Int. J. Morphol.,
36(3):1087-1094, 2018.
Catha edulis Forsk Mediates Embryotoxic
Effects in Rats: An Experimental Study
Catha edulis Forsk Modera los Efectos Embriotóxicos en Ratas: Un Estudio Experimental
Alaa Sayed Abou-Elhamd1, 2; Hussein Ageely3; Muhammad Abu-Elmagd4 & Ahmed Elzuhry Zayed1,2
ABOU-ELHAMD, A. S.; AGEELY, H.; ABU-ELMAGD, M. & ZAYED, A. E. Catha edulis forsk mediates embryotoxic effects in
rats: An experimental study. Int. J. Morphol., 36(3):1087-1094, 2018.
SUMMARY: Catha edulis Forsk leaves (Khat) is a flowering plant. A high proportion of the adult population in the Arabian
Peninsula and the Horn of Africa chews it for its mild stimulant effect. The aim of the current study was to investigate the embryotoxic
and teratogenic effects of the Khat extract using 60 female pregnant rats. These were divided to a Khat extract-treated group and a control
group. Methanolic extract of Khat was orally given to the treated group 4 days before mating and up to day 16 of pregnancy with a dose
of 100 mg/kg. Our results showed that significant number of embryos of the Khat-treated mothers were malformed and different in size
and shape compared to embryos from the mothers of the control group. At day 8 of pregnancy, malformed embryos had ill developed
primitive layers. By day 10 of pregnancy, neural tube and the somite were not formed compared to the control embryos. At later stages
of pregnancy, embryos of the Khat-treated mothers appeared severely abnormal with opened neural groove and visceral pouches. Disrupted
normal neural tube development, undifferentiated brain vesicles, incomplete closure of the brain flexures were also observed in these
embryos. Highly significant increase in the number of the resorbed embryos of the Khat-treated mothers were observed (P < 0.01). The
resorbed embryos appeared as a cellular collection in their placenta with some of their decidua had no visible embryonic tissues. In
conclusions, Khat induced embryotoxic effects as well as severely affected the early normal embryonic development in rat.
KEY WORDS: Khat; Embryo toxicity; Teratogenicity; Morphological & Histological analysis; Rat.
INTRODUCTION
Khat plant (Catha edulis Forsk) belongs to the family
Celastraceae (moonseed) that is frequently cultivated in
certain regions of the horn of Africa and the Arabian
Peninsula. The earliest scientific report about Khat was in
the eighteenth century by the botanist Peter Forskal (AlHebshi & Skaug, 2005) during his trip to Yemen. It has been
estimated that about 20 million people worldwide use Khat
as a pleasant mild stimulant (Al-Habori, 2005; El-Menyar
et al., 2015).
development of cancer and apoptotic changes in liver and
kidneys (Al-Motarreb et al., 2002; Ageely et al., 2014;
Ageely & Abou-Elhamd, 2015) have been extensively
studied, very little is known about the biological effects on
cells (Carvalho, 2003). Studies on the effects of Khat on the
developing neonates are scarce and only dealt with general
aspects of embryonic development such as birth weight,
length and head circumference (Eriksson et al., 1991; AbdEl-Aziz & Ahmed, 1998).
Khat contains the alkaloids cathinone, norephedrin
and cathine. The Khat’s stimulant effect is mainly due to
cathinone which has a similar mechanism of action to that
of amphetamine and hence is considered as a natural
amphetamine (Brenneisen et al., 1990; Kalix, 1996).
Although the adverse systemic effects of Khat such as
neurological disorders, hypertension, myocardial infarction,
Epidemiological studies carried out in Yemen showed
that the occasional and regular mothers’ users of Khat
especially during pregnancy gave a significant low birthweight babies compared to the non- Khat users (Eriksson et
al.). Neonates from the Khat-chewers’ mothers had a
significant decrease in all neonatal parameters such as birth
weight, head circumference and Apgar score compared to
Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.
3
Department of Internal Medicine, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia.
4
Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
1
2
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ABOU-ELHAMD, A. S.; AGEELY, H.; ABU-ELMAGD, M. & ZAYED, A. E. Catha edulis forsk mediates embryotoxic effects in rats: An experimental study.
