represents one of the most devastating complications after surgical repair of thoracoabdominal aneurysms. We therefore aimed to investigate the protective effect of resveratrol, a natural polyphenol antioxidant present in grapes and wine, in an experimental model of spinal cord ischemia-reperfusion injury.

METHODS: Sixteen rabbits were assigned either to group A (n = 8; receiving resveratrol, treated group) or group B (n = 8; control group, nontreated group) and underwent a 30-minutes period of spinal cord ischemia by clamping the abdominal aorta between the left renal artery and the aortic bifurcation. Fifteen minutes before clamping, rabbits received either intravenous resveratrol (100 µg/kg; group A) or normal saline (group B). Functional assessment with Tarlov score at 8, 16, and 24 hours postoperatively, histopathologic assessment of the spinal cord, measurements of malondialdehyde levels, and myeloperoxidase activity in the spinal cord were performed.

RESULTS: Neurologic impairment (Tavlov score for group A = 4.38 ± 1.19 and for group B = 0.38 ± 0.74, p < 0.001), malondialdehyde levels (47.71 ± 7.81 nmol/g versus 86.56 ± 11.39 nmol/g, p < 0.001), and myeloperoxidase activity (2.13 ± 0.72 nm/min versus 3.75 ± 0.78 nm/min, p = 0.002) were significantly lower in the resveratrol-treated animals. Additionaly, pathologically assessed outcomes were better in the resveratrol-treated group. The total number of motor neurons in the gray matter was significantly lower in the nontreated group than in the resveratrol-treated group (14.26 ± 2.94 versus 29.12 ± 3.64, p = 0.003).

CONCLUSIONS: Prophylactic use of resveratrol reduced neurologic injury and provided clinical improvement by attenuating the inflammatory milieu in the rabbit spinal cord ischemia/reperfusion model.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Despite recent advances in operative techniques, anesthetic management, and postoperative care, paraplegia still remains one of the most devastating complications after surgery of thoracoabdominal aneurysms, ranging in incidence from 2.9% to 32% [1]. Optimal protection of the spinal cord from ischemia-reperfusion (IR) injury is the cornerstone for success with thoracoabdominal aortic surgery. Therefore, different operative and nonoperative strategies have been developed to increase spinal cord tolerance to ischemia and minimize the incidence of neurologic complications after aortic surgery [2, 3].

Mechanisms of spinal cord injury are complex and multifactorial. In general, the process of IR injury consists of inadequate blood supply, hypoxic endothelial cell activation, leukocyte-endothelial cell interactions, and neutrophil-mediated injury [1, 4]. The endothelium has been shown to play a key role in the injury suffered after ischemia and reperfusion. Energy failure, excitotoxicity, and oxidative stress have been strongly implicated in the pathogenesis of neurologic injury after spinal cord ischemia [4, 5]. Neutrophil activation and oxidative stress lead to massive production of free O2 radicals, which in turn enhances inflammatory processes, such as lipid peroxidation, protein damage, and DNA damage [[5–7]. As a consequence, suppression of neutrophil activation and lipid peroxidation by decreasing oxidative stress appears to be an important mechanism in the protection of the spinal cord from IR injury [5, 6].

Resveratrol (3,5,4'-trihydroxy-stilbene), a natural polyphenol antioxidant present in grapes, and the active constituent of red wine, has been causatively associated with the cardiovascular benefits associated with moderate wine consumption (the so-called "French paradox") [8, 9]. In addition to its vasodilatory effects [9], resveratrol exerts significant antioxidant [9, 10], antiplatelet [10], and anti-inflammatory [11] effects. Moreover, resveratrol was recently found to enhance nitric oxide (NO) production in various organs, such as endothelial cells and heart [9, 12–14], and consequently to exert a beneficial effect on several organs in IR injury [9–14].

