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2 Teaching Hernia Surgery: TheExperience oftheItalian School
9
Table 2.1 Feedback form
1. How do you evaluate this basic training course?
(a) Very well
(b) Well
(c) Sufcient
(d) Insufcient
2. Do you consider appropriate the duration of this
course?
(a) Ye s
(b) No
3. Do you consider the topics to be considerable for
your updating in the hernia surgery?
(a) Very cosiderable
(b) Considerable
(c) Not considerable
4. Are you satised with the whole organization?
(a) Very satised
(b) Satised
(c) Sufciently satised
(d) Not satised
on with the description and analysis of the different meshes, both synthetic and biologic, available
on the market, carefully evaluating pros and cons
of each material. Then standardized surgical procedures for groin, umbilical, and ventral hernia
repairs are described step-by-step. The most performed open and endoscopic techniques are
shown with the help of a large number of lm
clips, particularly focusing on the need of standardization and reproducibility of procedures, in
order to minimize complications and recurrences.
These subjects will be discussed in the following
topics together with medicolegal issues.
The second day is entirely dedicated to a live-
surgery session with expert surgeons demonstrating some of the previously described open and
laparoscopic techniques, directly from the operative room, using a Visera 4K UHD system that
allows a ultrahigh denition and visualization of
the procedures. During each operation, different
technical options and devices are shown with a
special emphasis on the reasons leading to the
nal selection. A continuous interactive communication between audience and operating surgeons is strongly stimulated.
The third day is dedicated to particular aspects
of hernia surgery, as pre- and postoperative management, hernia in sportsmen, parastomal hernias, open abdomen and complex abdominal wall
Table 2.2 Key points of the basic course
– Historical aspects of hernia surgery and its state
of the art
– Prosthetic materials in hernia surgery and the
biology of repair process
– Anatomy of the groin abdominal wall
– EHS classication of groin and abdominal wall
hernias
– Open and laparoscopic surgery in groin hernias
– Postoperative complications and chronic pain
– Biological implants
– Open and laparoscopic surgery and component
separations in ventral hernia repair
– Pre- and postoperative management in complex
abdominal wall hernias
– Umbilical hernias
– Parastomal hernia repair
– Abdominal compartment syndrome (ACS) and
open abdomen
– Plastic surgeon’s keynotes
repairs, panniculectomy, and plastic and reconstructive techniques (Table2.2).
During the course, industries involved in the
Alliance for Hernia are invited to give short presentations regarding new techniques or incoming
materials and devices. Industries’ sponsorship
does not inuence any teaching or planned subjects neither the choice of devices to be implanted
in the live-surgery session. Teachers and participants are encouraged to have meals together to
promote their relationships and offer a further
chance of discussion.
Since the beginning of this experience (2010–
2017), a total of 396 surgeons and surgery residents have attended the basic course (Table2.3).
Results were monitored through participants’
response to the feedback form, and some contents were accordingly updated. Each edition of
the course recorded a high level of customers’
and teachers’ satisfaction increased over the
years (Tables 2.4, 2.5, 2.6 and 2.7).
A critical analysis of this experience reveals
that the Italian School should denitively be
improved with the implementation of practical
activities. A weak point seems to be the lack of
hands-on exercise with anatomy specimens, to
improve knowledge in anatomy of the groin. This
is the reason why a cadaver lab has been recently
organized to integrate the basic course, in spite of
10
060
10
20
30
40
50
60
70
80
90
2010 2011 2012 2013 2014 2015 2016 2017
ab
10
20
30
40
50
60
70
80
90
2010 2011 2012 2013 2014 2015 2016 2017
100
120
2010 2011 2012 2013 2014 2015 2016 2017
Table 2.3 (a) Courses participants 2010–2017. (b) Courses participants 2010–2017
P. Negro et al.
participants
0
Table 2.4 How do you evaluate this basic training course?
very well
well
sufficient
insufficient
%(n=396)
2017
2016
2015
2014
2013
2012
2011
2010
0102030405
Surgeons
Surgery residents
Table 2.5 Do you consider appropriate the duration of
this course?
adequate
not adequate
%(n=396)
80
60
40
0
the high costs of cadavers and, therefore, the
respective fees.
