![1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV
2
historical descriptions is the finding of the unusual natural transmission
of Mycobacterium leprae and Coccidiodes immitis infections in one of the nat-
ural hosts of SIV (sooty mangabey, a species from West Africa) [1–4]. Thus,
a sooty mangabey was found to spontaneously acquire M. leprae infec-
tion and when tissues from this animal were injected into other mang-
abeys, the recipients developed a lepromatous form of M. leprae, which
was at the time touted as the first description of a non-human primate
(NHP) model to study human leprosy and a major advance in the field
of leprosy research. The finding of C. immitis infection coupled with the
M. leprae infections unique to this species prompts the obvious question
as to whether the presence of the SIV infection of this natural host makes
this species uniquely susceptible or whether the immune system of this
species has evolved to confer this unique susceptibility to such microor-
ganisms. This issue still remains to be addressed.
This interesting historical perspective is followed by a chapter on the
prevalence and molecular epidemiology of SIVs in the wild, with the use
of innovative sequencing techniques that facilitate the understanding of
the evolution of these viruses. In addition, it is clear from this chapter
that it is likely that >90% of the approximately 70 Old World NHP species
in Africa are likely to be infected with species-specific SIVs, but we have
knowledge of only 45 such species. It is also clear from this and other
chapters that both SIV and the NHP species that harbor such viruses have
co-evolved, and adaptation is one of the key elements that need to be rec-
ognized. A cautionary note was also expressed by the authors with regard
to the pathogenicity of SIVs in natural hosts, citing the more recent studies
of the evidence for pathogenicity of SIVcpz in chimpanzees in the wild.
Thus, the blanket statement of disease resistance of natural hosts of SIV
that are being raised in captivity at the various primate centers needs to
be punctuated with the realization that detailed studies of its potential
to cause disease in the wild in the same natural hosts are lacking at pres-
ent. The idea being conveyed here is that there is likely to be continued
evolution of both SIVs and the natural hosts that results in survival of
only those within the species that co-evolve mechanisms that protect them
from developing disease.
Along similar lines, the book includes a chapter devoted to SIVcpz in
chimpanzees, with a more detailed description of the various chimpanzee
species and the characterization of viruses from such species. The authors
describe the differences and similarities between other natural hosts of SIV
and the SIVcpz that infects chimpanzees. As cautioned above, while the
previous paradigm predicated that the chimpanzees have been infected
for thousands of years and are to a large extent disease resistant, emerging
data have questioned this view. Thus, based on the fact that there is evi-
dence for pathogenicity of SIVcpz infection of chimpanzees, the argument
that transmission of SIV in this species is a more recent occurrence has](https://image.slidesharecdn.com/1435-250620164535-6e76dcf1/85/Natural-hosts-of-SIV-implication-in-AIDS-1st-Edition-Aftab-A-Ansari-12-320.jpg)
![1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV
4
expands on the overall concepts laid out in the previous chapter by out-
lining all the cellular characters that are involved in the dialogue between
the pro- and anti-inflammatory effects of the host immune system, with a
focus on those that are functional at the mucosal interface. Thus, the basic
tenets of this chapter are that natural hosts have developed a remarkable
array of regulatory mechanisms that can dampen/mute proinflamma-
tory responses and maintain homeostasis. It is clear from the gist of this
chapter that these unique regulatory mechanisms that have been acquired
by the natural hosts of SIV are the ones we need to exploit and target as
part of novel therapeutic strategies aimed to minimize the damage that
SIV (and, by implication, HIV) mediates against the gut mucosa. A related
chapter with regard to the mechanisms by which the natural hosts protect
themselves from the development of disease is the important finding of
differences in the phenotypically defined subset of cells that SIV targets in
the natural hosts. Thus, the findings outlined in this chapter suggest that
the natural hosts best studied so far, which include the sooty mangabeys
and the African green monkeys (AGMs), each have naturally evolved a
set of mechanisms that modulate the major receptors for SIV and promote
the infection of a subset of cells that are more dispensable for the host.
This deviation allows for the survival and function of the subset that is
critical for the host to maintain antigen-specific recall responses, immune
homeostasis, mucosal barrier integrity, and, importantly, lymphoid tissue
architecture [5]. Obviously, more detailed studies are required in efforts
to exploit this finding for therapeutic purposes because it is not clear how
this deviation evolved in the natural hosts over the millennia and is in fact
mediated at the molecular level. Once again, it does appear that the mech-
anisms are species specific; and thus, while there is a common endpoint
(disease resistance), the pathways are quite distinct, which can be viewed
as hurdles or can be viewed as multiple targets available for identifying
therapeutic strategies.
The next few chapters sequentially deal with the characteristics of the
innate and acquired humoral/cellular responses; each chapter covers not
only the subtle differences in the phenotype of cell lineages that execute
these functions, but also how these functions differ between the natural
hosts and the non-natural hosts of SIV. Acomprehensive description of the
various cell lineages that comprise the innate immune system and their
role in either influencing the quality and quantity of virus-specific immune
responses or regulating viral loads is described. Among the highlights of
this chapter is the description of the role of the plasmacytoid dendritic
cells (pDCs), whose trafficking from the periphery to the gut tissues and
their subsequent accumulation within the gut was shown to lead to high
levels of IFN-α in the non-natural hosts, associated with disease progres-
sion. On the contrary, such trafficking of pDCs in the natural hosts was
found to be transient following acute infection. These findings suggest a](https://image.slidesharecdn.com/1435-250620164535-6e76dcf1/85/Natural-hosts-of-SIV-implication-in-AIDS-1st-Edition-Aftab-A-Ansari-14-320.jpg)
![Overview 5
potentially important difference in the role of pDCs in natural versus non-
natural hosts. The coincident depletion of Th17/IL-22 synthesizing cells,
also uniquely in the SIV-infected non-natural but not the natural hosts,
suggests perhaps a linkage between these two events. Attempts to convert
the infection and disease profile of natural hosts to that of non-natural
hosts with the administration of IFN-α to promote innate immune signal-
ing, however, while inducing a transient increase in the activation of CD8+
T cells, failed to show CD4+ T-cell depletion and showed no major effects
on viral loads. An opposite strategy with the use of TLR7/9 antagonist
to block IFN-α signaling in SIV-infected non-natural hosts not only had
no effect on the depletion of CD4+ or CD8+ T cells, but—of interest—did
not affect the expression of interferon-stimulating genes, suggesting that
such manipulations in vivo perhaps are not effective because they do not
function individually and/or they represent a downstream event. Simi-
larly, attempts to administer lipopolysaccharides to the SIV-infected natu-
ral hosts to mimic the effect of microbial translocation in the non-natural
hosts induced a transient increase in plasma viral loads but did not lead to
disease, suggesting either that such manipulations do not faithfully rep-
licate the conditions noted in the non-natural hosts or that the disease-
inducing events are complex and require multiple system manipulations.
Another cell lineage that appears to be important is the innate lymphoid
cells (unique lineage only present in gut tissues). Their depletion/absence
in the SIV-infected non-natural hosts but continued presence in the
natural SIV-infected host, coupled with a role of these cells to maintain
Th17/IL-22 in the gut mucosa, prompts the need for further detailed
study of this difference. Of interest are the studies on the role of NK cells.
Depletion studies during acute infection using either in vivo depleting
antibodies or the use of a JAK3 inhibitor while showing varying levels of
depletion of this cell lineage failed to show any major difference in viral
loads. However, depletion of NK cell lineage using the JAK3 inhibitor dur-
ing acute infection did appear to influence plasma and cellular viral loads
during chronic infection by an as-yet-unidentified mechanism [6]. A role
of this cell lineage in mediating ADCC activity and to serve as enhanc-
ers of immune responses by adjuvants has also been highlighted in this
chapter. In all, it appears that much has yet to be learned on the role of the
innate immune network on influencing the course of disease in the natural
and non-natural hosts of SIV.
A summary of the humoral anti-SIV response in the natural host with a
focus on the sooty mangabeys and a comparative analysis of the antibody
response between sooty mangabeys and rhesus macaques is outlined in
the next chapter. To a large extent, it appears that natural SIV hosts do
not mount a robust virus-specific neutralizing antibody response and
the elimination of B cells in the natural hosts does not lead to increases
in plasma viral loads. While the author is clear that these are not likely](https://image.slidesharecdn.com/1435-250620164535-6e76dcf1/85/Natural-hosts-of-SIV-implication-in-AIDS-1st-Edition-Aftab-A-Ansari-15-320.jpg)
![1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV
10
2.
Role of “founder viruses”: The fact that sexual transmission of HIV-1
involves the transmission of only a single or a select few viral species,
leading to the term “founder viruses,” clearly prompts us to determine
whether this is also true in the natural hosts of SIV. Within this context,
it is important to perform these studies not only in the natural hosts
raised in captivity but also in those in the wild, a topic not easy to study.
In addition, the role of “env glycosylation” in viral transmission in the
natural versus the non-natural hosts and in MCT studies between the
natural and non-natural hosts needs to be addressed.
3.
Differences among various species of natural hosts: Another issue that
is important to keep in mind is that there are differences in the
immunological and virological findings even among the various
natural hosts of SIV, which requires one to analyze the data obtained
within this context. Thus, the mechanisms of transmission may differ
among each natural host of SIV and the findings from one species
may not be amenable to extrapolation. This subject is also discussed in
detail in several chapters.
4.
Gastrointestinal dysfunction: Reports of severe gastrointestinal
dysfunction with villous atrophy and crypt cell proliferation in
SIV-infected macaques and HIV-1-infected humans in the early
1990s established the occurrence of gastrointestinal pathology in
SIV- and HIV-infected individuals [7,8]. While initial SIV infection
of both natural and non-natural hosts leads to the same degree
of gastrointestinal pathology (with enteropathy and intestinal
permeability) during acute infection, this pathology is largely
reversible in disease-resistant natural hosts but irreversible in non-
natural hosts [9]. Notably, administration of antiviral therapy to
macaques as early as 1 week post infection did not influence the
loss of CD4+ T cells in the gut tissues but enhanced rapid restoration
with memory CD4+ T cells [10]. The data show that during the early
stages of infection there is not only a massive loss of CD4+ T cells
but also the apoptosis of epithelial cells that line the small and large
intestines of untreated SIV-infected macaques, which is likely to be a
driving force for gastrointestinal pathology [10]. Select studies have
documented the loss of Tregs [11] and Th17cells in the mucosal tissue
[12] of SIV infected macaques but not sooty mangabeys [13]. These
studies have been followed by the introduction of the concept of
microbial translocation [14] as a mechanism to explain the differences
in the outcome of SIV infection between natural and non-natural hosts
(discussed in several chapters). Attempts to use gene profiling [15]
and investigation of the dysfunction of the intracellular molecular
pathways in SIV-infected macaques have been performed [16,17].
However, the factors that lead to regeneration and reconstitution
of gastrointestinal tissues in the natural but not non-natural hosts](https://image.slidesharecdn.com/1435-250620164535-6e76dcf1/85/Natural-hosts-of-SIV-implication-in-AIDS-1st-Edition-Aftab-A-Ansari-20-320.jpg)
![Overview 11
require further investigation. Future studies should examine intestinal
dendritic cells that are involved in polarizing anti-inflammatory
responses inducing tolerance, gut-homing NK cells, and progenitor
stem cells that give rise to gut epithelial cells [18]. In addition, it is
possible that more knowledge of the proteins involved in regulating
intestinal permeability and intestinal epithelial regeneration,
particularly in the natural hosts of SIV, may pave the way for
identifying novel therapeutic strategies for HIV-infected humans.
5.
Models that attempt to explain the divergent clinical outcome of SIV
infection in the natural versus the non-natural hosts:
a.
Role of immune activation.
Although the contribution of CIMA to disease progression in HIV-
infected humans and SIV-infected non-natural hosts is a reasonable
and logical hypothesis, the lack of significant CIMA is probably not the
only mechanism underlying the distinct clinical outcome in natural
hosts. This view is supported by our finding that hyperimmunization
of a cohort of six SIV-infected sooty mangabeys at weekly intervals
for 12months sequentially with adjuvant-incorporated KLH,
tetanus toxoid, a mixture of allogeneic cells, and intranasal exposure
to immunogenic doses of influenza virus led to marked increases in
the frequencies and absolute numbers of in vivo activated CD4+ and
CD8+ T cells. Such levels of experimental immune activation of the
natural host did not induce detectable disease or a major increase in
plasma viral loads. These findings suggest that it may be the quality
and/or differences in the consequences of CIMA that play a role in
the different outcomes of SIV infection in the natural versus the non-
natural hosts of SIV. The experimental manipulation of the natural
host that leads to CIMA, which results in progression to disease, is
required to underscore the role of CIMA in disease progression.
b.
Role of host accommodation.
The symbiotic relationships that can exist between a vertebrate
host and certain microorganisms were first acknowledged
many years ago [19]. There are numerous examples in nature,
highlighted by the relationship between host and microbe within
the gastrointestinal tract under normal physiological conditions.
There is no detectable immune response against foreign organisms
at this site. Microorganisms establish a symbiotic relationship in
a natural host, in which it is not pathogenic, but when they infect
another species, they cause pathologic effects. For example, the deer
mouse is the natural host for the Hantaviruses, which often cause a
fatal disease in humans termed Hantavirus pulmonary syndrome.
The infected mice carry high levels of the virus in their respiratory
tract and have antibodies against the virus, but they have a normal
lifespan [20]. Herpes B virus, which causes a fatal encephalitis in](https://image.slidesharecdn.com/1435-250620164535-6e76dcf1/85/Natural-hosts-of-SIV-implication-in-AIDS-1st-Edition-Aftab-A-Ansari-21-320.jpg)
![1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV
12
humans, is commonly found in 70% of rhesus macaques, and 80%
of those that are infected also have detectable antibodies and remain
healthy. However, the mechanisms that underlie the accommodation
of such pathogenic organisms by their natural hosts, and the disease
resistance of the hosts, remain largely undefined. It is of importance to
note that the “MAJOR” decision making tissue site involved in recognition
of self versus nonself is at the gastrointestinal/liver intersection and the liver
in essence could be playing the critical role in dictating host/virus outcome
in the natural versus the non-natural hosts of SIV. The potential pathways
that result in polarized outcomes as a consequence of viral infection
resulting in viral clearance versus virus induced pathology (death)
are by reason distinct from those that result in chronic infection and in
turn the consequence of chronic infection range from slow progressive
disease (non-natural hosts) and a lack of detectable disease (natural
hosts) that is associate with host accommodation is depicted in
Figure 1.3. The question arises as to whether we can harness knowl
edge of how such “natural” host adaptation occurs and then attempt
to “experimentally” induce such host adaptation between HIV and
humans to limit the development of immunodeficiency disease.
