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ISBN: 978-0-12-800141-7
ISSN: 0065-2423
Printed and bound in United States of America

14 15 11 10 9 8 7 6 5 4 3 2 1
CONTRIBUTORS
Francisco V. Álvarez Menéndez

Clinical Biochemistry, Laboratory of Medicine, Hospital Universitario Central de Asturias,
and Biochemistry and Molecular Biology Department, University of Oviedo, Oviedo, Spain
Kaj Blennow
Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology,
The Sahlgrenska Academy at the University of Gothenburg, M€ olndal, Sweden
Fatima R. Freitas
Lipid Metabolism Laboratory, Heart Institute (InCor), Medical School Hospital, University
of São Paulo, São Paulo, Brazil
Gregory T. Jones
Department of Surgery, Dunedin School of Medicine, University of Otago, Dunedin,
New Zealand
Romy Kursawe
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut,
USA
Ronald Lautner
Rui-Chao Lin
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing,
PR China
Robert J. Lock
Immunology and Immunogenetics, Pathology Sciences, Southmead Hospital, North Bristol
NHS Trust, Bristol, United Kingdom
Raul C. Maranhão
Lipid Metabolism Laboratory, Heart Institute (InCor), Medical School Hospital, and Faculty
of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
Niklas Mattsson
Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The
Sahlgrenska Academy at the University of Gothenburg, M€ olndal, Sweden; Department of
Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, and
Department of Radiology and Biomedical Imaging, University of California, San Francisco,
California, USA
Belén Prieto
Clinical Biochemistry, Laboratory of Medicine, Hospital Universitario Central de Asturias,
Oviedo, Spain
ix
x Contributors
Christoffer Rosén
Nicola Santoro
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut,
USA
Pashtun Shahim
Tobias Skillbäck
David J. Unsworth
Immunology and Immunogenetics, Pathology Sciences, Southmead Hospital, North Bristol
NHS Trust, Bristol, United Kingdom
Henrik Zetterberg
The Sahlgrenska Academy at the University of Gothenburg, M€ olndal, Sweden, and
UCL Institute of Neurology, Queen Square, London, United Kingdom
Ying-Yong Zhao
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of
Education, The College of Life Sciences, Northwest University, Xi’an, Shaanxi, PR China
PREFACE
The third volume of the Advances in Clinical Chemistry series for 2014 is
presented.
In Chapter 1, the intravascular metabolism of HDL cholesterol is exam-
ined. The role of lipid transfer via cholesteryl ester and phospholipid transfer
proteins is examined with respect to risk of cardiovascular disease as well as
the atheroprotective properties of HDL cholesterol. In Chapter 2, diagnosis
of sepsis, a major cause of death in the acute care setting is reviewed. Dif-
ferentiation of infectious process in systemic inflammatory responses is cru-
cial to rapid identification and treatment. In Chapter 3, the complex
molecular and pathophysiologic mechanisms leading to nephrotoxicity
are explored. The role of metabolomics for screening a wide array of kidney
injury biomarkers is presented. In Chapter 4, metabolic syndrome in pedi-
atric patients is examined. The unique aspects of this syndrome in childhood
obesity are presented and the role of novel molecules and biomarkers in its
pathogenesis are explored. In Chapter 5, the neuropathology of Alzheimer’s
disease is reviewed. The development and use of classical and novel cerebro-
spinal fluid biomarkers are presented. Standardization of these analytical
approaches is critical for highly specific and sensitive diagnostics. In
Chapter 6, food allergy IgE mediated hypersensitivity, a growing problem
in the Western world, is examined. Appropriate screening tools and stan-
dardized methods are crucial to prevent this potentially life threatening con-
dition and aid treatment. In Chapter 7, the importance of biologic sampling
in matrix metalloproteinases is presented. These endopeptidases appear to
have an increasing role in many physiologic and pathophysiologic processes.
A comprehensive understanding of endogenous metabolism, activation of
proforms and preanalytical considerations is vital in understanding their role
in disease states.
I thank each contributor of Volume 65 and extend thanks to colleagues
who contributed to the peer review process. I would also like to thank
Helene Kabes for her expert editorial support at Elsevier.
I hope the third volume for 2014 will be enjoyed. Your comments and
feedback are always appreciated.
I would like to dedicate Volume 65 to my daughter Stephanie on the
occasion of her 13th birthday.
GREGORY S. MAKOWSKI
xi
CHAPTER ONE
HDL Metabolism and

Atheroprotection: Predictive
Value of Lipid Transfers
Raul C. Maranhão*,†,1, Fatima R. Freitas*
*Lipid Metabolism Laboratory, Heart Institute (InCor), Medical School Hospital, University of São Paulo, São
Paulo, Brazil
†
Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
1
Corresponding author: e-mail address: ramarans@usp.br
Contents
1. Introduction 2
2. HDL Composition 3
3. HDL Subclasses 4
4. HDL Metabolism and Reverse Cholesterol Transport 4
5. Other HDL Functions 7
6. Proatherogenic HDL 10
7. Cholesterol Ester Transfer Protein 10
7.1 CETP inhibitors 12
8. Phospholipid Transfer Protein 14
9. CETP and PLTP in CVD 17
10. Simultaneous Transfer of Lipids to HDL 18
11. Conclusion 30
Acknowledgments 31
References 31
Abstract
High-density lipoprotein (HDL) intravascular metabolism is complex, and the major HDL
functions are esterification of cholesterol and reverse cholesterol transport, in which
cholesterol from cells is excreted in bile. HDL has also several other antiatherogenic
functions: antioxidative, vasodilatatory, anti-inflammatory, antiapoptotic, anti-
thrombotic, and anti-infectious. Low HDL cholesterol is a major risk factor for cardiovas-
cular disease (CVD) and high HDL cholesterol may favor the many protective abilities of
HDL. However, aspects of HDL function can be independent of HDL cholesterol levels,
including the efflux of cholesterol from cells to HDL. Some populations show low inci-
dence of CVD despite their low HDL cholesterol. Lipid exchange between HDL and
other lipoproteins and cells is fundamental in HDL metabolism and reverse cholesterol
transport. By determining HDL composition, lipid transfers can also affect HDL functions
that depend on proteins that anchor on HDL particle surface. Cholesteryl ester protein
Advances in Clinical Chemistry, Volume 65 # 2014 Elsevier Inc. 1

