This document provides an overview of dentin, including its physical, chemical, and structural properties. It discusses the types of dentin such as primary, secondary, and tertiary dentin. It describes the development of dentin through odontoblast differentiation and matrix formation followed by mineralization. Key structures of dentin like dentinal tubules, peritubular dentin, and predentin are defined. Theories of pain transmission through dentin and age-related functional changes in dentin are also summarized.
2. CONTENTS
• INTRODUCTION
• PHYSICAL PROPERTIES
• CHEMICAL PROPERTIES
• STRUCTURES
• TYPES OF DENTIN
• INCREMENTAL LINES OF DENTIN
• INNERVATION OF DENTIN
• THEORIES OF PAIN TRANSMISSION THROUGH DENTIN
• AGE AND FUNCTIONAL CHANGES
• DEVELOPMENT OF DENTIN
• CLINICAL CONSIDERATIONS
• DEVELOPMENTAL DEFFECTS
4. • Dentin is the hard tissue of the tooth that surrounds the central core
of nerves and blood vessels and provides the bulk and general form
of the tooth
• Since it begins to form slightly before the enamel, it determines the
shape of the crown, including the cusps and ridges and the number
and size of roots
• Said to be a living tissue since the tubules present in it contains
processes of specialised cells, the odontoblast
5. PHYSICAL PROPERTIES
• In teeth of young individuals, the dentin is usually light yellowish in colour,
becoming darker with age.
• Dentin is viscoelastic and subject to slight deformation
• It is harder than bone but considerably softer than enamel
• The dentin of primary teeth is slightly less hard than that of permanent
teeth.
• The dentin is more radiolucent than enamel
6. PROPERTY VALUE
Colour Pale yellow
Thickness 3-10 mm
Modulus of Elasticity 15-20 GPa
Hardness 68 KHN
Carious Dentin 25 KHN
Sclerotic Dentin 80 KHN
Compressive strength 266 MPa
Tensile strength 50 MPa
Radiopacity Less than enamel
8. Organic (20%)
• The organic substance consists of collagenous fibrils embedded in the
ground substance of mucopolysaccharides
• Type I collagen is the principal type of collagen found in the dentin
• Ground substance:-
i. proteoglycans- chondroitin sulphates, decorin & biglycans
ii. Glycoproteins- dentin sialoprotein (DSP), osteonectin, osteopontin
iii. Phosphoproteins- dentin phosphoprotien (DPP), gamma
carboxyglutamate containing proteins and phospholipids.
• In addition, matrix contains growth factors like transforming growth factor
(TGF), fibroblast growth factor (FGF), insulin like growth factor (IGFs),
bone morphogenic proteins (BMPs), vascular endothelial growth factor
(VEGF), and angiogenic growth factor (AGF).
9. • Inorganic (65%)
• The inorganic component consist of hydroxyapatite.
• Each hydroxyapatite crystal is composed of several thousand unit cells.
• The crystals are plate shaped and much smaller than the hydroxyapatite
crystal in enamel.
• Dentin also contain small amounts of phosphates, carbonates, and sulfates.
• The crystals are poor in calcium but rich in carbon when compared to
enamel
11. DENTINAL TUBULE
• The course of the dentinal tubules follow a
gentle curve in the crown where it resembles
an S shape
• Starts at right angles at the pulpal surface,
the first convexity of this doubly curved
course is directed towards the apex of the
tooth
• These tubules end perpendicular to the DEJ
& CDJ
12. • It is almost straight near the root tip and along the incisal edges and cusps
• Dentin thickness ranges from 3-10mm or more
• No. of tubules per square millimetre varies from 15000
at the DEJ to 65000 at the pulp - density and diameter
increases with depth
13. • There are more tubules per unit area in the crown than in the root
• These dentinal tubules have lateral branches throughout dentin, which are termed
canaliculi or microtubules
• A few odontoblastic processes extend through the DEJ into the enamel several
millimetres. These are called Enamel Spindles
14.
15. PERITUBULAR DENTIN
• The dentin that immediately surrounds
the dentinal tubules is termed peritubular dentine
• Highly mineralized than intertubular dentin
(about 9%)
• Twice as thick in outer dentin (approx. 0.75μm)
than inner dentin(approx. 0.4μm)
16. • Studies with electron microscope show the
increased mineral density in the peritubular dentin
• Between the odontoblastic process and the
peritubular dentin, a space known as
periodontoblastic space is present.