Only few participants have undergone clinical
stages in accredited hernia centers, probably due
to economic problems and working distance. A
more active participation of trainee surgeons in
the operating table should improve their skills
with appropriate learning curve under the super-
20
0
vision of experienced surgeons. This is particularly true when performing laparoscopic repair,
whose learning curve is undoubtedly longer than
open procedures. Besides costs, difculties lay in
the selection of the training centers. In a recent
paper [5], the need was stressed to identify hospital units and referral centers accredited inabdominal wall reconstruction in Italy, with suitable
10
20
30
40
50
60
70
80
90
2010 2011 2012 2013 2014 2015 2016 2017
%(n=396)
10
20
30
40
50
60
70
80
90
2 Teaching Hernia Surgery: TheExperience oftheItalian School
11
Table 2.6 Do you consider the topics to be considerable
for your updating in the hernia surgery?
Very considerable
Considerable
Not considerable
0
Table 2.7 Are you satised with the whole organization?
%(n=396)
At the moment, the Italian School seems to
have contributed to the continuous learning and
education of Italian surgeons, with the regular
review of basic hernia care, and the knowledge of
new techniques, updating also materials and
devices, to ensure that hernia patients receive “tailored” care, leading to excellent outcomes. It has
been highlighted the need that expert surgeons
with particular skill in hernia surgery actively
train and educate a new generation of surgeons.
A systematic, standardized, and widespread
educational program of continuing training is
strongly advisable with the creation and the
development of local training courses in each
European country. The excellent experience of
the German-Austrian Hernia School [13] together
with the know-how of the Italian School should
perform as a model to promote the awareness of
standardized groundwork, updating surgeons’
knowledge and skills in hernia surgery, according
to the suggestion of the EHS.
0
2010 2011 2012 2013 2014 2015 2016 2017
very satisfied
satisfied
sufficintly satisfied
unsatisfied
structural and organizational features and quantitative and qualitative standards, useful also in the
educational training of hernia surgeons. In order
to be more competitive, these centers should have
more than one seat in different areas of the country and provide adequate human, structural, and
technological resources, with a sufcient yearly
number of procedures, the skill of training surgeons to perform all laparoscopic and open techniques for hernia repair with a low rate of
complications and adequate follow-up, and a
theoretical and updated knowledge in hernia
eld.
References
1. Reza Zahiri H, Park AE, Pugh CM, Vassiliou M,
Voeller G. “See one, do one, teach one”: inadequacies
of current methods to train surgeons in hernia repair.
Surg Endosc. 2015;29:2867–72.
2. Poulose BK, Shelton J, Phillips S, Moore D, Nealon
W, Penson D, Beck W, Holzman MD.Epidemiology
and cost of ventral hernia repair: marketing case for
hernia research. Hernia. 2012;16:179–83.
3. Simons M, Aufenacker T, Bay-Nielsen M, Bouillot
J, Campanelli G, Conze J, De Lange D, Fortelny R,
Heikkinen T, Kingsnorth A.European Hernia Society
guidelines on the treatment of inguinal hernia in adult
patients. Hernia. 2009;13:343–403.
4. Sanders DL, Kingsnorth AN, Windsor ACJ.Is there a
role for hernia subspecialist? Or is this a step too far?
Hernia. 2016;20:637–40.
5. Gossetti F, D’Amore L, Ceci F, Tuscano D.
Abdominal wall reconstruction (AWR): the need to
identify the hospital units and referral centers entitled to perform it. Updat Surg. 2017;69(3):289–90.
https://doi.org/10.1007/s13304-017-0428-x.
6. Kulacoglu H, Oztuna D.Current status of hernia cen-
tres around the globe. Indian J Surg. 2015;77(Suppl.3):
1023–6.
7. Hope WW, O’Dwyer B, Adams A, Hooks WB III,
Kotwall CA, Clancy TV.An evaluation of hernia education in surgical residency programs. Hernia. 2014;
18:535–42.
12
P. Negro et al.
8. Ipponi PL, Negro P, Gianetta E, Campanelli GP.The
Italian school of abdominal wall and hernia surgery.
Hernia. 2009;13(Suppl.1):S100.
9. Desyne M, Soroff HS.Must we specialize herniorrhaphy for better results? Am J Surg. 1990;160:239–40.
10. Negro P, Flati G, Gossetti F, Carboni M.Ruolo dei
corsi di perfezionamento in chirurgia dell’ernia inguinale. Groin Incisional Hernias News. 1994;2:74–5.
