The document discusses the endothelial glycocalyx layer (EGL), which is a complex mesh-like network made of sugars and proteins located on the surface of endothelial cells. The EGL plays three main roles: 1) it acts as a mechanotransducer of fluid shear stress to the endothelial cells, triggering biochemical responses; 2) it modulates permeability in the exchange of water between blood and tissues; 3) it regulates interactions between blood cells and endothelial cells, influencing inflammation and coagulation. The EGL is crucial for endothelial cell mechanosensing and transduction of blood flow forces, maintaining homeostasis of the circulatory system.
Slides a supporto del corso di formazione sull'intervento di analisi del benessere organizzativo. Partendo dalla concezione di salute, si passa alla descrizione delle varie tipologie di benessere, per giungere all'approccio aziendale. Il rifermento teorico è dato dal lavoro di Avallone e Palomatas.
Negli ordinamenti giuridici moderni, il referendum è un istituto di partecipazione diretta dei cittadini alla democrazia. uno dei primi teorici e sostenitori del referendum fu forse Rousseau, che considerava la democrazia diretta l’unico modo per garantire la formazione della volontà generale.
Slides a supporto del corso di formazione sull'intervento di analisi del benessere organizzativo. Partendo dalla concezione di salute, si passa alla descrizione delle varie tipologie di benessere, per giungere all'approccio aziendale. Il rifermento teorico è dato dal lavoro di Avallone e Palomatas.
Negli ordinamenti giuridici moderni, il referendum è un istituto di partecipazione diretta dei cittadini alla democrazia. uno dei primi teorici e sostenitori del referendum fu forse Rousseau, che considerava la democrazia diretta l’unico modo per garantire la formazione della volontà generale.
The ECIS is a turnkey system that provides researchers with an advanced, automated, non-invasive means to monitor cell behavior in real-time and without the use of labels.
Introduction: Aging-associated vascular stiffening augments cardiovascular disease risk in the elderly. Research to identify targetable cellular and molecular mechanisms is of key interest as no current therapies are available to specifically target vascular stiffening. In this context, enzymes that mediate remodeling of the vascular matrix and those that promote cellular dysfunction are attractive targets. In pre-clinical models, pulse wave velocity (PWV), the gold standard measure of in vivo vascular stiffness, can be measured longitudinally and non-invasively, to make inroads towards the discovery and validation of potential targets.
A novel target and model: We have identified a central role for tissue transglutaminase (TG2) in vascular stiffening during aging. TG2 is a multifunctional protein of the transglutaminase family, whose primary function is to assist in the formation of a strong and stable matrix by catalyzing crosslinking of matrix proteins. Recent studies have shown that TG2 has putative crosslinking-independent functions in aging-associated vascular stiffening and dysfunction. The crosslinking independent mechanisms of TG2 remain incompletely understood due to the lack of pre-clinical models and specific inhibitors that can selectively inhibit a single function of TG2. Thus, we developed a novel knock-in mouse, the TGM2-C277S mouse, by mutating the active site cysteine of TG2 using the CRISPR-Cas9 gene editing technology to selectively target its crosslinking function.
Results and conclusion: We first validated the TGM2-C277S mouse and confirmed that this mutation removes TG2’s crosslinking function but retains its crosslinking independent functions. We next compared PWV wild type (WT), global TG2 knockout (TG2-/-), and the TGM2-C277S mice, to identify the contributions of the crosslinking-dependent and crosslinking-independent functions of TG2 to vascular aging in vivo. PWV increased significantly with age in WT mice, and to a much lower magnitude in the TGM2-C277S mice. TG2-/- mice were further protected against aging associated increase in PWV. Together, these studies show that TG2 contributes significantly to overall vascular stiffening in aging through both crosslinking dependent and crosslinking independent functions.