We therefore sought to investigate whether intravenous administration of resveratrol could have a protective role in an experimental model of spinal cord IR injury. To assess the ability of resveratrol to prevent neurologic injury, we evaluated the following outcome variables in rabbits: hind-limb motor function, histopathology (in particular the number of motor neurons in the spinal cords), and the effects of resveratrol against oxidative stress and neutrophil activation. The latter was assessed by measuring spinal cord tissue malondialdehyde levels and myeloperoxidase activity.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Design
Sixteen male New Zealand white rabbits (weight: 2.7 ± 0.2 kg) were used according to a protocol reviewed and approved by the Institutional Animal Care and Use Committee at Columbia University (protocol no: AAAA2127), in accordance with guidelines of the American Association for the Accreditation of Laboratory Animal Care. All experiments were performed in the Research Institute of Columbia University. In this experiment, we used a rabbit model for spinal cord ischemia, because of its unique segmental arterial blood supply to the spinal cord from the infrarenal aorta.

Chemicals
Resveratrol at 99% purity was purchased from Sigma Chemical (St. Louis, Missouri). Resveratrol solution was prepared freshly in a sterile manner with normal saline, avoiding exposure of the solution to light before its use.

Surgical Procedure
Preoperatively, the animals had access to tap water and food without restrictions. Rabbits were anesthetized by intramuscular injection of xylazine (5 mg/kg) and ketamine hydrochloride (35mg/kg), and maintained with a continuous inhalation of isoflurane (2%). After ensuring adequate depth of anesthesia, a 24G ear vein catheter was placed for administration of intravenous fluids and additional medications. An ear arterial catheter was placed to monitor arterial blood pressure and obtain blood samples for analysis. The animals were then intubated with an endotracheal tube and ventilated at a respiratory rate of 50 breaths per minute (Ohmeda VMC Anaesthesia Machine, Ohmeda, England) with a mixture of 100% oxygen and 2% isoflurane. An esophageal probe

(Datascope, Paramus, New Jersey) and warming blanket were used to record and support core temperature, respectively. Finally, an additional 24G catheter was placed into the femoral artery for measurements of arterial blood pressure distal to the abdominal aorta. Cefazolin was injected intravenously with single dose at 10 mg/kg, and normal saline solution (20 mL·kg–1 ·h–1) was continuously infused during the experiment.

After sterile surgical preparation, the abdomen was opened with a midline laparotomy incision and the retroperitoneal abdominal aorta was exposed. A careful dissection of the abdominal aorta was carried out immediately caudal to the origin of the left renal artery and proximal to the aortic bifurcation. Heparin sodium (100 IU/kg) was administered intravenously before aortic cross-clamping. Heart rate was continuously monitored (Datascope PasportXG; Datascope, Paramus, New Jersey) throughout the operation. Similarly, mean arterial blood pressures proximal to the abdominal aorta (through the marginal ear artery) and mean arterial blood pressure distal to the abdominal aorta (through the femoral artery) were recorded.

Finally, rabbits in group A (treated group) received an intravenous injection of resveratrol (100 µg/kg) while group B (nontreated group) received the same volume of normal saline. We administered resveratrol 15 minutes before occluding the aorta so that drug could be evenly distributed throughout the circulation before we created ischemia. Fifteen minutes after resveratrol or saline administration, the abdominal aorta was cross-clamped using atraumatic vascular clamps immediately caudal to the left renal artery and above the aortic bifurcation. After 30 minutes of ischemia, the clamps were removed, allowing for reperfusion. The 30 minutes of ischemic insult is based on the results of our previous experiments with this model [15]. The abdomen was then closed. Of note, before laparotomy and before closure of the laparotomy, animals were given buprenorphine (0.01 mg/kg/im [Reckitt and Coleman, Inc, Delaware]) for complete pain relief. The animals were allowed to recover from anesthesia before being returned to the holding area, where they could move freely in their cages and were provided with food and water ad libitum.

Arterial blood samples were taken at the following times in groups A and B: T0 = baseline (before drug/saline treatment), T1 = immediately before aortic occlusion, T2 = during aortic occlusion (10 minutes), T3 = 30 minutes after reperfusion, and T4 = 24 hours after reperfusion. Similarly, arterial blood gases and glucose levels were measured.