11. Palumbo P, Turano R, Gallinaro LS, Bertagni A,
Montesano G, Forte A, Angelici AM.Inguinal hernia
repair in a teaching course for surgeons. A training
program. G Chir. 2001;22:321–4.
12. Simmermacher MKJ. Teaching hernia in Europe.
Hernia. 2009;13(Suppl 1):S1–S32.
13. Lorenz R, Stechemesser B, Reinpold W, Fortelny R,
Mayer F, Schroder W, Kokerling F.Development of
a standardized curriculum concept in hernia surgery:
German Hernia School. Hernia. 2016;21(2):153–62.
https://doi.org/10.1007/s10029-016-1566-7.
Alterations oftheExtracellular
Matrix oftheConnective Tissue
inInguinal Herniogenesis
GemmaPascual andJuanM.Bellón
3
3.1 Introduction
Inguinal hernia is still one of the most frequently
performed procedures by general surgeons. Their
socio-health and labor costs are important. In the
USA, this pathology has a cost of approximately
three billion dollars a year [1]. Its etiology and
pathogenesis are complex, with multiple factors
contributing to its development, including individual predisposition and some congenital alterations such as peritoneal-vaginal duct persistence.
Positive familial susceptibility to inguinal hernia
development has been demonstrated, suggesting
the role of genetic contribution in the etiology of
the disease, but site-specic familial factors
might exist [2]. Studies of families with inguinal
hernia propose a genetic trait for both primary
and recurrent inguinal hernias [3]. Mutations in
different collagen genes have been recently suggested to be associated with the development of
G. Pascual
Department of Medicine and Medical Specialties,
Faculty of Medicine and Health Sciences,
Networking Biomedical Research Centre on
Bioengineering, Biomaterials and Nanomedicine
(CIBER-BBN), University of Alcalá, Madrid, Spain
J. M. Bellón (*)
Department of Surgery, Medical and Social Sciences,
Faculty of Medicine and Health Sciences,
Networking Biomedical Research Centre on
Bioengineering, Biomaterials and Nanomedicine
(CIBER-BBN), University of Alcalá, Madrid, Spain
e-mail: juanm.bellon@uah.es
inguinal hernia [4], and four novel inguinal hernia susceptibility loci have been identied, showing an important role for two of these genes
(EFEMP1 and WT1) in connective tissue maintenance and homoeostasis [5].
From a general point of view, the integrity of
the abdominal wall at the level of the inguinal
region depends on the oblique orientation of the
inguinal canal, a sphincter-like structure that
forms part of the deep inguinal ring and the transverse fascia (TF) [6]. The latter structure, which
constitutes the posterior wall of the inguinal
canal, is the one that nally prevents hernia formation and, in a special way, direct hernias. Some
authors [7], after performing mechanical studies,
attribute to the integrity of TF, a containment
mechanism that would prevent the formation of
both direct and indirect type hernias.
The development of hernias at the abdominal
wall level and its recurrence has been shown to
occur more frequently in patients with connective
tissue disorders, not to mention some other
important factors such as smoking [8]. It has been
suggested that defective connective tissue metabolism is involved in the pathogenesis of both the
indirect and the direct types of inguinal hernia. In
diseases with connective tissue alterations, the
incidence of inguinal hernia is higher, such as
patients with aortic aneurysm, Marfan and
Ehlers-Danlos syndromes, cutis laxa, osteogenesis imperfecta, and congenital dislocation of the
hip [9, 10].
© Springer International Publishing AG, part of Springer Nature 2018
G. Campanelli (ed.), The Art of Hernia Surgery, https://doi.org/10.1007/978-3-319-72626-7_3
13
14
Physiological processes
G. Pascual and J. M. Bellón
An important database study [11] including a
large number of patients operated on inguinal
hernia has been published some years ago showing that patients with direct or recurrent inguinal
hernias are at a higher risk of developing ventral
hernia repair compared to patients with indirect
inguinal hernia. This fact was supported by previous studies demonstrating that the more important connective tissue alterations are found in
these patients suffering direct or recurrent inguinal hernia, suggesting future research that reveals
the specic alterations of the connective tissue.
This review paper aims to collect the experience and previous results of our group in the
study of the constituents of the abdominal wall
extracellular matrix of connective tissue, in the
development of inguinal herniogenesis.