The learning objectives are:
To understand changes in pulse wave velocity (PWV) with age in mouse models
To determine the specific role of tissue transglutaminase (TG2) in vascular aging
To evaluate the role of vascular matrix vs. VSMCs to overall in vivo stiffness described by PWV
The ECIS is a turnkey system that provides researchers with an advanced, automated, non-invasive means to monitor cell behavior in real-time and without the use of labels.
Introduction: Aging-associated vascular stiffening augments cardiovascular disease risk in the elderly. Research to identify targetable cellular and molecular mechanisms is of key interest as no current therapies are available to specifically target vascular stiffening. In this context, enzymes that mediate remodeling of the vascular matrix and those that promote cellular dysfunction are attractive targets. In pre-clinical models, pulse wave velocity (PWV), the gold standard measure of in vivo vascular stiffness, can be measured longitudinally and non-invasively, to make inroads towards the discovery and validation of potential targets.
A novel target and model: We have identified a central role for tissue transglutaminase (TG2) in vascular stiffening during aging. TG2 is a multifunctional protein of the transglutaminase family, whose primary function is to assist in the formation of a strong and stable matrix by catalyzing crosslinking of matrix proteins. Recent studies have shown that TG2 has putative crosslinking-independent functions in aging-associated vascular stiffening and dysfunction. The crosslinking independent mechanisms of TG2 remain incompletely understood due to the lack of pre-clinical models and specific inhibitors that can selectively inhibit a single function of TG2. Thus, we developed a novel knock-in mouse, the TGM2-C277S mouse, by mutating the active site cysteine of TG2 using the CRISPR-Cas9 gene editing technology to selectively target its crosslinking function.
Results and conclusion: We first validated the TGM2-C277S mouse and confirmed that this mutation removes TG2’s crosslinking function but retains its crosslinking independent functions. We next compared PWV wild type (WT), global TG2 knockout (TG2-/-), and the TGM2-C277S mice, to identify the contributions of the crosslinking-dependent and crosslinking-independent functions of TG2 to vascular aging in vivo. PWV increased significantly with age in WT mice, and to a much lower magnitude in the TGM2-C277S mice. TG2-/- mice were further protected against aging associated increase in PWV. Together, these studies show that TG2 contributes significantly to overall vascular stiffening in aging through both crosslinking dependent and crosslinking independent functions.
The learning objectives are:
To understand changes in pulse wave velocity (PWV) with age in mouse models
To determine the specific role of tissue transglutaminase (TG2) in vascular aging
To evaluate the role of vascular matrix vs. VSMCs to overall in vivo stiffness described by PWV
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stockrebeccabio
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Hot Selling Organic intermediates
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdf
Bucci anemo 2015 - Glicocalice endoteliale la centrale della periferia
1. Glicocalice endoteliale :
la centrale della periferia
Endothelial Glycocalyx:
headquarter of periphery
Lucio Bucci
UTI ‘‘Bozza’’
I SAR
A.O. Ospedale Niguarda Cà Granda
Milano
Programma DEFINITIVO
FINAL program
S. Donato Milanese
6-7 MARZO 2015
2015, 6th
-7th
March
SEDE CENTRALE
IRCCS Policlinico San Donato
P.zza Malan, 1 - San Donato Milanese
Direttore del Corso
Marco Pavesi
IRCCS - Policlinico S. Donato
www.anemo.it
SEDI REMOTE
Coordinatore: M.B. Rondinelli
Roma - Hotel Il Cantico
Coordinatore: A. Corcione
Napoli - C.T.O. Ospedali dei Colli
Strategie di Risparmio del Sangue
®
GE
e.
ngibile
al
e Verde
uliano.