It is of interest to note that in fact there have been numerous
examples of such “experimental” adaptation of host and foreign
microorganisms or antigens. Thus, the field of organ transplanta-
tion has provided us with a plethora of such examples. The term
“host accommodation” [21–23] refers to successful engraftment of
an organ or tissue in an allogeneic host in the presence of readily
detectable antibodies against the donor tissue. In a general sense,
host accommodation (HA) involves the induction of a coordinated
series of biological changes in the host that enable donor cells and
tissues to persist in the presence of antibodies against donor anti-
gens recognized as foreign by the host. The successful transplanta-
tion of ABO-incompatible donor organs in hosts that have high
level of anti-AB antibodies is a good example of such HA. Thus, a
similar relationship likely exists between SIV and its natural hosts
in that the host lives a normal healthy life with the foreign antigen
in the presence of readily detectable levels of antiviral antibodies.
We propose that host accommodation could be a viable
explanation for the absence of pathogenic disease in natural NHP
hosts of SIV. We propose that the trafficking of NK cells and select
subset of dendritic cells to the gastrointestinal tract during acute
SIV infection in the presence of a low frequency of CD4+CCR5+
cells regulates the level of inflammation and creates a Th2-like
environment that could contribute to the host accommodation in
natural hosts. This symbiotic host–virus relationship leads to readily
detectable antibodies and persistent viremia, but no overt pathology.](https://image.slidesharecdn.com/1435-250620164535-6e76dcf1/85/Natural-hosts-of-SIV-implication-in-AIDS-1st-Edition-Aftab-A-Ansari-22-320.jpg)
![References 17
immune response tolerance maybe difficult to achieve, we submit that
therein lies one of the challenges for the formulation of an effective HIV-1
vaccine.
Acknowledgments
Supported by NIH NIAID RO1 AI078773 and AI098628 (AAA).
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Takahashi Y, Byrareddy SN, Albrecht C, Bremeier M, Walter L, Mayne AE, et al. In vivo
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Brenchley JM, Douek DC. The mucosal barrier and immune activation in HIV patho-
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[14] Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial
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18
[15] George MD, Verhoeven D, McBride Z, Dandekar S. Gene expression profiling of gut
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[16] Lackner AA, Mohan M, Veazey RS. The gastrointestinal tract and AIDS pathogenesis.
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[17] Mohan M, Aye PP, Borda JT, Alvarez X, Lackner AA. CCAAT/enhancer binding pro-
tein beta is a major mediator of inflammation and viral replication in the gastrointes-
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[18] van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal
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[19] Lyte M. The microbial organ in the gut as a driver of homeostasis and disease. Med
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[20] Easterbrook JD, Klein SL. Immunological mechanisms mediating hantavirus persis-
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[21] Bach FH, Hancock WW, Ferran C. Protective genes expressed in endothelial cells: a
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[22] Soares MP, Lin Y, Sato K, Stuhlmeier KM, Bach FH. Accommodation. Immunol Today
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[23] Tang AH, Platt JL. Accommodation of grafts: implications for health and disease. Hum
Immunol 2007;68:645–51.](https://image.slidesharecdn.com/1435-250620164535-6e76dcf1/85/Natural-hosts-of-SIV-implication-in-AIDS-1st-Edition-Aftab-A-Ansari-28-320.jpg)
![Natural Hosts of SIV.
http://dx.doi.org/10.1016/B978-0-12-404734-1.00002-4 Copyright © 2014 Elsevier Inc. All rights reserved.
19
C H A P T E R
2
History of Simian
Immunodeficiency Virus
Discovery
Preston A. Marx
Chair, Division of Microbiology, Tulane National Primate Research Center,
Tulane University, Covington, LA, USA
SERENDIPITOUS PATHWAYS TO AN AIDS MODEL
AND SIV’S AFRICAN ORIGIN
Important discoveries are often serendipitous and obey the Law of
Unintended Consequences, which states, “The purposeful actions of
people and especially of governments always have effects that are unin-
tended” [1]. The pathway to discovering the African natural history of the
simian immunodeficiency virus (SIV) and development of the macaque
(mac) AIDS models began with a lymphoma outbreak in 1969 of unknown
cause at the California National Primate Research Center (CNPRC)
macaque colony located in Davis, California. This epizootic unintention-
ally led to the literal creation of SIVmac, which was eventually identified
at the New England Primate Research Center (NEPRC) in Southborough,
Massachusetts. This discovery led in turn to the discovery at the Tulane
National Primate Research Center (TNPRC) in Covington, Louisiana that
AIDS most likely had a simian origin on the African continent.
All of the above began with unrelated research projects at these three
primate centers. The SIVs and derivatives commonly used in AIDS animal
model research resulted from the unintended consequences of non-human
primate (NHP) model research unrelated to AIDS carried out by scien-
tists at three primate centers who were unaware of SIV’s existence; in fact
the research took place before AIDS was reported in humans in 1981 [2].
After SIV’s discovery, interest in the AIDS model grew exponentially. The](https://image.slidesharecdn.com/1435-250620164535-6e76dcf1/85/Natural-hosts-of-SIV-implication-in-AIDS-1st-Edition-Aftab-A-Ansari-29-320.jpg)
Natural hosts of SIV implication in AIDS 1st Edition Aftab A Ansari
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- 4. NATURAL HOSTS OF SIV IMPLICATION IN AIDS Edited by Aftab A. Ansari, PhD Professor Department of Pathology & Laboratory Medicine Emory University School of Medicine Atlanta, GA, USA Guido Silvestri, m.d. Professor Department of Pathology and Laboratory Medicine Emory University School of Medicine & Yerkes National Primate Research Center Atlanta, GA, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier
- 5. Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA Copyright © 2014 Elsevier Inc. All rights reserved. Except Chapter 7 which is in the public domain No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher. Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: permissions@elsevier.com. Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information. Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 978-0-12-404734-1 Typeset by TNQ Books and Journals www.tnq.co.in Printed and bound in United States of America 14 15 16 17 10 9 8 7 6 5 4 3 2 1 For information on all Academic Press publications visit our website at elsevierdirect.com
- 6. xi Epigraphy “An accomplished scientist does not always come up with the correct answers to complex biological problems BUT does put together knowl- edge in a logical order that serves the scientific community a foundation to formulate the right questions.” Ansari, 2014
- 7. xiii Contributors Daniel C. Anderson Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA AnnChahroudi DepartmentofPediatrics,EmoryUniversitySchoolofMedicine, Atlanta, GA, USA; The Yerkes National Primate Research Center, Emory Vaccine Center, Atlanta, GA, USA Aftab A. Ansari Department of Pathology and Laboratory Medicine, Emory University School of Medicine, and Yerkes National Primate Research Center, Atlanta, GA, USA Cristian Apetrei Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA Steven E. Bosinger Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA, USA Jason M. Brenchley Program in Tissue Immunity and Repair, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD, USA Lisa A. Chakrabarti Unité de Pathogénie Virale, Institut Pasteur, Paris, France Joyce K. Cohen Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA Cynthia L. Courtney Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA Cynthia A. Derdeyn Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA Anapatricia Garcia Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA Melanie A. Gasper Seattle Biomedical Research Institute, Seattle, WA, USA Edward J.D. Greenwood Department of Veterinary Medicine, University of Cambridge, Cambridge, UK Sanjeev Gumber Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA Jonathan L. Heeney Department of Veterinary Medicine, University of Cambridge, Cambridge, UK Amitinder Kaur Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, MA, USA
- 8. CONTRIBUTORS xiv Frank Kirchhoff Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany Florian Liegeois UMI233, TransVIHMI, Institut de Recherche pour le Développement (IRD), Montpellier, France and Université Montpellier 1, Montpellier, France Dongzhu Ma Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA Preston A. Marx Chair, Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, USA Kiran D. Mir Emory Vaccine Center, Yerkes Primate Center, Atlanta, GA, USA Mirko Paiardini Department of Pathology and Laboratory Medicine, Emory University, School of Medicine, Atlanta, GA, USA; Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA Ivona Pandrea Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA Martine Peeters UMI233, TransVIHMI, Institut de Recherche pour le Développement (IRD), Montpellier, France and Université Montpellier 1, Montpellier, France Molly R. Perkins Program in Tissue Immunity and Repair, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD, USA Sallie Permar Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA Roger Keith Reeves Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, MA, USA Namita Rout Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, MA, USA Daniel Sauter Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany Fabian Schmidt Department of Veterinary Medicine, University of Cambridge, Cambridge, UK Prachi Sharma Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA Guido Silvestri Department of Pathology and Laboratory Medicine, Emory University School of Medicine, and Yerkes National Primate Research Center, Atlanta, GA, USA Donald L. Sodora Seattle Biomedical Research Institute, Seattle, WA, USA Elizabeth Strobert Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA Vasudha Sundaravaradan Seattle Biomedical Research Institute, Seattle, WA, USA
- 9. CONTRIBUTORS xv Amalio Telenti Institute of Microbiology, University Hospital, University of Lausanne, Lausanne, Switzerland Thomas H. Vanderford Department of Pathology and Laboratory Medicine, Emory University, School of Medicine, Atlanta, GA, USA; Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA Francois Villinger Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA Lutz Walter Primate Genetics Laboratory, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg, Göttingen, Germany
- 10. xvii Introduction Natural non-human primate hosts of the simian immunodeficiency virus (SIV) do not develop AIDS despite carrying viral loads that normally lead to pathology and death in non-natural hosts. A large body of data that documents a variety of immunological and virological differences between SIV-infected natural versus non-natural hosts indicate that the clues to disease resistance are mostly host related and have evolved over 100 if not thousands of years. We now face the daunting task of identifying which of these differences (and by what mechanisms) contribute to dis- ease resistance in the natural hosts and ultimately exploit these findings for the design of novel interventions to treat or prevent HIV infection of humans.