3.2 Role oftheExtracellular
Matrix inHernia Pathology
The extracellular matrix is a complex integrated
system developing a structural network that supports and surrounds cell populations within the
connective tissue. It includes a set of tissue bers
such as collagen and elastic bers that are present
in variable amounts depending on the structural
needs or function of the connective tissue. In addition this matrix contains a variety of proteoglycans,
multiadhesive glycoproteins, and glycosaminoglycans that constitute the ground substance.
The mechanisms of the development of the
inguinal hernia involve changes in the expression
of different components of the extracellular
matrix detectable at the TF level, such as collagen turnover (collagen I/III ratio) and metalloproteinases (MMPs). In the same way, the elastic
component that forms part of the extracellular
brillar matrix may contribute to the development of this pathology.
The biological factors, proposed by the Read
group, involved in the development of hernia
have gained acceptance in recent years, conferring a particularly relevant role to metabolic factors in the development of inguinal hernia
[12–14]. Other groups such as Jansen etal. [15]
have located inguinal hernias in the context of a
condition generated by an abnormal composition
of the extracellular matrix.
Patients with inguinal hernia show some alterations in collagen metabolism and signicantly
altered collagen types I/III ratios [16, 17], but few
data are known about the elastic component of
the extracellular matrix and factors involved in
tissue remodeling that may affect the metabolism
of elastin.
The extracellular matrix is a very complex
integrated system, responsible for the mechanical
properties of the connective tissue. The different
constituents of the matrix interact with each
other, and any alteration of one of them may lead
to a disorganization of the extracellular matrix
and the development of different pathologies
such as inguinal hernia (Fig.3.1).
Among the most studied different constituents
of the extracellular matrix in relation to hernia
pathology, collagen and MMPs are found.
However, it has been demonstrated by our group
that other soluble mediators, such as certain
growth factors or enzymes related to the crosslinking of the matrix brillar proteins, may be
altered in patients suffering from hernias [18, 19].
Following, we will review the most studied
extracellular matrix constituents in relation to the
pathology of inguinal hernia, with special emphasis on the ndings obtained by our research group.
Extracellular Matrix
Structural components:
- Collagen Fibers
- Elastic Fibers, Elastin, Microfibrils
Soluble mediators/enzymes:
- Growth factors (TGF-β)
- Matrix metalloproteinases (MMPs)
- Lysyl oxidases (LOX/LOXL)
Increase / decrease
Component expression
Pathological processes
Matrix degradation
(MMPs, elastase)
PATHOLOGY
Inguinal hernia
Fig. 3.1 Scheme of the different constituents of the
extracellular matrix as a complex integrated system and
its disorganization in the development of different pathologies such as inguinal hernia
3 Alterations oftheExtracellular Matrix oftheConnective Tissue inInguinal Herniogenesis
15
3.2.1 Collagen Fibers
Collagen is the main and most abundant brillar
protein in the extracellular matrix. This protein is
mainly synthesized by connective tissue broblasts. In the process of collagen formation,
important hydroxylation reactions occur at the
intracellular level to form hydroxylysine and
hydroxyproline, which are essential in the synthesis process and confer stability to the collagen
molecule. This molecule is formed by three polypeptide α chains assembled at the intracellular
level in the form of a triple helix. It is secreted
into the extracellular matrix in the form of
procollagen, which after a process of cleavage of
its terminal uncoiled ends by procollagen peptidases, will become tropocollagen, assembling in
the form of collagen bril in the extracellular
space [20]. This cross-linking is mediated by
enzymes of the family of lysyl oxidases that promote the formation of highly resistant covalent
bonds between lysine and hydroxylysine residues
and provides strength and stability to collagen
bril, which are highly organized polymers that
further associated with each other to form larger
collagen bers. Some groups [21] have shown a
decrease in proline hydroxylation in TF accompanied by a signicant decrease in the content of
proline and hydroxyproline in the rectus sheath
[22] of patients with direct inguinal hernia, indicating a compromised collagen stability at the
level of the fascia.
The α chains that constitute the helix are not
all the same; to date at least 42 types of α chains
encoded by different genes have been identied.
There are more than 28 genetically different
types of collagens that have been categorized on
the basis of the combination of α chains [23].
