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BME 295C: Challenges in Biomedical Engineering
Traumatic Brain Injury
1. Identify a bio/clinical marker of Traumatic Brain Injury (TBI) and write a short summary
on current evidence from research.
Resources:
– Use PubMed and MeSH terms (as opposed to Google). Learn how to use PubMed here
or talk to our engineering library liaison about effectively searching and identifying
reliable online resources.
– Example keywords: biomarkers, blood biomarkers, clinical markers, mild traumatic
brain injury, concussion, severe traumatic brain injury.
– Note: You may find conflicting evidence on certain biomarkers. Try to understand both
the underlying biological process related to the marker as well as the statistical results
presented in studies.
– As a starting point, use Supplement Article I on D2L (you are not restricted to markers
described in this article).
2. Consider the following prognostic calculator that can predict 6-month outcome in severe
and moderate TBI patients: TBI IMPACT Score Calculator
Resources:
– Use Supplement Article II on D2L and other information on the IMPACT website to
better understand different variables in the calculator/model.
– You may enter different values for each variable and see how it impacts the patient
outcome. For example: Providing different values for GCS (see slides for details) will
allow for analyzing TBI severities (moderate versus severe TBI).
– Based on your experiments and research, comment on (a) how the model is
constructed and (b) the significance of different variables in the IMPACT model in
predicting the patient outcome.
FOCUS ON TRAUMATIC BRAIN INJURY
Biomarkers of mild traumatic brain injury
in cerebrospinal fluid and blood
Henrik Zetterberg, Douglas H. Smith and Kaj Blennow
Abstract | Mild traumatic brain injury (TBI), which is defined as a head trauma resulting in a brief loss of
consciousness and/or alteration of mental state, is usually benign, but occasionally causes persistent and
sometimes progressive symptoms. Whether a threshold for the amount of brain injury and/or individual
vulnerability might contribute to the development of these long-term consequences is unknown. Furthermore,
reliable diagnostic methods that can establish whether a blow to the head has affected the brain (and in
what way) are lacking. In this Review, we discuss potential biomarkers of injury to different structures and
cell types in the CNS that can be detected in body fluids. We present arguments in support of the need for
further development and validation of such biomarkers, and for their use in assessing patients with head
trauma in whom the brain might have been affected. Specifically, we focus on the need for such biomarkers
in the management of sports-related concussion, the most common cause of mild TBI in young individuals, to
prevent long-term neurological sequelae due to concussive or subconcussive blows to the head.
Zetterberg, H. et al. Nat. Rev. Neurol. 9, 201–210 (2013); published online 12 February 2013; doi:10.1038/nrneurol.2013.9
Introduction
A blow to the head can result in anything from a super­
ficial skin laceration to severe brain injury. The extremes
of this range are easy to recognize by clinical examina­
tion and neuroimaging, but whether the brain has been
injured by a blow to the head (in the presence of non­
specific symptoms such as dizziness, nausea or headache)
is more difficult to assess. The definition of mild traumatic
brain injury (TBI) has changed over the past 60 years,1
but the American Congress of Rehabilitation Medicine
currently defines mild TBI as head trauma resulting in
one of the following: loss of consciousness for less than
30 min, alteration of mental state for up to 24 h (being
dazed, confused or disorientated), or loss of memory for
events immediately before or after the trauma.2
The terms mild TBI and concussion have historically
been used interchangeably to suggest an inconsequen­
tial injury; however, mild TBI is far from trivial, since
it can induce selective swelling and disconnection of
white matter axons.3,4 Furthermore, repeated episodes
of mild TBI are associated with chronic and sometimes
progressive clinical symptoms and neuropathological
changes. 5 Although the mechanisms underlying the
association between single or repetitive mild TBI and
progressive neurodegeneration are not yet understood,
we can reasonably assume that accurate biochemical
tests of axonal, neuronal and astroglial injury would be
helpful to indicate whether a person with head trauma
has experienced an injury to the brain, to establish the
severity and nature of the injury, and to identify when
the injury has resolved.
Competing interests
The authors declare no competing interests.
The detection of brain injury in individuals who have
experienced a concussive or subconcussive blow to the
head is of particular relevance in sports such as boxing,
hockey, rugby and American football. Head injuries are
common in players of these sports, and several athletes’
careers have ended because of chronic neurological
or psychiatric symptoms.6 An objective test to deter­
mine whether an athlete can safely return to their sport
would, therefore, be highly desirable, and would reduce
the current over-reliance on CT scans (and the associ­
ated exposure to ionizing radiation) for this purpose
Another group of individuals at risk of brain injury is
military personnel, who might be exposed to several
types of brain trauma in the battlefield.7 In addition to
bio­markers for use in the acute and subacute phases of
mild TBI, develop­ment of biomarkers that will enable
clinical studies of the potential neuropathological cas­
cades in the chronic phase of mild TBI is also important.