• This space contain the dentinal fluid. The normal
flow of the fluid is outward from the pulp.
17. INTERTUBULAR DENTIN
• The main body of dentin is composed of intertubular dentin.
• Located between the dentinal tubules specifically between the zones of
peritubular dentin
• One half of its volume is organic matrix, specifically collagen fibers
18. • The fibrils range from 0.5-0.2μm in diameter and exhibit cross banding at
64μm intervals
• HA crystals are formed along the fibers with their long axis oriented parallel to
the collagen fibers
19. PREDENTIN
• Located adjacent to the pulp tissues
• 2-6μm, depending on the activity of odontoblast
• First formed dentin and is not mineralised
• The collagen fibres undergo mineralization at the
predentin - dentin JUNCTION, the predentin then
becomes dentin and a new layer of predentin forms
circumpulpally
20. DENTINO ENAMEL JUNCTION
• The DEJ is a complex and critical structure
uniting two dissimilar calcified tissues and acts
to prevent the propagation of cracks from
enamel into dentin.
• The DEJ has three level structure, 25-100 µm
scallops with their convexities directed
towards the dentin and concavities toward the
enamel; 2-5µm micro scallops and a smaller
scale structure.
• The convexities of the scallops are directed
towards the dentin. The concavities are
directed toward the enamel. The surface of the
dentin at DEJ is pitted.
21. ODONTOBLAST PROCESS
• Cytoplasmic extensions of the odontoblasts
• The odontoblasts reside in the peripheral pulp at
the pulp-predentin border and their processes
extend into the dentinal tubules
• The processes are largest in diameter near the
pulp and taper further into dentin
22. • The odontoblast cell bodies are approximately 7μm in
diameter & 40μm in length
• The junction between odontoblasts maybe of gap
juntions, tight junctions, and desmosomal junctions.
• The odontoblast process is composed of microtubules
of 20 µm in diameter and small filaments 5 to 7.5µm
in diameter.
DEJ
Odontoblast
ic process
Preodonto
blastic
space
Peritubular
dentin
Mantle
dentin
Circumpul
pal dentin
Predentin
Intertubu
lar dentin
Odontoblas
ts
25. PRIMARY DENTIN
• Dentin that is formed prior to eruption of a tooth, before root
completion
• Secreted at a relatively higher rate
• Constitutes major part of the dentin in the tooth
• Consist of mantle dentin and circumpulpal dentin.
26. 1) Mantle Dentine
• First formed dentin in crown underlying the DEJ
• 20 μm thick
• Fibrils found in this zone are perpendicular to DEJ
• Organic matrix - von korffs fibres (large diameter
fibrils- type III collagen fibrils)
• Less mineralized compared to circumpulpal dentin
27. 2) Circumpulpal Dentin
• Forms the remaining primary dentin or
bulk of the tooth.
• The fibrils are much smaller in diameter
(0.05micrometer) & are more closely
packed together.
• Slightly more mineral content than mantle
dentin.
28. SECONDARY DENTIN
• Formed after root completion
• Narrow band of dentin bordering the pulp
• Contains fewer tubules than primary dentin
• There is usually a bend in the tubules where
primary and secondary dentin interface
29. • Since it is formed after eruption, the odontoblasts
slightly change direction which contributes to
bending of dentinal tubules
• It is a slow continuous deposition of dentin.
• It is formed more slowly than primary dentin.
• Secondary dentin is not formed uniformly and
appears in great amounts on the roof and floor of
pulp chamber, where it protects pulp from exposure.
30. TERTIARY DENTIN
• Tertiary dentin is reparative, response, or reactive
dentin.
• This is localized formation of dentin on the pulp-
dentin border, formed in reaction to trauma such as
caries or restorative procedures.
• By pathologic process or operative procedures, the
odontoblastic processes are exposed or cut, the
odontoblasts die or survive, depending on the
extend of injury
31. • If they survive, dentin that is produced are
called reactionary or regenerated dentin
• Killed odontoblasts are replaced by the
migration of undifferentiated cells arising in
the deeper layers of the pulp to the dentin
interface
• This newly differentiated odontoblasts then
begin deposition of reparative dentin to seal
off the zone of injury as a healing process
initiated by the pulp,
32. • Resulting in resolution of the inflammatory process and removal of
dead cells
• This type dentin produced by a new generation of odontoblast-like
cells in response to appropriate stimulus after the death of original
odontoblasts is called Reparative dentin
• This reparative dentin has fewer and more twisted tubules than normal
dentin
• Histological difference between reactionary and reparative dentin is
that reactionary dentin is deficient in acid proteins so it doesn't stain.
