Effect of high saturated free fatty acids feeding on progression of renal failure in rat model of experimental nephrotoxicity.
Gentamicin is a widely used aminoglycoside antibiotic to treat various Gram +ve and Gram -ve infections. Its nephrotoxic action is attributed to its potential to damage the proximal convoluted tubules (PCT) and glomerular basement membrane . Oxidative stress mediated damage is the main character of its nephrotoxicity [2, 3]. Substituting the elementary dietary constituents by fats, rich in saturated free fatty acids (SAFFAs), has a negative impact on the ability of the body to cope with various patho-physiological conditions . In spite of that, these fats are used extensively in food industry. This is due to their physiochemical properties that give food products the besought texture . SAFFAs induce their deleterious effects through several mechanisms . They stimulate a specific type of immune system related receptors called TLRs (toll like receptors). TLRs are expressed in most body cells including myocytes, hepatocytes and adipocytes . Their activation triggers the inflammatory pathway related to insulin resistance [6, 7]. From the other hand, SAFFAs induce visceral obesity. When the visceral adipose tissue is engorged with fats, it does not merely act as a fat depot but it also acts as an endocrine gland releases the inflammatory cytokines related to insulin resistance . Disposition of the source of cellular energy from carbohydrates to fats rich in SAFFAs increases the release of free radicals during mitochondrial internal respiration. This results in higher oxidative stress . Our study aimed to find the impact of replacing the essential dietary elements in food by SAFFAs on progression of renal damage in rats model of gentamicin induced nephrotoxicity.
MATERIALS AND METHODS
Animals and diet
Male Sprague-Dawley rats, weighing 19014.7 g and obtained from animal house of Universiti Sains Malaysia, were used in the study. They were housed at the animal transit room with 4 animals per cage at room temperature with 12:12-h light-dark cycle. All the procedures were performed according to guidelines of the Animal Ethics Committee, Universiti Sains Malaysia for the use of animals in research. Time dependant effect for nephrotoxicity induction and the required sample size were estimated according to a preliminary study. In which 80 mg/kg/day gentamicin sulphate was injected intraperitoneally for 30 days with a continuous monitoring of body weight and urine flow rate. Serum and urine samples were collected throughout the treatment period to assess progression of renal dysfunction. Maximum nephrotoxicity was obtained on day 16 and sustained up to the end of the treatment period (Figure 1). Then twenty four days were chosen as the treatment period to all the treatment protocols. Before starting the experiment, rats were left for habituation and fed the standard commercial rodents chow with free access to water ad libitum. Rats were divided into four groups (10 animals for each); C; received a standard rodents chow for 8 weeks, HFD; received the experimental high fat diet during the same period, HFDG; received genatmicin sulphate intraperitoneally in a dose 80 mg/kg/day along with the high fat diet during the last 24 days of the feeding period and G; received the standard rodents chow and was given gentamicin sulphate as mentioned above. The experimental diet was formulated to supply equal quantity of all nutrients as a percentage of energy with the exception of fat and carbohydrates (Tablei). It was stored in refrigerator at 4[degrees]C after being prepared and was given daily to the animals. The main oil sources of the high fat diet were palm kernel oil and palm oil whose fatty acids profile contains lauric acid, myristic acid and palmitic acid (10). Cholesterol and cholic acid were added to induce hypercholestremia. Cholic acid suppresses cholesterol conversion to bile acids through interfering with the activity of 17-[alpha] hydroxylase enzyme .
[FIGURE 1 OMITTED]
Body weight and food intake (corrected for spillage) were monitored continuously during the treatment period. 24 hr urine and fasting tail vein serum samples were obtained on days (34, 50 and 58) of the high fat diet feeding period which corresponds to days (0, 16 and 24) of gentamicin treatment period. At the end, they were subjected to an acute study in which the rats underwent a surgical session under anesthesia for blood pressure measurement.
Serum and urine biochemical analyses
Serum and urine samples were collected to measure creatinine, sodium and potassium concentrations. Creatinine clearance (Cr c) and both absolute and fractional excretions of the electrolytes were calculated using the conventional equation. Creatinine was measured using Jaff reaction (picric acid test) while the electrolytes were measured using the flame photometer (Jenway PFP7). 24 hr urinary protein excretion was measured using Cromassia Brilliant Blue test.