- 11. Natural Hosts of SIV. http://dx.doi.org/10.1016/B978-0-12-404734-1.00001-2 Copyright © 2014 Elsevier Inc. All rights reserved. 1 C H A P T E R 1 Comparative Studies of Natural and Non-natural Hosts of SIV— An Overview Aftab A. Ansari, Guido Silvestri Department of Pathology and Laboratory Medicine, Emory University School of Medicine, and Yerkes National Primate Research Center, Atlanta, GA, USA OVERVIEW The overall objective of this book is to provide readers with a single reference resource that contains a series of chapters comprising results, views, and concepts formulated by various investigators involved in the comparative studies of the natural and non-natural hosts of primate lentiviruses such as human immunodeficiency virus (HIV) and simian immuno deficiency virus (SIV). It is reasoned that such a summary will provide a valuable foundation upon which future studies can be planned, discussions initiated, and critical experiments performed that will move this field forward. As the titles indicate, the initial chapters include a fascinating story of how SIV was accidentally transmitted in the 1970s from the disease- resistant natural hosts to the disease-susceptible non-natural hosts as an unintended consequence of scientific experimentation by the Nobel lau- reate Dr Carlton Gajdusek and his colleagues working on “kuru,” a rare disease transmitted by brain tissue in a population in New Guinea who practiced cannibalism. Another example of unintended consequences were studies being performed by scientists that were attempting to find a model other than the armadillo for human leprosy and thought that they had developed such a non-human primate model in the early 1980s, i.e., before HIV/SIV were isolated and identified. Concealed within these
- 12. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 2 historical descriptions is the finding of the unusual natural transmission of Mycobacterium leprae and Coccidiodes immitis infections in one of the nat- ural hosts of SIV (sooty mangabey, a species from West Africa) [1–4]. Thus, a sooty mangabey was found to spontaneously acquire M. leprae infec- tion and when tissues from this animal were injected into other mang- abeys, the recipients developed a lepromatous form of M. leprae, which was at the time touted as the first description of a non-human primate (NHP) model to study human leprosy and a major advance in the field of leprosy research. The finding of C. immitis infection coupled with the M. leprae infections unique to this species prompts the obvious question as to whether the presence of the SIV infection of this natural host makes this species uniquely susceptible or whether the immune system of this species has evolved to confer this unique susceptibility to such microor- ganisms. This issue still remains to be addressed. This interesting historical perspective is followed by a chapter on the prevalence and molecular epidemiology of SIVs in the wild, with the use of innovative sequencing techniques that facilitate the understanding of the evolution of these viruses. In addition, it is clear from this chapter that it is likely that >90% of the approximately 70 Old World NHP species in Africa are likely to be infected with species-specific SIVs, but we have knowledge of only 45 such species. It is also clear from this and other chapters that both SIV and the NHP species that harbor such viruses have co-evolved, and adaptation is one of the key elements that need to be rec- ognized. A cautionary note was also expressed by the authors with regard to the pathogenicity of SIVs in natural hosts, citing the more recent studies of the evidence for pathogenicity of SIVcpz in chimpanzees in the wild. Thus, the blanket statement of disease resistance of natural hosts of SIV that are being raised in captivity at the various primate centers needs to be punctuated with the realization that detailed studies of its potential to cause disease in the wild in the same natural hosts are lacking at pres- ent. The idea being conveyed here is that there is likely to be continued evolution of both SIVs and the natural hosts that results in survival of only those within the species that co-evolve mechanisms that protect them from developing disease. Along similar lines, the book includes a chapter devoted to SIVcpz in chimpanzees, with a more detailed description of the various chimpanzee species and the characterization of viruses from such species. The authors describe the differences and similarities between other natural hosts of SIV and the SIVcpz that infects chimpanzees. As cautioned above, while the previous paradigm predicated that the chimpanzees have been infected for thousands of years and are to a large extent disease resistant, emerging data have questioned this view. Thus, based on the fact that there is evi- dence for pathogenicity of SIVcpz infection of chimpanzees, the argument that transmission of SIV in this species is a more recent occurrence has
- 13. Overview 3 strengthened, also explaining the presence of pathology as a result of the lack of sufficient time to reach a peaceful co-adaptation between host and virus. Further studies are clearly in order to address this issue. These findings are logically followed by a detailed review of our current knowledge on the role of the various viral proteins, including the “acces- sory” proteins, that have been identified and sequenced and their func- tional consequences described. Thus, the repertoire of these virally encoded accessory proteins, including Nef, Vpu, and Vpx, that have evolved and the pathogenic consequences of such evolution are elegantly outlined. What is most striking is the list of unanswered questions that still remain with regard to these accessory proteins. In addition, a discussion of the role of the corresponding host antiviral restriction factors, which include TRIM-5α, tetherin, APOBEC3G, and SAMHD1, are presented with an emphasis that the role of such host proteins is still in its infancy and there are likely to be additional host factors that have yet to be identified. Understanding how such viral and host proteins have co-evolved will provide not only some important insights on the molecular mechanisms of host/parasite relation- ships but also crucial information that could be potentially harnessed for the design of candidate vaccines against HIV-1. One of the issues that has garnered serious attention during the past several years is the phenomenon termed “microbial translocation,” a term that has entered our lexicon in HIV/AIDS research. Indeed, a key biological event identified to date that differentiates pathogenic from non-pathogenic HIV/SIV infection, natural versus non-natural hosts of SIV, and the kinetics of disease progression is the occurrence of chronic immune activation (CIMA). Thus CIMA has been heralded as one of the most important correlates of pathogenic infection and the best marker for disease progression. It has been shown that CIMA is at least in part the result of microbial translocation that results from the loss of integrity of the gastrointestinal tissue barrier that separates the microbial flora from the lumen of the intestine to the systemic circulation. The chronic flow of microbiota and its products from the gut to the circulation induce both innate and adaptive immune cell activation with resulting toxic levels of cytokines, which dysregulate multiple biological systems, including, eventually, the coagulation cascade, leading to multiple organ system fail- ure and death. Thus, there are two chapters within this book that concern CIMA. One of the chapters is focused on outlining the physiological and immunological mechanisms that maintain mucosal integrity and how its breach leads to microbial translocation resulting in CIMA in the disease- susceptible hosts—while, interestingly, such a breach occurs only mildly and transiently in the natural hosts. An important side note of this chap- ter is an emphasis on the fact that the mechanisms that lead to reversal and subsequent maintenance of mucosal integrity in one natural host may not in fact be similar to those in another host. The second chapter
- 14. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 4 expands on the overall concepts laid out in the previous chapter by out- lining all the cellular characters that are involved in the dialogue between the pro- and anti-inflammatory effects of the host immune system, with a focus on those that are functional at the mucosal interface. Thus, the basic tenets of this chapter are that natural hosts have developed a remarkable array of regulatory mechanisms that can dampen/mute proinflamma- tory responses and maintain homeostasis. It is clear from the gist of this chapter that these unique regulatory mechanisms that have been acquired by the natural hosts of SIV are the ones we need to exploit and target as part of novel therapeutic strategies aimed to minimize the damage that SIV (and, by implication, HIV) mediates against the gut mucosa. A related chapter with regard to the mechanisms by which the natural hosts protect themselves from the development of disease is the important finding of differences in the phenotypically defined subset of cells that SIV targets in the natural hosts. Thus, the findings outlined in this chapter suggest that the natural hosts best studied so far, which include the sooty mangabeys and the African green monkeys (AGMs), each have naturally evolved a set of mechanisms that modulate the major receptors for SIV and promote the infection of a subset of cells that are more dispensable for the host. This deviation allows for the survival and function of the subset that is critical for the host to maintain antigen-specific recall responses, immune homeostasis, mucosal barrier integrity, and, importantly, lymphoid tissue architecture [5]. Obviously, more detailed studies are required in efforts to exploit this finding for therapeutic purposes because it is not clear how this deviation evolved in the natural hosts over the millennia and is in fact mediated at the molecular level. Once again, it does appear that the mech- anisms are species specific; and thus, while there is a common endpoint (disease resistance), the pathways are quite distinct, which can be viewed as hurdles or can be viewed as multiple targets available for identifying therapeutic strategies. The next few chapters sequentially deal with the characteristics of the innate and acquired humoral/cellular responses; each chapter covers not only the subtle differences in the phenotype of cell lineages that execute these functions, but also how these functions differ between the natural hosts and the non-natural hosts of SIV. Acomprehensive description of the various cell lineages that comprise the innate immune system and their role in either influencing the quality and quantity of virus-specific immune responses or regulating viral loads is described. Among the highlights of this chapter is the description of the role of the plasmacytoid dendritic cells (pDCs), whose trafficking from the periphery to the gut tissues and their subsequent accumulation within the gut was shown to lead to high levels of IFN-α in the non-natural hosts, associated with disease progres- sion. On the contrary, such trafficking of pDCs in the natural hosts was found to be transient following acute infection. These findings suggest a
- 15. Overview 5 potentially important difference in the role of pDCs in natural versus non- natural hosts. The coincident depletion of Th17/IL-22 synthesizing cells, also uniquely in the SIV-infected non-natural but not the natural hosts, suggests perhaps a linkage between these two events. Attempts to convert the infection and disease profile of natural hosts to that of non-natural hosts with the administration of IFN-α to promote innate immune signal- ing, however, while inducing a transient increase in the activation of CD8+ T cells, failed to show CD4+ T-cell depletion and showed no major effects on viral loads. An opposite strategy with the use of TLR7/9 antagonist to block IFN-α signaling in SIV-infected non-natural hosts not only had no effect on the depletion of CD4+ or CD8+ T cells, but—of interest—did not affect the expression of interferon-stimulating genes, suggesting that such manipulations in vivo perhaps are not effective because they do not function individually and/or they represent a downstream event. Simi- larly, attempts to administer lipopolysaccharides to the SIV-infected natu- ral hosts to mimic the effect of microbial translocation in the non-natural hosts induced a transient increase in plasma viral loads but did not lead to disease, suggesting either that such manipulations do not faithfully rep- licate the conditions noted in the non-natural hosts or that the disease- inducing events are complex and require multiple system manipulations. Another cell lineage that appears to be important is the innate lymphoid cells (unique lineage only present in gut tissues). Their depletion/absence in the SIV-infected non-natural hosts but continued presence in the natural SIV-infected host, coupled with a role of these cells to maintain Th17/IL-22 in the gut mucosa, prompts the need for further detailed study of this difference. Of interest are the studies on the role of NK cells. Depletion studies during acute infection using either in vivo depleting antibodies or the use of a JAK3 inhibitor while showing varying levels of depletion of this cell lineage failed to show any major difference in viral loads. However, depletion of NK cell lineage using the JAK3 inhibitor dur- ing acute infection did appear to influence plasma and cellular viral loads during chronic infection by an as-yet-unidentified mechanism [6]. A role of this cell lineage in mediating ADCC activity and to serve as enhanc- ers of immune responses by adjuvants has also been highlighted in this chapter. In all, it appears that much has yet to be learned on the role of the innate immune network on influencing the course of disease in the natural and non-natural hosts of SIV. A summary of the humoral anti-SIV response in the natural host with a focus on the sooty mangabeys and a comparative analysis of the antibody response between sooty mangabeys and rhesus macaques is outlined in the next chapter. To a large extent, it appears that natural SIV hosts do not mount a robust virus-specific neutralizing antibody response and the elimination of B cells in the natural hosts does not lead to increases in plasma viral loads. While the author is clear that these are not likely
- 16. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 6 contributing to the disease resistance of the natural hosts, it is indeed pos- sible that the blunting of vigorous virus-neutralizing antibody responses contributes to the disease-protective mechanisms in these natural hosts by preventing the development of hyperimmune activation, dysregula- tion, and perturbation of lymphoid tissue architecture that is characteristic of the non-natural hosts. One is thus left with the idea that the natural hosts have developed a potent regulatory mechanism that prevents the development of vigorous humoral virus-specific immune responses and its corollary: that vigorous virus-specific immune responses are contribut- ing to the development of disease. It is requested that the reader keep this thought in mind as we try to put this in context with all the other findings displayed in the chapters. The comparative analysis of SIV-specific humoral responses is followed by a chapter on the virus-specific cellular responses, including the responses of cells that form a bridge between humoral and cell-mediated immune responses. The findings of this chapter suggest that while the virus-specific cellular immune responses are noted in both the natural and non-natural hosts of SIV, the response in the natural hosts may in fact be more effective in limiting tissue damage and resulting immunopathology, particularly in secondary lymphoid tissues and in specific CD4+ T-cell subsets. The empha- sis is also being placed on the importance of regulatory mechanisms and specific molecules (PD-1, CTLA-4, LAG-2, 2B4, CD160 and GP149) that mediate such regulatory function of adaptive immune responses that have evolved selectively with enhanced function evolved in the natural hosts and, of importance, a constellation of mechanisms that maintain the pres- ence of normal frequencies and function of these so-called cell lineages that fall within the cusp of humoral and cellular immune responses (NK regs, NK-T cells and KIRs) are illustrated in Figure 1.1. This is followed by two chapters that address additional important roles in the field of natural and non-natural SIV infections, including the mecha- nisms of viral transmission and the role of genetic factors. With regard to the studies of viral transmission, it does seem ironic that even after three decades of research in the field of HIV/SIV, we still do not fully comprehend the impact of the route of transmission on disease outcome. Thus, while it is clear that the mucosal route is the major route of natural transmission, we do not fully understand how the different routes affect the generation of virus-specific humoral and cellular responses and the impact of the innate immune system in the localized environment that influences the outcome in natural versus non-natural hosts of SIV. This is because this subject encom- passes multiple routes and involves not only the transmission between adults but also mother-to-child transmission and how this differs between natural and non-natural hosts. There does seem to be a hierarchy, however, in the dose of virus required for transmission via the different routes in adults. Thus, the dose of virus required to transmit infection increases, in order, via
- 17. Overview 7 blood, rectal tissues, vaginal tissues, and oral tissues, respectively. It is also clear that vaginal transmission is a rare event, which has prompted the use of low-dose repeated intravaginal transmission as a model to better mimic HIV-1 transmission in humans. Germane to the major thrust of this book are studies of the differences between the natural versus the non-natural hosts of SIV. A number of points appear to be clear from the studies performed to date. First of all, the majority of SIV transmitted in the natural hosts is via the sexual route, and there is high concordance between age of the natural hosts and seroconversion and virus positivity. Secondly, one of the most important differences between the natural and non-natural hosts of SIV is the relative resistance from mother-to-child transmission in the natural hosts as com- pared with the non-natural hosts of SIV. This is true not only for natural epi- demiologic studies of animals in the wild but also for experimental studies FIGURE 1.1 Mechanisms that contribute to distinct outcomes of SIV infection in natural versus non-natural non-human primate hosts. Nature has built in a series of redundant effec- tor regulatory mechanisms to insure that the immune responses of the host stay in check and do not result in pathology. This regulatory process occurs during both (A) innate and (B) adaptive immune responses. For innate immune responses, regulation of the synthe- sis of interferon-stimulated genes is one good example. In the case of adaptive immune responses, the regulatory molecules include the gradual expression and upregulation of the inhibitory receptors (PD-1, CTLA-4, LAG-3, 2B4, CD160, and gp49), which generate nega- tive signals upon ligation, and the activation of regulatory T cells (Tregs) and regulatory NK cells (NKregs), which also function to kill immature dendritic cells to promote muting of the immune responses. Some of these regulatory mechanisms function systemically and others function in select tissues and organs, providing a multi-pronged safeguard to fine-tune the host anti-pathogen relationship. The natural hosts of SIV have evolved to optimally utilize such regulatory mechanisms, whereas dysregulation of such regulatory mechanisms charac- terizes the non-natural hosts of SIV.
- 18. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 8 in which the mother’s milk was experimentally manipulated to contain high viral levels. However, what is lacking in these studies are the precise mecha- nisms involved in the resistance of the infants of the natural hosts. One of the suggested mechanisms implicates the differences in the cell lineages that are targets for infection in the natural hosts, similar to the argument advanced above as a mechanism of disease protection. However, the molecular mech- anisms responsible for these differences in the type of target cells between natural and non-natural hosts remain incompletely understood. The subject of the role of genetic factors in differences in susceptibility to transmission, infection, and disease progression has been, unfortunately, the most difficult to study. This is because most studies being performed at primate centers involve a limited number of animals of each species and genetic association studies clearly require studies of large cohorts. This problem is further compounded by the lack of detailed knowledge of the sequences of the genes involved and the nature of the polymor- phisms of the select genes, particularly in the natural hosts. Thus, basic studies of the detailed characterization of the degree of MHC class I and II polymorphisms in the non-natural hosts are still lacking and there is very limited knowledge of the MHC genes of the natural hosts. Nonetheless, since there is now clear evidence for the role of MHC class I/II and those that involve NK cell function such as NK cell receptors, KIRs, and FcR on the pathogenesis of human HIV-1, it was important to include a chapter on this subject, which is very ably summarized herein. Finally, a very fascinating topic is covered by the last two chapters of this book. These chapters summarize what we know at present with regard to HIV-1-infected humans that show characteristics similar to natural SIV hosts. While there are clear differences between “elite controllers” of human HIV-1 infection and the natural hosts of SIV, which include low viremia and potent antiviral T-cell immune responses in the former but not the latter, the number of similarities is of great interest. This includes the absence of chronic immune activation, a downregulated IFN-α response, lower viral loads in lymph nodes, and relative sparing of the central memory and poten- tially the follicular helper CD4+ T cells. A similar theme is projected in the second chapter on this subject but also includes the remarkable description of a rare but interesting subset of HIV-1-infected humans that maintain high viral loads for a substantial time period, but with no loss of CD4+ T cells and no signs of disease progression (i.e., viremic nonprogressors or VNP). The authors also highlight our limited understanding of the biology and patho- genesis of HIV-2 infection in humans and that more detailed studies of these individuals, in concert with studies of elite controllers, VNPs, highly HIV- 1-exposed but noninfected humans, and normal and/or fast progressors, provide the entire spectrum of HIV-1-infected humans. A study of the dif- ferences in the pathogenic mechanisms of these cohorts is clearly in order and likely to be highly informative.