36. 1) Incremental lines of von Ebner
• Also known as Imbrication line or short period line
• The incremental lines of Von Ebner or imbrications
lines appear as fine lines or striations in dentin
• Run at right angles to the dentinal tubules.
• These lines reflect the daily rhythmic, recurrent
deposition of dentin matrix as well as hesitation in the
daily formative process
37. • The distance between lines varies from 4-8
µm in the crown to much less in the root. The
daily increment decreases after a tooth
reaches a functional occlusion
• The course of the lines indicates the growth
pattern of the dentin
• Cuspal dentin- 4 µm/day
• Root dentin- 2 µm/day
38. 2) Contour lines of Owens
• Some of the incremental lines are
accentuated because of disturbances in the
matrix and remineralisation process. Such
lines are known as contour lines of Owen
• These lines represent hypocalcified bands
39. 3) Neonatal line
• In the deciduous teeth and in the first
permanent molars, the prenatal and
postnatal dentin is separated by an
accentuated contour line, this is termed
the Neonatal line.
• This line reflects the abrupt change in
environment that occurs at birth .
• The dentin matrix formed prior to birth is
usually of better quality than that formed
after birth
40. 4) Andersons line
• Also known as long period line
• The term long period refers to the intrinsic
temporal repeat interval that is greater than one
day (in contrast to daily short period line). 16-
20um apart
• Between each long period line there are 6 - 10
pairs of short period lines.
• Cause for the 6 to 10 day periodicity is unknown.
41. GRANULAR LAYER
• There is a zone adjacent to the
cementum that appears granular
known as Tome's granular layer
• It slightly increases in amount from
the CEJ to the root apex
• Caused by coalescing and looping of
the terminal portions of the dentinal
tubules
42. INNERVATION OF DENTIN
•INTRATUBULAR NERVE
• Nerve fibers were shown to accompany 30 to 70% of
the odontoblastic process and these are referred to as
intratubular nerves
• Dentinal tubules contain numerous nerve endings in
the pre dentin and inner dentin no farther than 100 to
150 µm from the pulp
• Most of these small vesiculated endings are located in
tubules in coronal zone, specifically in the pulp horn.
43. THEORIES OF PAIN
TRANSMISSION THROUGH
DENTIN
Basic theories of pain conduction through dentin
• Direct neural stimulation
• Transduction theory
• Hydrodynamic theory
44. Direct Neural Stimulation
• According to which nerves in the dentin get stimulated.
Drawbacks:
• The nerves in dentinal tubules are not commonly seen and even if they are
present, they do not extend beyond the inner dentin
• Topical application of local anaesthetic agents do not abolish sensitivity
• Hence this theory is not accepted
45. Transduction Theory
• According to which the odontoblasts process is the primary structure
excited by the stimulus and that the impulse is transmitted to the nerve
endings in the inner dentin.
Drawback:
• Since there are no neurotransmitter vesicles in the odontoblast process
to facilitate the synapse or synaptic specialization
46. Hydrodynamic theory
Most accepted theory
• Various stimuli such as heat, cold, airblast
dessication or mechanical or osmotic
pressure affect fluid movement in the
dentinal tubules.
• This fluid movement either inward or
outward, stimulates the pain mechanism
in the tubules by mechanical disturbance
of the nerves closely associated with the
odontoblast and its process
• Thus these endings may act as
mechanoreceptos as they are affected by
mechanical displacement of tubular fluid
47.
48. AGE AND FUNCTIONAL CHANGES
Vitality of dentin
• Odontoblasts and its processes are an integral part of dentin
• And so vitality is understood to be the capacity of the tissue to react to
physiologic and pathologic stimuli, dentin must be considered a vital
tissue
49. • Dentinogenesis is a process that continues through out life
• Although after the teeth have erupted and have been functioning for a short
time, dentinogenesis slows and further dentin formation is at a slower rate.