This statement is valid not only for fluid biomarkers but
also for imaging and other markers.
In this Review, we provide an overview of the current
research on fluid biomarkers of mild TBI. We describe
the biomarkers that are already in clinical use and those
that require further development before they can be used
in clinical practice.
Pathophysiology of mild TBI
Mild TBI is a complex pathophysiological entity induced
by external mechanical forces on the brain. Typically,
mild TBI causes no gross pathology, such as haemor­
rhage or abnormalities that can be seen on a conventional
CT scan of the brain,8 but instead causes rapid-onset
neurophysiological and neurological dysfunction that,
NATURE REVIEWS | NEUROLOGY
Clinical Neurochemistry
Laboratory, Institute of
Neuroscience and
Physiology, Department
of Psychiatry and
Neurochemistry,
Sahlgrenska Academy
at the University of
Gothenburg, SE-431 80
Mölndal, Sweden
(H. Zetterberg,
K. Blennow). Penn
Medical Center for
Brain Injury and Repair,
Department of
Neurosurgery,
University of
Pennsylvania Medical
Center, 105 Hayden
Hall, 3320 Smith Walk,
Philadelphia, PA
19104-6316, USA
(D. H. Smith).
Correspondence to:
H. Zetterberg
henrik.zetterberg@
gu.se
VOLUME 9 | APRIL 2013 | 201
© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
¦¦ Biomarkers of neuronal, axonal and astroglial damage could be used to
diagnose mild traumatic brain injury (TBI) and predict clinical outcomes of
patients with head trauma
¦¦ Such biomarkers could provide important information for medical counselling
of at-risk individuals, such as military personnel and concussed athletes
¦¦ Cerebrospinal fluid markers are preferred over peripheral blood markers, owing
to their increased proximity to the brain and decreased susceptibility to the
confounding effects of various extracerebral factors
¦¦ Ultrasensitive assays are needed for reliable quantification of CNS-specific
biomarkers in blood, as their concentrations are below the lower limit of
detection by most standard immunoassays
¦¦ Clinical studies of serial biomarker measurements in conjunction with advanced
brain imaging during the acute and subacute phases of mild TBI are warranted
¦¦ Longitudinal studies of biomarkers in patients with chronic or progressive
symptoms after TBI might help to clarify the pathogenesis and clinical course
of chronic traumatic encephalopathy
in most patients, resolves in a spontaneous manner over
a fairly short period of time. However, approximately
15% of individuals with mild TBI develop persistent
cognitive dysfunction.9,10 Mild TBI is usually caused by
an impact to the head (contact loading) that induces
rotational acceleration of the brain (inertial loading). In
some patients, mild TBI occurs without an impact to the
head, such as after rapid rotational acceleration of
the head in restrained occupants during a motor vehicle
crash.11 At a neurophysiological level, these mechanical
and inertial forces result in the stretching of white matter
axons, leading to diffuse axonal injury.12
Although axonal disconnection rarely occurs at the
time of injury, the rapid stretching of axons causes an
unregulated flux in ion concentrations, including an
efflux of K+ and influx of Na+ from and into the axon
that, in turn, causes an increase in intra-axonal Ca2+ con­
centrations.13,14 As the concentration of Ca2+ increases,
the protease calpain becomes activated, triggering
­calpain-mediated proteolysis of cytoskeletal proteins,
which might translate into irreversible axonal pathol­
ogy.15 An increase in intra-axonal Ca2+ concentration
stimulates glutamate release and glutamate-mediated
activation of N-methyl-d-aspartate receptors, result­
ing in further depolarization of neurons.16,17 Increased
activity of various membrane pumps to restore the ionic
balance leads to increased glucose consumption, deple­
tion of energy stores, Ca2+ influx into mitochondria,
impaired oxidative metabolism, and glycolysis with
lactate production, which causes acidosis and oedema.
In addition to these ionic disturbances, ultrastructural
studies of axons show mechanical breakage and buckling
of microtubules at the time of injury, which can trigger
progressive microtubule disassembly.18 These com­
bined pathological processes result in interruption of
axonal transport and accumulation of protein products.