Type I collagen is the most resistant, widely distributed in the human body, including the fascia,
the integumentary system, the ligaments, and the
brous tissue. Type III collagen is found in small
amounts in the same tissues and in greater proportion in the initial stages of tissue repair and
wound healing [8, 23]. Type I confers mainly tensile strength, while type III is related to a temporal matrix during the tissue remodeling process.
Therefore, a change in the ratio of collagen in
favor of the type III would results in a loss of
resistance of the structures involved.
Several studies reported an imbalance between
type I collagen and type III collagen [16, 17].
When the collagen content in tissue samples is
analyzed, the result is frequently quantied by
the ratio of collagen type I:III.This collagen ratio
has been found that was signicantly decreased
in the TF of patients with indirect inguinal hernia
compared to controls [24]. In contrast, other
studies have shown an increase in type III collagen but do not report statistically signicant differences in the collagen I: III ratio in TF between
patients with inguinal hernia and controls [21,
25]. Other authors [7] have shown that TF of
patients with direct hernia shows higher levels of
immature type III collagen and that the total
amount of collagen is lower in direct hernia than
in indirect hernia [26]. Ultrastructural studies
using transmission electron microscopy have
focused on the study of the collagen and interbrillar matrix of the connective tissue of patients
with this pathology, showing the absence of alterations in the diameter of the collagen bers in the
TF of patients with inguinal hernia [27].
Our group [21], examining the TF ultrastructure of patients with direct and indirect hernia,
observed that there were no differences in the
uniformity of collagen brils nor in their characteristic banding pattern; however, the interbrillar matrix was more abundant in direct
hernias, showing a large amount of small particles with high electrodensity (Fig.3.2). In this
same work, and by using biochemical studies,
the degree of hydroxylation of the lysine and
proline, essential in the process of synthesis and
stability to the molecule of collagen, was analyzed. No differences were observed in proline
hydroxylation in different types of hernia, and
only a small decrease in lysine hydroxylation
was detected in patients with direct hernia of
more than 40years (Fig.3.3). The ratio of collagen type I:III studied by immunoenzymatic
analysis did not show statistically signicant
differences between controls and patients with
hernia pathology (Fig.3.4).
16
Hydroxylation grade
1
Control Direct Indirect
G. Pascual and J. M. Bellón
Control
Direct
Fig. 3.2 Transmission electron microscopy images of the
connective tissue of the transversalis fascia showing
absence of ultrastructural alterations of the collagen bers
Fig. 3.3 Hydroxylation
of proline and lysine in
the transversalis fascia
of the control groups
0,8
and direct and indirect
inguinal hernias,
depending on the age
factor of the population.
0,6
A signicant decrease in
lysine hydroxylation
was observed in the
direct hernias of the
older group compared to
the rest of the study
groups (
Pro, Hydroxyproline/
Proline ratio; Hyl/Lys,
*
p<0.05) (Hyp/
0,4
0,2
0
hydroxylysine/lysine
ratio)
in the different study groups. Lead citrate and uranyl acetate staining (Magnication 85,000×)
Hyp/Pro
20-40 years 41-60 years 20-40 years
Indirect
Hyl/Lys
*
41-60 years
Optical density (O.D)
12
Control Direct Indirect
3 Alterations oftheExtracellular Matrix oftheConnective Tissue inInguinal Herniogenesis
17
Collagen I:III Ratio
10
8
6
4
2
0
20-40 years
Fig. 3.4 Collagen I:III ratio observed in the different study
groups, taking into account the age factor of the population.
No signicant differences were observed between the different groups of patients (OD optical density)
41-60 years
3.2.2 Matrix Metalloproteinases (MMPs)
Matrix metalloproteinases (MMPs) are a family
of zinc dependent important proteins involved in
extracellular matrix remodeling, which is subjected to a constant dynamic balance between its
synthesis and degradation by the action of these
enzymes. The MMPs are known to regulate the
synthesis and degradation of collagen, but also of
many other components of the extracellular
matrix, such as proteoglycans, elastin, bronectin, etc. There are about 23 different types of
human MMPs that are grouped into collagenases,
gelatinases, stromelysins, matrilysins, membrane
MMPs, and other MMPs [28]. The classical
MMPs include collagenases like MMP-1, MMP8, and MMP-13, involved in the degradation of
type I, II, and III collagens, and the MMP-2 and
MMP-9 gelatinases involved in the degradation
of denatured type IV collagens and proteoglycans. However, MMP-2 is also capable of degrading native type I, II, and III collagens [29, 30].