Assessment of Neurologic Function
The neurologic function of the animals was evaluated by one member of the research team, without knowledge of the treatment group, at 8, 16, and 24 hours after operation according to the Tarlov score as follows: 0 = complete paralysis; 1 = minimal movement; 2 = standing with assistance; 3 = standing alone; 4 = weak hop; 5 = normal hop.

Histopathology and Analysis of Biochemical Markers of Neurologic Damage
Immediately after the functional assessment, the rabbits were anesthetized by intramuscular injection of xylazine (5 mg/kg) and ketamine hydrochloride (35 mg/kg). The marginal ear vein and artery were cannulated and arterial blood samples were obtained for analysis. After achievement of adequate depth of anesthesia with sodium pentobarbital (50 mg/kg, administered intravenously), all rabbits were sacrificed and the spinal cord specimens were taken for pathologic assessment as well as for measurements of biochemical markers of neurologic damage.

As a marker of oxidative stress and free O2 radical–mediated damage, malondialdehyde levels were measured at the lumbar segments of spinal cords removed from sacrificed animals 24 hours after reperfusion. Malondialdehyde levels were measured in spinal cord tissue according to the method we previously described [15]. Data were calculated in nmol/g protein. Accumulation of neutrophils in the ischemic tissue has been thought to be a major mechanism responsible for reperfusion injury. Therefore, myeloperoxidase activity, an enzyme occurring almost exclusively in neutrophils, was measured to determine the neutrophil recruitment to the spinal cord during the IR period. Myeloperoxidase activity was determined using the method of Mullane and associates [16]. Myeloperoxidase enzymatic activity was measured spectrophotometrically at 460 nm using a Power Wave-X microplate reader (Biotek Instruments, Winooski, Vermont). The results were expressed as {Delta}Abs 460 nm/min. Malondialdehyde and myeloperoxidase values were expressed as the mean ± SD of duplicate determinations, and all assays were measured without prior knowledge as to the group of origin of each rabbit.

Histopathologic assessment of the spinal cord was performed with hematoxylin and eosin staining. Serial transverse sections (5 µm) were obtained at the L4-L5 level and stained with hematoxylin and eosin for evaluation. In 5 serial sections of each rabbit, the total number of motor neurons in the gray matter was counted and averaged.

Statistical Analysis
All statistics were performed using SPSS statistical software (release 10.0; SPSS, Chicago, Illinois). All values are presented as mean ± SD. Statistical analysis for comparisons of continuous variables in the groups was performed using Friedman two-way analysis of variance (ANOVA). Post hoc pairwise comparisons were made by Wilcoxon paired signed ranks test with Bonferroni correction. Comparisons between groups were made by Mann-Whitney U test. A p value less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Perioperative Data
No adverse events occurred during surgery. Operative data are shown in Table 1. Heart rate, esophageal temperature, arterial blood gases, and glucose levels were similar in the two groups at each time point. After 30 minutes of reperfusion, proximal aortic blood pressure was significantly higher in the resveratrol-treated group (group A = 59.2 ± 7.8 versus group B = 47.8 ± 4.4 mm Hg, p = 0.043). Furthermore, distal aortic blood pressure (residual arterial pressure) after 10 minutes of crossclamping was significantly higher in the reveratrol-treated group (group A = 9.6 ± 1.15 mm Hg versus group B = 3.1 ± 0.54 mm Hg, p = 0.008).


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  		Table 1. Operative Data: Heart Rate, Mean Proximal and Distal Aortic Pressure, Esophageal Temperature, Arterial Blood Gas, and Glucose Levels in Rabbits
 