.
st,
gio.
i
IVA
4 Milano
MeL
ECM RICHIESTI
3. the human circolatory system :
400.000 miles long… Fu BM. and Tarbell JM WIREs Syst Biol Med 2013
the microcirculation : <100 μm diameter
10 billion capillaries lined
with endothelial cells Hernandez G et al. Curr Vascular Pharmacology 2013
the endothelium : >0.5 km2 surface area
Hernandez G. et al Curr Vascular Pharmacology 2013
the endothelial glycocalyx layer (EGL): a complex,
negatively charged, fragile sponge -like mesh network,
made of complex sugars and proteins up to 2 μm thick
Kolsen-Petersen JA. Acta Anesthesiologica Scandinavica 2015
7. Endothelial
Cells of Vessel
A carbohydrate-rich layer connected to the
endothelium via backbone proteoglycans
and giycoproteins. A complex network of
plasma- and epithelium-derived soluble
8. Endothelial
Cells of Vessel
A carbohydrate-rich layer connected to the
endothelium via backbone proteoglycans
and giycoproteins. A complex network of
plasma- and epithelium-derived soluble
cans have been the most extensively studied,
ntion recently shifting toward their ability
n as signal transduction molecules.19,21
The
ular transport and cell signaling throug
molecules, most notably endothelial-type
synthase (eNOS).
--K+, Na+, Ca++, L-arginine
--Albumin, bFGF, LPL, polycationic peptides
--Caveolin-1
--Cholesterol and glycosphingolipids
--K+, Na+, Ca++, L-arginine channels
--Hyaluronic acid
--Chondroitin sulfates
--Heparan sulfates
CD44
Glycoprotein
Sialic acids
A B
C
Glypican
Syndecans
Shedding
9. Endothelial
Cells of Vessel
A carbohydrate-rich layer connected to the
endothelium via backbone proteoglycans
and giycoproteins. A complex network of
plasma- and epithelium-derived soluble
cans have been the most extensively studied,
ntion recently shifting toward their ability
n as signal transduction molecules.19,21
The
ular transport and cell signaling throug
molecules, most notably endothelial-type
synthase (eNOS).
--K+, Na+, Ca++, L-arginine
--Albumin, bFGF, LPL, polycationic peptides
--Caveolin-1
--Cholesterol and glycosphingolipids
--K+, Na+, Ca++, L-arginine channels
--Hyaluronic acid
--Chondroitin sulfates
--Heparan sulfates
CD44
Glycoprotein
Sialic acids
A B
C
Glypican
Syndecans
Shedding
10. Endothelial
Cells of Vessel
A carbohydrate-rich layer connected to the
endothelium via backbone proteoglycans
and giycoproteins. A complex network of
plasma- and epithelium-derived soluble
cans have been the most extensively studied,
ntion recently shifting toward their ability
n as signal transduction molecules.19,21
The
ular transport and cell signaling throug
molecules, most notably endothelial-type
synthase (eNOS).
--K+, Na+, Ca++, L-arginine
--Albumin, bFGF, LPL, polycationic peptides
--Caveolin-1
--Cholesterol and glycosphingolipids
--K+, Na+, Ca++, L-arginine channels
--Hyaluronic acid
--Chondroitin sulfates
--Heparan sulfates
CD44
Glycoprotein
Sialic acids
A B
C
Glypican
Syndecans
Shedding
Starling Principle Revisited: Influence of the Glycocalyx
, endothelial cell; HPi, hydrostatic P in interstitial space; HPvL, hydrostatic P in vascular lumen; OPesL,
e layer; OPi, oncotic P in interstitial spaoe; OPvL, oncotic P in vascular lumen.
Above is intact glycocaiyx in
myocardial vessel tissue. To the
riglit is the same vasculature
tissue after a brief period of
ischemia with major erosion of
the highly fragile glycocalyx.