Int. J. Morphol., 36(3):1087-1094, 2018.
the non-Khat-chewers’ mothers (Hassan et al., 2007; AbdelAleem et al., 2015; Jerah et al., 2017). Trials for explaining
the adverse effects of Khat consumption in pregnant women
on neonatal growth have led to the suggestion that Khat
induces an effect on the utero-placental blood flow and
consequently impairs fetal growth and development
(Jansson et al., 1987). In rat, pregnant mothers treated with
high doses of Khat between days 6-15 showed fetal
resorption, reduced embryo size associated, and congenital
malformations (Islam et al., 1994). However, detailed
histological analyses of these malformations at early and
late stages of embryonic development were lacking. The
aim of the current study was to analyze the cytotoxic and
teratogenic effects of Khat extract on early and late
development using rat model. We show that Khat induces
different forms of embryo cytotoxic and teratogenic effects
at different stages of development including uterine
resorption, reduced litter size, and moderate to severely
malformed affected embryo.
MATERIAL AND METHOD
Khat extraction. Fresh Khat bundles were kindly provided
by Substances Abuse and Research Center, Jazan
University. The fresh bundles were transported to the
Biology Department, Faculty of Medicine for processing.
Khat was extracted by Methanolic as previously described
by (Dimba et al., 2004; Kimani et al., 2008). Briefly, the
fresh Khat leaves were separated from the shoots, and
washed thoroughly with distilled water, chopped on metal
plates and finally crushed using a blender. Crushed material was immersed in sufficient amount of methanol (SigmaAldrich) and kept on rotary shaker for few hours. Filtration
of the mixture was carried in two steps; firstly, using the
gauze rolls to separate the larger particles and secondly
with filtered throughout 11 mm filter (Grade 1, Whatman,
Kent, UK). The non-filtered plant material was re-extracted
in fresh methanol (Dimba et al.). The filtrate was collected
in a beaker and kept overnight on magnetic stirrer at 45 °C
to completely evaporate the methanol (Kimani et al.), thus
leaving dried material (i.e. the extract) which was kept as a
powder at 4 ºC. Fresh solution of Khat extract was prepared
by dissolving the powder of Khat extract in distilled water,
just prior to the daily oral administration to the rats. The
concentration of Cathine and Cathinone were measured in
Khat extract in Jazan poison control center (Jazan- Saudi
Arabia). The concentration of Cathine was 305 µg/ml and
that of the Cathinone was 114 µg/ml
Animal grouping and dosing: Sixty Sprague-Dawley (SD)
female rats weighting 180-200 g were used in this study.
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The animals were housed in group cages and given free
access to food and water. The rats were housed at 24 ˚C
room temperature and 12 h light/dark cycle. All rats were
acclimatized for one week before starting the Khat treatment.
The rats were divided to two main groups each consists of
30 animals: 1- the Khat extract-treated group and 2- control
(untreated Khat or distilled water treated) group. Each three
females were housed with one male. A pregnant female was
identified by the presence of the vaginal plug that forms
after a successful mating by the male. This plug was usually
visible by a simple visual examination of the valve and
mostly persisted for 16-24 hours post-copulation. Once the
plug was formed and seen, the day on which was considered
as day 0 of pregnancy.
The Khat extract-treated group was daily given an
oral dose of 100 mg/kg body weight Khat extract from 4
days before mating and up to day 16 of pregnancy. The control (untreated) group was orally given only distilled water
(volume equal to that of the dose of extract in the previous
group) daily throughout the period of the experiment. All
rats were observed daily for any sign of toxicity during the
course of the experiment until the sacrifice of the rats.
Tissue preparation and examination:
Sampling: After anesthesia by Isoflurane (Sigma Aldrich),
5 dams from each group were sacrificed at E-8, E-10, E-12,
E-14, E-15 and E-16 days of pregnancy, then the chest and
abdomen were opened, and few millimeters of blood were
taken off from the heart to facilitate intracardiac infusion of
the fixative; 4 % paraformaldehyde in 0.1 M Phosphate buffer solution was infused in the left ventricles of the heart to
allow rapid fixation of the tissue.