This accumulation gives rise to the two classic neuro­
pathological phenotypes of axonal swelling: singular
axonal bulbs (previously called retraction balls) and
axonal varicosities, which occur as a series of protru­
sions along individual axons.13,19 At a critical threshold
of axonal swelling, the axons disconnect at the location of
the injury (secondary axotomy).16,17,20,21 Neuronal damage
202 | APRIL 2013 | VOLUME 9
consisting of axonal bulbs and swellings is most com­
monly located in the deep gyri at the interface between
the grey and white matter.13,22 Studies using advanced
MRI techniques, such as diffusion tensor imag­i ng,
show that the extent of white matter abnormalities after
mild TBI correlates with the severity of postconcussion
co­gnitive problems.23–25
Many practicing clinicians have assumed that the
axonopathy and metabolic stress in patients with mild
TBI is reversed within 1–2 weeks, because this is when
clini­cal symptoms have most often disappeared.26 How­
ever, magnetic resonance spectroscopy findings, electro­
physiological data and neuropsychological assessments
suggest that patients’ physiological parameters return
to baseline after 30–45 days. 27,28 Moreover, neuro­
pathological analyses indicate that axonopathy might
continue for years after TBI.13 Another important con­
sideration affecting the patient’s recovery after mild TBI
is their age, since the developing brain seems to be more
vulnerable to repeated concussions than is the adult
brain,29 owing to differences in the degree of myelina­
tion, volume ratio of brain to water, elastic proper­ties,
and blood–brain barrier (BBB) integrity.30,31 This knowl­
edge, in conjunction with available biomechanical, radio­
logical and clinical data,32,33 should be communicated to
parents with the aim of discouraging the participation of
children in contact sports that target the head.
A form of TBI-induced early dementia was first
reported in 1928 among professional boxers, years after
their careers had ended.34 Initially termed dementia
pugilistica or punch-drunk syndrome, the prevalence
of this neuropsychiatric manifestation is now estimated
at around 20% in former professional boxers.35,36 These
observations aroused great interest in the long-term out­
comes of patients who developed chronic or progressive
symptoms after a single episode or repeated episodes
of mild TBI.37 Such symptoms can include changes in
cognition (memory and executive functioning), mood
(depression, apathy and suicidal thoughts), personality
and behaviour (poor impulse control and behavioural
disinhibition), and movement (including parkinsonism
and symptoms of motor neuron dysfunction), which
are similar to those described in ex-boxers.38 Some
investigators have started to describe this constel­lation
of symptoms as chronic traumatic encephalopathy
(CTE);39–41 however, vigorous debate is ongoing among
researchers regarding the definition of CTE from both
neuropsychiatr­ic and neuropathological perspectives.
The brains of former boxers with CTE also display
the hallmark pathologies of Alzheimer disease (AD),
including neurofibrillary tangles composed of hyper­
phosphorylated tau and amyloid-ß (Aß) plaques.42,43
Progressive axonopathy in these patients might underlie
the rapid formation of Aß plaques after TBI.44 The risk
factors for CTE in ex-boxers are a long career, many bouts,
high sparring exposure, many knockouts, poor perfor­
mance, and being able to tolerate many blows without
being knocked out, all of which are associated with cumu­
lative exposure to repetitive brain trauma.40 According to
one study, a positive apolipoprotein E e4 status, commonly

www.nature.com/nrneurol
© 2013 Macmillan Publishers Limited. All rights reserved
FOCUS ON TRAUMATIC BRAIN INJURY
associated with AD, is a risk factor for CTE in these indivi­
duals.36 Similarly, tau and Aß pathology, as well as TAR
DNA-binding protein 43 (TDP-43) deposition, have been
found in the brains of patients with CTE approximately
10 years after professional participation in contact sports
such as American football.45 Notably, neuritic Aß plaques
and neurofibrillary tangles have also been found in
patients a few years to four decades after a single episode
of moderate or severe TBI.46 However, TDP-43 deposi­
tion was not found in these patients, suggesting that this
pathological feature might be used to distinguish patients
with CTE due to a single episode of TBI from those with
CTE due to repetitive TBI.47
NSE, SBPs
and UCH-L1
Dendrites
Axon
Soma
Blood–brain barrier integrity
The BBB, which is formed from the endothelial cells
that line cerebral capillaries, has an important role in
maintaining a regulated microenvironment for reliable
neuronal signalling.49 The CSF:serum albumin ratio is a
standard biomarker of BBB function. 50 Albumin is
mainly synthesized in the liver and, consequently, most
albumin in CSF is derived from the blood via passage
across the BBB. An increase in this ratio indicates BBB
damage, which is found in patients with various CNS dis­
orders, such as infections, inflammatory diseases, brain
tumours or cerebrovascular diseases.48
Two studies have shown an increase in the CSF:serum
albumin ratio in patients with severe TBI associated with
a neuroinflammatory response.51,52 By contrast, no such
changes have been seen in studies of mild TBI in boxers
and military personnel with blast exposure,53,54 suggesting
that the BBB remains intact in individuals with mild TBI.