- 19. Overview 9 We have taken the prerogative as editors to highlight some of the issues that need emphasis with regard to the potential mechanisms that may be involved in the lack of disease progression, with the hope that the issues highlighted provide food for thought for the next generation of scientists involved in attempts to define the mechanisms by which the natural hosts of SIV actually live quite a long and healthy life despite chronic SIV infec- tion and with no detectable pathologic sequelae. A summary of what we understand with regard to net results of virus/host interaction in natural versus non-natural hosts (distinguishing effective from non-effective and moderate or muted immune responses) is depicted in Figure 1.2. Thus, highly effective immune responses result in lack of pathogenesis and pres- ence of strong but ineffective immune responses leads to a pathogenic out- come, while more moderate and focused immune responses have evolved in the natural hosts and successfully achieved a non-pathogenic balance between virus and host. As stated above, the issues that we would like to emphasize include: 1. In vivo viral passage: A virological issue that needs to be emphasized concerns the fact that viral isolates from the natural hosts of SIV generally need to be passaged in vivo in the non-natural hosts to identify isolates that can replicate efficiently in the new non-natural hosts and cause disease. Thus, not all SIV isolates from sooty mangabeys are equally pathogenic in macaques and not all SIV isolates from macaques replicate efficiently in activated CD4+ T cells from mangabeys. These findings suggest that SIV undergoes “species-specific adaptation” and that these are characteristics unique to both virus and host. FIGURE 1.2 The balancing act between SIV (the pathogen) and the immune response of the hosts. There are basically three distinct outcomes. Thus, either the immune response mediated by the host is not effective in eliminating the pathogen (as in the case of non-natural hosts, macaques), or the immune response is highly effective in eliminating the pathogen (not yet observed in the case of SIV), or the quality and quantity of the immune response has evolved such that the pathogen does not harm the host and a balance is achieved between the immune response and the degree of immunopathology (as in the case of the natural hosts, sooty mangabeys and AGMs), which is herein defined as host accommodation.
- 20. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 10 2. Role of “founder viruses”: The fact that sexual transmission of HIV-1 involves the transmission of only a single or a select few viral species, leading to the term “founder viruses,” clearly prompts us to determine whether this is also true in the natural hosts of SIV. Within this context, it is important to perform these studies not only in the natural hosts raised in captivity but also in those in the wild, a topic not easy to study. In addition, the role of “env glycosylation” in viral transmission in the natural versus the non-natural hosts and in MCT studies between the natural and non-natural hosts needs to be addressed. 3. Differences among various species of natural hosts: Another issue that is important to keep in mind is that there are differences in the immunological and virological findings even among the various natural hosts of SIV, which requires one to analyze the data obtained within this context. Thus, the mechanisms of transmission may differ among each natural host of SIV and the findings from one species may not be amenable to extrapolation. This subject is also discussed in detail in several chapters. 4. Gastrointestinal dysfunction: Reports of severe gastrointestinal dysfunction with villous atrophy and crypt cell proliferation in SIV-infected macaques and HIV-1-infected humans in the early 1990s established the occurrence of gastrointestinal pathology in SIV- and HIV-infected individuals [7,8]. While initial SIV infection of both natural and non-natural hosts leads to the same degree of gastrointestinal pathology (with enteropathy and intestinal permeability) during acute infection, this pathology is largely reversible in disease-resistant natural hosts but irreversible in non- natural hosts [9]. Notably, administration of antiviral therapy to macaques as early as 1 week post infection did not influence the loss of CD4+ T cells in the gut tissues but enhanced rapid restoration with memory CD4+ T cells [10]. The data show that during the early stages of infection there is not only a massive loss of CD4+ T cells but also the apoptosis of epithelial cells that line the small and large intestines of untreated SIV-infected macaques, which is likely to be a driving force for gastrointestinal pathology [10]. Select studies have documented the loss of Tregs [11] and Th17cells in the mucosal tissue [12] of SIV infected macaques but not sooty mangabeys [13]. These studies have been followed by the introduction of the concept of microbial translocation [14] as a mechanism to explain the differences in the outcome of SIV infection between natural and non-natural hosts (discussed in several chapters). Attempts to use gene profiling [15] and investigation of the dysfunction of the intracellular molecular pathways in SIV-infected macaques have been performed [16,17]. However, the factors that lead to regeneration and reconstitution of gastrointestinal tissues in the natural but not non-natural hosts
- 21. Overview 11 require further investigation. Future studies should examine intestinal dendritic cells that are involved in polarizing anti-inflammatory responses inducing tolerance, gut-homing NK cells, and progenitor stem cells that give rise to gut epithelial cells [18]. In addition, it is possible that more knowledge of the proteins involved in regulating intestinal permeability and intestinal epithelial regeneration, particularly in the natural hosts of SIV, may pave the way for identifying novel therapeutic strategies for HIV-infected humans. 5. Models that attempt to explain the divergent clinical outcome of SIV infection in the natural versus the non-natural hosts: a. Role of immune activation. Although the contribution of CIMA to disease progression in HIV- infected humans and SIV-infected non-natural hosts is a reasonable and logical hypothesis, the lack of significant CIMA is probably not the only mechanism underlying the distinct clinical outcome in natural hosts. This view is supported by our finding that hyperimmunization of a cohort of six SIV-infected sooty mangabeys at weekly intervals for 12months sequentially with adjuvant-incorporated KLH, tetanus toxoid, a mixture of allogeneic cells, and intranasal exposure to immunogenic doses of influenza virus led to marked increases in the frequencies and absolute numbers of in vivo activated CD4+ and CD8+ T cells. Such levels of experimental immune activation of the natural host did not induce detectable disease or a major increase in plasma viral loads. These findings suggest that it may be the quality and/or differences in the consequences of CIMA that play a role in the different outcomes of SIV infection in the natural versus the non- natural hosts of SIV. The experimental manipulation of the natural host that leads to CIMA, which results in progression to disease, is required to underscore the role of CIMA in disease progression. b. Role of host accommodation. The symbiotic relationships that can exist between a vertebrate host and certain microorganisms were first acknowledged many years ago [19]. There are numerous examples in nature, highlighted by the relationship between host and microbe within the gastrointestinal tract under normal physiological conditions. There is no detectable immune response against foreign organisms at this site. Microorganisms establish a symbiotic relationship in a natural host, in which it is not pathogenic, but when they infect another species, they cause pathologic effects. For example, the deer mouse is the natural host for the Hantaviruses, which often cause a fatal disease in humans termed Hantavirus pulmonary syndrome. The infected mice carry high levels of the virus in their respiratory tract and have antibodies against the virus, but they have a normal lifespan [20]. Herpes B virus, which causes a fatal encephalitis in
- 22. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 12 humans, is commonly found in 70% of rhesus macaques, and 80% of those that are infected also have detectable antibodies and remain healthy. However, the mechanisms that underlie the accommodation of such pathogenic organisms by their natural hosts, and the disease resistance of the hosts, remain largely undefined. It is of importance to note that the “MAJOR” decision making tissue site involved in recognition of self versus nonself is at the gastrointestinal/liver intersection and the liver in essence could be playing the critical role in dictating host/virus outcome in the natural versus the non-natural hosts of SIV. The potential pathways that result in polarized outcomes as a consequence of viral infection resulting in viral clearance versus virus induced pathology (death) are by reason distinct from those that result in chronic infection and in turn the consequence of chronic infection range from slow progressive disease (non-natural hosts) and a lack of detectable disease (natural hosts) that is associate with host accommodation is depicted in Figure 1.3. The question arises as to whether we can harness knowl edge of how such “natural” host adaptation occurs and then attempt to “experimentally” induce such host adaptation between HIV and humans to limit the development of immunodeficiency disease. It is of interest to note that in fact there have been numerous examples of such “experimental” adaptation of host and foreign microorganisms or antigens. Thus, the field of organ transplanta- tion has provided us with a plethora of such examples. The term “host accommodation” [21–23] refers to successful engraftment of an organ or tissue in an allogeneic host in the presence of readily detectable antibodies against the donor tissue. In a general sense, host accommodation (HA) involves the induction of a coordinated series of biological changes in the host that enable donor cells and tissues to persist in the presence of antibodies against donor anti- gens recognized as foreign by the host. The successful transplanta- tion of ABO-incompatible donor organs in hosts that have high level of anti-AB antibodies is a good example of such HA. Thus, a similar relationship likely exists between SIV and its natural hosts in that the host lives a normal healthy life with the foreign antigen in the presence of readily detectable levels of antiviral antibodies. We propose that host accommodation could be a viable explanation for the absence of pathogenic disease in natural NHP hosts of SIV. We propose that the trafficking of NK cells and select subset of dendritic cells to the gastrointestinal tract during acute SIV infection in the presence of a low frequency of CD4+CCR5+ cells regulates the level of inflammation and creates a Th2-like environment that could contribute to the host accommodation in natural hosts. This symbiotic host–virus relationship leads to readily detectable antibodies and persistent viremia, but no overt pathology.
- 23. Outlook 13 OUTLOOK While considerable advances have been made in identifying both phenotypic and functional differences in the immune responses of SIV- infected AIDS-resistant natural hosts as compared with SIV-infected AIDS- susceptible non-natural non-human primate hosts, unfortunately, at present the mechanisms responsible for such distinct clinical outcome remain incompletely understood. Select parameters such as high viral loads and/or degree of CD4+ T-cell depletion are not by themselves suffi- cient to lead to disease. Clearly, additional studies are required to define the mechanisms by which the natural hosts of SIV avoid disease progression FIGURE 1.3 The evolution of host accommodation for SIV infection: During acute infec- tion, virus replicates and if the host virus-directed innate followed by adaptive immune response is dominant, viral clearance is achieved. If the virus has developed a dominant means to evade host innate immune mechanisms, leading to dysregulated virus-specific adaptive immunity, such infection leads to death of the host. For select viruses including SIV, neither the host response nor the virus-mediated pathology is dominant, which leads to chronic infection. Thereafter, either (1) the virus becomes “dormant” and can revert back to induce pathology and death if the host becomes immune compromised, or (2) there is continuous virus replication, which can cause a slow, debilitating disease (as noted for Asian macaques), or (3) there is con- tinuous virus replication to varying degrees, with no discernible host pathology. SIV infection of natural African hosts is an example of the last alternative. What we are attempting to unravel is what has taken perhaps a million years of co-evolution to achieve, as is the case with herpes viruses.
- 24. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 14 and the non-natural hosts develop AIDS following SIV infection. One of the prevailing hypotheses for such distinct clinical outcomes concerns the role of chronic immune activation, which occurs in the SIV-infected non-natural hosts but not the natural hosts. It is reasoned that such CIMA leads eventually to immune exhaustion and loss of immune competence, which results in increased susceptibility to opportunistic infections and, finally, death. While this is a reasonable model, we submit that lack of CIMA alone does not explain the disease resistance of the natural hosts. Instead, host accommodation, broadly defined as the ability of the natu- ral host to mount a controlled innate and noninflammatory SIV-specific humoral and cellular immune response, which has evolved during a long evolutionary time period, is an additional potential explanation for such distinct clinical outcome. A list of immunological features of SIV infection in natural versus non-natural hosts is illustrated (Table 1.1). This list is not by any means complete but serves as a foundation for future additions and modifications as additional data become available. There continue to be significant gaps in our understanding of the bio- logical features that distinguish pathogenic from non-pathogenic SIV infection in the non-human primate hosts. These issues are summarized in Box 1.1. These include the need to define the relative efficiency of virus replication within CD4+ T cells from the natural versus the non-natural hosts. Thus, do the CD4+ T cells from the natural hosts produce more SIV per cell than the non-natural hosts, which leads to the protection of a higher frequency of CD4+ T cells from lysis and dysfunction? One of the characteristics of the SIV-infected natural hosts that has been reasoned to contribute to disease resistance is the lower frequency of CD4+, CCR5+ cells. However, the molecular mechanisms that regulate the expression of CCR5 remain unclear. While both natural and non-natural hosts dem- onstrate essentially similar gastrointestinal pathology during acute infec- tion, there is significant gradual recovery of the damage in the natural but not the non-natural hosts during chronic infection. The mechanism(s) for such differential response to gastrointestinal tissue injury remains to be defined. Also, while it is reasonable to assume that qualitative and quan- titative aspects of the immunological events that occur during the acute infection period may play a major role in setting the stage for disease resis- tance and/or susceptibility, further studies are required to reach a satisfac- tory understanding of the pathogenic role of these early events. What seems to be critical to solve many of these remaining issues is to determine whether and how we can experimentally convert the non- natural host of SIV into a disease-resistant host, a process that nature has accomplished over a long period of time—or, vice versa, whether and how we can induce AIDS in a natural AIDS-resistant host. Attempts to accomplish this by the in vivo depletion of cell lineages, while informa- tive, has not recapitulated the outcome of SIV infection in natural hosts
- 25. Outlook 15 as compared with non-natural hosts, as summarized in Table 1.2. Clearly, examples exist for such experimental manipulation, in particular, in stud- ies of tissue and organ transplantation. If and when such objectives are achieved, the question then arises as to how we can harness such knowl- edge in the formulation of novel approaches to treat and prevent HIV-1 infection in humans. While experimental induction of selective adaptive TABLE 1.1 Comparative Features of SIV Infection in Natural Disease-Resistant versus Non-natural Disease-Susceptible Non-human Primates Features Natural Hosts Non-natural Hosts Plasma viral loads Similar Similar Cellular viral loads Similar Similar Cell target for virus CD4+, macrophages CD4+, macrophages Antibodies against SIV Lower ⇑⇑⇑ High ⇑⇑⇑⇑ Antibodies against SIVgag ± + Depletion of CD4+ T cells (acute infection) ⇓ ⇓⇓ Depletion of CD4+ T cells (chronic infection) ⇓ ⇓⇓⇓⇓ Depletion of CD4+ T cells (gut, acute infection) ⇓⇓⇓ ⇓⇓⇓ Restoration of CD4+ T cells (gut) ⇑⇑⇑ – Levels of CD4+CCR5+ cells in PBMC Low 3–7% 10–15% Levels of CD4+CCR5+ cells in gut Low 2–5% 40–60% CD4 TH17 cells post SIV Preserved Depleted SIV-specific cellular response + or ± +++ SIV-specific TH1/TH2 response TH2 TH1 Gastrointestinal tissue pathology post SIV (acute infection) Marked Marked Gastrointestinal tissue pathology post SIV (chronic infection) 75% Reversed Continued IFN-α (acute to chronic infection) High to low High to high Chronic immune activation – ⇑⇑⇑⇑ Lymph node tissue architecture Normal Dysregulated Susceptibility to apoptosis of CD4+ T cells Low High Susceptibility to apoptosis of bystander cells Low Medium Potential to undergo anergy Resistant Susceptible
- 26. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 16 BOX 1.1 1. Can we determine the viral: burst size (amount of virus produced by unit number of CD4+, CCR5+ T cells) from natural hosts such as sooty mangabeys and the non-natural hosts such as macaques, and can the mechanisms that regulate the expression of CCR5 by CD4+ T cells be defined, which may shed light on the differences in the efficiency of virus replication in the target cells of the natural versus the non-natural hosts of SIV and its role in disease resistance? 2. Can one identify the cellular and molecular mechanisms that lead to reversible versus nonreversible pathology of the gastrointestinal tissues of the SIV-infected natural versus the non-natural hosts? 3. Can SIV-specific cellular tolerance be experimentally achieved in the non-natural hosts; and, if so, does this lead to the conversion of the disease-susceptible SIV-infected macaques into a disease-resistant state, much like mangabeys or AGMs? 4. Can events that occur during acute infection, such as the induction and subsequent regulation of innate immune responses that distin- guish non-pathogenic from pathogenic infection, be identified; and, if so, can the mechanisms unique to non-pathogenic hosts be experimen- tally induced in the non-natural hosts and lead to disease resistance? 5. Can strategies aimed at preventing and/or attenuating gastro- intestinal tissue pathology in the non-natural hosts during acute SIV infection alone and/or in combination with the institution of effective antiretroviral therapy lead to the generation of long-term nonprogressor status; and, if so, can this paradigm be utilized for HIV-1-infected humans? TABLE 1.2 In Vivo Cell Depletion Studies in Natural versus Non-natural Hosts of SIV Cell Lineage Depleted Effect on Natural Host Effect on Non-natural Host CD8 ½ log ⇑ in VL or no effect. No evidence of disease 1–3 log ⇑⇑⇑ in VL, accelerated disease progression CD4 ⇓⇓⇓⇓ in VL but transient, no evidence of disease No reports CD20 No difference in VL, no evidence of disease Play a role during acute infection CD16 No reports Transient ⇑ in VL, no effect on disease progression VL, viral load.