Fixation and embedding: For histological examination,
the uterus of each dam was examined for any morphological
changes and then opened, and the embryos were taken out
and immersed in 4 % paraformaldehyde buffer and
processed for paraffin embedding.
Sectioning, staining and examination: Paraffin-embedded
embryos were sectioned using microtome (Leica
Biosystems RM2245) at 5-7 µm thickness. Sections were
stained by routine histological stain (Hematoxylin & Eosin).
The sections were examined and photographed using
Olympus microscope with DP72 camera and cell software
for imaging.
Ethical Approval. Ethical approval to carry out this study
was obtained from the Research Ethics Committee of the
Medical Research Center, Jazan University (REC/ MRC/
JU, 30/ 01/ 2017).
ABOU-ELHAMD, A. S.; AGEELY, H.; ABU-ELMAGD, M. & ZAYED, A. E. Catha edulis forsk mediates embryotoxic effects in rats: An experimental study.
Int. J. Morphol., 36(3):1087-1094, 2018.
RESULTS
Daily administration of Khat to pregnant rats at a dose
100 mg/kg body weight resulted in a highly significant
increase in the mean number of the resorbed embryos (P<
0.01) compared to the control group (Fig. 1). This
consequently resulted in a significant reduction in the number
of live embryos in the Khat treated mothers when compared
to the control untreated mothers (Fig. 2). No abortion cases
were observed in the control as well as the Khat treated
groups.
At day 10 of pregnancy, the control embryos had
nearly equal size and similar normal morphology with their
somites and neural tube fully formed. Khat treated embryos
had different sizes and shapes and their neural tube and the
somites not formed (Figs. 4C-D). Trophoblast giant cells of
different sizes and shapes were also observed.
At day 8 of pregnancy, the control embryos showed
that the three germ layers were formed and started the
differentiation normally (Fig. 3A); while in the treated
embryos the primitive layers were ill-developed (Fig. 3B).
At day 12 of pregnancy, control embryo appeared normal with closed visceral arches and cervical sinuses; tongue
and limb buds formed, head folds were particularly prominent
and neural closure occurred normally (Figs. 5A, B). Normal
embryonic development was also including heart, liver, gut,
and mesonephros (Fig. 5B). The embryos of the Khat-treated
mothers appeared morphologically abnormal with different sizes
Fig. 1. Mean number of resorbed embryos. Graph showing a
significant increase in the mean number of the resorbed embryos
in the Khat treated mothers (P< 0.01) compared to control.
Fig. 2. Mean number of live embryos. Graph showing a significant
reduction in the mean number of the live embryos in the Khat treated
mothers (P< 0.01) compared to control.
Fig. 3. E-8 Khat treatment outcome.
(A): Sagittal section through E-8 control embryos showing normal
development and differentiation of the
three germ layers. (B): Sagittal section
through a Khat-treated embryo after 8
days showing ill developed primitive
layers. Ec, ectoderm; En, endoderm;
M, mesoderm; Y, yolk sac. Inset:
higher magnification of marked area
in (B). Haematoxylin and Eosin stain,
A&B (scale bar=100µm); inset (scale
bar= 20 µm).
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ABOU-ELHAMD, A. S.; AGEELY, H.; ABU-ELMAGD, M. & ZAYED, A. E. Catha edulis forsk mediates embryotoxic effects in rats: An experimental study.
Int. J. Morphol., 36(3):1087-1094, 2018.
Fig. 4. E-10 Khat treatment outcome. (A):
Control embryos at day 10 of pregnancy in
their placenta showing normal development
with the embryos nearly of equal size and similar shape. (B): Sagittal section through an
embryo in (A) showing normal development
of the somites (arrows) and neural tube
(asterisks). (C): Embryos from Khat-treated
mothers with different size and shape. (D):
Sagittal section through an embryo in (C)
showing delayed neural tube and somite
development with the trophoblast giant cells
of different size and shape (arrowheads). Am,
amniotic cavity; db, decidua basalis; L,
Labyrinth; Mt, metanephros; Ms,
mesonephros. Haematoxylin and Eosin stain,
B&D (scale bar=100µm).
and shape (Fig. 5C) and opened visceral pouches (Fig. 5D).