ISSN 0065-2423 All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-800141-7.00001-2
2 Raul C. Maranhão and Fatima R. Freitas
(CETP) and phospholipid transfer protein facilitate lipid transfers among lipoprotein clas-
ses, but the role of the lipid transfers and transfer proteins in atherosclerosis and other
diseases is not well established. CETP has become a therapeutic target because CETP
inhibitors increase HDL cholesterol, but to date the clinical trials failed to show benefits
for the patients. Recently, we introduced a practical in vitro assay to evaluate the simul-
taneous transfer from a donor nanoemulsion to HDL of unesterified and esterified cho-
lesterol, phospholipids, and triglycerides. Groups of subjects at different clinical,
nutritional, and training conditions were tested, and among other findings, lower trans-
fer ratios of unesterified cholesterol to HDL were predictors of the presence of CVD.
1. INTRODUCTION
An important aspect of lipoprotein metabolism is that the lipoprotein
particles continuously exchange their constituent lipids and proteins. Lipid
transfers among lipoprotein particles may enrich or deplete lipoprotein clas-
ses of given lipid species. Lipid transfers are determinant of changes in the
composition and metabolism of lipoproteins. The implications of those pro-
cess in the genesis of atherosclerosis and other degenerative diseases are still
largely unknown and lead to a fascinating avenue of research.
The initial observations on the exchange of phospholipids and choles-
terol between lipoproteins were made by Hagerman et al. during investiga-
tions on lipid exchanges between membranes published in 1951 [1]. The
shift of cholesteryl esters from high-density lipoprotein (HDL) to low-
density lipoprotein (LDL) was firstly documented by Rehnborg and Nichols
in 1964 [2]. Zilversmit et al. reported the protein-mediated nature of the
lipid transfers [3]. Those authors showed that an acidic protein stimulated
the transfer of cholesteryl esters between VLDL and LDL. This protein
was described as a large molecular weight glycoprotein, which promotes
the exchange of cholesteryl esters between all classes of lipoproteins in
the human plasma [4]. In 1980, Ihm et al. found another glycoprotein that
also mediates the exchange of phospholipids between lipoproteins [5]. At
present, it is established that the main proteins involved in lipid transfers
are cholesteryl ester transfer protein (CETP) and phospholipid transfer
protein (PLTP). CETP facilitates the transfer of cholesteryl esters, triglycer-
ides, and phospholipids, whereas PLTP mostly favors the transfers of phos-
pholipids [6]. Although the transfer of unesterified cholesterol is less
influenced by transfer proteins, it may also be increased by PLTP action [7].
CETP mediates the transfer of triglycerides from the triglyceride-rich
lipoproteins such as VLDL to HDL and, in the opposite direction, the
Lipid Transfers as Disease Predictors 3
transfer of cholesteryl ester from the core of HDL particles to VLDL [6]. In
fact, those lipid shifts are bidirectional but the result is depletion of
cholesteryl esters in HDL and enrichment of HDL with triglycerides. This
leads to the formation of large HDL particles that are an appropriate substrate
for hepatic lipase and removal by the liver [8]. In hypertriglyceridemia, accu-
mulation of VLDL and other triglyceride-rich lipoproteins in the blood
leads, by mass action law, to increase in HDL triglyceride content and
increased HDL clearance by the liver consequent to the hepatic lipase action.
Resulting from this chain of events is the so-called triglyceride–HDL cho-
lesterol seesaw, a phenomenon that is commonly observed in the clinical
practice: when serum triglycerides increase, HDL cholesterol decreases
and vice versa [8]. It is worthwhile that the driving forces for the seesaw
are the variations in VLDL and not in HDL concentration.
Although the process of lipid transfers involves all the lipoprotein clas-
ses, the effects on composition and metabolism are less important in regard
to VLDL or LDL than to HDL, as exemplified above by the seesaw effect.
The pharmacological inhibition of CETP results primarily in rise in HDL
cholesterol concentration; LDL cholesterol decreases, but at much smaller
rates. Rise of HDL cholesterol by CETP inhibition has become a new
therapeutic target for antiatherosclerosis treatment. The fact that lipid
transfers play a key role in HDL composition, concentration, and metab-
olism in the plasma suggests opportunities to establish new markers for
HDL function and participation in pathological processes. A better com-
prehension of the implications of lipid transfers involving HDL is also nec-
essary for the correct evaluation of pharmacological interventions on HDL
metabolism.
2. HDL COMPOSITION
The HDL plasma fraction is constituted of spherical or discoidal par-
ticles of high hydrated density, ranging from 1.063 to 1.21 g/mL, due to
elevated protein content (>30% by weight) compared with other lipopro-
teins [9]. Discoidal HDLs are the smallest HDL particles, constituted of apo-
lipoprotein (apo) A-I embedded in a monolayer of phospholipids and
free cholesterol [10]. Spherical HDL is larger and contains a hydrophobic
core formed by cholesteryl esters and small amounts of triglycerides sur-
rounded by a monolayer of phospholipids and unesterified cholesterol [9].
Apolipoproteins and a variety of other proteins in smaller amounts are
anchored to the lipoprotein surface.
Apo A-I (MW: 28 kDa) is the major structural apolipoprotein of HDL

and makes up approximately 70% of total HDL protein, whereas the second
major HDL apolipoprotein, apo A-II, accounts for roughly 20%. The
remaining 10% of the protein moiety includes apo E, apo A-IV, apo
A-V, apo J, apo C-I, apo C-II, and apo C-III [11].
HDL particles also carry enzymes involved in lipid metabolism, such
as lecithin-cholesterol acyltransferase (LCAT), with antioxidative activity,
such as platelet-activating factor-acetyl hydrolase (PAF-AH), paraoxonase 1
(PON1), and glutathione selenoperoxidase (GSPx), and other proteins and
peptides, such as serum amyloid A (SAA), a major positive acute-phase reactant,
a-1-antitrypsin, a potent inhibitor of serine proteinases, and amyloid-b [9].
3. HDL SUBCLASSES
Within the HDL density range, there are heterogeneous groups of par-
ticles differing not only in density and size but also in lipid and protein com-
position and electrophoretic mobility [12]. Based on the physical–chemical
characteristics, those HDL subclasses can be resolved by different techniques.
By sequential ultracentrifugation, HDL can be separated into two main sub-
fractions: large, light, lipid-rich HDL2 (density 1.063–1.125 g/mL) and
small, dense, protein-rich HDL3 (1.125–1.21 g/mL). HDL2 and HDL3
can be further resolved by gradient gel electrophoresis into five distinct
subpopulations, according to their size: HDL3c (7.2–7.8 nm), HDL3b
(7.8–8.2 nm), HDL3a (8.2–8.8 nm), HDL2a (8.8–9.7 nm), and HDL2b
(9.7–12.9 nm) [13]. By two-dimensional electrophoresis, it is possible to
separate HDL by charge and size in more than 10 subspecies. HDL can also
be separated on the basis of apolipoprotein composition into subpopulations
by immunoaffinity methods [13].
The HDL subspecies profile reflects the overall steps of the lipoprotein
metabolism and can be modified by myriads of variables in the factors that
intervene in this metabolism, such as the lipid transfers, enzymatic activities,
the kinetics, and concentration of the several lipoprotein classes and sub-
classes in the circulation, among many others.
4. HDL METABOLISM AND REVERSE CHOLESTEROL

TRANSPORT
HDL metabolism is more complex than that of the other lipoprotein
classes because, different from the apo B-containing lipoprotein classes,
HDL is mostly assembled in the plasma by lipidation of apo A-I secreted by

the liver and the intestine [14,15] (Fig. 1.1).
HDL formation begins with the lipidation of apo A-I [10]. It is postu-
lated that the initial phospholipidation of apo A-I occurs in the endoplas-
mic reticulum [16], and did not depend on the ATP-binding cassette A-I
receptor (ABCA1), that is expressed mainly in the liver, intestine, and mac-
rophages [17]. Subsequently, ABCA1 promotes the transport of phospho-
lipids and unesterified cholesterol to lipid-poor apo A-I in the plasma,
forming beta HDL, the discoid nascent form of HDL [18]. Unesterified
cholesterol and phospholipids can also be transferred to nascent HDL
apo A-I during the lipolysis of triglyceride-rich lipoproteins, such as
VLDL and chylomicrons, as excess surface lipids detach from the shrinking
lipoproteins [19].
The next important step is the esterification of HDL cholesterol by
LCAT using apo A-I as cofactor [19]. LCAT is synthesized by the liver
and circulates bound to lipoproteins, mainly to HDL, or as free, unassociated
molecule [20]. Cholesteryl esters are more hydrophobic than unesterified
cholesterol, so that after esterification cholesterol is dislocated from the sur-
face lipoprotein monolayer to the core of the particles, where it is seques-
tered from the aqueous medium that surrounds the lipoprotein particle [21].
This results in the formation of the mature spherical HDL2 and HDL3 par-
ticles that form the bulk of the HDL plasma fraction.
Cholesterol esterification prevents the spontaneous back exchange of
cholesterol from HDL to cells and thus promotes the net cellular removal
of cholesterol [21]. Cholesterol esterification creates a gradient for the lipo-
protein surface to receive additional unesterified cholesterol from the other
lipoproteins and cells. On the other hand, it stabilizes the cholesterol plasma
pool by avoiding escape of unesterified cholesterol from the surface lipopro-
tein layer to the plasma, to where it could easily diffuse and precipitate. In
fact, although cholesterol esterification also occurs at some degree in other
lipoprotein fractions, the HDL fraction is the site wherein most of the pro-
cess takes place. This occurs because the HDL fraction offers optimal con-
ditions for the enzyme-catalyzed reaction due to the high affinity of LCAT
for the HDL surface and the high content of apo A-I in the HDL, the
enzyme cofactor [21]. Transfer of unesterified cholesterol to the large ester-
ification machinery housed in the HDL fraction is therefore a major driving
force for the functioning of the mechanisms destined to promote cholesterol
homeostasis in the body. In one of those major mechanisms, the reverse cho-
lesterol transport process, unesterified cholesterol is transferred from the cells
Figure 1.1—CONT’D
of the extrahepatic tissues and vessels to HDL, where it undergoes the ester-
ification reaction.
Remodeling of HDL is also promoted by PLTP that favors the phospho-
lipid efflux to HDL from peripheral cells and from triglyceride-rich lipopro-
teins, during the degradation of chylomicrons and VLDL by lipoprotein
lipase [7].
In the final step of the reverse cholesterol process, cholesteryl esters of
HDL are directly shuttled to the liver where the scavenger receptor class
B member 1 (SR-BI) takes up the lipoprotein particles and their cholesterol
content is excreted in the bile. Alternatively, HDL cholesteryl esters are
beforehand transferred to apo B-containing lipoproteins, by the action of
CETP, thereby being excreted in the bile after uptake of those lipoproteins
by the liver [15].
5. OTHER HDL FUNCTIONS