The rats were fasted for (12-14h) with free access to drinking water before starting with the acute study. They were anaesthetized with 60 mg/kg (body weight) of sodium pentobarbital (Nembutal[R], CEVA, France) and kept at 37[degrees]C to maintain body temperature. After that neck incision was performed and the right jugular vein was catheterized with polyethylene tubing (PE50, Portex limited Hythe, Kent, England) to supply fluids during the surgery (N/S was given at rate 6 ml/h). For the blood pressure measurement, the left carotid artery was cannulated with a fluid filled catheter (PE50, Portex limited). It was connected to pressure transducers (P23 ID Gould, Statham Instrument, Nottingham, UK) linked to a computerized data acquisition system (Power Lab[R], ADInstrumentat, Sydney Australia). At the end of the experiment, the animals were euthanized with the lethal dose of pentobarbital sodium (200 mg/kg). Then the fat depot was collected for obesity index measurement and both kidneys were collected for measuring kidney index and to perform biochemical studies on renal homogenate and histological studies.
Renal homogenate study
One kidney from each rat was homogenized using 1 ml for each gram of kidney tissue of ice chilled 150 mM potassium chloride solution and tissue homogenizer (Homogenizer MSE, England). TBARS (thio-barbituric-acid-releasing-substance) level was measured according to the established method.
Tissues were fixed using formalin solution. Then they were subjected to the conventional histology procedures; procession, sectioning, staining and slide mounting. Hematoxylin and eosin were used to stain the slides.
Results were expressed as mean [+ or -] s.e.m. One way ANOVA followed by Tukey test was used for statistical analysis at 95% confidence level using students pack SPSS program version 16.
Gentamicin co-administration along with the high fat diet has reduced the weekly increment of the body weight as compared to the other groups. This was accompanied by an observable decline in calories uptake through out the gentamicin treatment period (Figures 2 and 3). Urine flow rate dropped consistently throughout the high fat diet feeding period. It was increased substantially after gentamicin injection for rats injected with the standard rodents chow and for those fed with the high fat diet (Table 2).
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
Results of renal function study showed a higher decline in renal function for HFDG as compared to G group. This was obviously seen in results of serum creatinine and creatinine clearance. Creatinine clearance dropped to half the value of the control for G group and dropped to about the quarter for HFDG group while serum creatinine was as twice as its control for G group and thrice for HFDG group at the end of the treatment period (Table 2). Tubular function study revealed higher fractional excretion for both sodium and potassium in renal failure groups. The increase was higher for HFDG group that FE [Na.sup.+] has increased by about 10 times for HFDG group as compared to control and by about four times for G group while FE IK has multiplied by about three times the control for G group and about eighteen times for HFDG group at the end of the treatment period (Table 2). Urinary protein excretion was obviously increased for HFDG group as compared to other groups without showing any statistical significance. Moreover, it did not show any change for G group as compared to control. The results suggest higher glomerular and tubular dysfunction for HFDG group as compared to G group (Table 2). These observations were confirmed in the histology study (Table 3, Figure 4). Acute tubular necrosis of the PCT (proximal convoluted tubules) was spotted in all the slides of HFDG group. The intensity of the damage was ranging from mild to moderate to severe. While for G group, it was ranging from very mild to mild and the damage was not observable at all in some slides (Table 3, Figure 4). The slides showed also glomerular changes as characterized by glomerular congestion, mesangial hyperproliferation, glomerular membrane hyalinization and DCT (distal convoluted tubules) ectasia by protein cast. The changes were ranging from mild to severe in HFDG while they were mild or absent in G group (Table 3, Figure 4). These histological changes were accompanied by a noticeable increase of kidney index in HFDG group while it was slightly increased in G group. From the other hand, MDA (malonyldialdehyde), a biomarker of oxidative stress was elevated in the renal homogenate of all gentamicin treated groups. The increase was highly increased after gentamicin co-administration along with the high fat diet (Table 2).
[FIGURE 4 OMITTED]
Unlike the other treated groups, HFD group showed significantly higher blood pressure parameters (DBP, SBP and MAP) (p < 0.05) as compared to control. Gentamicin co-administration along with high fat diet has dropped the blood pressure as compared to that in the rats with the high fat diet feeding (Table 2).
