Int J Clin and Biomed Res.

2016;2(1): 41-49
Journal homepage: www.ijcbr.com

Review Article

AUTHOR DETAILS
1Asst.

Professor, Dept. of Biochemistry,

All India Institute of Medical Sciences
(AIIMS), Bhubaneswar-19, Odisha.
2Asst.

professor,
Dept.
of
Ophthalmology, SCB Medical College and
Hospital, Cuttack, Odisha.

ARTICLE INFO
Received: 12th Dec 2015,
Accepted: 14th Jan 2016.
*Corresponding author email:

suchitrakumari76@gmail.com

ABSTRACT
Diabetes being considered as an epidemic, long term untreated complicated diabetes
resulting in retinopathy will be a leading cause of blindness worldwide. Many crosssectional studies reported a strong relationship between chronic hyperglycaemia and
development, progression of retinopathy, however the underlying mechanism that
cause retinal microvascular damage following prolonged hyperglycaemia, yet to be
revealed. Continued research worldwide focuses on understanding the molecular basis
with the ultimate goal to prevent diabetic retinopathy by developing newer therapeutic
targets. This article reviews multiple biochemical pathways that are implicated in
diabetic retinopathy. Recent advancement in the molecular basis of the disease as well
as clinical trials undertaken to target these molecules in order to block the signalling
cascade prevailing in diabetic retinopathy is also discussed. This review highlights the
recent therapeutic targets to prevent the onset as well as the progress of retinopathy in
diabetes.

KEYWORDS
Hyperglycaemia, microvascular damage, molecular basis, therapeutic targets, signalling
cascade.

INTRODUCTION
Increased prevalence of Type-2 diabetes mellitus and insulin
resistance (a pre diabetic condition) is a major health concern
in India. As per International Diabetic Federation (IFD)
estimates , the number of patients with diabetes is expected
to be more than double by 2030.Diabetes has many
underlying interrelated pathways that lead to potentially
blinding complications like diabetic retinopathy.[1,2] Diabetic
retinopathy is the most frequent microvascular complication
of diabetes and is one of the major causes of vision loss
worldwide. Review of population based studies revealed
approximately 34.6% of diabetics have retinopathy.[3] Diabetic
retinopathy occur both in type 1 and type 2 diabetes and is
strictly related to poor glycaemic control over a prolonged
duration of disease, however there are substantial differences
between type 1 and type 2 diabetes in terms of clinical
presentations and prevalence. Prevalence of retinopathy is
more in type 1 than in type 2 diabetes and more in males than
in female.[4] Intensive glucose control early in the course of
the disease produced significant benefits on microvascular
complications i.e. retinopathy both in type1 and type2
Diabetes mellitus.[5] In addition to the extent and duration of
chronic hyperglycaemia , other biochemical mechanisms like
Polyol accumulation, Protein Kinase C pathway, Oxidative
damage, non-enzymatic protein glycosylation, increased
hexosamine pathway flux as well as recently documented
Kumari Suchitra et al.

endothelium related dysfunction of the coagulant and

anticoagulant pathway, cytokines, interleukins, Endothelin 1
also play a role in the pathogenesis of diabetic retinopathy. All
these pathways ultimately lead to increased oxidative stress,
inflammation, and vascular occlusion that cause upregulation
of factors such as vascular endothelial growth factor (VEGF),
insulin like growth factor (IGF), stromal derived factor-1 (SDF1), angiopoietins (Ang-2), tumour necrosis factor (TNF), and
basic fibroblast growth factor-2 (bFGF) leading to capillary
damage, ischaemia with unregulated angiogenesis that is
pathognomic of diabetic retinopathy.[6]
Genetic studies revealed involvement of a number of genes in
diabetic retinopathy. Aldose reductase (ALR2),receptor for
advanced glycation end products (RAGE) ,endothelial nitric
oxide synthase (eNOS), vascular endothelial growth factor
(VEGF),
paraoxonase1(PON1),
plasminogen activator
inhibitor1 (PAI) are some of the important genes found to be
associated with diabetic retinopathy. Polymorphisms at the
regulatory regions of these genes have been evaluated as risk
alleles for the progression of diabetic retinopathy.[7]
According to the Diabetes Control and Complications Trial
(DCCT) intensive treatment and improved glucose control
delayed the onset of retinopathy and slowed down its
progression in comparison to conventional treatment.[8] Laser