11. Endothelial Glycocalyx Layer (EGL):
three main functions (to date…)
• mechanotransduction of fluid shear
stress to the endothelial cell (EC)
cytoskeleton with the resulting
biochemical responses
• modulation of permeability in the
transcapillary exchange of water :
Starling revisited
• regulation of red and white blood
cells interactions with EC triggering
inflammatory response and
relationships with coagulation system
Weinbaum S et al. Annu Rev Biomed Eng. 2007
18. T
he endothelial glycocalyx (EG) is a complex and mul-
ticomponent layer of macromolecules at the luminal
surface of vascular endothelium. This concept was
proposed more than 70 years ago and its composition is
well studied as detailed in 2 reviews1,2
; however, its role
in mechanisms of endothelial protection and injury and
subsequent clinical implications have just recently become
evident. The EG consists of a variety of endothelial mem-
brane–bound molecules, including glycoproteins and pro-
teoglycans, that provide the basis for plasma–endothelial
cell interaction. EG structure, although well characterized
in vitro, is poorly defined in vivo because of its dynamically
changing composition by self-assembly and enzymatic deg-
radation or shear-dependent shedding of its elements. Its
major constituents are hyaluronic acid and the negatively
charged heparan sulfate proteoglycans. Together with gly-
cosaminoglycans (GAGs) and plasma proteins, the EG layer
as a whole forms the endothelial surface layer (ESL) that
acts as a barrier to circulating cells and large molecules.
Considerable prognostic and therapeutic promise lies with
the emergence of the EG as a key mediator of endothelial
dysfunction in pathogenic states, particularly with regard to
vascular permeability and edema formation. Several studies
have demonstrated the role of the EG in plasma/interstitial
fluid balance and solute exchange,3–5
mechanotransduction
that couples intravascular pressure and shear stress (i.e.,
biomechanical forces) to endothelial cell responses (i.e., bio-
chemical signals),6
and the inflammatory response cascade
via physical blockade of neutrophils to the endothelial cell
surface.7–9
This review explores the emerging evidence for
the role of the EG in vascular permeability, examines evi-
dence for modulation by the EG of inflammatory processes
that lead to edema formation, and provides insight into the
role of the EG in the development of pulmonary edema and
lung injury. The concept of the glycocalyx as a mechano-
transducer of pathophysiologic signals in the pathogenesis
of lung injury after pulmonary resection surgery is also
explored.
THE STARLING EQUATION AND PULMONARY
EDEMA
Our understanding of vascular permeability as well as
plasma/interstitial fluid movement and edema formation
has changed with recognition of and insight into the EG, a
meshwork of proteins and soluble components that forms
a major barrier to water and plasma protein exchange. The
fundamental principle guiding microvascular filtration and
transcapillary fluid shifts was proposed in 1896 by Starling10
;
however, this traditional model has been revised given our
current, more sophisticated view of the endothelial barrier
and its dynamic components. Starling10
initially devised a
series of experiments showing that fluid movement across
the walls of capillaries (and postcapillary venules) is pas-
sive and dependent on pressure gradients across the endo-
thelium. He suggested that fluid filtration is a balance
between opposing hydrostatic and colloid (protein) osmotic
pressures. Since hydrostatic pressure decreases along a
capillary, it follows that filtration occurs along the arterial
end of capillaries and reabsorption at the venous end of
capillaries, though this model has been challenged in more
recent years.11,12
Not until decades later did Starling’s initial
observations become expressed in mathematical format,13,14
The endothelial glycocalyx is a dynamic layer of macromolecules at the luminal surface of
vascular endothelium that is involved in fluid homeostasis and regulation. Its role in vascular
permeability and edema formation is emerging but is still not well understood. In this special
article, we highlight key concepts of endothelial dysfunction with regards to the glycocalyx and
provide new insights into the glycocalyx as a mediator of processes central to the development
of pulmonary edema and lung injury. (Anesth Analg 2013;XX:00–00)
The Endothelial Glycocalyx: Emerging Concepts
in Pulmonary Edema and Acute Lung Injury
Stephen R. Collins, MD,* Randal S. Blank, MD, PhD,* Lindy S. Deatherage, MD,†
and Randal O. Dull, MD, PhD‡
T
he endothelial glycocalyx (EG) is a complex and mul-
ticomponent layer of macromolecules at the luminal
surface of vascular endothelium. This concept was
proposed more than 70 years ago and its composition is
well studied as detailed in 2 reviews1,2
; however, its role
in mechanisms of endothelial protection and injury and
subsequent clinical implications have just recently become
evident. The EG consists of a variety of endothelial mem-
brane–bound molecules, including glycoproteins and pro-
teoglycans, that provide the basis for plasma–endothelial
cell interaction. EG structure, although well characterized
in vitro, is poorly defined in vivo because of its dynamically
changing composition by self-assembly and enzymatic deg-
radation or shear-dependent shedding of its elements. Its
major constituents are hyaluronic acid and the negatively
charged heparan sulfate proteoglycans. Together with gly-
cosaminoglycans (GAGs) and plasma proteins, the EG layer
as a whole forms the endothelial surface layer (ESL) that
acts as a barrier to circulating cells and large molecules.