- 27. References 17 immune response tolerance maybe difficult to achieve, we submit that therein lies one of the challenges for the formulation of an effective HIV-1 vaccine. Acknowledgments Supported by NIH NIAID RO1 AI078773 and AI098628 (AAA). References [1] Gormus BJ, Martin LN, Baskin GB. A brief history of the discovery of natural simian immunodeficiency virus (SIV) infections in captive sooty mangabey monkeys. Front Biosci 2004;9:216–24. [2] Gormus BJ, Wolf RH, Baskin GB, Ohkawa S, Gerone PJ, Walsh GP, et al. A second sooty mangabey monkey with naturally acquired leprosy: first reported possible monkey- to-monkey transmission. Int J Lepr Other Mycobact Dis 1988;56:61–5. [3] Meyers WM, Walsh WM, Brown HL, Binford CH, Imes Jr GD, Hadfield TL, et al. Lep- rosy in a mangabey monkey–naturally acquired infection. Int J Lepr Other Mycobact Dis 1985;53:1–14. [4] Pappagianis D, Vanderlip J, May B. Coccidioidomycosis naturally acquired by a mon- key, Cercocebus atys, in Davis, California. Sabouraudia 1973;11:52–5. [5] Chahroudi A, Bosinger SE, Vanderford TH, Paiardini M, Silvestri G. Natural SIV hosts: showing AIDS the door. Science 2012;335:1188–93. [6] Takahashi Y, Byrareddy SN, Albrecht C, Bremeier M, Walter L, Mayne AE, et al. In vivo administration of a JAK3 inhibitor during acute SIV infection leads to significant increases in viral load during chronic infection. PLoS Pathog 2014;10:e1003929. [7] Heise C, Miller CJ, Lackner A, Dandekar S. Primary acute simian immunodeficiency virus infection of intestinal lymphoid tissue is associated with gastrointestinal dysfunc- tion. J Infect Dis 1994;169:1116–20. [8] Heise C, Vogel P, Miller CJ, Halsted CH, Dandekar S. Simian immunodeficiency virus infection of the gastrointestinal tract of rhesus macaques. Functional, pathological, and morphological changes. Am J Pathol 1993;142:1759–71. [9] Brenchley JM, Douek DC. The mucosal barrier and immune activation in HIV patho- genesis. Curr Opin HIV AIDS 2008;3:356–61. [10] Verhoeven D, Sankaran S, Silvey M, Dandekar S. Antiviral therapy during primary sim- ian immunodeficiency virus infection fails to prevent acute loss of CD4+ T cells in gut mucosa but enhances their rapid restoration through central memory T cells. J Virol 2008;82:4016–27. [11] Chase AJ, Sedaghat AR, German JR, Gama L, Zink MC, Clements JE, et al. Severe deple- tion of CD4+ CD25+ regulatory T cells from the intestinal lamina propria but not periph- eral blood or lymph nodes during acute simian immunodeficiency virus infection. J Virol 2007;81:12748–57. [12] Cecchinato V, Trindade CJ, Laurence A, Heraud JM, Brenchley JM, Ferrari MG, et al. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol 2008;1:279–88. [13] Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, et al. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 2008;112:2826–35. [14] Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006;12:1365–71.
- 28. 1. COMPARATIVE STUDIES OF NATURAL AND NON-NATURAL HOSTS OF SIV 18 [15] George MD, Verhoeven D, McBride Z, Dandekar S. Gene expression profiling of gut mucosa and mesenteric lymph nodes in simian immunodeficiency virus-infected macaques with divergent disease course. J Med Primatol 2006;35:261–9. [16] Lackner AA, Mohan M, Veazey RS. The gastrointestinal tract and AIDS pathogenesis. Gastroenterology 2009;136:1965–78. [17] Mohan M, Aye PP, Borda JT, Alvarez X, Lackner AA. CCAAT/enhancer binding pro- tein beta is a major mediator of inflammation and viral replication in the gastrointes- tinal tract of simian immunodeficiency virus-infected rhesus macaques. Am J Pathol 2008;173:106–18. [18] van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009;71:241–60. [19] Lyte M. The microbial organ in the gut as a driver of homeostasis and disease. Med Hypotheses 2009;18:634–8. [20] Easterbrook JD, Klein SL. Immunological mechanisms mediating hantavirus persis- tence in rodent reservoirs. PLoS Pathog 2008;4:e1000172. [21] Bach FH, Hancock WW, Ferran C. Protective genes expressed in endothelial cells: a regulatory response to injury. Immunol Today 1997;18:483–6. [22] Soares MP, Lin Y, Sato K, Stuhlmeier KM, Bach FH. Accommodation. Immunol Today 1999;20:434–7. [23] Tang AH, Platt JL. Accommodation of grafts: implications for health and disease. Hum Immunol 2007;68:645–51.
- 29. Natural Hosts of SIV. http://dx.doi.org/10.1016/B978-0-12-404734-1.00002-4 Copyright © 2014 Elsevier Inc. All rights reserved. 19 C H A P T E R 2 History of Simian Immunodeficiency Virus Discovery Preston A. Marx Chair, Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, USA SERENDIPITOUS PATHWAYS TO AN AIDS MODEL AND SIV’S AFRICAN ORIGIN Important discoveries are often serendipitous and obey the Law of Unintended Consequences, which states, “The purposeful actions of people and especially of governments always have effects that are unin- tended” [1]. The pathway to discovering the African natural history of the simian immunodeficiency virus (SIV) and development of the macaque (mac) AIDS models began with a lymphoma outbreak in 1969 of unknown cause at the California National Primate Research Center (CNPRC) macaque colony located in Davis, California. This epizootic unintention- ally led to the literal creation of SIVmac, which was eventually identified at the New England Primate Research Center (NEPRC) in Southborough, Massachusetts. This discovery led in turn to the discovery at the Tulane National Primate Research Center (TNPRC) in Covington, Louisiana that AIDS most likely had a simian origin on the African continent. All of the above began with unrelated research projects at these three primate centers. The SIVs and derivatives commonly used in AIDS animal model research resulted from the unintended consequences of non-human primate (NHP) model research unrelated to AIDS carried out by scien- tists at three primate centers who were unaware of SIV’s existence; in fact the research took place before AIDS was reported in humans in 1981 [2]. After SIV’s discovery, interest in the AIDS model grew exponentially. The
- 30. Another Random Scribd Document with Unrelated Content
- 31. 1863, February 25, passage of the National Bank Act. 1863, July 1 to 3, Battle of Gettysburg. 1863, September 19, Battle of Chickmauga. 1864, March 6 to 8, Battle of the Wilderness. 1864, June 19, the Warship Kearsarge sank the Alabama. 1864, September 2, General Sherman captured Atlanta, Georgia. 1865, April 9, General Lee surrendered at Appomattox. 1865, April 14, John Wilkes Booth assassinated President Lincoln. 1867, March 30, Treaty for the purchase of Alaska signed. 1869, May 10, completion of the Union Pacific Railroad. 1871, October 8, great fire at Chicago. 1881, July 2, President Garfield shot by Charles J. Guiteau. 1886, May 4, Haymarket riot at Chicago. 1889, May 31, great flood at Johnstown, Pennsylvania. 1893, February 14, the Hawaiian Islands annexed to the United States. 1897, June 14, Venezuela boundary line treaty ratified by Congress. 1898, February 15, United States Battleship Maine blown up in Havana Harbor. 1898, April 21, Severance of diplomatic relations between Spain and the United States. 1898, April 27, Matanzas, Cuba, fired upon by American warships. 1898, May 1, Admiral Dewey destroyed the Spanish fleet at Manila. 1898, May 6, United States fleet bombarded Santiago, Cuba. 1898, May 12, Admiral Sampson fired upon San Juan, Porto Rico. 1898, June 3, Hobson sank the Merrimac in the harbor of Santiago, that he might block the channel. 1898, June 22, first landing of the United States troops in Cuba. 1898, July 3, the Spanish fleet destroyed at Santiago. 1898, July 16, Santiago surrendered. 1898, August 13, Manila surrendered. 1898, November 28, end of the Spanish-American War. 1901, September 6, President McKinley killed by Leon Czolgolz.
- 32. 1901, September 16, Hay-Pauncefote Canal Treaty ratified by Congress. 1902, July 4, Declaration of Peace with Philippine Islands, and amnesty granted to all insurgents. 1904, May 4, the United States took control of the Panama Canal. University Extension.—A scheme for extending to people at large the advantages of a university education, by means of courses of lectures and classes in various important cities. The scheme originated at the University of Cambridge, England, in 1872, and was introduced into the United States in 1890. University Settlements.—Homes established in the poorer parts of cities, where educated and cultured people may live and try to improve the lives of their neighbors. Lectures, studies, and various other devices are resorted to. The movement started in England in 1867, and appeared in New York in 1887, as a Neighborhood Guild. University settlements are now found in all the chief cities of the United States. Utopia.—An imaginary island, with an ideal commonwealth, the inhabitants of which enjoy perfect laws and institutions. It is described in Sir Thomas More's political romance, De Optimo Reipublicae Statu, deque Nova Insula Utopia, published in Latin in 1516, and translated into English in 1551. His purpose was to describe his idea of social arrangements by which the people's most absolute happiness and improvement might be secured. Vaccination.—Vaccination, a preventive of smallpox, was discovered by Dr. Edward Jenner of England. It consists of injecting into the blood a virus made from the sores or scabs of cows suffering from cowpox, or the virus may be taken from the sore coming from vaccination itself. Comparatively few people, properly vaccinated, can have the smallpox, and are largely exempt from any disease resembling it, except that which is known as varioloid, which is a mild form of smallpox. It is not known how long vaccination remains a preventive, but probably for seven years, when one should be vaccinated again. The prejudice against vaccination, which was very intense at its discovery, no longer exists except among a few. Practically every physician advocates it, and it is compulsory in some towns and cities. Deaths have occurred from it, but they are very infrequent. Vacuum.—The perfect vacuum, which it is impossible to produce, is space without air or atmosphere. Vacuums are made by pumping all the air out of a receptacle or chamber. In a vacuum, everything falls at the same rapidity, as there is nothing to buoy it up, a feather descending as rapidly as lead shot. Vedas.—Sacred writings of the Hindus, hymns, prayers, and liturgies, said to have been compiled by Vyasa about 1200 B. C. They are written in Sanskrit, and divided into four parts. Voodooism.—A degraded form of religion prevalent among the negroes of Hayti and the Southern States of America. Supposed to be a relic of the religion of
- 33. equatorial Africa. Watered Stock.—It is said that the late Commodore Vanderbilt originated what is known as watered stock. Watered stock is capitalizing an industry at a figure in advance of its real value. For example: a railroad has tangible assets of $10,000,000, and an earning capacity sufficient to pay a 6 per cent. dividend on its capitalization; financial giants manipulate the stock and increase it to, say, $20,000,000, watering it to the extent of 100 per cent. In other words, the real value of the stock then is one-half of what it was in the first place. Stock watering has become epidemic, and is the cause of hundreds of thousands of financial failures. The stock waterers, however, as a rule, win, the public being the victims. Wealth of the Nations.—The estimated wealth of the principal nations of the earth is given in billions: United States, 130; Great Britain and Ireland, 80; France, 65; Germany, 60-1/2; Russia, 40; Austria-Hungary, 25; Italy, 20; Belgium, 9; Spain, 5.4; Netherlands, 5; Portugal, 2.5; Switzerland, 2.4. Weather Flags The Weather Bureau maintained by the United States Department of Agriculture displays at its stations flags which indicate probable changes in the weather. A white flag indicates clear or fair weather. A blue flag, rain or snow. A flag with the upper half white and the lower half blue, local rain or snow. A black triangular flag indicates temperature. A white flag with black square in center, a cold wave. When the black triangular flag is placed above the white flag, the black flag or the white and blue flag, it indicates warmer weather; when below, colder. When the black triangular flag is not displayed at all, the temperature is likely to remain stationary. Flags are displayed by the Weather Bureau as storm warnings in the following manner: Small Craft Warning: A red pennant indicates that moderately strong winds are expected. Storm Warning: A red flag with a black center indicates that a storm of marked violence is expected. The pennants displayed with the flags indicate the direction of the wind—white, westerly (from southwest to north); red, easterly (from northeast to south). The pennant above the flag indicates that the wind is expected to blow from the northerly quadrants; below, from the southerly quadrants.