41

Int J Clin and Biomed Res. 2016;2(1): 41-49

photocoagulation and Focal/grid photocoagulation have been
effective in reducing further vision loss in diabetic
retinopathy[9] ; however, these procedures are associated
with potential complications.[10] To avoid these complications,
new drugs and therapeutic targets must be identified which
can disrupt the cascade of events underlying the
pathogenesis of Diabetic retinopathy. So there is a need for
better understanding of molecular basis of diabetic
retinopathy in greater details so that newer therapeutic
interventions can be developed for effective management.
Biochemical mechanisms of diabetic retinopathy:
Diabetes control and complications trial (DCCT) and United
Kingdom Prospective Diabetes Study (UKPDS) group reported
strong association between chronic hyperglycaemia and
development and progression of diabetic retinopathy.[11,12]
According to DCCT mean risk for development of any
retinopathy was reduced by 76% in the intensive therapy
compared to the conventional therapy. With established
retinopathy the intensive group had a higher incidence of
progression during the first year whereas from 3 years
onwards, the progression of retinopathy was reduced in the
intensive group by 54%.United Kingdom Prospective Diabetes
Study (UKPDS) showed that patients who were assigned to
intensive glucose control had less need for retinal
photocoagulation .Both studies showed that glycaemic
control is protective .Hyperglycaemia is involved in the
pathogenesis of diabetic retinopathy (Figure 1), nephropathy,
neuropathy and macro vascular disease via the following
mechanisms i.e. increased flow through the aldose-reductase
pathway ; non enzymatic glycation and glycoxidation with
formation of advanced glycation end products (AGEs);
increased de-novo synthesis of diacylglycerol from glucose,
causing protein-kinase C (PKC) activation; oxidativenitrosative stress with overproduction of reactive oxygen
species (ROS).[13,14] Therefore beside the optimal glycaemic
control , pharmacologic inhibition of these pathways might
prevent loss of retinal pericytes, micro aneurysm formation,
changes in retinal hemodynamics that ultimately result in
neovascularization a characteristic feature in diabetic
retinopathy.

Figure 1. Hyperglycaemia induced biochemical alterations

in diabetic retinopathy

A) Increased glucose flux through polyol pathway:

Aldose Reductase (AR) present in the retina reduces glucose
into sorbitol using nicotinamide adenine dinucleotide
phosphate (NADPH) as a cofactor. Sorbitol dehydrogenase
(SDH) with NAD+ as cofactor subsequently converts sorbitol
into fructose. Since sorbitol is impermeable to cellular
membranes, it accumulates within the cell and later
metabolised to fructose. Built up of sorbitol (Figure 2) is an
important cause of osmotic damage to retinal cells. [15]
Fructose can be phosphorylated to fructose-3-phosphate
that later can be degraded to 3-deoxyglucosone, both of
which are strong glycating agents and result in the production
of Advanced Glycated End Products i.e. AGEs.[16] Increased
utilisation of NADPH as a cofactor in the polyol pathway
results in less NADPH availability for use by glutathione
reductase (enzyme involved in generation of reduced
glutathione).Reduced glutathione being a free radical
scavenger , its decreased level diminishes protective response
against oxidative stress.[17] Exaggerated NADH oxidase activity
due to increased cytosolic NADH/NAD+ ratio by SDH results in
increased production of reactive oxygen species(ROS) within
retinal cells.[18] Under euglycemic conditions, hexokinase
enzyme has higher affinity for glucose hence the formation
of sorbitol is very low . However, in hyperglycaemic state
there is a substantial increase in intracellular sorbitol levels.
Aldose reductase has a high capacity and a low affinity for
glucose but sorbitol dehydrogenase (SDH) has a high affinity
and a low capacity for sorbitol. So only during hyperglycaemic
state Aldose reductase activity is increased and sorbitol
oxidation is relatively independent of the sorbitol
concentration within the physiological ranges.[19,20]
In diabetes, the sorbitol pathway activity is more in tissues like
retina, kidney, peripheral nerves and blood vessels where
insulin is not required for cellular glucose uptake. The polyol
pathway seem to be an important mechanism for the
ganglion cell apoptosis and Mller glial cell activation.[21,22]
Aldose reductase is found in Ganglion and Mller cells of the
retina. Since neuroglial changes may cause vascular changes
the inhibition of the polyol pathway could also prevent the
vascular abnormalities of diabetic retinopathy. Inhibition of
aldose reductase was also able to prevent the early activation
of complement in the retinal vessel wall as well as the
apoptosis of vascular pericytes and endothelial cells and the
development of acellularcapillaries.[23] Retinal endothelial
cells showed aldose reductase immunoreactivity, and human
retinas exposed to high glucose in organ culture increased the
production of sorbitol.[24] Experimental evidences suggest
that defects in the polyol pathway may produce thickening of
the capillary basement membrane, loss of mural pericytes
and micro aneurysm formation ,the vascular changes
characteristics of diabetic microangiopathy. So polyol
pathway has been an extremely attractive target for the
treatment of diabetic retinopathy. Animal data showed that
aldose reductase has an early role in the pathogenesis of
diabetic retinopathy but studies of inhibition of polyol
pathway in vivo have yielded inconsistent results .The Sorbinil
trial also indicated that sorbinil did not prevent the worsening
of the disease except for a slower progression rate.[25] Animal