the role of
dence for m
that lead to
role of the
lung injury
transducer
of lung in
explored.
THE STAR
EDEMA
Our under
plasma/in
has change
meshwork
a major ba
fundament
transcapill
however, t
vascular endothelium that is involved in fluid homeostasis a
permeability and edema formation is emerging but is still no
article, we highlight key concepts of endothelial dysfunction
provide new insights into the glycocalyx as a mediator of proc
of pulmonary edema and lung injury. (Anesth Analg 2013;X
Endothelial Glycocalyx
Figure 3. Schematic illustrating the hypothesized role of the glycocalyx in lung vascular mechanotransduction. Left: During static conditions,
the glycocalyx maintains barrier function over the intercellular junction. Right: During increased vascular pressure, the increased hydraulic
flow through the glycocalyx deforms or stresses the glycosaminoglycan (GAG) fibers, which in turn activates endothelial nitric oxide synthase
(eNOS) and leads to barrier dysfunction. ∆Pc = change in capillary pressure; Q = flow; ZO-1 and ZO-2 = zonula occludens-1 and -2; vin =
vinculin; VE-Cad = vascular endothelial cadherin; ECM = extracellular matrix. Adapted from Dull et al.25
22. Endothelial Glycocalyx Layer (EGL):
three main functions (to date…)
• mechanotransduction of fluid shear stress to
the endothelial cell (EC) cytoskeleton with the
resulting biochemical responses
•modulation of
permeability in the
transcapillary exchange of
water : Starling revisited
•regulation of red and white blood cells
interactions with EC triggering inflammatory
response and relationships with coagulation system
Weinbaum S et al. Annu Rev. Biomed Eng. 2007
23. The importance of being Ernest :
THE STARLING LAW (1896)
• Pc is the capillary hydrostatic pressure
• Pi is the interstitial hydrostatic pressure
• πc is the capillary oncotic pressure
• πi is the interstitial oncotic pressure
• Kf is the filtration coefficient – a proportionality constant
• σ is the reflection coefficient
Starling EH. J Physiol 1896
30. Revised Starling equation and the glycocalyx model
of transvascular fluid exchange: an improved paradigm
for prescribing intravenous fluid therapy
T. E. Woodcock1* and T. M. Woodcock2
1
Critical Care Service, Southampton University Hospitals NHS Trust, Tremona Road, Southampton SO16 6YD, UK
2
The Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia
* Corresponding author. E-mail: tom.woodcock@me.com
Editor’s key points
† The classic Starling
principle does not hold
for fluid resuscitation in
clinical settings.
† The endothelial
glycocalyx layer appears
to have a major role in
fluid exchange.
† A revision of Starling
incorporating the
glycocalyx model
appears to explain better
the responses seen
clinically.
