Formation of Cerebrospinal fluid

Actively secreted and transported by ventricular blood vessels and cuboidal

and columnar epithelia Ependymal cells surrounding capillary dispersions

encased within the choroid plexus of the lateral ventricles, located at the
superior part of the inferior horn.

Mainly kept within the cisterna magna, mesencephalic cistern and

subarachnoid space.

Flow of CSF starts from the plexuses of the lateral ventricles through the
interventricular foramina of Monro, passing within the iii rd ventricle,
transversing the cerebral aqueduct of Sylvius it empties into the ivth ventricle.

Subsequently passing through the foramina of magendie and luschka thus

reaching the subarachnoid space, which together with its parallel surrounds of
pia mater, dura mater and arachnoid of the meningeal sheaths.
http://webeye.ophth.uiowa.edu/ips/IIH/1_iih.jpg
Circulation of CSF within the cranium region
http://www.cerebrospinalfluidresearch.com/content/figures/1743-8454-5-10-2-l.jpg
Principles of Neuroscience, ivth ed , Kandel ER et al, 2000
Csf from the arachnoid space is then released into the spinal canal and the current also
arises over the brain’s convexity thus infusing its entire surface area.

Flow is then diverted along vessels of Virchow Robin spaces within sulci and concaves
of the cerebral cortex.

Csf and interstitial fluid within this perivascular spaces exchange small solutes via
diffusion, generating a current which enables metabolites to arise from deep within
cerebral hemispheres to the ventricular system and corticle subarachnoid spaces.

Absorption occurs through arachnoid granulations and villi clustered within

herniations of the arachnoid membrane through the dura mater and within the lumen
of the venous networks and superior sagittal sinus.

An even bi directional dispersion is possible as actively secreting choroid plexus villi

cells are involved in vacuole formations.

.
http://neuromedia.neurobio.ucla.edu
http://academic.kellogg.edu/herbrandsonc/bio201_McKinley/f14-6_cellular_organi
za_c.jpg
 within the subarachnoid spaces, granulation valves aid in a single
directive of CSF towards venous blood. even though the brain
capillaries are permeable to solutes, proteins, molecules and
microorganisms and red blood cells.

the brain is protected by a blood brain barrier made up of intricately

interlinked podocyte foot processes , through size segregations.

Permeable brain vessels are located within the fenestrated capillaries

of the posterior pituitary and circumventricular organs of the
subfornical and subcommissural organs, neurohypophysis, area
postrema, median eminence and laminar terminalis.

Another barrier is existent at the choroid plexus epithelia calls, they

function via active transport enabling the continuous CSF secretions
within the central nervous system and molecular exports into vessels
• http://academic.kellogg.edu/herbrandsonc/bio201_McKinley/f14-6_cellular_organiza
http://www.elp.manchester.ac.uk/pub_projects/2002/MNQJ9PP2/images/brain-blood-
PICTURE.jpg
http://www.nature.com/nrn/journal/v7/n1/images/nrn1824-f3.jpg
 osmotic equilibrium between csf and blood is achieved through the
creation of an osmotic gradient from the active molecular transport due to
kinetics. main solutes within the CSF are water, protein, glucose, sodium,
potassium, calcium, magnesium, chloride.

Ph is mildly alkali at 7.33.

in comparism to plasma which has less water, lower acidity and higher
concentrates of protein, magnesium, chloride, potassium, bicarbonates,
glucose, calcium however the sodium concentrates are equal.

CSF is turned over iii - iv times a day, at a rate of 0.35 ml / min and 500 ml /
day.

fluid switches of ions, metabolites and ions between CSF and blood
function as a density separation medium, between cranial CSF, extra
neuronal fluid, cisternal fluid, spinal fluid and blood compositions.
 Interactions between CSF and blood circuit

http://www.pharmainfo.net/files/images/stories/article_images/Morphology%20of%20Bl
ood%20Cerebrospinal%20Fluid%20Barrier.jpg
http://education.vetmed.vt.edu/Curriculum/VM8054/Labs/Lab9/IMAGES/CHOROID%20
PLEXUS%20COMPOSITE%20copy.jpg
 Homeostatic maintenance of water and solutes is carried out by the kidneys. water
balance and osmolality is regulated by thirst while elimination of excess is mediated by
the nephronic system. volumes of the vascular system and the extracellular fluids are
sodium chloride dependent, the concentration of which is kidney regulated.
extracellular fluids are maintained within a slim range.