In addition to the HDL primary functions in cholesterol homeostasis,
cholesterol esterification, and reverse cholesterol transport, other increas-
ingly numerous protective functions have been ascribed to this lipoprotein.
HDL antioxidative activity is typically observed as inhibition of LDL
oxidation [9]. HDL protects both lipid and protein moieties of LDL and
inhibits accumulation of various oxidation products in the LDL fraction,
including oxidized phospholipids [22]. HDL is also able to inhibit the
Figure 1.1 Metabolism of HDL. Synthesized by the liver and the intestine, apolipoprotein
A-I (apo A-I) acquires phospholipid (PL) into the cells. Unesterified cholesterol (UC) and
PL efflux from the peripheral cell, via ABCA1, and are taken up by the lipid-poor apo
A-I to form pre-b1-HDL particle. The progressive action of lecithin:cholesterol acyl trans-
ferase (LCAT) on nascent HDL generates a spectrum of mature, spherical HDL particles:
small cholesteryl ester-poor, protein-rich HDL3, and large cholesteryl ester-rich HDL2.
These mature HDL particles have a neutral lipid core of cholesteryl ester (CE) and triglyc-
eride (TG) and can acquire additional lipids, via efflux mediated by ABCA1. The phospho-
lipid transfer protein (PLTP) promotes phospholipids efflux to HDL from peripheral cells
and from triglycerides-rich lipoprotein, during the degradation of chylomicrons and
VLDL by lipoprotein lipase. Unesterified and esterified cholesterol content of mature
HDL is shuttled to the liver by an uptake process involving the hepatic scavenger recep-
tor class B member 1 (SR-BI). The cholesterol ester transfer protein (CETP) facilitates the
exchange of triglycerides in apoB-containing lipoproteins (VLDL, IDL, and LDL) for
cholesteryl ester in HDL. CETP is also responsible to the CE transfer among HDL sub-
classes. Both the unesterified and esterified cholesterol content of apoB-containing lipo-
proteins are taken up by the liver, predominantly via the low-density lipoprotein
receptor (LDLR). Henceforth, the cholesterol content is excreted in the bile
generation of reactive oxygen species (ROS) in vitro [23,24] and in vivo [25].
The antioxidative activity of HDL is related to the presence of apo A-I and
apo E and enzymes with antioxidative properties that are associated to the
HDL particles. It appears that apo A-II is a major component of the
antioxidative activity of HDL, which can prevent or delay the LDL oxida-
tion by removing oxidized phospholipids from LDL and from arterial wall
cells [26,27]. Apo E possesses antiatherosclerotic activity, which is attributed
to its properties in lipid transport [28]. Finally, HDL is able to function as a
preventive antioxidant through its ability to bind metal ions, potent cata-
lyzers of LDL oxidation [29].
Major HDL-bound antioxidative enzymes are PON1 and PAF-AH [9].
PON1 is an esterase/lactonase calcium dependent, hydrolyzes a variety of
oxidized fatty acids from phospholipids, and prevents the accumulation of
oxidized lipids in lipoproteins, mainly in LDL [30–32]. HDL provides
the optimal physiological acceptor complex for PON1, stimulating enzyme
secretion and stabilizing the peptide [33]. PON1 activity is inversely related
to the risk of cardiovascular disease (CVD), independent of all other coro-
nary risk factors, including HDL cholesterol [34].
PAF-AH is a Ca2+-independent enzyme of the phospholipase A2 family
involved with the antioxidant and anti-inflammatory functions of HDL
[35,36]. PAF-AH has two main functions against the oxidation process: it
hydrolyzes PAF, a phospholipid mediator with proinflammatory properties,
and degrades oxidized phospholipids [35,37]. PAF accumulates within the
atherosclerotic plaques of individuals with CVD, suggesting that this phos-
pholipid mediator may be actively involved in the pathophysiology of
atherosclerosis [37,38]. Thus, PAF-AH may function as antiatherogenic
enzyme via degradation of phospholipids [38].
The anti-inflammatory activity of HDL is showed by the ability of
the lipoprotein to decrease cytokine-induced expression of adhesion mol-
ecules on endothelial cells and to inhibit the adhesion of monocytes to those
cells [9]. HDL efficiently inhibits in vitro the expression of the vascular
cell adhesion molecule, intercellular adhesion molecule, and E-selectin,
induced by tumor necrosis factor-a (TNF-a), interleukin 1, or endotoxin
[39–41].
The anti-inflammatory action of HDL involves the inhibition of TNF-
a-stimulated activation of sphingosine kinase and production of
sphingosine-1-phosphate (S1P), which induces the expression of adhesion
molecules in endothelial cells [42]; TGF-b may function as an important
mediator of the anti-inflammatory activity [43]. In addition, HDL attenuates
IL-6 production in endothelial cells exposed to proinflammatory stimuli,

such as TNF-a and endotoxin [44]. In fact, this potent anti-inflammatory
activity observed in vitro was confirmed in a rabbit model of acute arterial
inflammation wherein inhibition of adhesion molecule expression and
decrease in neutrophil infiltration in the arterial wall was observed after
injection of reconstituted HDL [25].
The HDL anti-inflammatory action also involves hydrolysis of oxidized
lipids by HDL-associated enzymes (PAF-AH and PON1) and is mechanis-
tically superimposed to the antioxidative activity of HDL [45,46]. Oxidized
phospholipids possess potent proinflammatory activities and can trigger arte-
rial inflammation [47]. Inactivation of oxidized lipids by HDL may be asso-
ciated with decreased expression of adhesion molecules in endothelial cells,
which decreases macrophage adhesion to the endothelium [46,48].
HDL may provide additional cardiovascular benefits by antagonizing
platelet activity and inactivating the coagulation cascade. It was shown that
apo A-I levels correlated with the anticoagulant response to activated pro-
tein C/protein S that promotes the inactivation of factor Va [49]. HDL also
favors the restoration of the endothelial function [50].
HDL can inhibit the apoptosis of endothelial cells induced by oxidized
LDL [51] or TNF-a [52] and decrease the intracellular generation of
ROS and levels of apoptotic markers [23]. In addition, HDL contains
lysophospholipids that increase the nitric oxide (NO) production, thereby
reducing apoptosis of endothelial cells [53–55].
Another important protective function of HDL is the vasodilatory
action of the lipoprotein, which is accomplished by three different mecha-
nisms involving endothelial NO synthase (eNOS). First, HDL stimulates
the release of NO by endothelial cells, through the mobilization of intracel-
lular Ca2+ and phosphorylation of eNOS [56]. Second, not only the
release but also the production of endothelial NO is stimulated by HDL,
by upregulation of eNOS expression [50]. Finally, binding of HDL to
SR-BI receptors plays a role in the activation of eNOS, a process that
involves eNOS binding to apo A-I [57].
Other mechanism whereby HDL promotes vasodilation is through stim-
ulation of the production of prostacyclin, which possesses potent
vasorelaxing activity [58]. The vasoactive effects of HDL can be mediated
by S1P acting via the lysophospholipid receptor S1P3 [54]. S1P may be
equally important for mitogenic effects of HDL on endothelial cells and
for the inhibitory action of HDL on the migration of vascular smooth muscle
cells [59,60].
HDL has also an antithrombotic activity, by inhibiting the factors that

promote blood coagulation, including tissue factor, factors X, Va, and VIIIa
[9]. This effect may be related to the presence of cardiolipin and phospha-
tidylethanolamine in the HDL composition, two phospholipids with anti-
coagulant properties [61]. Stimulation of the production of NO by HDL
also accounts for the inhibitory action of HDL on platelet aggregation [62].
HDL also has anti-infectious activity. Through the direct interaction
with apo A-I [63], the lipoprotein binds and removes circulating endotoxins
for excretion in the bile, decreasing the endotoxin-induced TNF produc-
tion, and the CD14 expression on monocytes [64,65].
6. PROATHEROGENIC HDL
In some conditions like inflammatory states, diabetes, or metabolic
syndrome, apo A-I can be modified by ROS [66]. Apo A-I oxidative mod-
ification can hamper the HDL action in cholesterol efflux from the cells by
impairing the apo A-I interaction with the ABCA1 complex that pumps out
cholesterol from the cell [66]. The antioxidant enzymes associated with
HDL can also be inactivated, and oxidized proteins and lipids can accumu-
late in HDL particles, thus compromising the anti-inflammatory function
of the lipoprotein [67,68]. Substitution of SAA for apo A-I in the HDL
particle structure can revert HDL function and the lipoprotein becomes
proinflammatory and proatherogenic [68–70]. This may occur in conditions
associated with high SAA levels in the serum, such as metabolic syndrome,
diabetes, and renal chronic disease [68–70].
7. CHOLESTEROL ESTER TRANSFER PROTEIN