Summary. I.V. fluid therapy does not result in the extracellular volume distribution expected
from Starling’s original model of semi-permeable capillaries subject to hydrostatic and
oncotic pressure gradients within the extracellular fluid. Fluid therapy to support the
circulation relies on applying a physiological paradigm that better explains clinical and
research observations. The revised Starling equation based on recent research considers
the contributions of the endothelial glycocalyx layer (EGL), the endothelial basement
membrane, and the extracellular matrix. The characteristics of capillaries in various
tissues are reviewed and some clinical corollaries considered. The oncotic pressure
difference across the EGL opposes, but does not reverse, the filtration rate (the ‘no
absorption’ rule) and is an important feature of the revised paradigm and highlights the
limitations of attempting to prevent or treat oedema by transfusing colloids. Filtered fluid
returns to the circulation as lymph. The EGL excludes larger molecules and occupies a
substantial volume of the intravascular space and therefore requires a new interpretation
of dilution studies of blood volume and the speculation that protection or restoration of
the EGL might be an important therapeutic goal. An explanation for the phenomenon of
context sensitivity of fluid volume kinetics is offered, and the proposal that crystalloid
resuscitation from low capillary pressures is rational. Any potential advantage of plasma
or plasma substitutes over crystalloids for volume expansion only manifests itself at
higher capillary pressures.
Keywords: fluid therapy; intensive care
Twenty-five years ago, Twigley and Hillman announced ‘the
end of the crystalloid era’. Using a simplified diagram of
plasma, interstitial and intracellular fluid compartments,
and their anatomic volumes, they argued that colloids
could be used to selectively maintain the plasma volume.1
Plasma volume being about 20% of the extracellular fluid
Africa demonstrated no advantages of bolus therapy with
albumin compared with ISS, and a survival advantage for
slow ISS resuscitation without bolus therapy.8
A series of
volume kinetics experiments have demonstrated that the
central volume of distribution of ISS is much smaller than
the anatomic ECF volume,9
and an editorial had to conclude
atOSPEDALENIGUARDACA'GRANDAonJanuaryhttp://bja.oxfordjournals.org/Downloadedfrom
Revised Starling equation and the glycocalyx model
of transvascular fluid exchange: an improved paradigm
for prescribing intravenous fluid therapy
T. E. Woodcock1* and T. M. Woodcock2
1
Critical Care Service, Southampton University Hospitals NHS Trust, Tremona Road, Southampton SO16 6YD, UK
2
The Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia
* Corresponding author. E-mail: tom.woodcock@me.com
Editor’s key points
† The classic Starling
principle does not hold
for fluid resuscitation in
clinical settings.
† The endothelial
glycocalyx layer appears
to have a major role in
fluid exchange.
† A revision of Starling
incorporating the
glycocalyx model
appears to explain better
the responses seen
clinically.
Summary. I.V. fluid therapy does not result in the extracellular volume distribution expected
from Starling’s original model of semi-permeable capillaries subject to hydrostatic and
oncotic pressure gradients within the extracellular fluid. Fluid therapy to support the
circulation relies on applying a physiological paradigm that better explains clinical and
research observations. The revised Starling equation based on recent research considers
the contributions of the endothelial glycocalyx layer (EGL), the endothelial basement
membrane, and the extracellular matrix. The characteristics of capillaries in various
tissues are reviewed and some clinical corollaries considered. The oncotic pressure
difference across the EGL opposes, but does not reverse, the filtration rate (the ‘no
absorption’ rule) and is an important feature of the revised paradigm and highlights the
limitations of attempting to prevent or treat oedema by transfusing colloids. Filtered fluid
returns to the circulation as lymph. The EGL excludes larger molecules and occupies a
substantial volume of the intravascular space and therefore requires a new interpretation
of dilution studies of blood volume and the speculation that protection or restoration of
the EGL might be an important therapeutic goal. An explanation for the phenomenon of
context sensitivity of fluid volume kinetics is offered, and the proposal that crystalloid
resuscitation from low capillary pressures is rational. Any potential advantage of plasma
or plasma substitutes over crystalloids for volume expansion only manifests itself at
British Journal of Anaesthesia 108 (3): 384–94 (2012)
Advance Access publication 29 January 2012 . doi:10.1093/bja/aer515
Revised Starling equation
of transvascular fluid exc
for prescribing intraveno
T. E. Woodcock1* and T. M. Woodcock2
1
Critical Care Service, Southampton University Hospital
2
The Australian School of Advanced Medicine, Macqua
* Corresponding author. E-mail: tom.woodcock@me.com
Editor’s key points
† The classic Starling
principle does not hold
for fluid resuscitation in
clinical settings.