Some of the embryos were resorbed (Fig. 5C) which appeared
as a cellular aggregation in their placenta (Figs. 3E-F).
At day 14 (Fig. 6), 15 (Fig. 7) and 16 (Fig. 8) of
pregnancy, control embryos showed normal morphology (Figs.
6A, 7A and 8B) as well as normal histological internal organs
development including brain, nose, heart, lung, liver, gut, and
tail buds (Figs. 6B, 7B, and 8C). On the other hand, Khattreated embryos appeared morphologically abnormal and
different in shapes and sizes (Figs. 6C, 7C, and 8E). A number
of the Khat-treated embryos showed normal morphology (40
%) were smaller in size (Figs. 6C, 7C and 8D-E). However,
some of these embryos suffered from interrupted neural tube
(Fig. 6D), undifferentiated brain vesicles (Fig. 6E) and
incomplete closure of the brain flexures (Fig. 7E). Other KhatFig. 5. E-12 Khat treatment outcome. (A): Control embryos at day 12 of
pregnancy showing normal development of different organs. (B): Sagittal
section through the embryo in (A) showing normal development with
closed visceral arches and cervical sinuses; tongue and limb bud, head
folds are particularly prominent and proper neural closure occurred. (C):
Embryos from the Khat-treated mothers appeared abnormal with different
size and shape and opened neural groove (arrowheads), some of the
embryos were resorbed (double arrowheads). (D): Sagittal section of an
embryo in (C) showing opened visceral pouches (arrows) and abnormal
head development. (E, F): Sagittal sections through absorbed embryos,
which appeared as a collection of different types of cells in their placenta.
Fv, fourth ventricle; G, gut; H, heart; Li, liver; Mn, mesonephros; Tv,
third ventricle; T, tongue; Tb, tail bud. Haematoxylin and Eosin stain, B,
D, E & F(scale bar=100 µm).
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ABOU-ELHAMD, A. S.; AGEELY, H.; ABU-ELMAGD, M. & ZAYED, A. E. Catha edulis forsk mediates embryotoxic effects in rats: An experimental study.
Int. J. Morphol., 36(3):1087-1094, 2018.
treated embryos showed severe teratogenic effects including
loss of recognizable internal organ structures with some of
the deciduae had no visible embryonic tissues (Figs. 6F-G,
7D, 8F,G). Compared to the number of the control uteri, at
least (60 %) embryos were reabsorbed in each treated pregnant
mother (Figs. 1 and 8A, D).
Fig. 6. E-14 Khat treatment outcome. (A): Control embryo at
day 14 of pregnancy showing normal development of different
organs. (B). Transverse section through the embryo in (A)
showing normal development of all embryonic organs. (C):
Embryos from the Khat-treated mothers appeared varied in shape
and size; some of these embryos were resorbed (C, 1), with severe
morphological abnormalities (C, 2 & 3). A number of these
embryos appeared normal but smaller in size (C, 4). (D): Sagittal
section of embryo in (C, 4) showing disrupted neural tube
development (arrow). (E): Sagittal section showing an example
of normally looking Khat-treated embryo but with
undifferentiated brain vesicles (asterisks). (F, G): Sagittal sections
through Khat-treated embryos with no visible embryonic tissues
observed in the deciduae. Db, decidua basalis; N, Nose snout
projection; Fv, fourth ventricle; H, heart; Fl, forelimb; Hl, hind
limb Li, liver; Lv, lateral ventricle; T, tongue; Tb, tail bud; Th,
Thalamus. Haematoxylin and Eosin stain, B & E- G (scale
bar=100 µm).
Fig. 7. E-15 Khat treatment outcome. (A): Control embryo at day
15 of pregnancy showing normal development of different organs.
(B): Sagittal section through the embryo in (A) showing normal
development of all embryonic organs. (C): Embryos from the Khattreated mothers showing variation in size and shape some of which
were resorbed (C, 1) and others with smaller in size (C, 3 and 4).