CETP, a hydrophobic glycosylated, 476 aa, 75-kDa single polypep-
tide protein, is secreted primarily by the liver, adipose tissue, enterocytes,
and spleen [71] and circulates in the plasma associated principally with
HDL [72].
CETP can only promote the net mass transfer of lipids between lipo-
protein subclasses that have different cholesteryl ester/triglycerides mass
ratios [72]. Therefore, CETP mediates the transfer of cholesteryl esters from
HDL to apo B-containing lipoproteins in exchange for triglycerides and the
transfer of triglycerides from apo B-containing lipoproteins in exchange for
cholesteryl esters [73–75]. CETP also favors the cholesteryl ester transfer
among HDL subparticles (pre-b-HDL, -HDL3, and -HDL2) [73].
CETP activity is dependent on both its concentration and ability to

interact with lipoproteins. The interaction can be stimulated by free fatty
acids generated during hydrolysis of dietary triglycerides [72] or inhibited
by specific apolipoproteins, such as apo C-I or apo F [76,77]. Most of the
cholesteryl esters in the plasma originates from the LCAT-catalyzed esteri-
fication reaction that occurs mainly in the HDL fraction [20]. Triglycerides
in the circulation are mostly present in chylomicrons and VLDL before
hydrolysis by lipoprotein lipase [72].
As a regulator of cholesterol flux through the reverse cholesterol
transport system, CETP may be viewed as potentially having both
proatherogenic and antiatherogenic properties. In its proatherogenic action,
CETP-mediated cholesteryl ester transfer may decrease the flux of choles-
terol through HDL to hepatic SR-BI in the direct reverse cholesterol trans-
port pathway concomitantly increase the mass of cholesterol transported by
atherogenic VLDL, IDL, and LDL, from the arterial wall and an increase in
atherogenic LDL levels [15,78]. In consequence, it would tend to enhance
the cholesterol deposition in peripheral tissues and the arterial wall [78].
CETP also interacts with triglyceride lipases to generate small, dense LDL
which is the most atherogenic LDL subclass [79] and HDL [80]. The
CETP-mediated reduction in HDL particle size is accompanied by the dis-
sociation of lipid-poor apo A-I from the particle [81,82].
On the other hand, CETP may exert antiatherogenic effects, as it pro-
motes the flux of cholesteryl ester to the liver via indirect reverse cholesterol
transport, with hepatic cholesteryl ester uptake predominantly through the
antiatherogenic LDL receptor route [73]. Furthermore, CETP contributes
to the optimization of LDL particle structure and of apo B100 conformation
for high-affinity binding to LDL receptors [83].
The level of CETP activity is determinant in the partition of the
cholesteryl ester plasma pool between LDL and HDL. However, excess
CETP activity increases the bidirectional transfers between HDL and
LDL without importantly changing the distribution of cholesteryl esters
between the two lipoprotein plasma fractions [74]. When the level of VLDL
is normal, CETP-mediated transfers of HDL cholesteryl esters are directed
preferentially to LDL, but when VLDL accumulates in the serum, HDL
cholesteryl esters are preferentially transferred by CETP to VLDL particles
[84,188].
The crystal structure of CETP by X-ray crystallography consists of an
elongated boomerang-shaped asymmetric conformation with N- and
C-terminal b-barrels, a central b-sheet between the two b-barrels, and a
hydrophobic central cavity, with the curvature of the concave surface likely
fitting to the convex curvature of the lipoprotein surface [85]. This cavity is
filled by two cholesteryl ester molecules and communicates with two open-
ings near the central b-sheet domain. These pores, which are occupied by
two phospholipid molecules, could be gates for the interaction of the central
cavity with the aqueous environment or lipoproteins [85].
In respect to the mechanisms through which CETP acts in lipid
exchanges, some hypotheses have been proposed. CETP would transport
cholesteryl esters between donor and acceptor lipoproteins, through the
aqueous phase [86]. Alternatively, in a sort of tunnel mechanism, CETP
would bridge two lipoproteins; HDL binds on N-terminal and LDL or
VLDL binds on C-terminal end. A transient ternary complex is formed, with
neutral lipids flowing from the donor to acceptor lipoprotein through the
CETP molecule [87,88]. In a modified tunnel hypothesis, lipids would
be tunneled in a CETP dimer [72].
The decrease in HDL levels and antiatherogenic functions and the
increase in proatherogenic factors that occur in metabolic syndrome and
in type 2 diabetes mellitus (T2DM) patients coexists with high CETP con-
centration in the plasma [89,90]. On the other hand, treatment with
pioglitazone decreased the hepatic triglyceride content and increased the
HDL cholesterol levels while simultaneously decreased CETP [91]. In
normal-weight subjects, there is an inverse correlation between CETP level
and visceral fat gain and CETP level and body mass index [92].
7.1. CETP inhibitors

Increased CETP plasma levels can reduce HDL cholesterol [189], and
CETP deficiency is associated with elevated HDL cholesterol [190]. Aiming
to expand the HDL fraction, several chemical CETP inhibitors have been
developed, including torcetrapib (Pfizer, USA), dalcetrapib (Roche, Swit-
zerland), anacetrapib (Merck, USA), and evacetrapib (Lilly, USA). The
molecular mechanisms of CETP-mediated lipid transfers among lipopro-
teins are still largely unknown.
Torcetrapib, a 3,5-bis(trifluoromethyl)phenyl derivative, is a potent
inhibitor of CETP activity, which enhances the association between CETP
and HDL to form a complex that inhibits the transfer of lipids between HDL
and other lipoproteins [93]. Torcetrapib was able to increase HDL choles-
terol level by 72% and to decrease LDL cholesterol by 25% [94]. However,
despite the favorable lipid changes, torcetrapib failed to diminish maximum
carotid intima-media thickening in patients with familial hypercholesterol-