Neurologic Functional Evaluation
As depicted in Figure 1, the mean Tarlov scores at each time point were significantly higher in the resveratrol-treated group that in the nontreated group, implying an improved functional neurologic outcome due to the use of resveratrol. At 8 hours, the Tarlov score was 4.38 ± 1.19 in the treated group and 0.50 ± 0.93 in the nontreated group, while at 16 and 24 hours, it was 4.38 ± 1.19 in the treated group and 0.38 ± 0.74 in the nontreated group. In the resveratrol-treated group, the neurologic status of all animals remained unaltered throughout the observational period as opposed to in the nontreated group, where 1 rabbit showed functional deterioration 8 hours after operation. In greater detail, 7 rabbits were in grade 5 and 1 rabbit in grade 3 at 8, 16, and 24 hours postoperatively in the resveratrol-treated group, as compared with in the nontreated group where 6 rabbits were in grade 0 and 2 rabbits in grade 2 at 8 hours, and 6 rabbits were in grade 0, 1 rabbit in grade 1, and 1 rabbit in grade 2 at 16 and 24 hours postoperatively. These result indicate that resveratrol protected the ischemic spinal cord from IR injury which translated into a clinical benefit.



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  		Fig 1. Mean neurologic scores of animals demonstrated a significant difference (p < 0.001) between control and treatment groups at each time point (8 hours, 16 hours, and 24 hours).

 
Histopathologic Evaluation
Histopathologic findings in the treated group were better than those in the nontreated group (Fig 2). The total number of motor neurons in the gray matter was significantly lower in the nontreated group than in the resveratrol-treated group (group A = 29.12 ± 3.64 versus group B = 14.26 ± 2.94, p = 0.003; Fig 3). Additionally, in the nontreated group, there was evidence among the remaining motor neurons of shrinkage and chromatic agglutination, eosinophilic neuronal degeneration, inflammatory cell accumulation, swollen motor neuron cells, and vacuolization of gray matter. Conversely, in the resveratrol-treated group, large motor neurons with no evidence of histologic change and minimal inflammatory cell accumulation were observed in the anterior horn (Fig 2).



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  		Fig 2. Hematoxylin and eosin staining (magnification, x100). (A) Group A, resveratrol-treated rabbits. (B) Group B, nontreated rabbits.

 


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  		Fig 3. Total number of motor neurons in the gray matter.

 
Malondialdehyde Levels
The malondialdehyde levels of resveratrol-treated groups were significantly lower than those of the nontreated group (group A = 47.71 ± 7.18 nmol/g versus group B = 86.56 ± 11.39 nmol/g; p < 0.001; Fig 4), thus indicating decreased oxidative stress in presence of resveratrol.



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  		Fig 4. Effect of resveratrol pretreatment on spinal cord neutrophil accumulation in rabbits 24 hours after surgery. Myeloperoxidase (MPO) activity ({Delta}Abs 460 nm/min) was determined to quantify neutrophil deposition in the ischemic reperfused spinal cord tissue.

 
Myeloperoxidase Activity
Spinal cord myeloperoxidase activity was significantly lower in the treated group as compared with the nontreated group (group A = 2.13 ± 0.72 nm/min versus group B = 3.75 ± 0.78 nm/min; p = 0.002; Fig 5). This suggests that resveratrol may act as an inhibitor of neutrophil adherence to the endothelium of spinal cord during the IR period.



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  		Fig 5. Malondialdehyde (MDA) levels of lumbar spinal cord segments 24 hours after reperfusion.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Surgery of the descending and thoracoabdominal aorta has been associated with post-operative paraparesis or paraplegia. The incidence of spinal cord ischemia and subsequent neurologic complications is primarily associated with the duration and severity of ischemia, as well as reperfusion injury [1, 5]. Therefore, different operative strategies have been developed in an attempt to minimize the incidence of neurologic complications after aortic surgery [1–3].

The endothelium has been shown to play a key role in spinal cord injury after IR. Additionally, oxidative stress has been significantly implicated in the pathogenesis of neurologic injury after spinal cord ischemia [4–7].

There is increasing evidence that free O2 radicals are generated in substantial quantities by ischemia and reoxygenation of the energy-depleted cells, and that they contribute to tissue injury [7]. Unstable radicals are potent initiators of protein degradation and lipid peroxidation, which in turn can lead to cell membrane dysfunction and eventually cell death [5, 7]. These radicals also directly induce endothelial damage and cytokine production in brain cells via the activation of transcriptional factors, and coordinate with them to enhance neutrophil chemotactic mechanisms [6] Finally, free O2 radicals produce lipid peroxidation as well as protein and DNA damage [5, 7] It has been demonstrated that free O2 radical–mediated lipid peroxidation is a self-perpetuating process that can spread to the circumferential undamaged neuronal tissue, leading to further collapse of microcirculation and to irreversible damage to myelin and axons [5].