This is secondary dentin
• Pathologic changes in dentin such as dental caries, abrasion, attrition or the
cutting of dentin in operative procedures cause changes in dentin. They are
the dead tracts, sclerosis and the addition of reparative dentin
50. 1) Dead tracts
• In dried ground section the odontoblastic
processes disintegrate and the empty tubules
are filled with air
• Appear black in transmitted light and white
in reflected light
• Degeneration is often observed in areas of
narrow pulp horns because of crowding of
odontoblasts
51. • These degenerated empty areas
demonstrate decreased sensitivity
• Seen to a greater extend in older
teeth
• Dead tracts are probably the
initial step in the formation of
sclerotic dentin
53. 3) Sclerotic dentin
• Caries, attrition, abrasion, erosion or cavity
preparation causes collagen fibres and
apatite crystals to begin appearing in the
dentinal tubules
• This blocking of tubules may be considered
as a defensive reaction of dentin
• These apatite crystals are initially only
sporadic in a dentinal tubule but gradually
fill it with a fine meshwork of crystals
54. • As this continues, the tubule lumen is
obliterated with mineral which appears
very much like the peritubular dentin
• Dentin in such areas become transparent
• Transparent in transmitted and dark in
reflected light
• There is decreased permeability of
dentin
56. DENTINOGENESIS
• Formation of dentin is called dentinogenesis, it starts before
amelogenesis
• Dentin is formed by odontoblast cell
• It takes place in two phases, first the formation of organic collagen
matrix and second, the deposition of hydroxyapatite crystal
57. • Dentin formation begins when the tooth germ
has reached bell-stage of development.
• Under the influence of inner enamel
epithelium, the outermost ectomesenchymal
cells of dental papilla differentiate into
odontoblasts.
• Initially, the cells of the dental papilla are
small, undifferentiated and have few
organelles.
58.
59. • Inner enamel epithelium releases transforming growth factor, insulin growth
factor and bone morphogenetic protein for the differentiation of odontoblasts.
• Differentiation begins adjacent to the deepest invagination of the enamel
organ, the portion of the future cusp tip.
• The cells of dental papilla immediately adjoining the acellular zone enlarge to
become preodontoblasts, which change their shape from ovoid to columnar
and differentiate into odontoblasts.
• The nucleus is oriented towards the base (away from the inner enamel
epithelium) and increased amounts of protein- synthesizing organelles appear
in cytoplasm.
60.
61. MATRIX FORMATION
• Matrix formation begins with the appearance of large diameter collagen
fibrils (0.1-0.2 micrometres) known as Vonkroff's fibres.
• These fibres are laid down at right angles to the future DEJ.
• Once the mantle dentin is laid, the remaining collagen fibres are laid
parallel to the DEJ.
• As the odontoblast forms the matrix and move towards the pulp, several
fibres join to form the processes that are embedded in the dentinal tubules
62. • Dentin is formed at a rate of about 4 micrometres/day till the crown is
formed and the tooth erupts. After this the dentin production slows to
about 1µm/day
• As each increment of the matrix is formed, it remains for a day before
it is calcified and the next increment of the matrix forms.
• The rate of matrix formation is slower in the radicular dentin and it
contains collagen fibres which is parallel to the CEJ.
63.
64. Formation of pre dentin
• The first indication of pre dentin formation is the development of
bundles of fibrils among the fully differentiated odontoblast
• These bundles are known as Von korff’s fibers, that form the major
component of the of the first formed thickness of dentin
• Are attached to the basement membrane of inner enamel epithelim
65. MINERALIZATION
• First crystal deposition is in form of very fine plates of hydroxyapatite on the surface of
collagen fibrils and in the ground substance.
• The crystal associated with collagen fibrils are arranged in an orderly fashion, with their
long axis paralleling the fibril long axis and in rows conforming to the 64 nm striation
pattern
• Mineralization usually occurs by matrix vesicle in which odontoblast release membrane
bound vesicles into the organic matrix.
• The general calcification process is gradual, but the peritubular region becomes highly
mineralised at very early stage
66. • The apatite crystal of dentin resemble those found in bone and
cementum. They are 300 times smaller than those formed in
enamel.
• Dentin sialoprotein present in mineralizing dentin affects the
rate of mineral deposition while other proteoglycans present
more in predentin, inhibits premature calcification of the
predentin
• Many genes are implicated in dentinogenesis, the newer ones
being MAP1B for odontoblast differentiation, and PHEX for
dentin mineralization.