emia [95] and in mixed dyslipidemia [96]. In 2006, the ILLUMINATE
study was prematurely finished due to the adverse effects of the drug, excess
of deaths, and CVD [94].
Further analysis of the trial data revealed other undesirable effects of tor-
cetrapib, including increased blood pressure, sodium, bicarbonate, and aldo-
sterone levels, and decreased potassium levels [94,97]. Hypertension resulted
from increased production of adrenal steroids, such as aldosterone and cor-
tisol. It is currently understood that the adverse events caused by torcetrapib
are molecular-specific and do not relate to the mechanism of CETP inhibi-
tion [15]. Studies with animal models demonstrated increase in the aortic
wall expression of endothelin in response to torcetrapib administration [98].
Together with data of human adrenal cell assays [99], these results suggest
that these off-target effects are related to the stimulation of aldosterone syn-
thesis by torcetrapib via pathways independent of CETP inhibition [15].
Structure–activity investigations have provided further evidence that the
hypertensive effects of torcetrapib are unrelated to CETP inhibition [100].
Dalcetrapib, a benzenethiol derivative, was the first small molecule
showed to inhibit CETP and to possess an antiatherogenic effect in vivo
[101]. It binds CETP irreversibly but, in contrast to torcetrapib, dalcetrapib
does not appear to induce the formation of a CETP–HDL complex at ther-
apeutic plasma concentrations [102]. Dalcetrapib is considerably less potent
than torcetrapib as HDL raiser. In healthy individuals, daily treatment with
600 mg of dalcetrapib increased HDL levels by 23%, after 4 weeks [103] and
by 28% in type II patients receiving pravastatin, with decrease LDL choles-
terol levels by 7% [104]. After 24 weeks, dalcetrapib (900 mg/day) was able
to raise HDL cholesterol levels by 33% in patients receiving atorvastatin, but
levels of LDL cholesterol did not alter [105]. Despite the effects on HDL
cholesterol, some encouraging imaging observations and the warrant from
the safety data, dalcetrapib failed to achieve reduction of cardiovascular
events and the clinical trials were stopped in 2012.
Anacetrapib is other 3,5-bis(trifluoromethyl) phenyl derivatives used as
CETP inhibitor, by forming a tight reversible bond with this protein [106].
Anacetrapib inhibits the transfer of cholesteryl esters from HDL to LDL and
from HDL3 to HDL2 [106]. In both normolipidemic individuals and dys-
lipidemic patients treated with atorvastatin, anacetrapib (300 mg/day) was
able to increase the HDL cholesterol levels by 130%, apo A-I by 47%,
and decrease the LDL cholesterol levels by 40% [107,108]. Anacetrapib
treatment does not increase blood pressure or aldosterone synthesis
Metabolic syndrome vs. # # # # $ MetS: 50 10 y; [173]
control 10 M, 10 F
Control: 45 7
y; 6 M, 4 F
Type 2 diabetes mellitus $ $ " " $ T2DM: 59 5 y; [174]
vs. control 7 M, 8 F
Control: 55 6
y; 5 M, 6 F
Type 1 diabetes mellitus $ $ $ $ $ T1DM: 26 7 y; [175]
vs. control 16 M
Control: 28 6
y; 15 M
Familial $ # " $ " FH: 39 15 y; [176]
hypercholesteromia vs. 26 M, 45 F
normolipidemia NL: 38 11 y;
27 M, 39 F
Polycystic ovary $ $ $ $ $ PCOS: 23 3 y; [177]
syndrome vs. control 18 F
Control: 27 5
y; 10 F
PCOS obese vs. PCOS $ $ $ $ $ Obese: 26 5 y; [177]
nonobese 15 F
Nonobese:
23 3 y; 8 F
Continued
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pintle yoke, and top carriage, the trail, the wheels and axle. The gun
slides in recoil on the upper surface of the cradle and the cradle
contains the recoil controlling parts.
In the design of the carriage the constructional difficulty lies not so
much in preventing the carriage from recoiling but in preventing the
wheels from rising off the ground on the shock of discharge. The
force of the recoil of the gun, acting in the line of motion of the center
of gravity of the recoiling parts, tends to turn the carriage over
backwards about the point of the trail or center of the spade. This
force is resisted by the weight of the gun and carriage, which tends
to keep the wheels on the ground. The leverage with which the
overturning force acts is due to the distance of its line of action
above the center of the spade; the leverage with which the
overturning force acts is that due to the horizontal distance of the
center of gravity of the gun and carriage from the center of the
spade.
It follows that the steadiness of the carriage for a given muzzle
energy may be promoted by four factors.
(a) Increasing the weight of the gun and recoiling parts. This
reduces the recoil energy.
(b) Increasing the length of recoil allowed. This reduces the
overturning pull.
(c) Keeping this gun as low as possible either by reducing the
height of the wheels, or by cranking the axle downwards. This
reduces the leverage of the overturning force.
(d) Increasing the length of the trail. This increases the leverage of
the steadying force.
The well designed gun carriage is one that combines these factors
in a practical way so as to give the greatest possible steadiness to
the carriage at the same time keeping within the limits of weight
imposed by the necessity of mobility.
Gun carriages are constructed so as to permit movement of the
tube in the vertical and generally in the horizontal plane. These two
motions may be made simultaneous if so desired by proper
combination of the two motions and the axis of a gun aligned in any
desired direction within the limits of motion of its mount. The two
motions referred to are designated as follows: (a) Rotation of the
piece about a vertical axis, its inclination with the horizontal
remaining unchanged is called “traverse.” (b) Movement of the piece
in a vertical plane, the direction of the horizontal projection of the
axis of the bore remaining unchanged is called “elevation.”
In order to permit of the two motions mentioned, gun carriages are
provided with mechanisms for giving the piece accurately controlled
motion in both elevation and traverse. The elevating gear of most
American guns is an application of the Chinese or Telescopic screw.
This gives a short assembled length with the necessary extended
length required for modern ranges. It also gives the necessary
rapidity for action. An entirely different mechanism is used in our
howitzers and American 75s. In this case motion is communicated to
the rockers, which carry the gun and cradle, through the
engagement of worms with teeth cut on the lower circular edge of
the rockers, the latter being pivoted on the cradle trunnions.
TRAVERSING MECHANISMS.
Movement of the gun in traverse is accomplished in two general
ways.
(a) Pivot on the gun carriage axle.
1. The gun and cradle move around a vertical pintle or pivot
placed in a saddle or rocker which itself pivots on horizontal
trunnions or bearings usually attached to the axle. The rear end of
the rocker forms a seat or bearing on which the cradle and gun move
in traverse. The upper end of the elevating screw is also attached to
the rear end of the rocker. This allows the rocker and cradle to be
moved together in elevation and the cradle to move on the rocker in
traverse.
2. The gun and cradle are mounted by means of horizontal cradle
trunnions on a top carriage. The top carriage moves in traverse
around a vertical pintle or bearing attached over the axle and
between the front end of the trail flasks. The rear end of the top
carriage moves on bearings attached to the top of each side of the
trail flasks. This allows the gun, cradle and rocker to move in
elevation with respect to the top carriage and the top carriage
bearing the gun, cradle rocker and elevating mechanism to move in
traverse with respect to the bottom carriage.
(b) The gun, cradle and trail move in traverse by sliding along the
axle of the carriage on bearings provided for that purpose. In this
case the trail spade is the point of pivot.
The first system is the one generally used on all American gun
carriages except the 155-mm Howitzer. It gives ease and speed in
the manipulation of the piece in traverse, but has the disadvantage
of rendering the carriage less stable in firing due to the fact that the
direction of recoil of the gun is in the direction of the line joining the
trail spade and the central pivot, only when the gun is absolutely in
the center of its traverse. In all other positions, which will be the
usual case, there is a component at right angles to the line of trail
spade-central pivot which tends to throw the gun off from its proper
direction making it necessary to relay each time the gun is fired. The
second method is that in use on the French 75-mm gun and the
French and American 155 howitzer. While not so easy of
manipulation and giving less freedom of movement in traverse
(about 106 mils) it still has the advantage in that it gives greater
stability in firing due to the fact that the gun always recoils along the
line through the trail spade, perpendicular to the axle.
ELEVATING MECHANISMS.
There are two general classifications of gun carriages according to
the manner in which the laying for elevation is effected. The 3” gun is
an example of one type in which the total quadrant angle of
departure is laid off as one angle necessitating at each resetting of a
range a new resetting of the range bubble. It is evident that this
militates against both speed and accuracy in laying for elevation.
The other type is illustrated by the American 75 and by the French
and British 75-mm gun carriages which have what is called the
“independent line of site.” It differs from the other type in that there is
placed between the top carriage and the cradle an intermediate
carriage or rocker arm pivoting on the gun trunnions at one end, and
carrying at the other the support for the elevating device which gives
to the cradle and the gun the proper elevation for the range. This
intermediate carriage or rocker arm has a toothed edge geared with
a pinion fastened to the trail flask, by means of which, gun cradle
and elevating device may be moved in elevation without disturbing
the relation between itself and the gun, this being done by gears
independent of the elevating mechanism. An angle of site may be
set off for the intermediate carriage and after the bubble is centered
this actuating pinion may be blocked and no further concern be paid
to the angle of site. A cannoneer therefore has only to set his range
accurately on the index to give the changes in range ordered.
Elevation is accomplished by telescoping screws, by circular racks
and pinions, and by worms and arcs. Telescoping screws are good
for from 15 to 20 degrees in elevation only, as for greater angles they
become rather too large and cumbersome. The elevating arc is
attached on the top, on the bottom or on the side of the cradle and, if
possible, at its center. When the latter is not possible, two arcs are
generally used to prevent torsional strains developing. Top racks are
exposed to fire, side circular racks or arcs interfere with the traverse,
with the placing of the sights, and with the general handling of the
carriage. The bottom of the cradle is perhaps the best location for
the rack. As in the traversing mechanism, a train of bevelled gears
transmits the power from the hand wheel to the elevating
mechanism.
In both the traversing and elevating mechanism, strength,
simplicity, power, accessibility, non-interference and absence of lost
motion are the features sought. To secure these is one of the most
difficult things in gun-carriage design; for, since the traversing and
elevating are the last two elements considered, they must, therefore,
be the ground for modification and the means of adapting the great
main elements—namely, wheels, axle, trail, recoil mechanism and
gun—into a unit.
RECOIL MECHANISM.
The recoil system of the gun carriage consists of a recoil brake, a
counter recoil mechanism and a counter recoil brake. The function of
each part is apparent from its name. Various systems of checking
recoil on field guns have been used, among them may be
mentioned; friction devices including brakes on the wheel, inclined
planes, pneumatic and hydraulic brakes. All have either been
superseded by the last named or are used in connection with
hydraulic brakes. The power of the brake lies in the pressure
produced in the cylinder through the resistance to motion offered by
the liquid flowing through apertures. By varying the size of these
apertures the braking effect may be controlled so as to fulfill the
conditions demanded by the service. In designing the brake, the
effect of the counter recoil system, angle of fire, length of recoil,
friction and pressure within the cylinder must all be considered. In
howitzers which are designed to be fired at high angles of elevation,
the recoil must be shortened to prevent the breech striking the
ground, a condition successfully met. Since the pressure due to
recoil is ultimately led into the ground through the trail and spade,
consideration must be given to the problem of the moment of inertia
about the trailspade. The tendency to turn over backward about the
spade as the center is offset by the amount of the weight of the
carriage with respect to the same point. This raises the question as
to how much pressure may be allowed to act to the rear; all of which
must be considered in designing the carriage. The counter recoil
systems in general use are two: spring or pneumatic. The former is
illustrated in our 3” and 75-mm field guns, the latter by the French
75-mm gun and 155-mm howitzer. Their purpose, of course, is to
return the gun “into battery” after it has recoiled on the carriage.
The recoil mechanism is a study in itself, of which there are two
schools—the advocates of the spring and of the air recuperators.
Great Britain, Germany and the United States have been the
advocates of spring recuperation and France of air recuperation.
Great Britain and the United States were of the spring school,
undoubtedly, because of the lack of a satisfactory air recuperating
system; which is rather strikingly proven by the fact that both
countries have adopted air recuperation since they have procured or
developed satisfactory types.
Both schools have grounds for their position, however. The spring
school has in its favor simplicity of design and manufacture and ease
of replacement, which can be done in the field. On the other hand,
spring recoils have many breakages and greater weight combined
with a high replacement of weakened springs, the life varying from
3000 to 8000 rounds.
The air school has in its favor a high order of efficiency—smoother
action, general all around efficiency and less weight. But the air
recuperator is difficult to manufacture, costly, and when damaged
must go to the rear to be repaired; which, however, it seldom needs.
In mounting the spring recuperator, the most recent practice has
separated the recoil mechanism from the springs in order to
distribute the piston rod pull, thus preventing whip and allowing easy
access to the various parts for replacement, refilling and repairs. In
order to lower the center of gravity, the gun is slung under the recoil
cylinder with the two spring recuperators below and on either side.
Air recuperators are invariably located below the gun for protection
and because of their large size and shape, which adapt them for
attaching the elevating mechanism.
BATTERY OR FIRING POSITION
IN-BATTERY OR FIRING POSITION
HYDRO-SPRING RECOIL SYSTEM
HYDRO-PNEUMATIC RECOIL SYSTEM WITH FLUID IN DIRECT CONTACT
WITH THE AIR
In either system, the recoil is taken up by means of oil or glycerine