We therefore investigated the potential protective properties of resveratrol, a polyphenolic compound present in grapes and red wine, that has recently been studied as an effective antioxidative agent [9, 10], especially with respect to its cardioprotective properties [8, 9]. Besides its antioxidant effect, several biological actions of resveratrol, such as its vasodilatory effects on blood vessels and anti-inflammatory effects, have been well documented [10, 11, 13]. Several studies in non neuronal organs, such as heart and kidney, have demonstrated the ability of resveratrol to reduce IR injury [17, 18]. In vivo antioxidant properties of resveratrol have been attributed to its stimulation of NO formation [10, 14] as well as its ability to act as a potent scavenger of free O2 radicals generated by both neutrophils and the endothelium [11, 18]. Resveratrol-induced brain protection has been demonstrated by several authors. Wang and colleagues [19] demonstrated that resveratrol can cross the blood–brain barrier and reduce the infarct size in rats subjected to focal cerebral ischemia. Huang and associates [20] showed that resveratrol, in lower doses than used in our experiment, can reduce infarct size in Long-Evans rats subjected to focal cerebral ischemia. Sinha and associates [21] demonstrated that chronic treatment with resveratrol for 21 days can significantly improve motor performance in rats as well as significantly decrease infarct volume. Wang and associates [22] demonstrated that resveratrol can decrease oxidative stress by increasing heme oxygenase activity and suppressing the inflammatory response through inhibition of interleukin-6 production in mixed glial cells. The neuroprotective effects of resveratrol has been attributed primarily to membrane protection by means of neutralization of free O2 radicals [22], as well as through improvement of brain perfusion [20].

In our study, the spinal cord malondialdehyde levels (indicative of oxidative stress lipid peroxidation in spinal myelin) at 24 hours after aortic occlusion were significantly elevated in the nontreated group, implying the involvement of free O2 radicals in neuronal injury. Conversely, we observed a less considerable increase in malondialdehyde content of spinal cord after IR when resveratrol was administred before aortic occlusion.

Leukocyte-endothelial cell interaction and subsequent leukocyte adhesion to vascular endothelium, which is a crucial step in the cell-mediated damage, is important in the pathophysiology of spinal cord tissue injury. Expressed on endothelial cells, ICAM-1, VCAM-1, and P-selectin are important in leukocyte-endothelial cell interactions. They mediate the binding of leukocytes to endothelial cells through interactions with their counterreceptors on leukocytes [23]. Circulating leukocytes adhere to the vessel wall using these molecules and enter the tissue, release toxic substances, such as proteolytic enzymes and cytokines, generating free O2 radicals and causing a considerable amount of damage to the vascular endothelium and adjacent tissues [23]. Furthermore, leukocyte recruitment to the ischemic tissue may contribute significantly to spinal cord injury by reducing microvascular blood flow, initiating postischemic microvascular thrombosis, and releasing free O2 radicals [20, 24]. It has been demonstrated that endothelial free O2 radical generation plays an important role in spinal cord injury by upregulating intercellular adhesion molecules and increasing leukocyte recruitment to the ischemic spinal tissue [24] Therefore, it is possible that attenuation of leukocyte adhesion to the vessel wall and infiltration to the ischemic tissue as well as decreasing oxidative stress during the IR period may be potentially beneficial in preventing spinal cord ischemia/repefusion injury. In our study, myeloperoxidase activity, as a marker of leukocyte activation in the ischemic tissue, increased after spinal IR in the nontreated group but was significantly reduced in the resveratrol-treated group. These data, which confirm the neuroprotective effects of resveratrol in spinal cord ischemia, suggest that the mechanism of this action may involve inhibition of leukocyte infiltration in the injured spinal cord.