- 34. By night a red light indicates easterly winds, and a white light below a red light, westerly winds. Hurricane Warning: Two red flags with black centers, displayed one above the other, indicate the expected approach of a tropical hurricane, or one of those extremely severe and dangerous storms which occasionally move across the Lakes and Northern Atlantic coast. No night small craft or hurricane warnings are displayed. Wedding Anniversaries.—First, cotton; Second, paper; Third, leather; Fourth, fruit and flowers; Fifth, wooden; Sixth, sugar; Seventh, woolen; Eighth, India rubber; Ninth, willow; Tenth, tin; Eleventh, steel; Twelfth, silk and fine linen; Thirteenth, lace; Fourteenth, ivory; Fifteenth, crystal; Twentieth, china; Twenty-fifth, silver; Thirtieth, pearl; Fortieth, ruby; Fiftieth, golden; Seventy-fifth, diamond. Weights and Measures LONG MEASURE 12 inches 1 foot 3 feet 1 yard 2 yards 1 fathom 16-1/2 feet 1 rod 4 rods 1 chain 10 chains 1 furlong 8 furlongs 1 mile 3 miles 1 league SQUARE MEASURE 9 square feet 1 square yard 30-1/4 square yards 1 square rod 40 square rods 1 rood 4 roods 1 acre 640 acres 1 square mile An acre is 43,560 square feet. DRY MEASURE 2 pints 1 quart 8 quarts 1 peck
- 35. 4 pecks 1 bushel LIQUID MEASURE 4 gills 1 pint 2 pints 1 quart 4 quarts 1 gallon TROY WEIGHT 24 grains 1 pennyweight 20 pennyweights 1 ounce 12 ounces 1 pound AVOIRDUPOIS WEIGHT 16 drams 1 ounce 16 ounces 1 pound 25 pounds 1 quarter 4 quarters 1 hundred 20 hundreds 1 ton APOTHECARIES' WEIGHT 20 grains 1 scruple 3 scruples 1 dram 8 drams 1 ounce 12 ounces 1 pound CUBIC MEASURE 1728 cubic inches 1 cubic foot 27 cubic feet 1 cubic yard 16 cubic feet 1 cord foot 8 cord feet 1 cord 128 cubic feet 1 cord
- 36. LAND MEASURE 7.92 inches 1 link 25 links 1 rod 4 rods 1 chain 80 chains 1 mile CIRCULAR MEASURE 60 seconds 1 minute 60 minutes 1 degree 30 degrees 1 sign 60 degrees 1 sextant 90 degrees 1 quadrant 360 degrees 1 circle METRIC SYSTEM MEASURES OF WEIGHT (Unit Gramme) Grains Oz. Troy Lbs. Avoir. Cwt. Centigramme 0.15432 ..... ..... ..... Decigramme 1.54323 0.003 ..... ..... Gramme 15.43235 0.032 0.002 ..... Decagramme 154.32349 0.321 0.022 ..... Hectogramme 1543.23488 3.215 0.220 0.001 Kilogramme 15432.34880 32.150 2.204 0.019 MEASURES OF LENGTH (Unit Metre) Inches Feet Yards Miles Millimetre 0.03937 0.003 0.001 ..... Centimetre 0.39371 0.032 0.010 .....
- 37. Decametre 393.70790 32.808 10.936 0.006 Metre 39.37079 3.280 1.093 ..... Decimetre 3.93708 0.328 0.109 ..... Hectometre 3937.07900 328.089 109.363 0.062 Kilometre 39370.79000 3280.899 1093.633 0.621 BOARD AND TIMBER MEASURE BOARD MEASURE In board measure boards are assumed to be one inch in thickness. To compute the measure of surface in square feet— When all dimensions are in feet, multiply the length by the breadth, and the product will give the surface required. When either of the dimensions are in inches, multiply as above and divide by 12. When all dimensions are in inches, multiply as before and divide product by 144. TIMBER MEASURE To compute the volume of round timber— When all dimensions are in feet, multiply the length by the square of one-quarter of the main girt, and the product will give the measurement in cubic feet. When length is given in feet and girt in inches, multiply as before and divide by 144. When all the dimensions are in inches, multiply as before and divide by 1,728. Sawed or hewed timber is measured by the cubic foot. To compute the volume of square timber— When all dimensions are in feet, multiply the product of the breadth by the depth by the length, and the product will give the volume in cubic feet. When either of the dimensions are in inches, multiply as above and divide the product by 12.
- 38. When any two of the dimensions are in inches, multiply as before and divide the product by 144. WHAT TO DO IN EMERGENCIES Many books and pamphlets have been written advising the layman what to do in a case of emergency, and in the absence of a physician or surgeon. Much of the information presented is altogether too technical, and is not likely to be understood by the public at large. The author has attempted to cover, in a few pages, the fundamentals of first aid to the injured, and has carefully avoided technical and medicinal terms. No amount of information, no matter how carefully or plainly written, can take the place of the physician or surgeon. Self-doctoring and -dosing is, or should be, considered a crime, and no one is justified in attempting to relieve any one suffering from accident or any other ailment, if it is of possible seriousness, unless a good physician or surgeon cannot be procured. First and always, keep your head, and keep cool. Don't get excited. Work rapidly, but deliberately. If the injury or trouble is at all serious, summon a surgeon or physician immediately. If you are alone with the sufferer, it may not be safe for you to leave him, but unless he is in immediate danger, it is better to call a competent physician, even though you have to absent yourself from him for a few moments. If the accident occurs in a crowd, solicit some one who looks trustworthy, and request him to telephone or otherwise communicate with a doctor. If you know the cause of the accident or trouble inform the physician in advance, so that he may be better prepared to meet it and bring with him instruments and remedies. The patient or sufferer should be placed in a comfortable position, a doctor or surgeon summoned, and in the interval the layman may follow the instructions presented here. If he does so, no harm will be done, and in many cases suffering will be relieved, and death or serious illness prevented. But the author again, and most emphatically, urges the layman to send for a physician or surgeon, and to follow the instructions or information given in this chapter only as preliminary to the arrival of the doctor or surgeon, unless the injury be of slight consequence. If possible, remove the patient to a quiet place, where there is plenty of air, and where the temperature is normal. If there are many people about, request them to keep away. Place the injured person in a comfortable position, usually upon his back, and straighten out his legs and arms. If the head is injured, better lift it above the level of the body; but if it is not, allow the body to lie on a level.
- 39. If the patient is breathing hard, it may be well to lift him into a sitting position. Loosen his collar, waist-band, and clothing. If he faints, his head should be slightly lower than his feet. If an arm or leg is injured, lift it slightly and place it upon a cushion, pillow, or other support. If the one injured is unconscious, watch him very carefully. If he is vomiting, or that tendency is apparent, turn him over on one side so that the discharge will run out easily and not go into the lungs. If he is wounded, cut away the clothing covering the wound, but don't remove any more than is necessary. If he has been burned, pour lukewarm water, containing a little saleratus or bicarbonate of soda, over the clothing before you remove it. If he is bleeding severely, stop the bleeding before dressing the wound. After the wound is dressed there is nothing for the novice to do, except bring the patient to consciousness, if unconscious, and remove him to a place of safety and comfort. If the accident or injury be serious, or the patient is unconscious, it is well to request more than one bystander to summon a physician, because the first one sent may fail, or the physician he telephones to or calls upon may be unavailable. Use the telephone, if there is one at hand or nearby, and tell the physician what you think is the matter with the sufferer or what caused the accident, that he may be better prepared to bring with him the instruments necessary. If you are alone with the patient, and cannot notify a physician or surgeon without leaving the patient, you must use your best judgment; but you should make every possible effort to reach a physician at the earliest possible moment. Remain with the patient long enough to place him in a comfortable position, and to stop the flow of blood, if bleeding; then make all haste to notify a physician or surgeon. The author acknowledges his indebtedness to Johnson's First Aid Manual, published by Johnson Johnson of New Brunswick, N. J., and to Jay W. Seaver, M. D., of New Haven, Conn., and recently of Yale University. Accidents.—Convey the sufferer to a place of safety, and give him plenty of air. If a shock follows, follow instructions given for shock. Do not touch the wound with the bare hand. Wear absolutely clean gloves or wrap the fingers in clean cloth or gauze. Do not attempt to cleanse the wound. Summon a surgeon immediately. Apparent Death.—Never assume that a person is dead because he appears to be. Summon a physician. A fairly good test of death is to hold the hand of the person apparently dead before a candle or other light, with the fingers stretched out, each touching the other. Gaze intently between the fingers, and if the person is alive, a red or pink color will undoubtedly be seen where the fingers touch each other. Another method is to take a cold piece of polished steel, like a razor blade or table knife, and hold before the mouth or nose of the person apparently dead. If moisture does not gather on it, it may be safe to assume that breathing has stopped; but these tests are not infallible.
- 40. Bandaging.—There are two kinds of bandages,—the roller bandage or the triangular or handkerchief bandage. They may be purchased at any drug store or be made on the spot in an emergency. The purchased bandages are made of gauze, or muslin, crinolin, elastic webbing, rubber, or other material. The roller bandages are absorbent, and are very thin and pliable. They should be placed next to the wound and hold the fluids. Muslin bandages are stronger than those made of gauze, and should be used for pressure and outside bandages. Bandages should be kept in a perfectly clean place, and always covered, either by being enclosed in a box or wrapped in paper. If an improvised bandage is used, care should be taken to use a clean cloth. The triangular bandage is made by cutting a piece of cloth about 36 inches square into two pieces diagonally. It can be purchased at a drug store, or any clean cloth can be used if it is of firm texture. Baths.—Cold baths may be taken to reduce fever and in sunstroke and other cases when the temperature is high. It is well to have the temperature in the bath at 70° or 80° Fahrenheit, and to reduce the water until it reaches 60° or 65°. Tepid baths have a temperature of 80° or 90°, and warm baths are of a temperature from 90° to a little less than 100°. Hot baths may be used in case of shock, apparent drowning, depression, and similar troubles. The temperature of the water should vary from 98° to 110°. When the patient leaves the bath, he should be dried quickly and put to bed. Hot baths may produce fainting, and should be taken in the presence of an attendant. Do not guess at the temperature of the water; use a thermometer. Bleeding.—Arterial blood, or blood coming from the arteries, is bright red, and is discharged in spurts or jets. Such bleeding is very dangerous, and unless a physician arrives almost immediately the patient is not likely to survive. Venous blood, which comes from the veins, is of dark purple color and flows freely and steadily. Capillary bleeding comes from injured small veins. It flows slowly, and such bleeding is dangerous only if it continues. Always summon a surgeon or physician, and put in a hurry call for him. Force the patient to lie down in a level position, preferably upon his back. If the leg or arm is wounded, elevate it. Cut away the clothing quickly, so that it may be exposed. Press the bleeding places, but cover your finger with gauze or a clean handkerchief, or compress the part by using a strong cloth bandage. If the bleeding comes from an artery, cover your finger with a few thicknesses of gauze or clean cloth, and press hard upon the wound and maintain the pressure, which may stop the bleeding. If the wound is large, crowd a lot of gauze into it, and push it in, then press on the flesh a little distance above the wound, that is, between the wound and the heart. This can be done by winding a bandage, a piece of rubber tubing, string, or rope, or a pair of suspenders may be used, above the wound.
- 41. If the arm or leg is crushed, do not press on the wound, but bring pressure to bear above it. Bleeding from the Veins.—Lay a piece of gauze over the wound and bind it on with a firm bandage. Be very careful not to apply your naked fingers or hand to the wound unless you have washed them in some antiseptic, but even then it is better to cover your fingers with clean gauze or cloth. If the bleeding is very severe, apply cracked ice wrapped in gauze, and hard pressure below the wound. Varicose veins occasionally bleed. Elevate the arm or leg and bandage it very tightly, the bandage to be placed directly over the bleeding spot. Bleeding from Capillary Veins.—As the blood oozes, and does not flow rapidly, expose the wound to the air for a short time, which will usually check it. The application of hot water is advisable, but warm water should not be used. Extremely cold water or cracked ice will stop some bleeding. If copious bleeding occurs around a tooth, it may be stopped by packing the place with plaster of Paris, or absorbent cotton may be used. In every case, keep the places warm. After the bleeding is stopped, give hot drinks, like hot tea, coffee, or milk, if much blood has been lost. Broken Bones.—Do not attempt to set the break. Handle the patient carefully. Place him in a comfortable position and undress him, removing the clothing by cutting it to save time. If it is necessary to carry him a distance, improvise a splint made of wood or heavy pasteboard and fasten it around the broken part with bandages. Carry him to a physician or summon one at once, but let him lie quietly if a physician can reach him. It is well to have two splints, one on each side, to be held in place by the same bandages. If the arm is broken, bandage it and place it in a sling. In every case, summon a physician or carry the patient to one. Chilblains.—Keep the feet warm and dry. Don't warm them at a fire or place them in hot water, but bathe them in cold water and rub with a dry towel. Apply turpentine, camphorated spirits, or oil of wintergreen. Cleanliness It is said that cleanliness is next to godliness. Good health is dependent upon the care of the body, and the body will not remain in a healthful state unless frequently bathed. The fact that thousands of persons enjoy good health without even taking an infrequent bath, must not be used as an argument against regular bathing. These persons, if in health, live out of doors, and Nature seems to take care of them; but it is obvious that they would be healthier and stronger if they gave proper attention to bodily cleanliness. The majority of city dwellers, and a large proportion of those living in the country, work indoors, and their health is dependent upon their personal cleanliness.