and water passing through an orifice created by a slotted piston
passing over ribs of varying height, or through a valve on the
pressure side of the piston, or by a solid or perforated piston passing
through a perforated intermediate cylinder.
The latter type is particularly adapted to variable recoil guns as the
intermediate cylinder can be rotated, thus throwing varying orifices
into position for the flow of oil.
Counter recoil is accomplished by the springs or by the air
pressure in the hydro-pneumatic system, in which the air pressure is
sufficient to hold the gun in battery at all elevations and is built up at
recoil.
In all counter recoil systems, it is necessary to insert a buffer to
take up the remaining energy of the springs or air pressure so as to
bring the gun into battery without appreciable jar. Numerous types
have been developed and perfected.
The counter recoil brake or buffer in our 3”-gun is a slightly
tapered bronze rod, tightly fitting in the cylindrical bore of the piston
rod. The retardation caused by forcing the oil in the piston rod out
through the small clearance between the buffer and bore of the
piston rod eases the return to battery without jar to the gun, which
has been forced back by the counter recoil springs.
The physical law that action and reaction are equal has a peculiar
emphasis when applied to the firing of a piece of high powered
artillery. The force exerted to throw a heavy projectile 7 miles or
more from the muzzle of the gun is toward the breech of the weapon
in its recoil. How some of these forces are handled safely and easily
by mechanical means are almost beyond the mind’s grasp. Not long
ago a touring car, weighing two tons, traveled at the rate of 210 miles
an hour along a Florida beach. Conceive of such a car going 337
miles an hour—which is much faster than any man ever traveled;
then conceive of a mechanism which would stop this car, going
nearly six miles a minute, stop it in 45 inches of space and one-half a
second of time without the slightest damage to the car. This is
precisely the equivalent of the feat performed by the recuperator of a
heavy howitzer after a shot.
SHIELDS.
Although cover for the cannoneers had been used off and on since
the invention of guns, it had fallen into disuse until it was firmly
established as an essential feature by the French on their 75-mm in
1897. All modern field guns have such protection both for the
cannoneers and for the delicate parts of the material which would be
damaged by shrapnel balls or shell fragments. The shield is made of
hardened steel capable of withstanding the impact of a bullet of a
service rifle at a 100 yds. range at a standard velocity. For
convenience the shield is divided into three parts known as the top
shield, main shield and apron, with suitable ports equipped with
shutters for the line of vision from sights. The main is fastened to the
axle and is rigid. The apron is hinged to the main shield or the axle-
swinging forward for the traveling position. The top shield is fastened
to the main shield by hinges and swings forward and downward for
traveling position.
SIGHTS.
The sights serve three important functions. They improve the
vision of the gunner and lay the gun in elevation and direction. The
simplest sight is the one over the line of metal which lays for
direction only, the second is the tangent sight mounted on a range
arc centered on the axis of rotation in elevation usually having a
deflection scale to correct for drift and to lead the moving target. This
unit lays for range and direction. The last sight is the telescopic or
panoramic sight which is mounted on a range arc and lays for
direction only, it is the unit for indirect fire, laying for direction, and
markedly improving the vision of the gunner. The latest model of the
American panoramic sight is superior to any in existence.
For precision in indirect fire, practically all carriages are equipped
with some form of range quadrant, containing a means of setting off
the angle of site and the range angle. All instruments are equipped
to compensate for difference in wheel level. The British carriage
automatically corrects for deviation, simplifying the firing date by that
element.
WHEELS.
The height of the wheels affects the draft, weight, clearance, and
stability of the carriage both as to road stability—i. e., low center of
gravity; and firing stability—i. e., the overturning movement about the
end of the trail. It is now believed that entirely too much stress has
been laid on road clearance. Reducing the height of wheel reduces
the weight and road clearance, lowers the center of gravity and
increases the firing stability; but it also reduces the angle of gun
elevation unless the trail is shortened. Firing stability in general is
increased by adding to the weight of the gun, lengthening the recoil,
slinging the gun as low as possible and lengthening the trail. The
less the height of the wheel exceeds four feet the better, despite the
poor draft feature, which is compensated for to some extent by a
reduction in weight and turning radius.
AXLES.
Axles are straight or of the offset type. The straight axle is stronger
for its weight. The drop axle allows the center of gravity to be
lowered.
TRAILS.
Most modern trails are of the sectional built-up type. Some,
however, are of tubular and telescopic. The most variable portion of
the trail is the spade. It consists of two parts, the spade proper and
the float. The former prevents recoil, the latter the burying of the trail.
The spades proper are of three types: the fixed, as in the French 75-
mm; semi-fixed, as in the 155-mm howitzer; and driven, as in the
Deport and American 1916 75-mm. Each has advantages and
disadvantages. The driven spade is considered essential for the split
trail carriage, as the latter has no means of seating itself; and should
one spade take, and not the other the carriage might be damaged
when the gun is fired at an extreme traverse.
Split trails introduced a novelty in field gun carriages, in that a
compensating device became necessary to adjust for the difference
in ground level of the two spades.
CONCLUSION.
Guns are designed to function in a certain way. They are not
temperamental. They follow absolutely and certainly fixed
mechanical laws. If they fail there is a reason and it can be
remedied. Certain parts are given certain shapes and forms, are
machined to nice adjustments, and in taking down and assembling
them, brains and dexterity are the tools to use rather than force and
sledge-hammers. Learn from your text when and how to apply force
and above all when not to use it. Treat these guns as you would a
friend on whom you know you can depend. They will not fail you.
CHAPTER IV
MODERN ARMAMENT.
THE ARTILLERY OF A FIELD ARMY; ITS