67.
68. • Several proteins are released to regulate the deposition of minerals.
• OSTEONECTIN - it can inhibit hydroxyapatite crystals growth & promote Calcium
& phosphorous binding to collagen
• OSTEOPONTIN - promotes mineralization
• DPP (Dentin phosphoproteins) concentration elevated - inhibits mineralization
• CHONDROITIN SULPHATE - properties vary depending on whether they are in:
PREDENTIN - prevent transport and diffusion of crystals(inhibitors)
MINERALIZING DENTIN -promote hydroxyapatite crystal formation.
69. CLINICAL CONSIDERATIONS
Exposure of Dentinal Tubules
• tooth wear, fractures, caries, cavity cutting procedures etc. lead to exposure of
dentinal tubules.
• 1 mm exposed dentin damages 30000 living odontoblasts
• The rapid penetration and spread of caries in the dentin is the result of tubule
system in the dentin
70. • The dentinal tubules provide a passage for invading bacteria and their
products through either thick or thin dentinal layer.
• Advised to seal dentin surface with nonirritating, insulating substance
such as bonding agents, varnishes or restoration
71. Dentinal Hypersensitivity
• Short, sharp pain arising from exposed dentin in response to a stimuli
typically thermal, evaporative, tactile, osmotic or chemical and which can’t
be ascribed to any other form of dental defect or pathology.
• The sensitivity of the dentin has been explained by the hydrodynamic
theory, that alteration of the fluid and cellular contents of the dentinal
tubules causes stimulation of the nerve endings in contact with these cells.
• Most pain inducing stimuli increase fluid flow within the dentinal tubule,
giving rise to a pressure change throughout the entire dentin
• This in turn activates the intra dentinal nerves at the pulp-dentinal interface,
or within the dentinal tubules thereby generating pain.
72. • ETIOLOGY-
a) Exposure of dentinal tubules
b) Loss of enamel
c) Attrition, abrasion and erosion
d) Loss of cementum
e) Gingival recession
• MANAGEMENT-
a) Block the dentinal tubule
b) First line of treatment- use of dentifrices containing potassium nitrate/ stannous
fluoride.
c) Lasers have been used in the treatment of hypersensitivity.
73.
74. Smear layer and smear plugs
• smear layer- term most often used to describe the
grinding debris left on dentin by cavity preparation
• Cutting debris when forced into dentinal tubules, it
forms plugs known as smear plugs
• Smear layer- 1-3 µm; smear plug- 40µm
• Significance- lowers the permeability of dentin
surface and occludes the tubule
• Disadvantage: prevents the adhesion of restorative
materials in the dentin
• Therefore this layer has to be removed by etching and
a rough porous surface should be created for bonding
agent to penetrate
76. OPERATIVE INSTRUMENTATION
• Avoid- excessive cutting, heat generation, continuous drying
• Use- air-water coolant, sharp hand instruments
• Tungsten carbide burs to cut vital dentin, less heat generation.
77. DEVELOPMENTAL DEFFECTS
1. Dentinogenesis imperfect
• Group of hereditary conditions charecterised by abnormal dentin formation
• It is an autosomal dominant condition.
• This condition causes tooth to be discoloured and translucent
• It can affect both primary teeth and permanent teeth
• Divided into:-
1) Type 1 – occurs with osteogenesis imperfect
2) Type 2 – hereditary opalescent dentin
3) Type 3 – brandywine isolate
78.
79. CLINICAL FEATURE:-
• Tulip shaped teeth, bluish grey- yellow/brown translucent
• Enamel chips away- exposed dentin, rapid attrition
• Amber appearance, excessive wear, multiple pulp exposures.
• The tooth usually involved and more severely affected are deciduous
teeth in type 1whereas in type 2, both the dentition are equally
affected.
• Radiographically, the teeth appears solid, lacking pulp chambers and
root canal.
80. TREATMENT
• In patient with DI, one must first be certain which type he/she are dealing
with.
• Severe cases of DI type 1 associated Osteogenesis imperfecta can present
significant medical management problems. Careful review of the patient's
medical history will provide clues as to the severity of bone fragility based
on the number of previous fractures and which bones were involved.