- 42. Opinions differ, and some hygienists do not consider the daily bath essential, but the majority of those who have studied the subject maintain that perfect health requires the daily bathing of the entire body. Without the daily bath one does not begin his work refreshed or with exhilaration. A scrub is not to be recommended more than once a week, but a bath should be taken daily, and the entire body rubbed with a dry towel, a bath towel to be preferred. Emersion in a tub of water is not necessary, although it is the best and easiest way of taking a bath, next to a shower bath. A sponge bath answers all purposes. A cold plunge should not be taken without the advice of a physician. The shower bath is very refreshing. A hot bath is seldom advisable. It is better to have the water of a temperature not much higher than that of summer heat. A pure soap should be used, and care should be taken to rinse it from the body. The daily bath is the best preventive of colds. Comparatively few people who bathe daily suffer from more than transient colds. The bath should not be taken in a draught. If the room is cold, work rapidly and use additional time for rubbing, continuing it until the skin glows. The practice of partial bathing is not to be recommended. When you take a bath, take it all over. If away from home, and sleeping in a hotel bed, which may have been occupied by a diseased person, it is well to go over the body carefully in the morning with an antiseptic soap. Every hotel, and all public conveyances, are laden with germs, and a bath will prevent many diseases. A few drops of ammonia or a teaspoonful of borax placed in the water in which you bathe will remove the odor of perspiration, but ammonia should not take the place of good soap. Clothing Afire.—Force the person afire to lie down and roll him over and over. Wrap him in a rug or blanket, or anything else at hand. Throw water upon him, but do not wait for water. Wrapping him in a blanket is sure to extinguish the flames. Under no circumstances allow the person afire to run about or out of doors. Colds.—Use simple remedies, such as hot lemonade, but if the cold does not soon abate, consult a physician. Diphtheria.—Consult your physician. Never go near a case of diphtheria or allow a dog, cat, or other animal to enter the sick-room. Be careful of every utensil, and do not allow any one else to use them until they have been washed in antiseptics. Never handle any clothing or other articles in a sick-room. Disinfectants
- 43. The reader is warned against placing reliance upon any disinfectant, because it smells of carbolic acid, or has any other strong odor. Many of the advertised disinfectants are worthless, and some of them are merely deodorizers, which destroy smell and don't disinfect. Sulphur or brimstone is probably the best fumigator. Sulphite of iron (copperas) is cheap and should be used for sewers and drains. Dissolve a pound and a half in a gallon of water. Two parts of sulphate of zinc to one part of common salt, dissolved in a gallon of water, is a good disinfectant for clothing, bed linen, etc. Carbolic acid is an excellent disinfectant, but is efficacious only when used at considerable strength, 3 to 5 per cent. Its strong odor suggests qualities which do not exist, if it is much diluted. There are many disinfectants upon the market, many of them being advertised to be efficacious. Some of them are thoroughly reliable, but others are almost worthless. I would advise the reader not to purchase or use a disinfectant which is not recommended by a reliable physician. Disinfecting Cellars, Yards, Cesspools, etc.—Use a solution made of 60 pounds of copperas dissolved in a barrel of water. Sprinkle freely over cellar and put a pailful in a cesspool. Disinfecting the Sick-Room.—Plenty of fresh air and cleanliness are to be first considered. The clothing, bed linen, and towels should be washed in a tub containing a zinc chloride solution, and the water should be boiling hot. A solution of copperas and water should be immediately placed in all vessels containing discharges. Dislocations.—The novice should never attempt to treat a dislocation. All he can do is to place the patient in a comfortable position, using a sling or cushion to support the part injured. A physician should be summoned. Dog Bites.—Wash the wound with antiseptic soap or pure soap and water, with borax dissolved in it to the strength of a teaspoonful to a pint. Hydrophobia occurs very infrequently, and many dogs, supposed to be mad, are suffering from some other ailment; but a surgeon should be summoned in all cases whenever it is possible to do so. The bite of a rat, cat, or other animal is not generally dangerous, but the wound should be washed with borax and water, as above. Better summon a surgeon. Suck the wound vigorously before applying washes. There is no danger to the person sucking a wound of this nature, unless the skin on his lips or in his mouth is cracked or bleeding, but he may wash his mouth with borax water if he feels uneasy about it. Drowning
- 44. If the person is conscious tell him that you will save him, which will prevent him from losing his nerve. If you swim out for him, and he is struggling, seize him by the hair and turn him over on his back. Swim on your side, towing him along as you would a log of wood. You may hold his head with one arm, but do not attempt to support his entire body. If he struggles violently, hold his head under water until he is unconscious, so that you can better handle him. Loosen his clothing, drain water out of lungs by inverting body, clean out his mouth, and pull his tongue forward. Immediately begin artificial respiration, each movement to last from four to five seconds. Apply warmth and rubbing, and when he is conscious give him hot water, coffee, or lemonade. Artificial breathing is of greatest consequence. Do not give up. Many persons have been resuscitated after many hours of incessant labor. Artificial respiration may be performed in the following way: First—Immediately loosen the clothing about the neck and chest, exposing them to the wind, except in very severe weather. Get the water out of the body, first by tickling throat with a feather, or applying ammonia to the nose; give a severe slap with the open hand upon the chest and soles of feet; if no immediate result, proceed as follows: Second—Lay the body down in the open air with the head hanging down and with its weight on the stomach across any convenient object, such as a keg, box, boat timber, or your knees. Open the mouth quickly, drawing the tongue forward with handkerchief or cloth to let the water escape. Keep the mouth clear of liquid. To relieve the pressure on the stomach, roll the body gently from side to side and then back on the stomach. Do this several times to force the water from the stomach and throat. Third—Lay the body on the back, make a roll of a coat or any garment, place it under the shoulders of the patient, allowing the head to fall back. Then kneel at the head of the patient. Open patient's mouth and place some small object between teeth. With tongue pliers or fingers covered with gauze or cloth, grasp his tongue and draw it out. Tie it down to his chin with cloth or rubber band. Grasp the patient's arms at the middle of the forearms, fold them across his stomach, and raise them over his head to a perpendicular position, drawing them backward, straight, then forward overhead to the sides again, pressing the arms on the lower part of the ribs and side, so as to produce a bellows movement upon the lungs. Do this about fifteen times a minute. Apply smelling salts, camphor, or ammonia to the nostrils to excite breathing. Fourth—On signs of life, or when breathing is restored, remove the clothing, dry the body, wrap the patient in warm blankets or hot cloths. To encourage circulation briskly rub his limbs under the blankets toward the heart; brandy or aromatic spirits of ammonia may be given in small doses, with care to avoid strangulation.
- 45. Another Method Another simple method of restoring breathing, one that is being rapidly adopted, is that known as the Schafer, or prone, method. It has the great advantage that it can be performed by one man alone. This method has just been endorsed as the preferable one by a commission representing the American Medical Association, the National Electric Light Association, and the American Institute of Electrical Engineers. First—Lay patient on stomach with his head to side and withdraw his tongue, which itself then will hang out if teeth are held apart with small object. The operator then kneels astride the patient's thighs and with his hands across the lower ribs swings his body back and forth rhythmically, pausing about two seconds as his weight falls upon and is removed from patient. This movement is to be continued at the rate of about fifteen times a minute. To Prevent Drowning.—The human body weighs, in the water, about one pound; that is, it is approximately one pound heavier than the water which it displaces. A stool, chair, or small box or board will overcome the tendency to sink and will keep the head above water. The feet, and the hand which is not clinging to an object, should be used as paddles. Every one should learn to swim. If he can take only a few strokes, the chances of death by drowning are small, for he is likely to be able to reach something which will support him. So much do I believe in the necessity of knowing how to swim, that I consider it a crime not to understand this art. Electrical Accidents.—Immediately shut off the current, but do not handle the wire with your naked hands. If rubber gloves are not handy, cut the wire with an ax or knife, with a piece of woolen cloth wrapped around the handle. If you pull the sufferer away from the wire, do not touch him with your bare hands, but cover them with woolen cloth, or wear rubber or woolen gloves, or remove him by the use of a rope. The ordinary electric shock will not cause death unless the patient continues to receive it. Summon a doctor at once. Place the patient in the open air, with something under his shoulders. Loosen his clothing, open his mouth, and pull out the tongue. Clear the mouth from saliva. Force air into his lungs by pressing the base of the ribs about once in four seconds, then attempt to resuscitate him as you would a drowning person. Emergencies with Children.—If the child suddenly suffers from vomiting, purging, and prostration, send for a doctor at once. In the meantime place him in a hot bath and then carefully dry him with a warm towel and wrap in warm blankets. If the hands and feet are cold, apply hot water bottles to the feet and hands. A poultice made of flaxseed meal (3/4) and mustard (1/4) should be placed over the body. Five drops of brandy in a teaspoonful of water may be given every 15 minutes. For sudden diarrhœa, administer one teaspoonful of castor oil or of spiced syrup of rhubarb. Allow the child to drink freely of cold water that has been boiled. Always summon a physician.
- 46. Emergency Medicines .. The writer would emphatically discourage self-medication and dosing, and would oppose the taking of medicines of any kind, except the simplest remedies, without the advice of a physician. Hundreds of thousands of people have been made sick, because the wrong medicine was administered to them, and many more have taken medicine when they didn't need it. The following emergency medicines are presented, with a distinct understanding that they should not be used except in simple cases: Ammonia.—What is known as ammonia water, or liquor of ammonia, or as spirits of hartshorn, or hartshorn, is of several strengths and is highly irritating and poisonous if taken internally. Applied externally, if of considerable strength, it will cause blisters and pain. Ammonia should not be applied to an open wound or irritated surface, except in case of snake bites or stings of insects, where it is intended to neutralize the poisons. The vapor of ammonia water, inhaled through the nostrils, affects the nervous system and may be used in fainting or epilepsy, but always with caution, for a strong preparation of ammonia applied to the nose may produce a violent shock. It is better to saturate a handkerchief or wad of cotton and hold it a short distance from the nostrils. The buyer is cautioned against the use of the strongest ammonia water. Aromatic Spirits of Ammonia.—This is a stimulant, and may be used in cases of sick headache, hysteria, cholic, or fainting, in doses of from 10 to 30 drops in sweetened water. Arnica.—Tincture of arnica is supposed to be of value in accidents, and especially efficacious for sprains and bruises. It has some value, mainly from the alcohol it contains and partly because it is applied with friction. It is a poison, and never should be taken internally. For external use it should not be applied at full strength, as it is apt to cause inflammation if the skin is tender. Bicarbonate of Soda.—Bicarbonate of soda, commonly known as baking soda or saleratus, is distinct from sal soda or washing soda. It is of great value in the treatment of burns, and may be used as an antidote in poisoning by acids. Camphor.—Camphor is purchased in gum or in liquid form. It never should be taken internally, except by advice of a physician. Nor should it be applied in its full strength directly to the wounds or to irritated or inflamed surfaces. Ginger.—The essence or extract of ginger is a very popular remedy for trouble with the digestive organs, bowel complaints, etc., and should be taken in doses of from 10 to 40 drops in sweetened water, milk, or other liquid. It never should be used habitually, because it may establish a drug habit; nor should large doses be taken to check diarrhœa, as it is often inadvisable to too rapidly check the discharges.