systemic fluids are segregated within differing membrane enclosed compartments in

varying compositions and composites. these make up xxxxxx % of an entities body
weight which is adipocyte dependent, a greater content of which reduces fluid
retentions. total systemic fluids are both intra and extra cellular, due to cellular
compositions, intracellular fluid is more that cellular externals, they make up ii / iii of
total systemic fluid content.

total systemic fluid amounts can be discovered by multiplying a predetermined 0.6 by an

entity's weight, the average of which ought to be about xxxxii litres. while intracellular
fluid is reflected by 0.4 multiplied by body weight, averaging about xxviii litres, and
extracellular fluid determined with multiplications of 0.2 by weight, this is often
averaged at xiv litres.

interstitial fluid arises from the extracellular, composing iii/iv of the total which is about
x.v litres. with a partitioning capillary wall, the remaining i/iv of extracellular fluid is
made up via plasma at iii .v litres.
faculty.weber.edu/jkelly/fluidcompartments.gif
Relationship between intracellular and extracellular fluids, systemic outreaches
Sources and electrolyte constituents

http://www.nature.com/ki/journal/v72/n4/images/5002288f3.jpg
Cardiac passage of intestitial fluid through capillary bed linkage

http://www.biosbcc.net/doohan/sample/images/CO%20and%20MAP/0313filtration.jpg
http://www.mfi.ku.dk/PPaulev/chapter1/images/n1-4a.jpg
Passage of solutes within the nephrons for osmolality regulations
http://img.medscape.com/pi/emed/ckb/sports_medicine/84611-88013-88484-88634.jpg
 interstitial fluids is fluid surrounding cells within various systemic tissue, this
includes bone water mass and circulations within dense connective tissue.

the major variance between plasma and interstitial fluid lies within their
respective compositions, plasma contains greater concentrates of proteins,
other molecular entities are similar in concentrations.

the key solutes that contribute towards the osmolality of extracellular fluids are
sodium, chloride and bicarbonate, other lesser contributors are urea, glucose,
potassium, phosphate and calcium.

intracellular fluids have a ph of vii . i while extracellular fluids are more alkali at
vii. iv, the main cations and anions within are chloride, bicarbonate,
potassium, sodium, calcium, and inorganic phosphate. Ineffective osmoles
are mediated by membrane transversing ions, with water remaining outside
due to the lack of aquaporins thus cellular compositions are unaffected.
sodium and anions contribute to effective osmoles these affect body
fluids and changes systemic osmolality, varying ionic particle
concentrates within the extra and intracellular fluids thus affect their
volumes.

the inherent permeability of cell membranes and capillary walls

ensures that water is in an osmotic equilibrium, thus plasma
osmolality is in direct synchrony with the osmolality of extracellular,
intracellular and interstitial fluids.

there is minute quantities of sodium within the intracellular fluids, it

is mainly just potassium, maintenance is carried out by a ubiquitous
sodium, and potassium ATPase pump.

with intracellular fluid anions less in content than that inherent within
the extracellular, this is due to a lesser concentrate of chloride,
bicarbonate with a greater constituent of organic anions, phosphates
and proteins.
 as water transverses the various compartments smoothly, this mobility
is mainly affected by hydrostatic pressure and osmotic pressure, the
hydrostatic pressure created is generated by the pumping heart,
gravity upon blood flowing within veins, , osmotic and oncotic
pressure of plasma proteins, it is an important determination of fluid
pressure across capillary walls .

the cellular membrane is highly permeable to water, mediating a high

variance between intra and extra cellular fluids within these regions,
thus they are often in osmotic equilibrium, if any changes arise, these
are transient, membrane transports facilitate ionic movements, water
mobility affects fluid movements between the intra and extracellular
fluids.

apart from the nephrons, other routes of fluid exit include the skin,
lungs, through sweat, urine and waste these routes are non regulated.
the renal fluid output is tightly regulated for the maintenance of water
balance with intake a precise match for water loss , if intake is high,
there is positive water loss and osmolality of body fluid declines, if loss
increases, negative water balance results and systemic fluid osmolality
shoots up.
Channels within the membrane for water and ion passage

http://nobelprize.org/nobel_prizes/chemistry/laureates/2003/public.html
 disorders of water balance change the osmolality of body fluids, which
can be monitored by measuring plasma osmolality, major
determinants of which include sodium, chloride and bicarbonate, any
changes with in the plasma sodium balance would bring about
resultant variations in the volume of the extra cellular fluid
compositions, but will not affect its osmolality.

hypoosmolality would results in a decline in plasma osmolality this shift

of fluid within cells causes cellular swellings., which brain cells are
highly susceptible to.