The results of the present study show that intravenous administration of resveratrol prior to ischemia had a protective effect on rabbit spinal cord motor neurons. Histopathology demonstrated that the total number of motor neurons in the gray matter was significantly lower in the nontreated group than that in the resveratrol-treated group. Additionally, in the nontreated group, there was evidence among the remaining motor neurons of shrinkage and chromatic agglutination, eosinophilic neuronal degeneration, inflammatory cell accumulation, swollen motor neuron cells, and vacuolization of gray matter. Finally, the histopathologic benefits of resveratrol treatment were confirmed during the neurologic functional assessment. The mean Tarlov scores at each time point were significantly higher in the resveratrol-treated group that in the nontreated group, implying an improved functional neurologic outcome due to the use of resveratrol.

Spinal cord is a very sensitive organ to oxygen deprivation, therefore maintainance of blood flow to spinal cord is vital to maintain its integrity and functions. Interruption of blood flow to the spinal cord sets in motion molecular processes that prime the vasculature for amplification of the inflammatory response, which can rapidly lead to tissue injury on reestablishment of flow. Various components of the ischemic vascular milieu can potentially affect the subsequent reperfusion response including reduced oxygen tension, substrate deprivation, waste product accumulation, or pH. Various studies of the mechanisms underlying neuronal death due to spinal ischemia have indicated the importance of inadequate blood supply in this complex pathology. Eventually, exposure of spinal tissue to reduced blood supply initiates numerous biochemical events leading to loss of functional integrity and ultimately to cell death. Thus, factors or agents that modulate blood flow to ischemic spinal cord tissue during aortic crossclamping may be important in decreasing spinal cord injury formation after aortic crossclamping. Therefore, in this experiment, we measured proximal and distal aortic blood pressures during crossclamping and examined the impact of the vasodilatatory effects of resveratrol on the vasculature as well as it effect on spinal cord injury. It is interesting that in the resveratrol-treated group, whose spinal integrity was better preserved, there were higher residual arterial pressures during clamping compared with the nontreated group. It is possible that higher pressures during clamping promoted enhanced collateral flow to the ischemic segment of cord.

This study is part of a set of experiments in which our group has focused on the protective effects of resveratrol on various tissues in different experimental models. Before conducting these experiments, we performed a detailed Medline research regarding resveratrol, and we examined the dosages of resveratrol used in previous experiments for brain protection and for the other organs. Before the current experiment, we investigated protective effects of resveratrol (at various concentrations) on heart and lung tissues in a mouse heart-lung transplantation model (presented at The European Society for Cardiovascular Surgery 2004 meeting, and papers are under evaluation), on the endothelium of arterial and venous coronary artery bypass grafts [25]. Thus, based on the encouraging results of our previous experiments with resveratrol, we selected this concentration in this experiment. The findings of this study indicate that resveratrol exerts protective effects on the spinal cord of rabbits at 100 µg/kg. However, the dose of resveratrol used in this study may not be the optimal dose to obtain maximal resveratrol protection. Therefore, its optimal protective dose or dose range for spinal cord and for other tissues should be determined by conducting additional studies.

In conclusion, preischemic infusion of resveratrol protects the spinal cord from IR injury in rabbits. This protection is probably related to decreased oxidative stress in the ischemic spinal cord tissue and decreased neutrophil infiltration. Moreover, the resveratrol-treated group had higher residual arterial pressures during clamping. This suggests that resveratrol treatment may have promoted enhanced collateral flow to the ischemic segment of spinal cord. Despite further studies being required for a more complete understanding of the underlying protective mechanism, correct dosage, and timing of administration, this natural antioxidant polyphenol may represent a useful tool in the armamentarium of surgeons for the prevention of neurologic deficits associated with surgical treatment of descending aortic and thoracoabdominal aortic pathology.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by Institutional Research Funds of Columbia University. Doctor Kaplan was supported by a research grant from the Turkish Ministry of Health. The authors wish to thank Erdem Karabulut, PhD, Department of Biostatistics, Hacettepe University, Ankara, Turkey, for the statistical analysis.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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