FUNCTIONS.
The artillery assigned to a field army should be of such mobility,
power, variety and number as to insure the success of its purpose
and to enable this success to be gained with the minimum of
casualties. The latter point must receive careful consideration in
studies of organization, for without adequate artillery preparation and
support the successes of the most gallant infantry can in a series of
actions become little more than pyrrhic victories. Many actions of our
divisions in France resulted in casualties whose numbers decreased
in proportion to the number of guns with which divisions were
supported. The proportion of guns to the thousand gross strength of
infantry, cavalry, and machine guns adopted by the armies of the first
class powers before the opening of the present European War in
1914 was:
British, 6.8; French, 4.6; German, 6.4; American 3.2 (Greble
Board).
During the war this proportion was constantly increased until at the
close under conditions of position or entrenched warfare it was
between 8 and 12 per thousand; this varied of course with the
activity in different sectors. In quiet sectors and under conditions of
maneuver, or open warfare, which necessitated leaving much
artillery behind, it was about 6 per thousand.
A program of types of artillery weapons should be founded on the
object and the means—that is, the destruction of the target and the
projectile to accomplish this. In the study of an artillery program there
are two methods of approaching the subject. First, by starting with a
minimum weight of projectile and working up to a reasonable
maximum, according to some law and taking the corresponding
calibers, a theoretical series of guns and howitzers can be
expressed. For instance, if the law be doubling the weight of the
projectile the series of types could be:
Projectile of 13 pounds, caliber 3”.
The second and more logical method, and one followed in our
service, is to consider the artillery missions and determine the types
best suited irrespective of any theoretical series of weights and
calibers. However, in the discussion of artillery missions and the
proper types for their fulfillment there is a remarkable degree of
unanimity of thought on these subjects; and the above table actually
contains, with slight variations, the types that are most strongly
recommended. While granting the great variety of artillery missions
that often shade into each other, it is believed that they can best be
considered in three great classes that follow the tactical composition
of a field army: those of division, corps and army artillery.
DIVISION ARTILLERY.
Missions. The division artillery, first of all, must have the mobility
that will permit it to accompany the infantry of a division and the
maximum power consistent with that mobility; its object must be
primarily the infantry of the opposing division. It is therefore bound to
its own infantry with the closest bonds and its tactical use cannot be
separated from that of the infantry. The division artillery must fire,
accurately, a man killing projectile and be prepared for quick
changes of targets; it must have a great range because of depth,
both of its own and the enemy division; it must continually harass the
enemy, prevent his movement and force him into cover or protected
trenches. On the defensive it must break up the opposing infantry
formations by preparing a counter-offensive fire and by annihilating
fire on points from which the enemy attacks emerge; and, failing in
these, be prepared to use the barrage and shrapnel fire at close
range. In the offensive the division artillery must play its part in the
complex schemes of artillery preparation by cutting wire, destroying
machine gun nests, gassing areas, concentrating on infantry
positions and taking the principal part in the deep barrage that
should precede the infantry attack. Its fire, accompanying the infantry
movement, requires its own movement and by its mobility it often
becomes for some time the sole artillery protection in the preparation
and holding of a position which has been taken.
Light Gun and Howitzer. The consensus of opinion of artillery
officers is that the division artillery missions are best fulfilled by a
light field gun and a light field howitzer having a range of at least
11,000 yards. While differing in mechanical features, the field guns of
the different European countries are practically of the same type
and, though constant effort is being made to improve details, they
can be stated as generally satisfactory to their own governments and
not liable to any radical changes. The general type of field gun, while
capable of fulfilling most of the division artillery missions, must be
supplemented by a proper howitzer. There are many instances
where the terrain or the lay of the land offers such protection to the
infantry that the field gun cannot bring an effective fire. The howitzer
has the great advantage that with the proper set of propelling
charges and, therefore, choice of trajectories for the same range,
protected positions can be chosen for howitzers that guns could not
use, and angles of fall obtained on objectives that the normal
ammunition of guns would not give. The low muzzle velocity of
howitzers admits of their almost continuous use in harassing fire and
allows the use of a projectile double the weight of that of a field gun.
Such a howitzer renders excellent service in wire cutting and is a
useful projector of gas shells. To insure the mobility required of all
divisional artillery the weight of the howitzer and carriage should not
exceed that of the field gun, or about 4,500 pounds.
Light Gun Discussion. The consensus of opinion of all artillery
officers—French, English and American—is that the 75-mm gun, or
approximately this caliber, firing a 15-pound projectile or a projectile
of approximately this weight, and having a range of not less than
11,000 yards, is a satisfactory weapon at the present time for use
with the division artillery. The projectile in question, whether a
shrapnel or a high explosive shell, satisfies adequately the criterion
of man-killing. At the close of the war the nations were not entirely in
accord with respect to their conception of an up-to-date carriage for
a light field gun. All the nations whose tendencies have been
considered in this report have experienced to a varying degree with
field gun carriages, particularly in a desire to design a carriage
permitting a greater angle of elevation and greater movement of the
gun in the traverse. The Italians have expressed themselves in the
modified Deport Carriage; this vehicle is of the split trail type and
permits an elevation in excess of 75 degrees, and a traverse on
each side of the center of the carriage of about 20 degrees—about
356 mils. Up to the time that the board left France it was not possible
to learn the French decision in the matter of a split trail carriage for
their light field gun. It is known, however, that several types of this
carriage have been designed and tested; it is known, also, that
considerable favor has been found with the American 1916, which
type has been tested under the auspices of the French Government.
In England, however, the board was not able to develop any
enthusiasm for the split trail type, although the matter had been
seriously considered. In that country the up-to-date field gun carriage
appears to be adequately expressed in their new 18-pounder. The
vehicle upon which this gun is mounted permits an elevation of 37
degrees and an axle traverse of 4½ degrees on each side. The trail
is a box trail and the carriage is simple and steady in its construction
and lends itself to rapid production.
Motorization. At some time in the future it is probable that all the
division artillery will be motorized. The result of such a change in the
prime mover would be to remove the present restriction as to weight
of gun and carriage. The board senses a demand in the near future
for a light field gun having a maximum range of approximately
15,000 yards; such a range may be achieved by increasing the
muzzle velocity and, perhaps, the weight of the projectile, although
change in the form of projectiles will give some improvement over
the present ranges. It is probable that the limiting features in the
design of field guns of the future will be the requirement that it should
pass safely over temporary pontoon bridges and that the weight and
form and size of ammunition must be such that the present rate of
fire will not be slowed down. The board is of the opinion that, except
as to perfection of details, the limit of carriage design, as expressed
by the most modern type of box-trail and split-trail carriages, has
been reached; and feels that with the advent of motor transportation
the tendency will be toward a gun mounted on a self propelling
carriage and expressing the desires of the field artillery with respect
to maximum horizontal and vertical arcs of fire.
Light Gun. Ideal. A gun of about 3” caliber on a carriage
permitting a vertical arc of fire of from 5 degrees depression to 80
degrees elevation and a horizontal arc of fire of 360 degrees; a
projectile weighing not over 20 pounds, shrapnel and high explosive
shell of satisfactory man-killing characteristics with maximum range
of 15,000 yards; fixed ammunition, smokeless, flashless propelling
charge; time fuse for shrapnel. With shell having safe fuses with
different lengths of delayed action after they land. The high explosive
shell should be of one type only. Two propelling charges should be
furnished, a normal charge for about 11,000 yards range and a super
charge for maximum range. The proportion should be 90% of the
former and 10% of the latter. A maximum rate of fire of 20 rounds per
minute is deemed sufficient.