(D, E): Sagittal sections of Khat-treated with no recognizable
embryonic structures in decidua (D) and/or incomplete closure of
the brain flexures (E, arrow). Db, decidua basalis; Fv, fourth
ventricle; Fl, forelimb; Hl, hind limb bud; L, Labyrinth; Li, liver;
Lu, lung bud; N, Nose snout projection; Tv third ventricle; T, tongue.
Haematoxylin and Eosin stain, B, D & E (scale bar=100 µm).
DISCUSSION
The current study shows that Khat has adverse effects
on embryos at the early stages of development after oral
administration of the pregnant mothers with 100 mg/kg body
weight. Such treatment led to a highly significant increase
in the number of the resorbed embryos compared to the control as well as a highly significant difference in the number
of live embryos between the embryos of the control and Khat
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ABOU-ELHAMD, A. S.; AGEELY, H.; ABU-ELMAGD, M. & ZAYED, A. E. Catha edulis forsk mediates embryotoxic effects in rats: An experimental study.
Int. J. Morphol., 36(3):1087-1094, 2018.
treated mothers. Several studies have shown that Khat extract
has a profound effect on cell proliferation and may be
responsible for chromosomal and embryonic abnormalities
(Islam et al.; Kassie et al., 2001; Masood & Al-Mansoob, 2015;
Muema et al., 2016; Nakajima et al., 2017). A study on
pregnancy outcome on women who chewed Khat during
pregnancy showed a significant increase in low-birth-weight
full-term infants among the offspring in comparison to women
who were non-chewers during pregnancy (Eriksson et al.).
Khat chewing during pregnancy has a negative impact on
maternal and fetal wellbeing (Abdel-Aleem et al.). The
neonates of Khat chewing mothers during pregnancy had a
significant decrease in all neonatal parameters in comparison
with those of mothers who did not chew Khat during pregnancy
such as reducing total fetal fat and weight and by inducing
some changes in the chemical composition of fetal organs,
particularly the liver, heart and kidneys. This effect was
attributed to depletion of carbohydrate material and
suppression of DNA and protein synthesis in the fetal organs
(Abd-El-Aziz & Ahmed).
In the current experiment, we did not study the maternal toxicity of Khat since this was addressed by Islam et al.
who showed that there was no change in the food efficiency
index during treatment (days 6-15 of gestation) and the
reduction in the food intake had no effect on fetal growth during
the early stages of development. These findings were supported
by Jansson et al. who reported that there was no correlation
between fetal weight and placental blood flow in guinea pigs
at the early stages of development.
Fig. 8. E-16 Khat treatment outcome. (A) Dissected reproductive tract
of a control pregnant rat at day 16 showing considerable number of
normally looking embryos in the uterus. (B) An embryo dissected out
from the uterus in (A) showing normal looking embryo with normal
organ structures. (C): Sagittal section of the embryo in (B) showing
normal internal embryonic structures. (D): Dissected reproductive tract
of day 16 of pregnancy showing resorbed embryo (arrow) in the uteri
of the treated mothers. (E): Reabsorbed embryo appeared
morphologically abnormal. (F): Sagittal section through the resorbed
embryo showing undifferentiated embryonic tissue. Arrowheads in
(B) and (C) indicate the eye; double arrows in (C) indicate the nose
snout projection, asterisks in (A) and (D) indicate the ovaries. Fl,
forelimb; Hl, hind limb Li, liver; Lu, lung bud; Lv, lateral ventricle.
Haematoxylin and Eosin stain, C & F (scale bar=100 µm).
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From the results of the present work, we found many
teratogenic effects at the early stages of development resulted
from the oral administration of Khat during rat pregnancy
including opened neural groove and visceral pouches,
discontinuity in the neural tube, undifferentiated brain vesicles
and incomplete closure of the brain flexure. Similar study was
performed by Islam, et al. but they analyzed the teratogenic
effects of Khat in full term fetuses. Khat induced apoptotic
changes in liver and kidney cells (Ageely et al.; Ageely &
Abou-Elhamd) by sustained activation of the JNK pathway,
which in turn resulted in increase in cell apoptosis (Abid et
al., 2013). In addition, it had cytotoxic effects on cultured
mammalian cells (Al-Ahdal et al., 1988). Many
chemotherapeutic agents have teratogenic effects and they
inhibit DNA synthesis but the relationship between them is
not clear (Wilson et al., 1977; El Gendy et al., 2015). However,
Celiloglu et al. (2000) reported that inhibition of DNA
synthesis with both hydroxyurea and busultan causes growth
retardation and congenital malformation. Khat has cytotoxicity
and inhibits DNA and RNA synthesis in cultured mammalian
cells (Al-Ahdal et al.) and this could be the reason for the
congenital malformations we observed in our experiments.