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Int J Clin and Biomed Res. 2016;2(1): 41-49

models suggest that AR inhibitor fidarestat, is active in the
treatment of diabetic retinopathy. Fidarestat (Figure 5) being
an inhibitor of aldose reductase neutralizes diabetesassociated retinal oxidative stress and
(ADP-ribose)
polymerase formation.[26] This indicates the rationale for the
development of aldose reductase inhibitors for counteraction
of polyol pathway.[27].In the streptozotocin diabetic rats,
fidarestat treatment decreased sorbitol and fructose
concentrations in the retina. Similarly in the rat model with
retinal ischemia reperfusion injury, fidarestat treatment
caused increased AR expression and cell death with
decreased sorbitol pathway intermediate accumulation.[28]
Fidarestathas a role in ICAM-1 mRNA expression and
leukocyte accumulation in the retina. Immunohistochemical
study also revealed the suppressive effect of fidarestat on the
expression of ICAM-1.[29] A double-blind study in patients with
diabetic neuropathy documented the efficacy of sorbinil, an
aldose reductase inhibitor, against morphological signs of
degeneration associated with a decrease in the nerve sorbitol
level.[30] Zenarestat , another aldose reductase inhibitor also
reported same results.[31] Sorbinilretinopathy trial indicated
that sorbinil had no clinically important effect on the course
of human diabetic retinopathy.[25] However Zenerestat had a
positive effect on diabetic neuropathy progression[32] thus
creating a hope in the use of Aldose reductase inhibitors in
diabetic retinopathy that needs further clinical trials.

CML and the degree of retinopathy pointing its role in

Diabetic retinopathy.[35] AGEs are involved in microvascular
and macrovascular complications through the formation of
covalent crosslinks with molecules of the basement
membrane of the extracellular matrix and the vessel wall
components. Binding of AGEs with a variety of cell-surface
AGE binding receptors( receptor for advanced glycation end
products i.e. RAGEs)
leads to cellular activation of
prooxidant,
proinfammatory events .Various signalling
pathways (Figure 4) that are activated by AGE receptor
binding include tyrosine phosphorylation of Janus kinase
(JAK)/signal transducers and activators of transcription
(STAT)[36], recruitment of phosphatidylinositol 3 kinase to
Ras[37], activation of protein kinase C[38] and oxidative stress by
NFk Band AP-1 transcription[39] .CML interact with vascular
endothelium via RAGE activating nuclear factor kappa B (NF B), that increase expression of adhesion molecules and
secretion of tumour necrosis factor alpha (TNF) and VEGF.