Light Gun. Practical. For the present, arm brigades with 75-mm
materiel. Models 1916, 50%, and 1897 (French), 50%.
Transport. Ideal. Mechanical transport is the prime mover of the
future. The introduction of mechanical transport will undoubtedly
cause far-reaching changes in the types of gun carriages. It is not
possible now to state just how far this will go or whether a gun
mounted on a self propelled vehicle or one mounted on some type of
trailing vehicle will be the final result. Both types may be necessary.
It is urgent that study and development be carried along these lines,
as we are on the verge of changes fully as radical as the introduction
of the long recoil field gun and carriage, and the country first utilizing
the new capabilities opened up by mechanical traction and the
caterpillar will have a great advantage in the next war. A limit of
4,500 pounds behind the team has heretofore been imposed on the
artillery of this class. The corresponding limit in the future will
probably be that imposed by pontoon bridges.
Transport. Practical. Therefore it is thought that four regiments of
75-mm guns (two regiments of French Model 1897, and two
regiments of U. S. Model 1916) should be immediately equipped with
motors, the remainder to be horsed; mechanical transport to
gradually replace horse only after the tractor demonstrates its
superiority in service.
Light Howitzer Discussion. The consensus of opinion of
American army officers consulted is that a howitzer about 4” in
caliber, firing a projectile weighing from 25 to 30 pounds at a
maximum range greater than 10,000 yards, is required. This opinion
is concurred in by the French, Italians and English, and it appears to
be definitely established that the mobility of the light field howitzer
should be practically the same as that of the light field gun. The
British army was equipped with a 4½” howitzer, firing a projectile
weighing 35 pounds and with a maximum range of 7,700 yards; the
weight of the howitzer limbered is 4676 pounds—150 pounds more
than the weight of the 18-pounder field gun. No evidence was found
that the British Government intended making any alterations in the
design of this howitzer; naturally they will attempt to increase the
range, power and accuracy of the projectile by change in its weight,
its capacity and its form. The French artillery was not equipped with
the light field howitzer of approximately the same weight as the 75-
mm field gun. During the war it was found impracticable to construct
a lighter howitzer without interfering with the production of other
calibers which were considered more important. In the earlier stages
of the war the Italian artillery was not equipped with a light field
howitzer; however, before the end of 1917 orders were placed for
several hundred howitzers of the 105-mm type. It should be noted
that several hundred howitzers of this caliber were being constructed
before the armistice and that many have been captured from the
Austrians by the Italians; this, so far as the Italians were concerned,
makes it certain that a light field howitzer will be furnished by the
Italian army. The German and Austrian armies were equipped with a
howitzer of the light field type; this weapon had a caliber of 105-mm
type.
It fired a projectile weighing 34.54 pounds at a maximum range of
10,500 yards. (Streamline shell.) The weight of the howitzer limbered
was 4,500 pounds. In the opinion of the board, the Germans have
proceeded on sound principles in their development of the light field
howitzer. Their ’98 model was a companion piece to their ’96 field
gun and in the years that passed from 1898 to 1916, which included
their early war experience, they kept to the idea of the relation of the
two pieces even to the extent of including in a field artillery regiment
one battalion of light howitzers. Their 1916 models of both light gun
and howitzers show the endeavor to keep the pieces in the same
class; that is, the weight of the gun and howitzer in action nearly the
same, 2,750 pounds and 2,700 pounds; the weight of the gun
limbered and the howitzer limbered are the same, 4,500 pounds; the
elevation of both the same—minus 10 to plus 40 degrees; the
carriages are of the same type; and the extreme ranges of gun and
howitzer are respectively 11,700 and 10,500 yards. From the
foregoing it is seen that all the important belligerents except the
French and the Americans were equipped with a light field howitzer
firing a projectile about twice the weight of the light field gun
projectile and having otherwise the same general characteristics.
There is no evidence to show that the fire of the French and the
American artillery was not fully effective as that of any other artillery;
however the testimony of the French and American artillery officers
is to the effect:
(a) That the lightest howitzer in use, i. e., the 155-mm, was not
sufficiently mobile to be a suitable companion piece for the 75-mm
gun.
(b) That many times the fire of the 75-mm gun proved ineffective
due to its flat trajectory; a howitzer would have been more effective
in the attack of certain targets.
(c) That a large volume of fire is necessary.
(d) That while the 155-mm howitzer is more powerful than the light
field howitzer its consumption of ammunition for many purposes is
wasteful and extravagant and its volume of fire is insufficient.
(e) That the light howitzer is particularly suited for the destruction
of wire entanglements; its better accuracy and more powerful
projectile make it more suitable than the field gun for that purpose.
(f) That the 75-mm field gun projectile is not so satisfactory a gas
shell as the howitzer projectile which has greater weight.
Light Howitzer. Idea. A weapon of about 105-mm caliber on a
carriage permitting a vertical arc of fire from minus 5 degrees to plus
65 degrees, and a horizontal arc of fire of 360 degrees. Efforts
should be made to develop a carriage which can be used
interchangeably for the division light gun referred to above and this
howitzer. The projectile should weigh about 30 to 35 pounds and
should include both shell and shrapnel. A maximum range of 12,000
yards will be satisfactory. Semi-fixed ammunition with varying
charges should be used, otherwise the ammunition should be similar
to that provided for the 75-mm guns.
Light Howitzer. Practical. For the present, the division should be
armed with the 155 howitzer, Schnieder, but active development and
test should be made on a type as stated under “Ideal” above, and
with the ammunition and other accessories to it. Upon the
development of the carriage as nearly approximating the ideal as
may be practically possible, efforts should be made to secure
quantity production in order that it may be incorporated in the
division as recommended. In addition, a split trail carriage for this
howitzer should be developed.
Transport. The light howitzer should have the same means of
transport as the light field gun and the same remarks heretofore
made as to the probable future development of the field gun also
apply to the howitzer carriage.
CORPS ARTILLERY.
Missions. It will be noted above that the division artillery missions
did not include their own protection against the enemy artillery. This
counter-battery work is the principal mission of the corps artillery.
The corps artillery has also the mission of extensive harassing and
interdicting fire along the corps front and to a greater depth than the
capabilities of the division artillery; also of destructive fire on strong
points as well as on railroad facilities and points of supply. For the
accomplishment of these corps artillery missions there are two types
of artillery necessary, a gun and a howitzer, each having 16,000
yards range and each weighing with the carriage about 11,000
pounds. There is another class of artillery called anti-aircraft artillery
to be considered. This is used first in providing anti-aircraft defense
for army zones, for certain areas in rear of armies or along a certain
line of anti-aircraft defense.
Medium Gun Discussion. The consensus of opinion of artillery
officers—Italian, English and American—is that a medium gun of
about 6” caliber is necessary. The medium type gun furnished to the
American army was the 4.7 (Model 1906). This gun has a maximum
elevation of 15 degrees with a corresponding maximum range of
8,750 yards. The British army was equipped with the 5” gun—the
carriage permits a maximum elevation of 21 degrees and 30
minutes, giving a maximum range of 12,500 yards. The French army
was equipped with, to a certain extent, the 105-mm and the 140-mm
gun. The 105-mm gun a maximum elevation of 37 degrees, with a
maximum range of 13,900 yards. The 140-mm gun has a maximum
elevation of 30 degrees and, with a high velocity, has a maximum
range of 19,500 yards. The French 105-mm gun is a modern
weapon (1913). The German artillery was equipped with a 105-mm
gun (M-1917) with a maximum elevation of 45 degrees, and a
maximum range of 16,000 yards. The German army was also
equipped with the 130-mm gun, having a maximum range of 16,500

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HDL Metabolism and

Advances in Clinical Chemistry, Volume 65 # 2014 Elsevier Inc. 1

Apo A-I (MW: 28 kDa) is the major structural apolipoprotein of HDL

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HDL is mostly assembled in the plasma by lipidation of apo A-I secreted by

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CETP activity is dependent on both its concentration and ability to

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carotid intima-media thickening in patients with familial hypercholesterol-

In either system, the recoil is taken up by means of oil or glycerine

THE ARTILLERY OF A FIELD ARMY; ITS

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