ABOU-ELHAMD, A. S.; AGEELY, H.; ABU-ELMAGD, M. & ZAYED, A. E. Catha edulis forsk mediates embryotoxic effects in rats: An experimental study.
Int. J. Morphol., 36(3):1087-1094, 2018.
Our study does not cover the molecular causes for the
embryo toxicity and teratogenicity and hence we suggest
further molecular-based studies including target gene and
protein pathway(s) analysis such as in situ hybridization,
proteomics and/or immunostaining to unravel the impaired
genes due to Khat treatment. In conclusion, oral
administration of Khat at 100mg/ kg body weight had adverse
embryonic effects.
ACKNOWLEDGMENTS. Authors are grateful to the
technical staff of the Biology Department, Faculty of
Medicine, Jazan University, for their help and valuable
technical assistance for carrying out this study. We would like
to thank the animal house staff at the Faculty of Medicine,
Jazan University. The project was funded by Dean of the
Scientific Research, Jazan University (Ref: JUP7//00046),
under the name of Dr. Alaa Abou-Elhamd.
ABOU-ELHAMD, A. S.; AGEELY, H.; ABU-ELMAGD, M. &
ZAYED, A. E. Catha edulis forks modera los efectos embriotóxicos
en ratas: Un estudio experimental. Int. J. Morphol., 36(3):10871094, 2018.
RESUMEN: Catha edulis (Khat) es una planta floreciente. Una alta proporción de la población adulta en la Península
Arábiga y el Cuerno de África la mastica por su efecto estimulante. El objetivo del presente estudio fue investigar los efectos
embriotóxicos y teratogénicos del extracto de Khat utilizando 60
ratas hembras preñadas. Estas se dividieron en un grupo tratado
con extracto de Khat y un grupo control. El extracto metanólico de
Khat se administró por vía oral al grupo tratado 4 días antes del
apareamiento y hasta el día 16 de preñez con una dosis de 100 mg
/ kg. Los resultados mostraron que una cantidad significativa de
embriones de las madres tratadas con Khat tenían malformaciones
y eran diferentes en tamaño y forma en comparación con los embriones de las madres del grupo control. En el día 8 de preñez, los
embriones malformados tenían capas primitivas mal desarrolladas. Para el día 10 de preñez, el tubo neural y el somito no se
formaron en comparación con los embriones del grupo control. En
etapas posteriores de la preñez, los embriones de las madres tratadas con Khat parecían severamente anormales con surcos neurales
abiertos y bolsas viscerales. También se observaron alteraciones
en el desarrollo normal del tubo neural, vesículas cerebrales
indiferenciadas y el cierre incompleto de las flexiones cerebrales
en estos embriones. Se observó un aumento altamente significativo en el número de embriones reabsorbidos de las madres tratadas
con Khat (P <0,01). Los embriones reabsorbidos aparecieron como
una colección celular en su placenta con algunas de sus deciduas
sin tejidos embrionarios visibles. Khat indujo efectos embriotóxicos
y afectó severamente el desarrollo embrionario normal temprano
en la rata.
PALABRAS CLAVE: Khat; Toxicidad embrionaria;
Teratogenicidad; Análisis morfológico e histológico; Rata.
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Corresponding author:
Alaa Sayed Abou-Elhamd, Ph.D.
Department of Anatomy
Histology and Embryology,
Faculty of Veterinary Medicine
Assiut University
Assiut
EGYPT
Email: alaa88@yahoo.com
Received: 07-03-2018
Accepted: 25-05-2018