Figure 3. Formation of Advanced Glycation End products

Figure 2. Polyol Pathway and role of Aldose reductase

Inhibitor
A) Non enzymatic Protein Glycosylation:
Chronic hyperglycaemia leads to accumulation of Advanced
Glycation End Products (AGES) that play an important role in
pathogenesis of retinopathy in diabetes.[33] AGEs are
heterogeneous molecules formed by nonenzymatic reaction
of free amino groups of proteins, lipids and nucleic acids with
the reducing sugars . Schiff base is formed that undergoes
spontaneously rearrangement (Maillard reaction) on itself to
produce an Amadori adduct (Figure 3). Most glycated proteins
are eliminated in physiological conditions, they accumulate in
the presence of diabetes and undergo further glycation and
molecular rearrangement that lead to the formation of
AGEs.[34]
Some of the AGEs in human are Carboxymethyllysine (CML),
Carboxyethyllysine (CEL) and Pentosidine out of which CML
have been localized to retinal blood vessels of diabetes
patients and significant correlation has been found between

Recent investigations suggest that the AGE-RAGE interaction

might increase VEGF gene transcription by NADPH oxidasemediated ROS generation and nuclear factor- .B (NF-.B)
activation via Ras mitogen activated protein kinase (MAPK)
pathway.[40,41] Knocking down of integrin-linked kinase (ILK)
gene expression with siRNA inhibited the expression of VEGF
and intercellular adhesion molecule 1 (ICAM-1) that indicates
the ILK response to high glucose and its role in pathogenesis
of diabetic retinopathy (DR).[42,43]
Evidences from animals studies suggest that exposure to high
levels of AGEs cause vascular and renal complications.[44,45,46]
Diabetic rats when treated with Aminoguanidine
hydrochloride (AGE inhibitor), accumulation of AGE was
significantly reduced that prevented formation of micro
aneurysms, acellular capillaries and pericyte loss.[47]
Treatment with vitamin B6 derivatives, an AGE inhibitor also
found to be protective against capillary drop out in diabetic
rats.[44] Such observations suggest that AGE accumulation and
its interaction with RAGE are interconnected mechanisms in
Diabetic retinopathy and inhibition of these pathways could
be an important therapeutic avenue.[48] Current treatments
focus on preventing the AGE formation, breaking established
crosslinks and reducing receptor-ligand interactions .Recently
Park et al. reported that the Wnt pathway inhibitor that i.e. a
Pigment Epithelium-Derived Factor (PEDF), a serine
proteinase inhibitor overexpression could attenuate Wnt
signaling induced by retinal ischemia.[49] PEDF is also found to
inhibit NADPH oxidase mediated ROS generation and VEGF

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Kumari Suchitra et al.

Int J Clin and Biomed Res. 2016;2(1): 41-49

expression thus preventing AGE induced oxidative stress and
apoptosis in retinal pericytes.[50] Yamagishi et al documented
that injection of AGEs to normal rats increases RAGE and
ICAM-1 expression that could be prevented by treatment
with PEDF by inhibiting superoxide generation and NFkB
activation in endothelial cells.[51] Aminoguanidine, a potent
inhibitor of AGE mediated cross-linking, has been shown to
reduce diabetic vascular complications including retinopathy
in experimental animals.[52]
B) Oxidative stress:
Imbalance between the level of ROS and the antioxidant
defence mechanisms in a biological system leads to oxidative
stress. Hyperglycemia induces overproduction of ROS and
oxidative stress (Figure 4) reflected by increased
Malondialdehyde, isoprostane, nitrotyrosine or 8-hydroxy-2
deoxyguanosine levels and decreased antioxidant status.[53,54]
Reactive oxygen species are produced by glucose autooxidation, protein glycation, increased flux through the polyol
pathway, and prostanoid production. ROS and reactive
nitrogen species (RNS) act on lipids, protein and DNA
molecules leading to cross-link formation, lipid peroxidation
and protein modification. Pericytes are highly sensitive to the
oxidative stress and increased rate of apoptosis due to
decreased level of antioxidant enzymes.[55] Progressive
Pericyte loss leads to pore formation in the blood vessel wall
thus proteins are leaked , a characteristic finding in non
proliferative diabetic retinopathy i.e. hard exudates.

diabetes-induced increase in nitrotyrosine and activation of

NF-B , decrease VEGF and oxidatively modified proteins in
the rat retina.[60] Vitamin E through non enzymatic
mechanisms act as free radical scavenger in DR.[61] Trolox
prevent the loss of pericytes in diabetic rats [62] Carotenoid,
lutein and zeaxanthin prevented progression of DR and
maintained normal retinal function, mitochondrial
homeostasis and inflammatory mediators.[63]
C)