The obesity index was significantly higher for the group fed with the high fat diet while it was reduced after gentamicin co-administration (Table 2).
Gentamicin is a nephrotoxic drug. Our preliminary study showed maximum nephrotoxicity after 16 days of gentamicin injection, which stayed high up to the end of the treatment period. Latency time and pattern of nephrotoxicity induction rely on so many factors; as the dose, its timing, number of times the dose is given and the responsiveness of the animal to the nephrotoxic action . Both glomerulonephritis (GN) and proximal convoluted tubules (PCT) tubulonephritis were the prominent outcomes of gentamicin-induced nephrotoxicity. They were more severe in the renal failure group fed with the high fat diet. Gentamicin as a cationic amino glycoside has an aptitude to bind to glomerular basement membrane glycoproteins. This results in glomerular damage characterized by glomerular congestion, leukocyte infiltration, mesangial hyper proliferation and hyalinization of the glomerular basement membrane [2, 3]. Mesangium plays a role in regulation of the glomerular filtration rate. When the glomerular membrane destruction occurs, the mesangium contract and hyperproliferate and this results in reduction of the single nephron glomerular filtration rate . From the other hand, gentamicin is selectively taken by the brush border membrane of the PCT lining cells resulting in accumulation of gentamicin intracellularly. When the intracellular concentration exceeds the toxic threshold, it induces lysosomal, mitochondrial and cell membrane damage. This results in loss of the reabsorptive function and some degenerative and necrotic changes that lead to exodus of cellular constituents and sloughing of the lining cells. Consequently tubular occlusion and decrease in glomerular filtration incur [2, 3]. These changes were obviously correlated with the results of the biochemical study that showed a decline in creatinine excretion and tubular handling of electrolytes which are related to the loss of glomerular filtration and tubular reabsorptive functions respectively. The higher severity of nephrotoxicity in the rats fed with the experimental high fat diet confirms the negative impact of the SAFFAs on the ability of cells to cope with toxic effect of drugs. It was suggested that, uptake of high amount of SAFFAs create some intracellular biochemical changes characterized by increasing the preparedness of the mitochondria to unleash more free radicals after being subjected to any injury. Mechanism of gentamicin induced nephrotoxicity is closely related to oxidative stress . Gentamicin interferes with the oxidative phosphorelation in the mitochondria resulting in higher oxidative stress . MDA (Malonyl dialdehyde) which is one of the famous biomarkers of the oxidative stress was increased in gentamicin injected groups. The increase was higher in rats which were under the experimental high fat diet feeding. This confirms the role of oxidative stress in gentamicin induced nephrotoxicity and the cooperative role of the SAFFAs for its increase. It is suggested that SAFFAs promote the inflammatory pathway. It was found that, SAFFAs activate a specific type of receptors called TLRs (toll like receptors). TLRs are immune system related receptors. They are expressed in muscles, immune cells and hepatocytes. A subtype of these receptors (TLRs13) is affected by SAFFAs. Its activation triggers a cascade of sequential reaction of intracellular pathways related to more inflammatory genes expression [4, 15]. This results in an outflow of cytokines as; interleukine-1, interleukine6 and interleukine-8 and tumor necrotic factor [alpha] (TNF-[alpha]), acute phase proteins as C-reactive proteins (CRP) and some chemo-attractant factors as MIF (Macrophage inhibitory factor) and macrophage chemotactant factor (MCP-1) . From the other hand, Uptake of high amount of SAFFAs triggers engorgement of the visceral adipose tissue with fat . This effect was obviously seen in results of obesity index which was significantly increased after the experimental high fat diet ingestion. Some recent studies found that, visceral adipose tissue does not merely act as fat depots. It acts also as an endocrine gland secrete the mentioned inflammatory cytokines and macrophage chemotactant factors . The histology slides showed higher inflammatory response for rats injected with gentamicin along with the high fat diet (Table 4, Figures 4). Distal convoluted tubules ectasia by protein cast was one of the prominent outcomes of gentamicin induced renal failure. It results from leakage of some low g.m.wt proteins as