Thus a speedy decline in plasma osmolality affect neurological functions

inducing nausea, malaise, confusion, headaches, seizures, lethargy
and eventually even a comatose state.

vasopressin is the key regulator of kidney osmolality and volume.

water diuresis and diluted urine would bring about a decline in plasma
vasopressin. when vasopressin rises, antidiuresis results and fluid
outflow becomes concentrated.
a vasopressin molecule is made up by ix amino acids, this tiny polypeptide
is synthesized within neuroendocrine cells located within the supraoptic
paraventricular nuclei of the hypothalamus, storage is within the
neurohypophysis ( posterior pituitary ).

vasopressin secretions are influenced by body fluid osmolality, volume,

pressure of vascular system, nausea, natriuretic peptides, angiotensin ii,
nicotine, downregulation is brought about via ethanol, a dip in blood
volume or arterial pressure.

osmotic receptors senses changes in body fluid osmolalities through

swelling and shrinkages, they are responsive to solutes that are effective
osmoles such as sodium chloride.

when an increase in osmolality occurs, signals are received by the

supraoptic and paraventricular nuclei.

Vasopressin dissolves fast within plasma, thus when release ceases,

circulations come to a halt which is why the vasopressin system is so
efficiently speedy and responsive
Vasopression molecule

http://www.3dchem.com/imagesofmolecules/Vasopressin.jpg

http://www.endotext.org/neuroendo/neuroendo2/figures/figure2.jpg
www.ncbi.nlm.nih.gov
 Mechanisms of action and production of vasopressin

http://www.frca.co.uk/article.aspx?articleid=100852
hemodynamics influences its secretions with receptors located in both
the low pressure site of the left atrium and pulmonary vessels and the
high pressure sites at the aortic arch and carotid sinuses of the
circulatory systems.

low pressure receptors are located within the high compliance sites of
the venous system which carries majority of blood, the high pressure
receptors are responsive to arterial pressures, while baroreceptors
within the cardiac zones senses stretch from cardiac atrial and arotic
arch walls.

the signals conveyed from these baroreceptors are carried via the vagal
and glossopharyngeal nerves to the brainstem control centres just
beneath the medullary oblongata that regulate heartbeats and thus
blood pressures, signals are then further relayed from the brainstem
region to vasopressin secretary cells of the supraoptic and
paraventricular hypothalamic nuclei, decreases in blood volume and
arterial pressures which were genetically predefined , steps it down to
lower osmotic values.
 Vasopressin increases the permeability of the collecting duct at the
medullary portion which thus becomes receptive to urea passage, vii
receptor bindings upon the basolateral membranes of a cell, coupled
with adenyl cycvlase via stimulatory G protein.

vasopressin initiates this receptor bindings, with intracellular levels

of cyclic adenosine monophosphate accumulating and thus
activating protein kinase A, this brings about an insertion of
intracellular vesicles of aquaporin ii which creates water channels at
the apical membranes of the cell through exocytosis from within, as
vasopressin initiates formation of aquaporins, they transform non
permeable cells into highly permeable entities.