† The endothelial
glycocalyx layer appears
to have a major role in
fluid exchange.
† A revision of Starling
incorporating the
Summary. I.V. fl
from Starling’s
oncotic pressu
circulation relie
research obser
the contributio
membrane, an
tissues are re
difference acro
absorption’ rule
limitations of a
returns to the
British Journal of Anaesthesia 108 (3): 384–94 (2012)
Advance Access publication 29 January 2012 . doi:10.10
Intraoperative fluids: how much is too much?
M. Doherty1* and D. J. Buggy1,2
1
Department of Anaesthesia, Mater Misericordiae University Hospital, University College Dublin, Ireland
2
Outcomes Research Consortium, Cleveland Clinic, OH, USA
* Corresponding author. E-mail: margaretdoherty@yahoo.com
Editor’s key points
† Both too little and excessive fluid
during the intraoperative period can
adversely affect patient outcome.
† Greater understanding of fluid
kinetics at the endothelial glycocalyx
enhances insight into bodily fluid
Summary. There is increasing evidence that intraoperative fluid therapy
decisions may influence postoperative outcomes. In the past, patients
undergoing major surgery were often administered large volumes of
crystalloid, based on a presumption of preoperative dehydration and
nebulous intraoperative ‘third space’ fluid loss. However, positive perioperative
fluid balance, with postoperative fluid-based weight gain, is associated with
increased major morbidity. The concept of ‘third space’ fluid loss has been
emphatically refuted, and preoperative dehydration has been almost
British Journal of Anaesthesia 109 (1): 69–79 (2012)
Advance Access publication 1 June 2012 . doi:10.1093/bja/aes171
Downloadedfrom
Intraoperative fluids: how
M. Doherty1* and D. J. Buggy1,2
1
Department of Anaesthesia, Mater Misericordiae Univ
2
Outcomes Research Consortium, Cleveland Clinic, OH,
* Corresponding author. E-mail: margaretdoherty@yaho
Editor’s key points
† Both too little and excessive fluid
Sum
dec
und
British Journal of Anaesthesia 109 (1): 69–79 (2012)
Advance Access publication 1 June 2012 . doi:10.1093/
Intraoperative fluids: how much is too much?
M. Doherty1* and D. J. Buggy1,2
1
Department of Anaesthesia, Mater Misericordiae University Hospital, University College Dublin, Ireland
2
Outcomes Research Consortium, Cleveland Clinic, OH, USA
* Corresponding author. E-mail: margaretdoherty@yahoo.com
Editor’s key points
† Both too little and excessive fluid
during the intraoperative period can
adversely affect patient outcome.
† Greater understanding of fluid
kinetics at the endothelial glycocalyx
enhances insight into bodily fluid
Summary. There is increasing evidence that intraoperative fluid ther
decisions may influence postoperative outcomes. In the past, patie
undergoing major surgery were often administered large volumes
crystalloid, based on a presumption of preoperative dehydration
nebulous intraoperative ‘third space’ fluid loss. However, positive periopera
fluid balance, with postoperative fluid-based weight gain, is associated w
increased major morbidity. The concept of ‘third space’ fluid loss has b
emphatically refuted, and preoperative dehydration has been alm
British Journal of Anaesthesia 109 (1): 69–79 (2012)
Advance Access publication 1 June 2012 . doi:10.1093/bja/aes171