• Patients not exhibiting enamel fracturing , rapid wear crown placement and
routine restorative techniques may be used.
81. • Bonding of veneers may be used to improve the esthetics
• In more severe cases, where there is significant enamel fracturing and rapid
dental wear, the treatment of choice is full coverage crowns.
• However in case of DI 3 with thin roots are not good cases for full coverage
because of cervical fractures
• Occlusal wear with loss of vertical dimension:-
metal casting
newer composite
82. 2. DENTIN DYSPLASIA
• Rootless teeth
• Rare Dental Anomaly
• Normal Enamel, Atypical Dentin, Abnormal Pulp Morphology
• CLASSIFICATION: (Acc. To WHITKOP) -
a) TYPE I- RADICULAR
b) TYPE II - CORONAL
83. DENTIN DYSPLASIA TYPE 1
• Radicular dentin dysplasia
• Characterized by :-
• Both dentition are affected
• Normal appearing crown
• No or only rudimentary root
development
• Incomplete or total obliteration of pulp
chamber
• Teeth may exhibit extreme mobility
and exfoliate prematurely
DENTIN DYSPLASIA TYPE 2
• Coronal dentin dysplasia
• Characterized by :-
• Deciduous teeth have yellow, brown or
bluish grey appearance.
• Partial pulp obliteration
• Flame shaped coronal pulp chamber
• thread like root canals
• Usually the absence of periapical
radiolucencies
• Teeth roots are of normal shape and
contour
84. Management
• Preventive care is of most importance
• Directed towards specific symptoms that are apparent in each individual
• Recommended treatment- regular monitoring by dentist and preventive
dental care.
• Conventional endodontic therapy will require mechanical creations of pulp
path
85. 3. DENS EVAGINATUS
• Cusp like elevation of enamel located in
central groove or lingual ridge of the
buccal cusp of premolar or molar
• Consist of enamel and dentin with pulp
present in half of the cases
• Radiographically the occlusal surface
exhibits a tuberculate appearance and
often pulpal extension is seen in cusp.
• Occlusal problem which leads to pulpal
death
• Removal of cusp is indicated
86. 4. DENS IN DENTE
• Dentin and enamel forming tissue
invaginate the whole length of tooth
• Arise as a result of an invagination in
surface of tooth crown before the
calcification.
• Most frequently involved – maxillary
lateral incisor.
• Radiographically – “tooth within tooth”
• Food lodges in the cavity to cause caries
which rapidly penetrates the distorted
pulp chamber
• To prevent caries, pulp infection and
premature loss of tooth, the condition
must be recognized early and the tooth
should be prophylactically restored.
87. MANAGEMENT OF CHILDREN WITH
DEVELOPMENTAL DEFECT OF DENTIN
• Early diagnosis and preventive care are essential for successful
management of dentin defects
• Children who have family history of dentine defects such as
dentinogenesis imperfecta or those associated with medical conditions
known to be associated with dentin defect should be screened early
for dental problems
• As DI is associated with rapid tooth wear and crown fracture,
protection from tooth wear is recommended soon after eruption.
• Prophylactic coverage of tooth is necessary to protect the pulp soon
after eruption
Seow WK. developmental defects of enamel and dentine: challenges for basic science research and clinical management. Aust
Dent J. 2014 Jun; 59 Suppl 1:143-54. doi: 10.1111/adj.12104. Epub 2013 Oct 27. PMID: 24164394
88. REFERENCES
• Orban’s oral histology and embryology – G.S Kumar – Thirteenth edition. P93 -
116
• Ten Cate’s oral histology – development, structure and function – Antonio Nanci –
Sixth edition. P67 - 98
• Pathways of pulp – Cohen. Hargreaves – Ninth edition. P113-117
• Shafer’s Textbook of Oral Pathology – Shafer, Hine, Levy – 8th edition. P38 - 61
• Oral and Maxillofacial pathology – Neville – Third edition. P64-78
• The art and science of Operative dentistry – Theodore Sturdevant – Fourth edition
• Manual of Oral Histology and Oral Pathology – Maji Jose – Second edition. P35 –
43.
• Seow WK. developmental defects of enamel and dentine: challenges for basic
science research and clinical management. Aust Dent J. 2014 Jun; 59 Suppl
1:143-54. doi: 10.1111/adj.12104. Epub 2013 Oct 27. PMID: 24164394