Protein Kinase C pathway:

Protein kinase C (PKC) is a family of 10 enzymes, in which the

1/2 isoforms are closely associated with the development
of diabetic retinopathy.[64] So far 12 PKC isoforms have been
isolated and can be divided into 3 groups i.e. classical, novel
and typical. Classical isoform (PKC-, ,) are enhanced by
Diacylglycerol (DAG) and have been linked to vascular
dysfunction and pathogenesis of DR.[65] Hyperglycaemia
increase glucose flux through the glycolytic pathway, which
increases DAG , the key activator of PKC.[66] activation of PKC
has a cascade-like effect on several other pathways that
influence endothelial permeability, retinal hemodynamic,
and expression of vascular endothelial growth factor (VEGF)
in the retinal along with
leukocyte adhesion.[67,68]
Upregulation of PKC contribute to the pathogenesis of
diabetic retinopathy i.e. extracellular matrix (ECM)
remodelling, differential synthesis of extra cellular matrix
proteins, release of angiogenic factors, endothelial and
leukocyte dysfunction leading to vascular changes pertaining
to DR.[69]
PKC inhibitors are new potential therapeutics useful in DR.
They can delay the onset or prevent the progression of
vascular
complications
of
diabetes.
Isoquinoline
sulphonamides and staurosporine the first and second
generation PKC inhibitors are of therapeutic interest.[70,71,72,73]
Ruboxistaurin mesylate was reported in science.[74] Vitamin E
can inhibit PKC activity by decreasing DAG contents by
activation of DAG kinase.[75,61] PKC inhibitor Ruboxistaurin
(Figure 5) reduces the mitogenic response to VEGF, in contrast
with PKC- inhibition.[76] Selective inhibition is very crucial to
develop clinically safe therapeutic PKC inhibitors. Tuttle et al
documented that PKC isoform selective inhibitors can be used
for chronic clinical treatment with nominal side effects.[77] So,
selective PKC inhibitors are likely new potential therapeutics
in DR. Endothelium related dysfunction of the coagulant and
anticoagulant pathway has been documented in diabetes.[78]

Figure 4. Interrelationship of Biochemical Mechanisms in

diabetic retinopathy
Animal studies documented that oxidative stress cause
development of retinopathy in diabetes and it prevent
retinopathy to reverse even after euglycemic state is
achieved.[56] In diabetes the antioxidant enzymes i.e. SOD,
glutathione reductase, glutathione peroxidase, catalase are
found decreased in the retina.[57] It is also reported that type
2 diabetes mellitus is associated with reduced plasma total
antioxidant status and increased plasma oxidisability with
reduced plasma ascorbic acid and vitamin E.[58] Lipoicacid
scavenge ROS and reduces glutathione to maintain a healthy
cellular redox state.[59] Lipoic acid supplementation prevents

D) Miscellaneous Mechanisms:
In case of proliferative diabetic retinopathy a
hypercoagulable state is present due to conversion of the
endothelium from a thermoresistant to a thermogenic
surface with activation of extrinsic haemostatic pathway.
Moreover finding of anti-pericyte and phospholipid binding
autoantibodies (eg. Leupus anticoagulants) as well as
presence of T lymphocytes, B lymphocytes , HLA DR/DQ
expressing cells ,macrophages and Ig deposits in the
vitreous and the pre retinal membrane suggest
immunological basis of diabetic retinopathy.[79,80]

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Kumari Suchitra et al.

Int J Clin and Biomed Res. 2016;2(1): 41-49

parameters were correlated with the severity of fundus
findings.[107] Recently VEGF & IL-6 relationship & their
levels in vitreous fluid has been documented[108,109] thus
pointing towards the usefulness of their measurement as
an analytical marker of pathogenesis of DR and to predict
the progression of retinal diseases.