Neuroinflammation
The findings of a large number of studies confirm that
an acute inflammatory response occurs within the CNS
after severe TBI, which is reflected in the concentra­
tions of various CSF components.51,52,55–64 In general,
levels of inflammatory proteins, such as IL-6, IL-8 and
IL-10, are increased in CSF in response to severe TBI.
The magnitude of the rise correlates with the patient’s
outcome, and in some studies also with the extent of BBB
dysfunction, as shown by the CSF:serum albumin ratio.
This rise is an important confounder, since inflamma­
tory protein levels in plasma are normally much higher
than in CSF; passive leakage of inflammatory proteins
across an impaired BBB may lead to elevated CSF levels
in the absence of neuroinflammation. However, studies
Myelin sheath
Astroglial
cell
Currently available fluid biomarkers
CSF biomarkers of acute brain injury
The cerebrospinal fluid (CSF) is in direct contact with
the extracellular matrix in the brain, and its composi­
tion reflects biochemical changes that occur in this
organ.48 For these reasons, the CSF might be considered
an optimal source of biomarkers of brain injury. Several
CSF biomarkers of brain injury have already been estab­
lished, including proteins that indicate BBB integrity
and neuroinflammation, as well as axonal, neuronal and
astroglial damage, as described below (Figure 1, Table 1).
Tau
protein
NFL
Axon
terminals
Capillary
MBP
S100-B
GFAP
Interleukins
and cytokines
Amyloid
plaques
APP and amyloid-ß
Cerebrospinal fluid:serum albumin ratio
Figure 1 | Possible biomarkers of traumatic brain injury. These molecules include
NSE, SBPs and UCH-L1, which are all enriched in the neuronal cytoplasm. NFL is a
biomarker of injury to large-calibre myelinated axons. Total tau is a biomarker of
injury to thin nonmyelinated axons. APP and amyloid-ß are produced in axon
terminals and might be involved in synaptic activity and plasticity. Overproduction
of amyloid-ß in response to trauma could result in formation of diffuse amyloid
plaques. Injury to astroglial cells may lead to release of S100-B and GFAP into the
extracellular matrix, which might increase S100-B levels in both cerebrospinal fluid
and blood. Astrogliosis and post-injury neuroinflammation can result in increased
production of interleukins and cytokines. Integrity of the blood–brain barrier is
indicated by the cerebrospinal fluid:serum albumin ratio. Abbreviations: APP,
amyloid precursor protein; GFAP, glial fibrillary acidic protein; MBP, myelin basic
protein; NFL, neurofilament light polypeptide; NSE, ?-enolase; SBPs, spectrin
breakdown products; UCH-L1, ubiquitin carboxyl-terminal hydrolase isoenzyme L1.
on markers of neuroinflammation in patients with mild
TBI are lacking. Many of the studies listed above analysed
samples of ventricular CSF, which has a different protein
composition from lumbar CSF. This approach makes the
results of these studies less relevant to patients with mild
TBI, in whom CSF samples—if collected at all—tend to
be obtained by lumbar puncture.
Acute axonal injury
The two best-established CSF biomarkers of axonal
injury are total tau and neurofilament light polypeptide
(NFL). These two proteins have distinct regional distri­
butions in the brain, which might be helpful in determin­
ing which areas of the brain have been affected by TBI:
tau protein is highly expressed in thin, nonmyelinated
axons of cortical interneurons,65 whereas NFL is most
abundant in the large-calibre myelinated axons that
project into deeper brain layers and the spinal cord.66
Initial studies of tau protein as a marker of TBI com­
pared total tau levels in ventricular CSF samples from
patients with severe TBI, with the concentration of total
tau in samples of CSF obtained by lumbar puncture from
various control groups. These studies showed higher
levels of total tau in the TBI group than in the control
groups,67,68 but did not consider that tau protein levels
are normally higher in CSF obtained from brain ven­
tricles than in samples obtained by lumbar puncture.69
NATURE REVIEWS | NEUROLOGY
VOLUME 9 | APRIL 2013 | 203
© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
Table 1 | Potential fluid biomarkers of mild …
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