over at the basolateral membraneous region, lie aquaporin ii and iv

which are always water permeable, water is thus easily shunted from
the apex through the cell and out from its basal membrane, this
results in overall water absorptions from the tubule lunmens into
peritubular blood.
http://www.biolcell.org/boc/097/0885/boc0970885f01.htm
Representation of the postulated molecular mechanisms for regulation of AQP2 trafficking
Binding of vasopressin (AVP) to its receptor (vasopressin type 2 receptor, V 2R) activates adenylate cyclase (AC) via the G-protein G s.
This then increases cAMP levels and induces PKA-mediated phosphorylation of AQP2 that is necessary for AQP2 sorting to the apical
membrane. Alternatively, stimulation of prostaglandin E 3 receptor (EP3R) by prostaglandin E2 (PGE2) inhibits AC via the G-protein Gi.
In addition, EP3R activates Rho which promotes the formation of F-actin. F-actin polymerization functions as a barrier for AQP2
trafficking. cGMP–PKG pathway stimulated by sodium nitropruside (SNP) or atrial natriuretic factor (ANF) via guanylate cyclase (GC)
also induces AQP2 sorting. Microtubule-associated motor proteins, including dynein and dynactin, are involved in AQP2 trafficking.
AQP2 binds to SPA-1 and G-actin. It is speculated that SPA-1 binding to AQP2 reduces the levels of Rap1GTP that may trigger F-actin
disassembly in a restricted area around AQP2, resulting in the promotion of the AQP2 sorting. The targeting, docking and fusion of
Vasopressin effect upon its ii different receptors thus affecting circulation and arterial
pressure
http://www.cvpharmacology.com/vasoconstrictor/AVP.gif
dem repeats of three membrane-spanning  helices. Two connecting loops, each containing an Asn-Pro-Ala (NPA) motif, are suppos
 

Aquaporins proteins are channels that permit faster transport of water through cell
membranes. Initially discovered in plants during 1994 (Maurel et al. 1994). ii tandems of
iii membrane-spanning  helices linked via connecting loops, with an axis of Asn-Pro-Ala
(NPA) thus creating a central pore passage for water entry
http://www.nature.com/jcbfm/journal/v22/n4/fig_tab/9591227f1.html
Translocation of an excess proton
in either direction is opposed by a
free-energy barrier centered at
the NPA region. Both hop and
turn steps of proton translocation
are opposed by the electrostatic
field of the channel. Notably, the
10-12-kcal-per-mole barrier to
proton translocation peaking at
the NPA region results from a
combination of factors. These
include not only the orientational
control of water molecules but
also desolvation penalties and
electrostatic effects caused by the
charge distribution in the
channel.

N. CHAKRABARTI, E.
TAJKHORSHID, B. ROUX and R.
POMES.
"Molecular Basis of Proton
Blockage in Aquaporins"
Structure 12, 65-74 (2004). [
PubMed ]
 sensations of thirst arise from the thirst centre within the
hypothalamus, this response is triggered by angiotensin ii and sodium
chloride, which would increase body fluid osmolality, decrease blood
pressure, an extremely potent initiator of the thirst response is
hyperosmolality, with a ii to iii % increase in plasma osmolarity or a x
% decline in blood volume or arterial pressure initialising an intense
desire for fluids.

concert and synchrony is thus achieved by vasopressin and the

hypothalamic thirst centre for the overall maintenance of systemic
water balance.

Other mechanisms of renal sodium chloride and water output involve

fine tuning by the sympathetic nervous system, when their activities
are upregulated, a decline in sodium chloride occurs, other aspects of
action include downregulating glomerular filtration rates,
upregulating secretions of rennin and increasing sodium chloride
reabsorptions within the thick ascending loops of henle , proximal
tubules, distal tubules and collecting duct.
 Osmolality affects neuronal firings which initiate vasopressin release
http://www.nature.com/ki/journal/v73/n7/fig_tab/5002788f3.html
Hypothalamic thirst centre within the hypotalamus and the organs targeted
http://www.creationofman.net/chapter3/chapter3_14.html
http://www.mfi.ku.dk/PPaulev/chapter24/images/24-6.jpg
 as homeostatic mechanisms are a duo way mechanism of signal
conveyance, integrations and response, vascular sensors exist for the
detecting of varying fluid volumes, these are alerted by declining pressures
and situated within the cardiac atria and pulmonary vasculatures. an
increase in pressure is sensed by receptors within the arotic arches, carotid
sinus and juxtaglomerular apparatus of the kidneys, other sensors are
located within the central nervous system and hepatic regions.

congestive heart failure could have been due to a number of factors such as
a congenital heart defects, history of heart attack, narrowed myocytes
arteries, diabetes, alcohol abuse, coronary artery disease, myocardial
infarction, endocarditis of cardiac valves, myocarditis, cardiac fibrosis, high
blood pressure, overworked myocytes that have increased in size and
number to a maximal and their subsequent necrosis, heart valve disease
due to rheumatic fever or cardiomyopathy.