Collagenases and gelatinases are probably the
most important MMPs in relation to hernia
formation.
In general MMPs are expressed at very low
level; however, their expression may be induced
as a consequence of different pathological mechanisms. Pro-inammatory cytokines, growth fac-
tors, and hormones are important regulators of
MMPs expression. The proteolytic activity of
these enzymes, latently secreted, is mainly controlled by the activation of tissue inhibitors of
MMPs known as TIMPs [29, 31]. It has been
shown that doxycycline administration, as MMPs
inhibitor, results in signicantly improved
strength of repair fascial interface tissue along
with a remarkable increase in collagen I, II, and
III ratios [32, 33].
Experimental studies performed by different
groups have shown that there are no signicant
differences in the levels of the MMP-1, MMP-9,
and MMP-13 enzymes in the TF of patients with
direct or indirect hernia compared to controls
[34, 35]. Unlike other studies that found signicantly higher values of MMP-1, MMP-2, and
MMP-9, in inguinal hernia cases [36]. Other
authors have found signicantly elevated levels
of MMP-2in patients with direct inguinal hernia
compared to indirect hernia or control, accompanied by a signicant decrease in their inhibitor
TIMP-2 [37, 38].
The degradation of the extracellular matrix
by the effect of MMPs on the TF has also been
the objective of our investigations. Four different types of MMPs (MMP-1, MMP-2, MMP-3,
and MMP-9) were analyzed by our group in tissue sections, using immunohistochemical techniques with specic monoclonal antibodies.
However, we found only signicant differences
in the protein expression of MMP-2 [21], where
a signicant overexpression of the enzyme was
observed in the direct hernias of the young
patients group with respect to the rest of the
groups (Fig.3.5).
After this study we carried out a second
invitro phase [39], using broblasts, in order to
check whether the overexpression of MMP-2
observed in tissue was maintained in the cultured
cells obtained from TF.The results obtained with
immunocytochemical, immunoblotting, and
zymography techniques corroborated that
MMP-2 would be involved in the degradation
process of the TF matrix in patients with direct
hernia. The persistence of alterations in MMP-2
18
*
20
16
12
8
MMP-2 Activity
4
0
20-40 years
Direct
Control Direct Indirect
G. Pascual and J. M. Bellón
41-60 years
Indirect
Fig. 3.5 Immunohistochemical staining images for the
detection of MMP-2in tissue sections of transversalis fascia. An increase in expression may be observed in the
group of direct inguinal hernia (Magnication 200×).
levels in cell cultures seems to suggest a genetic
defect or irreversible change as the origin of this
pathology rather than environmental factors that
may later be involved in the development of the
disease (Fig.3.6). These works were the rst in the
literature to implicate MMP-2in the pathogenesis
of a type of hernia, namely, direct hernia in patients
under 40years of age, where this hernia is often
bilateral.
Our research group has even more previous
experience [40] related to MMP-2 and its modulators, using human skin biopsies obtained from
patients suffering inguinal hernia repair. In this
study immunocytochemical and immunoblotting
techniques were used in intact tissue and broblast cell cultures, as well as zymography techniques to analyze the degradative activity of
MMP-2. These results indicate an overexpression
of the active form of MMP-2 in the group of
direct hernias that could point to an abnormal
Quantication of MMP-2 activity in the different study
groups, depending on the age of the population. A signi-
*
cant (
p < 0.05) increase in expression was observed in
direct hernias in the group of patients younger than 40years
systemic metabolism as a risk factor for the
development of this type of hernia.
3.2.3 Growth Factors
Cytokines or growth factors like TGF-β (transforming growth factor beta) are involved in
remodeling processes of different types of tissues. TGF-β is a multifunctional secretion protein that regulates many aspects of cellular
function, including cell proliferation, differentiation, and metabolism of the extracellular matrix,
[41] through its binding to specic cellular receptors. Five different isoforms have been described,
and three of them are found in all species of
mammals. TGF-β1 is most widespread and is a
25,000 Kd molecular weight homodimeric protein composed of two identical 12.5 Kd proteins
linked by a disulde bridge [42, 43]. A wide vari-