Figure 5. Biochemical basis and emerging molecular

targets
A number of growth factors have been associated with the
development of Diabetic Retinopathy.[81,82] Basic fibroblast
growth factor (b FGF).[83] Insulin like growth factor 1(IGF1).[84] Angiopoitin 1 and 2[85,86], stromal derived factor 1
87 ,
Epidermal growth factor(EGF)[88], Transforming growth
factor 2(TGF- 2)[89], Platelet derived growth factor[90] and
Erythropoitin91 have been found associated with DR.
Anti VEGF agents are recently developed as a treatment
modality in DR. Pegaptenib, Ranibizumab, Bevacizumab are
some of the current anti VEGF agents.[92-95] Recent advances
suggest cautious use of anti VEGF agents on long term basis
to treat DR due to the fact that VEGF has a role as retinal
neuron survival factor and its inhibition may lead to
destruction of cells i.e. photoreceptors, muller glia that are
involved in visual function.[96]
Many studies highlighted the importance of subclinical
inflammation in the development of DR.[97-99]
Hyperglycaemia , hypertension, oxidative stress ,Advanced
Glycation End products all contribute to inflammation and
inflammatory response in tern regulates these pathways via
cytokines, VEGF signalling, adhesion molecules, Enhanced
RAGE expression, NFkB signalling. Leucostasis is another
hallmark in the pathogenesis of DR as it causes capillary
occlusion, ROS mediated cell death that enhance
inflammatory response locally in retinal tissues.[100]
Therefore subclinical inflammation in the retina leads to
increased intra ocular pressure, formation of new, weak
vessels and their increased permeability due to VEGF that
cause retinal haemorrhage. Activation of microglia and
immune cells is also revealed by many researchers.[101] This
fact has been supported by the use of Minocyclin, an
antibiotic and anti-inflammatory agent that block the
activation of Microglia and prevent DR.[102] The use of
intravitreal Triamcinolone acetonide and non-steroidal
anti-inflammatory drugs i.e. Nepafenac has been reported
to reduce VEGF expression, normalize vascular
permeability and reduce apoptosis , leucostasis that
improve visual acuity.[103,104] There is also great deal of
interest in intraocular implants that deliver antiinflammatory steroids.[105,106]

Matrix Metalloproteinases (MMP) 2.9 and their tissue

inhibitors (TIMP) were found elevated in vitreous of
diabetic patients and were correlated with severity of
retinopathy.[110, 111] MMP activity represent the final
common pathway in retinal neovascularisation from
whatever cause and therapeutic inhibition at this level may
be more effective then targeting individual pathway.
Endothelin-1 (ET-1) is a peptide produced by the
endothelial cells that induces vasoconstriction. Studies
reported that hypoxia induces ET-1 gene expression in
endothelial cells.[112] A position association between ET-1
expression and PKC activation in early diabetes reflected
the fact that PKC inhibitors could be able to reverse the
upregulation of ET-1.[113] Therapeutic effect of long-term
selective blockade of endothelin A (ETA) receptor has been
recently evaluated in a genetic mouse model of non obese
type-1 diabetes.[114] Such studies suggest a new strategy for
preventing development of retinopathy in diabetes.
Fenofibrate (Peroxisome proliferator activated receptor
PPAR- agonist) is used to treat high triglycerides and low
HDL or as adjunct to statin therapy. It regulates the expression
of many genes that work against lipids, inflammation,
angiogenesis, and cell apoptosis. The ACCORD Eye Study
group involved a subset of 2,856 participants reported that
the rates of progression of diabetic retinopathy were
significantly reduced in the intensive glycemic control group
and in the fenofibrate group.[115]

CONCLUSION
The pathogenesis of DR is very complex and many
biochemical mechanisms have been proposed which are
interactive and interdependent. This review provides better
understanding of complex biochemical mechanisms and
treatment modalities of recent Interest. At proliferative
phase of retinopathy therapeutic interventions are effective
but in advanced stage hypoxia induced VEGF production
leads to disease progression. Overexpression of growth
factors i.e. VEGF, IGF-1, stromal derived GF-1, angiopoetin- 1
& 2, fibroblast Growth Factor act in synergy in mediating
process of angiogenesis and endothelial are proliferation. As
there is a complex interplay between the biochemical
pathways, understanding the molecular basis of these
pathways in greater details will help in exploring newer
pharmacological agents targeted to block different pathways
that could provide a better insight in preventing the disease
progression in Diabetic Retinopathy.

CONFLICT OF INTEREST
Nil.

A significant relationship between VEGF and IL-6 was

reported by Funatsu et al. Aqueous levels of these two

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Kumari Suchitra et al.

Int J Clin and Biomed Res. 2016;2(1): 41-49

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