as the cardiac pump can no longer shunt blood to the other systemic
organs, a couple of characteristic symptoms would be fatigue, pneumonia,
reduction in exercise capabilities, nausea, lack of appetite, abdominal pain,
visible as edema at peripherals, ascites, shortness of breadth while prone,
during exercise and sleep.
Congestive cardiac
failure and a healthy
cardiac

(Top) Gross
examination revealed
massive cardiomegaly
of transgenic heart
(×1.8). (Middle) Four-
chamber section of
hearts (×1.8)
demonstrates
massive enlargement
of both ventricles and
atria with atrial filling
by organized
thrombus. (Bottom)
Cardiac histology
(left ventricular free
wall, ×18) shows mild
edema and pale,
hypertrophied
myocytes without
significant
inflammation in
transgenic heart.
http://www.pnas.
org/content/94/1
5/8121/F4.expansi
on.html
 as a characteristic combination of these symptoms are inherent in the
patient, congestive heart failure could be a contributor, however unless
systemic confirmations are seen, other probabilities cannot be ruled
out as different configurations of systemic malfunctions or injuries
could result in the same symptomic set.

confirmations can be carried out via myocardiocyte biopsy, detecting

accumulates of extra fluid in the body by peripheral edema, breath
sounds, size of neck veins or ascites as well as an in depth investigation
of overall cardiac condition through measurements of pulse rate,
cardiac size, sounds, and murmurs.

an axial essential for confirmation is the echocardiogram, whereby

echo location through ultrasound and the resultant bounce back of
sound waves as structural contact occurs, this aids in clarity of vision
of cardiac zones, pulmonary state, myocytes, valve structures, blood
flow patterns and morphological variances. apart from being non
invasive and insightful, causes and results are accurately defined.
Another viable method is via chest radiography while patient is erectly positioned. At
an early stage, due to difference in the blood flow gradient, the pulmonary lobes may
be of an irregular morphology, with expansions of the upper lobes, thus easily
indicated upon the films.

As pulmonary pressure heightens from fluid build up from a weakly circulating blood
stream brought about by the damaged left ventricle, interstitial pulmonary edema
occurs indicated via perihilar and perivascular haziness, peribronchial cuffing, a
thickened interlobular septa, and artery-bronchus ratio deflections.

Congestive heart failure expands the cardiac silhouette. However blood ejection has
little to do with size. Structural shifts depend more upon the degree of deflections of
capillary wedge pressure which is an indirect estimate of left atrial pressure, indicative
of left ventricle failure and also the severity of valve stenosis as these aspects slow
mobility and thus affect pressure within the left atrial affecting the overall readings.

During severe situations, pleural effusions and airway edema might also be indicated.
Intensive care unit patients tend to reflect such findings, other supine radiographical
discoveries may include bronchus intermedius fibrosis, increase in pulmonary artery–
bronchus ratio in the upper vs. lower lung lobes during supine radiograph. As blood
flow is affected by posture, this factor is considered and findings thus interpreted
accordingly .
Findings that favour CHF are an enlarged cardiac silhouette, Kerley lines, and pleural
effusions. Lobar pneumonia and abscess, pulmonary infarction, lung masses or
nodules, and focal pleural disease are usually readily distinguishable from CHF.

Radiation free Magnetic Resonance Imaging works via emission of a strong magnetic
field within the system, just as gravity is to earth bond creatures, all photons are
bonded by electromagnetism ( interactions between them an thus the subsequent
exchange of photons, during which a force is generated ), this field resonates within
correlating with their respective spins, collisions, exchanges and interactions thus
bringing about corresponding imaging from their width, height, depth and
concentrate differences.

the variance in spectrum thus produces clearly defined shades , scanner detectable,
which eventually paint a morphological shaded outline with varying tones for greater
insight.
 Directional navigations is carried out with radio waves which are fields directed
within the enclosed space, creating mobility of the photons ( force carrying bosons,
spin = i ) thus inducing their scatter and interactions, like waves with sand. This
increases the spin of water molecules especially hydrogen ( valence, only one
electron thus the lightest and most susceptible to mobility and electron exchanges)
which through increased rotations, fuels interactions, thus generating greater spins.

Atoms with spin one half greater or lesser than the other tend to be attracted most
to each other.

Thus this method portrays an extremely sharp image of size, morphology and
density within cardiac zones, the valves, myocytes and valves. Interpretations
permit an understanding of function, ejection quantum, and structural well beings.