albumin in the tubular filtrate after glomerular membrane damage. Proteins in the tubular filtrate precipitate a specific type of glycoprotein called Tamm Horsfall protein. This protein is normally secreted by distal convoluted tubules (DCT) and precipitates when proteins exist in the filtrate . Presence of protein cast was mild in some slides of renal failure rats under standard rodents chow feeding while it was higher in the renal failure rats under the experimental high fat diet feeding (Table 3, Figure 4). This also confirms the higher incidence of glomerular damage for rats, which were under the high fat diet feeding. This view is closely related to with the observed protein urea in the renal failure rats fed with the high fat diet. In spite of polyurea, serum concentrations of both sodium and potassium were slightly decreased for HFDG group without showing any statistical significance and were indifferent for the other groups. This may be due to loss of equimolar amount of water along with the lost amount of sodium and the elaborate mechanism the body uses to maintain [K.sup.+] concentration constant through regulation of cellular [Na.sup.+]-[K.sup.+] pump and renal excretion of potassium . The observed decline in the weekly increment of the body weight in HFDG group can be ascribed to the stronger incidence of nephrotoxicty. Reduction of body weight in renal failure occurs due to fluid loss or the hyperuremia which triggers anorexia and cachexia . Our results showed that high fat diet administration has increased the visceral obesity. Previous studies revealed that visceral fat does not merely act as a fat depot but it acts also as an endocrine gland releases inflammatory cytokines. This in turn triggers a higher inflammatory response to any injurious factor . Our results showed a higher inflammatory reaction to gentamicin when it is co-administered along with the high fat diet. Although our results showed that gentamicin intervention has interfered with building up of adiposity. This may be attributed to the anorexia which accompanied the renal failure . In spite of polyurea and fluid loss, results of acute study did not show any change in hemodynamic parameters for G group. This may be due to the compensatory mechanisms that regulate the pressure . High fat diet produced a prominent increase in pressure parameters. Previous studies showed that ingestion of high amount of SAFFAs induces hyperinsulinemia. Hyperinsulinemia causes salts and fluid retention and encourages sympathetic outflow . The fluid retention was obvious in results of tubular function assessment for the HFD group in which the values of the absolute and fractional excretion of electrolytes was dropped. Beside that SAFFAs relent purging of inflammatory cytokines which are culminated in deteriorating the endothelial function. Endothelium plays an important role in blood pressure regulation [22, 23]. Gentamicin co-administration along with high fat diet has decreased the pressure parameters as compared to HFD group. This may be attributed to the persistent polyurea that accompanied renal failure up to the end of treatment period . Although in renal failure, over-activation of the renin angiotensin system is expected. Overall, co-administration of high fat diet along with gentamicin significantly intensifies the progression of gentamicin induced nephrotoxicity.
Feeding behaviour has a great impact on progression of pathophysiological conditions. Ingestion of saturated fat rich food hastens progression of diseases in a mechanism related to elevation of oxidative stress. Furthermore, ingestion of the saturated fat rich food hastens toxicity of drugs. Therefore, it is very important to monitor the feeding behaviour along with drugs administration.
School of pharmacy/ Universiti Sains Malaysia is gratefully acknowledged for financial support. We also thank The Advance Medical and Dental Institute (AMDI) USM for technical support in the experiment.
DECLARATION OF INTEREST
All the authors declare that the research was carried out with the support of IPS-University Sains Malaysia. The facilities were supported by school of pharmacy/ Universiti Sains Malaysia. The authors declare that conflicts of interest do not exist.
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Zaid O. Ibraheem (1) *, Munavvar A. Sattar (1), Nor A. Abdullah (2), Hassaan A. Rathore (1), Edward J. Johns (3)
(1) School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, 11800 Penang, Malaysia; (2) Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; (3) Department of Physiology, Aras Windle, University College Cork, College Road, Cork, Ireland.