An effective method often employed for insight about differentiations of congestive

cardiac ailments, ischemia, valve dysfunctions, cardiomyopathy and various other
cardiac states which could have been misinterpreted due to the closeness of
symptoms portrayed.
http://personal.tcu.edu/~mfanelli/imastro/imastro_starstuff_files/molecular_emission1.j
pg
Rotations within a
Magnetic field

www.symmetrym
agazine.org
http://www.piyavate.com/images/cardiovascular-mri-md.jpg
 www.mplsheart.com/.../MRI_fig2.ashx

MRI cardiac images

http://www.mplsheart.com/About/HeartHeadlines/~/media/Images/HeartHeadlineIm
ages/MRI_fig1.ashx

http://www.mplsheart.com/About/HeartHeadlines/CardiacMRI.aspx
further diagnostic confirmations could include the electrocardiogram and
chest x-ray to locate cardiac enlargement, previous cardiac attacks,
fibrosis, arrhythmias, and pulmonary fluid accumulates.

an increase in the extracellular fluid volumes, which also results in

pulmonary edema as fluid accumulates within the lungs as the
pulmonary vasculature is mediated by the left side of the cardiac zone.

peripheral edema would also occur from the dysfunction pumping action
of the heart, with the legs mostly affected due to gravity and
peripherals are often most susceptible as they are at the outreaches of
the system and blood is thus shunted there less and at a longer
duration as compared to the axial areas.

Which brings about the characteristic swellings at the calf regions in

patients of congestive cardiac failure
this would also weaken the strength of calf musculature and the smooth
muscles within the tunica media which aids in deoxygenated blood
transport back up to the cardiac.

these high performance myocytes are dependent upon the presence of

adequate blood for nutrients, glycogen and ATP for contractions and
subsequent actin and myosin cross bridge release.

as endothelia valves of tunica intima inverginations prevent pooling of

blood and the accompanying fluids, lack of a proper blood supply to
these regions might also result in cellular death, and a reduction in
cellular size.

these factors contribute to the eventual shrinkages and dysfunctions of

these valves which would impeded preventions of backflows.

Further contributing to calf edema.

 kidney's retention of sodium chloride and water would also increase
extracellular volume within the interstitial fluid compartments, as
blood pressure and cardiac output decline, an overall weakness in
cardiac pumping occurs.

these pressure changes are sensed by vasculature sensors and a

response is carried out which increases kidney sodium chloride and
water retention, this is meant to dilute the blood thus encouraging its
distribution within the system and preventing cessation of flows.

in congestive heart failure, another main organ which is heavily blood

dependent due to the high volume of metabolic activities carried out
within- the liver which is connected to the hepatic artery and portal
vein becomes damaged.

this is the outcome of severe right sided congestive cardiac failure for
an extended duration, thus leading to lack of perfusions resulting in
chronic liver injury, ensuring inflammation and cumulating in fibrosis.
http://www.co
lorado.edu/int
phys/Class/IP
HY3730/image
/figure13-8.jpg
http://www.warriorpages.com/i
mages/Venous_System.JPG

Circulatory networks with axial

cardiac as mobility contributing
pump
as venous circulation is affected, blood would stagnate within major
veins bringing about an engorged liver.

ascites of large volumes of fluid would also accumulate within the

peritoneal cavities in the event of a worsening condition which
would have resulted in hepatic cirrhosis an advancement of which
would bring about the pooling of blood within the splanchnic
circulation ( mesenteric and splenic capillary beds emptying within
the hepatic bed) as a damaged liver would impede the blood
drainage from splanchnic circulation via the portal vein.

as the volumes and pressures are reduced within areas of the

vasculature system where sensors are located, venous pressures
within the portal systems increase and this deflection in fluid
transudates within the peritoneal cavities thus arise. thus the
kidneys react to this hike in extracellular volume, increasing
sodium chloride and water concentrates which would eventually
bring about an increased ascite severity.
 reference
Principles of Neuroscience
Iv th edition
Kandel Eric R
Schwartz James H
Jessell Thomas M
McGraw Hill
2 000

Principles of Physiology
Iv th edition
Matthew N. Levy,
Bruce M. Koeppen,
Bruce A. Stanton
Elsevier Mosby
2006