* Corresponding author: Zaid O. Ibraheem, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia. Tel: 0060173735338 Eemail@example.com
Submitted: 5 May 2011 / Accepted: 15 September 2011
TABLE 1. Composition of the experimental diet as compared to the standard chow diet as a percent of total calories. Constituents Standard chow diet Experimental diet Wt (gm) Calories Wt (gm) Calories Protein 0.22 0.88 0.22 0.88 Carbohydrates 0.47 1.88 0.122 0.49 Fat 0.03 0.27 0.181 1.66 cholesterol -- -- 0.01 -- Cholic acid -- -- 0.0025 -- Calcium 0.012 -- 0.012 -- Phosphate 0.012 -- 0.012 -- Sodium 0.021 -- 0.021 -- potassium 0.007 -- 0.007 -- Fiber 0.05 ? 0.05 ? Ash 0.08 ? 0.05 ? Moisture 0.13 ? 0.13 ? Total 1 3.03 0.76 3.03 TABLE 2. Metabolic and hemodynamic parameters. The renal function study was for days 0, 16 and 24 which correspond to the 34th, 50th and the 58th days of the ad libitum a high fat diet feeding period. Results are expressed in mean [+ or -] S.E.M. * Indicates statistical significance as compared to control (p<0.05). # indicates statistical significance as compared to HFD group (p<0.05). ** indicates statistical significance as compared to HFDG group (p<0.05). ([section]) indicates statistical significance as compared to G group (p<0.05). Control HFD UFR d0 2.18 [+ or -] 0.2 1.40 [+ or -] 0.1 [micro]l/ d16 2.19 [+ or -] 0.18 1.42 [+ or -] 0.10 min/100 **, ([section]) **, ([section]) gm B.W d24 2.06 [+ or -] 0.13 1.35 [+ or -] 0.08 **, ([section]) **, ([section]) Abs. Na+ d0 17. [+ or -] 1.60 11 [+ or -] 1.00 * excretion #, ([section]) X 10-3 d16 16 [+ or -] 1.50 10 [+ or -] 0.80 Mmol/hr ([section]) ([section]) d24 18 [+ or -] 1.70 10 [+ or -] 0.90 ([section]) ([section]) Abs. K+ d0 0.07 [+ or -] 0.01 0.05 [+ or -] 0.01 * excretion #, ([section]) mmol/hr d16 0.08 [+ or -] 0.01 0.055 [+ or -] 0.01 ([section]) d24 0.07 [+ or -] 0.01 0.05 [+ or -] 0.01 ([section]) ([section]) FE Na+ d0 0.51 [+ or -] 0.06 0.37 [+ or -] 0.034 d16 0.49 [+ or -] 0.03 0.32 [+ or -] 0.02 ([section]) d24 0.49 [+ or -] 0.03 0.39 [+ or -] 0.021 ([section]) FE K+ d0 61 [+ or -] 5.94 39 [+ or -] 3.7 d16 56 [+ or -] 3.58 43 [+ or -] 3.58 ([section]) ([section]) d24 67 [+ or -] 6.87 49 [+ or -] 3.21 ([section]) ([section]) Ser cr. d0 77 [+ or -] 5.1 68 [+ or -] 4.1 [micro] d16 80 [+ or -] 3.7 71 [+ or -] 3.6 mol/l ([section]), ** ([section]), ** d24 90 [+ or -] 5.8 71 [+ or -] 3.8 ([section]), ** ([section]), ** Cr cl./ d0 0.16 [+ or -] 0.02 0.16 [+ or -] 0.03 100 g B.W. d16 0.13 [+ or -] 0.01 0.13 [+ or -] 0.01 ([section]), ** ([section]), ** d24 0.14 [+ or -] 0.02 0.11 [+ or -] 0.01 ([section]), ** ([section]), ** Urinary d0 0.64 [+ or -] 0.007 0.539 [+ or -] 0.05 protein d16 0.57 [+ or -] 0.055 0.597 [+ or -] 0.07 excretion d24 0.49 [+ or -] 0.038 0.612 [+ or -] 0.07 mg/hr MDA in 65.4 [+ or -] 2.3 74.1 [+ or -] 1.9 nmol/ g kidney tissue Kidney 0.67 [+ or -] 0.01 ** 0.67 [+ or -] 0.02 ** index Obesity 1.97 [+ or -] 0.10 # 3.95 [+ or -] 0.33 index *,([section]), ** MAP mmHg 109 [+ or -] 2.4 # 128 [+ or -] 3.5 * DBP mmHg 98 [+ or -] 2 2 115 [+ or -] 3.3 * SBP mmHg 129 [+ or -] 2.1 152 [+ or -] 4.1 HFDG G UFR d0 1.74 [+ or -] 0.12 * -- [micro]l/ d16 5.29 [+ or -] 0.50 4.40 [+ or -] 0.60 * min/100 *,# gm B.W d24 4.75 [+ or -] 0.76 4.17 [+ or -] 0.27 * *,# Abs. Na+ d0 9 [+ or -] 1.10 * - excretion X 10-3 d16 45 [+ or -] 4.20 *,# 36 [+ or -] 4.70 *,# Mmol/hr d24 40 [+ or -] 6.20 36 [+ or -] 2.80 # *,# Abs. K+ d0 0.04 [+ or -] 0.00 * -- excretion mmol/hr d16 0.19 [+ or -] 0.02 0.18 [+ or -] 0.03 * *,# d24 0.20 [+ or -] 0.03 0.17 [+ or -] 0.015 * *,# FE Na+ d0 0.33 [+ or -] 0.031 --- d16 5.61 [+ or -] 1.10 2.18 [+ or -] 0.18 *,# d24 4.81 [+ or -] 0.8 1.77 [+ or -] 0.175 *,# FE K+ d0 48 [+ or -] 6.94 -- d16 659 [+ or -] 173 *,# 337 [+ or -] 34.40 d24 926 [+ or -] 215 255 [+ or -] 33.77 *,#,** ([section]) Ser cr. d0 78.6 [+ or -] 4 -- [micro] d16 292 [+ or -] 35 *,# 203 [+ or -] 17 *,# mol/l d24 274 [+ or -] 37 *,# 182 [+ or -] 12 *,#,([section]) Cr cl./ d0 -- -- 100 g B.W. d16 0.042 [+ or -] 0.01 0.06 [+ or -] 0.05 *,# *,# d24 0.039 [+ or -] 0.039 0.08 [+ or -] 0.07 Urinary d0 0.466 [+ or -] 0.032 -- protein d16 0.805 [+ or -] 0.3 0.63 [+ or -] 0.086 excretion d24 0.975 [+ or -] 0.4 0.57 [+ or -] 0.053 mg/hr MDA in 91 [+ or -] 4.4 79 [+ or -] 5.8 nmol/ g kidney tissue Kidney 0.94 [+ or -] 0.05 0.7 [+ or -] 0.03 index *,# Obesity 2.04 [+ or -] 0.21 # 2 [+ or -] 0.36 # index MAP mmHg 118 [+ or -] 2.9 109 [+ or -] 3.4 DBP mmHg 106 [+ or -] 3.1 96 [+ or -] 2 8 SBP mmHg 118 [+ or -] 2.9 109 [+ or -] 3.4 TABLE 3. Histological changes grading for the HFDG and G groups at the end of the treatment period. Histological Glomerular Mesengial PCT change/ congestion hyper- damage rat proliferation HFDG 1 +++ +++ +++ HFDG 2 + + + HFDG 3 +++ +++ +++ HFDG 4 Nill Nill + HFDG 5 + Nill HFDG 6 + + ++ HFDG 7 ++ + + ++ HFDG 8 + Nill + G1 + Nill Minimal G2 Nill Nill +++ G3 + Nill + G4 Nill Nill Nill G5 Nill Nill Nill G6 Nill Nill Nill G7 + Nill + G8 + Nill ++ G9 + Nill ++ G10 Nill Nill Nill Histological Interstitial DCT Final change/ PMNs ectasia decision rat infiltration by protein cast HFDG 1 Nill + Severe HFDG 2 Nill Nill Mild HFDG 3 + + + + Severe HFDG 4 Nill Nill V mild HFDG 5 Nill + Mild to Moderate HFDG 6 + + Moderate HFDG 7 Nill + + Moderate to severe HFDG 8 Nill Nill Mild G1 Nill Nill Very mild G2 Nill Nill Mild G3 Nill Nill Mild G4 Nill Nill Normal G5 Nill Nill Normal G6 Nill Nill Normal G7 + + Mild G8 + + Mild G9 + + Moderate G10 Nill Nill Normal
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|Author:||Ibraheem, Zaid O.; Sattar, Munavvar A.; Abdullah, Nor A.; Rathore, Hassaan A.; Johns, Edward J.|
|Publication:||Bosnian Journal of Basic Medical Sciences|
|Date:||Feb 1, 2012|
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