- 47. Glycerin.—Glycerin may be used for burns, and, mixed with equal parts of rose water, it is a good lotion for chapped hands or lips, but it is irritating to the skin of some people. Peppermint.—The essence of peppermint may be used for stomach-ache and bowel complaints, the usual dose being from 10 to 20 drops on sugar or in sweetened water. Oil of peppermint should not be taken, except when prescribed by a physician. Turpentine.—Turpentine is the base of most liniments, and it has some value, but mustard plasters are safer. Turpentine is inflammable, and never should be applied near an open fire. Turpentine should not be given internally, unless prescribed by a physician. Whisky.—Whisky, brandy, wine, and all other spirits should be used sparingly. They are likely to do more harm than good. Hot water, hot coffee, hot tea, or aromatic spirits of ammonia are to be preferred. Children should never be given spirituous liquids, except in extreme cases, and then only 10 to 20 drops in water. Witch Hazel or Hamamelis.—Used as a remedy for sprains, wounds, and swelling. It is a mild application for chapped hands, and used by the laity for burns, scalds, cuts, etc. It is not irritating, and is a good substitute for arnica. Its use externally is absolutely safe. Vaseline.—It is to be recommended for burns, scalds, etc. It is nonirritating and is not poisonous. It can be used frequently. Cold Cream.—A perfectly safe article to be used for chapped hands and lips, and skin roughness. Emetics and Stimulants.—In practically all cases, and where poison has entered the stomach, it is well to empty the stomach immediately. If a stomach pump cannot be procured, an emetic should be administered. Doctors would administer ipecac, apomorphine, sulphate of zinc, tartar emetic, and other drugs, but none of them are likely to be available before the physician arrives. When notifying the physician tell him, if possible, the kind of poison taken, so he may be prepared. A dessert-spoonful of ground dry mustard in a glass of warm water is likely to produce vomiting. Follow the first dose with a second one. Then push the forefinger down the throat as far as possible, that the patient may vomit. Dissolve a teaspoonful of salt in water and give to the patient, or administer a teaspoonful of ipecac every few minutes to a child, and a tablespoonful to an adult. Follow the dose with a glass of water and then insert the forefinger in the throat. One who has taken opium does not vomit easily and strenuous efforts should be made to produce vomiting. If one emetic does not work, give another, and keep on repeating it. Exercise
- 48. Physical exercises are absolutely essential to health. The working man, however, is likely to obtain enough of it from his daily action, but those of sedentary habits, especially those who work indoors, will not receive sufficient exercise from their labor. While the gymnasium is to be recommended, and while it has done much to make weak people strong, I would not advise any one to take more than very simple gymnasium exercises without the advice of a physician. Exercises may be taken in the bedroom, with the use of light dumb bells, or without the use of any apparatus at all. Walking is the best of all, for it can be enjoyed by those in poor health or physically weak. It takes one out of doors, and exercise out of doors is far better than that taken in a closed room. If you exercise at home, open all of the windows. Every one should walk at least two miles a day in the open air, unless he is very weak. Select a companion, as exercise is more efficacious if enjoyed and is not mere exercise by itself. Take long breaths in the open air every morning. Overexercise, and much of that practiced by athletes, injure the heart and work opposite from the intention. No strenuous exercise should be taken after mid-life without the advice of a physician. Any good doctor will prescribe a course of exercises for you at a nominal fee, most of them not charging more than a dollar for advice. Then, those who exercise need more food and a different kind of food from that required by those who do not exercise. As cases differ, it is inadvisable for me to prescribe proper food. Consult your physician. Extinguishing Fires from Coal Oil.—Do not attempt to smother the flame by water. Smother it with a carpet or cloth. Fainting Ordinary fainting is distinct from that which occurs from shock or collapse, the latter following serious injuries, while fainting is common with some people, and may not be serious. Those who are subject to frequent fainting spells should consult a physician that he may locate the cause. If fainting is caused from any disease of the heart, or from a weak heart, death may follow, and such persons should be under the care of a physician. When fainting occurs, place the patient on his back with his head as low or lower than the body. Raise the legs. He should have plenty of fresh air. If fainting occurs in a crowd, ask the spectators to move away. If in-doors, open all doors and windows, loosen the clothing, and sprinkle water upon the face, at the same time applying smelling salts or spirits of camphor held close to the nose, but not touching it. The
- 49. body may be rubbed to assist the circulation. If the person does not quickly revive, apply gentle heat or a mustard plaster to the pit of the stomach. When he recovers give him hot tea or coffee, and never more than a moderate amount of alcoholic stimulants. Keep him in a reclining position for some time after he has recovered. Feeding an Invalid.—If the illness is at all serious, consult a physician. He will tell you what and what not to give the patient in the way of food. Never cook the food in the presence of the invalid, and keep the smell of cooking away from him. Don't eat in his presence, as it may annoy him. Serve everything attractively, with spotless napkin, table cloth, and ware. Be careful not to spill anything. Hot articles should be served very hot, and cold ones very cold, as lukewarm viands are not acceptable. Everything brought into the sick-room should be covered with dishes or napkins. Better bring in too little than too much, more to be served if the patient desires it. Fire in the House.—When the house is afire cover the head, if possible, with a wet cloth, or dry one if there is no facility for wetting it, cutting holes for the eyes. Creep on the floor and don't stand up or walk, for the air is clearer next to the floor, as smoke rises. Unless there are plenty of exits, a knotted rope should be attached to a staple. It is easier to climb down a knotted rope than one which is smooth. If necessary to jump from an upper story, throw out a mattress or something else which is soft, and attempt to land upon it. When at a hotel or boarding house, ascertain the means of exit before retiring. Fits.—Generally speaking, the treatment should be similar to that given to one who has fainted. If the patient is hysterical, apply mustard plasters or ice to the soles of his feet and the wrists, but do not dash water in the face or use strong emetics or heroic measures. If the fit is caused by epilepsy (in this case the person is rigid), do not attempt to stop the patient from struggling. Lay him on his back with his head somewhat raised, and loosen his clothing. If necessary, hold his arms and legs gently, but do not use force. Place a stick or knife handle between the teeth to prevent biting the tongue. Always summon a physician. Frost Bite.—Never place the patient near a fire. Undress him carefully and pack frozen parts with cloths wet with ice water. Rub adjacent parts vigorously. Administer hot coffee or tea. If breathing appears to have stopped, treat him as you would one apparently drowned. When the patient begins to revive, place him in a warm, but not a hot, room, cover him with blankets, and rub him with a cloth wrung out of hot water; give him the ordinary stimulants, but not alcoholic ones. Fumigating a Sick-Room.—Formalin is probably the best fumigator. Place the articles to be fumigated in a closed room, and pour formaldehyde over towels or bed linen and place on the floor. The room should remain closed for 24 hours. A room containing 100 square feet of floor surface requires at least a pint of formaldehyde. Getting Things into the Eye, Nose, Ear, etc.
- 50. Eye.—Sometimes complications result of a most serious nature. A physician should be sent for immediately. In the interval the following directions may be followed: Articles like cinders, dust, and other small objects may be removed from the eye, if one has a steady hand; but the eye should not be rubbed, and should be kept closed, except when one is trying to remove the foreign substance. The tears by themselves will often wash out ordinary dust or cinders. If the substance is hidden from view, one or two grains of whole flaxseed may remove it. Catch the upper lid by the lashes and pull away from the eyeball over the lower lid, holding it there for a moment, and request the patient to blow his nose vigorously. Visible articles may be removed with a piece of gauze on the hand, or an absolutely clean cloth; but don't touch the eye with the finger. As the eye is a very delicate organ, the novice should not attempt to operate upon it. Nose.—Blow the nose very hard, and close one side of the nostril by pressing your finger against it. Tickle the nose or give snuff to excite sneezing. Sometimes the article will be removed if the patient takes a long breath and closes his mouth, then give him a sharp blow on the back. If the body is not discharged, call a physician. Ear.—There is great danger in tampering with the ear. Never insert needles or pins in an attempt to remove foreign substances. Better send for a physician. If live insects enter the ear, pour a small quantity of sweet oil or glycerin into the ear and very gently syringe it with warm water. Throat.—Send for a physician immediately, and tell him what you think the matter is, so he may bring the necessary instruments. If there is no difficulty in breathing, wait for the physician. Slap the person on the back when the body is bent forward with face downwards, which will cause him to cough. Elevate him so that his head is lower than his body and slap him on the back while in this position. Getting Wet.—Many colds are contracted on account of exposure to rain and moisture. Unless able to change your clothes, keep moving. It is said that very few colds are contracted while one is exercising. Headaches.—Under no circumstances take a headache powder, or any drug whatsoever, without the advice of your physician. Many headache powders contain dangerous drugs, which work upon the heart, sometimes causing death. Headaches almost invariably come from a cause not located in the head itself. Do not attempt to cure it yourself. The headache powder may relieve the headache temporarily at the expense of the system. Hiccoughs.—Drink a glass full of cold water as rapidly as possible. Breathe deeply. If the hiccoughs continue, call a physician. How to Avoid Accidents Never cross the street without looking both ways.
- 51. Do not get off of a car or other vehicle while it is in motion. Never thrust your head or arms out of the car or other vehicle. When it is lightning, avoid trees and metallic articles. Never allow firearms to be lying about. Have some one place for them and be sure that no one can get at them. Move quickly when it is cold; and when any part is frozen, do not go near the fire, but rub with snow. Always change wet clothing as soon as possible, and keep moving until you have opportunity to change. Never walk on a railroad track. Do not light a fire with kerosene or other inflammable fluid. Never enter a cellar or anywhere else where gas is escaping with a light in your hand. Under no circumstances touch a wire hanging in the street. Maintain a medicine chest containing all of the common remedies, but don't select them without the advice of your physician. Mark each bottle plainly, with directions under the label. Never take medicine without looking at the label beforehand. Illuminating Gas.—Summon a physician, and before he arrives proceed as follows: Remove the patient into fresh air and walk him around. Place his arms about your shoulders, and if there are two rescuers place one arm around the shoulders of each. A glass of Weiss beer should be given while the patient is walking, as it removes gas from the stomach. In five minutes give half a teaspoonful of aromatic spirits of ammonia in a third of a glass of water. Repeat this dose every 15 minutes until four doses have been given. The neck of the beer bottle may be forced into the patient's mouth. Infectious Diseases.—It is now generally supposed that all contagious and communicable diseases are contracted by the germs which pass into the body or system. These germs are so small that millions of them may enter the body through the nose, throat, and skin. They do little or no harm to a healthy person, for the healthy body is opposed to their growth, but if one is weak, or suffering from a slight cold, or is depressed, they may multiply and cause diseases. These germs may be widely scattered,—in the clothes, bedding, carpets, and in the hair and skin. They cling to walls and ceilings and they will multiply on almost any kind of food. No one can wholly prevent coming into contact with them, but he can, if he will, avoid most of the contagious diseases by never sitting down in the sick-room, especially avoiding the bed, and keeping away from the walls and furniture. He should wash his hands with antiseptic soap after handling the patient. Exercise regularly in the
- 52. open air. Nurses should wear washable dresses, which are frequently changed and a washable cap should cover their hair. When in the sick-room do not approach the patient near enough to catch his breath. Do not touch with your lips any food, dish, or utensil which has been in the sick-room. Do not eat or drink in the sick-room. Wear no clothing that the patient wore before being taken sick. Never touch the sick person if your hands are sore or scratched, and be sure to wash them after contact with him. Never allow the dishes used by the patient to be used by any other unless they are very carefully washed and scalded in boiling water. All articles of food not eaten by the patient should be burned, and milk and food should never be allowed to stand in the sick-room. All bodily discharges should be immediately removed and covered with disinfecting solution, and the vessels should be washed with antiseptics before being brought back into the room. Lockjaw.—Do not attempt to cure it. Consult your physician. It will probably be fatal. Mustard Plasters.—Plasters occasionally are efficacious, but most give more apparent than real relief. They should not be used indiscriminately or without the advice of a physician. Neuralgia.—This is often incurable, but may be relieved. Certain liniments are efficacious, but are not to be recommended indiscriminately. Better consult your physician. Poison Poisons taken into the system through the mouth, and not through the blood, require a different treatment. Poisons may be classified as follows: 1. Irritant, in which the symptoms appear entirely at the location of the poison. 2. Systemic, in which the poison affects the system at large in addition to producing local irritation. 3. Narcotic or sleep- producing. 4. General, in which there is no local irritation. In the first mentioned, it is best not to cause vomiting. Give dilute acids to neutralize alkalis, and dilute alkalis to neutralize acids. Then administer oil, raw egg, or flour and water. Small doses of opiates may be given to quiet the pain, and whisky or other spirituous liquor to relieve weakness. In the second class (except for arsenic or similar poisoning) no emetic should be given. The poison may be counteracted by bland doses of oil, flour, and water, white of eggs; and stimulating drinks should be given to counteract depression. In the third class, make strenuous effort to produce vomiting, then give strong coffee or other stimulating drinks, and make every effort to keep the patient awake, even if you have to keep him walking.
- 53. Fourth class. Give emetics, and follow with stimulating drinks to relieve weakness and pain. The patient should be allowed to rest. Poisoning. Poisoning by Acids.—For sulphuric, muriatic, nitric, and acetic acids give immediately a solution of baking soda or magnesia, chalk, lime, soap-suds, or chalk tooth powder, followed by raw eggs, milk, or sweet oil. For Carbolic Acid or Creosote.—Give alcohol and, immediately, castor oil, sweet oil, raw eggs, or milk, followed by an emetic. For Oxalic Acid.—Administer lime, chalk, or magnesia. Lime may be scraped from the wall or ceiling and dissolved in water, but don't use soda, potash, or ammonia. For Prussic Acid.—Generally the patient dies immediately, but if he is still living, do not stop to give emetics, but administer stimulants. Apply hot and cold douches and use artificial respiration. For Aconite Poisoning.—Wash the stomach with a stomach tube and avoid emetics. Use stimulants. Apply warmth to the extremities and place mustard plasters over the heart and legs. If the patient is insensible, use artificial respiration. For Camphor.—Give emetics, oils, and eggs. Apply warmth to the extremities. For Chloroform.—If caused by inhalation, resort to artificial respiration and apply friction. Place the patient in the fresh air, keeping the head very low. Alternate hot and cold applications. If it occurs from internal use, administer large doses of bicarbonate of soda in water. Administer artificial respiration if the patient is insensible. For Nux Vomica.—Tobacco, chewing or smoking, and animal charcoal, dissolved in water. Follow with emetics. Use artificial respiration when necessary. For Opium.—Administer an emetic, such as mustard or ipecac. Apply water to the head, face, and spine. Give strong coffee, but do not give alcoholic stimulants. Keep the patient aroused by walking, whipping, or other means. Use artificial respiration if necessary. For Arsenic.—Give emetics immediately, including draughts of hot, greasy water or salt and water. Administer in large doses magnesia or lime scraped from the walls or ceilings. Give castor oil, sweet oil, or equal parts of sweet oil and lime water, or raw eggs. Use stimulants well diluted. For Corrosive Sublimate.—Administer an emetic and large doses of white of eggs, milk, mucilage, barley water, or flour and water. Force the patient to swallow large quantities. Use the stomach pump. For Belladonna.—Give emetics and stimulants. Apply warmth to extremities and mustard plasters to the feet. Use artificial respiration if necessary.
- 54. For Poisonous Mushrooms.—Give emetics, castor oil, stimulants, and apply heat. Pulse.—The average rate of the pulse in adults is 76 beats every minute; but it varies according to age. At birth it is from 130 to 140; 1st year, 115 to 130; 2d year, 100 to 115; 3d year, 95 to 105; between 7 and 14, 80 to 90; between 14 and 21, 75 to 80; between 21 and 60, 70 to 75; in old age, from 75 to 80. The female pulse is from 10 to 15 beats quicker than that of the male of the same age. To count the pulse, place the finger over the artery at the wrist; count the beats for 15 seconds, multiply this by four, and the result is the number of beats a minute. Do not use the thumb, as there is a sort of pulse in it which interferes with counting. Rheumatism.—So far as is known, there is no certain cure for rheumatism, notwithstanding the many nostrums that are advertised as sure cures. Rheumatism may be helped by avoiding meat and other nitrogenous foods, confining the diet to vegetables and similar foods, and drinking water freely. Rheumatism, however, is too serious to be treated by other than a physician. Scalds and Burns Place the patient in a comfortable and safe place and remove the clothing rapidly with a knife or scissors. If it sticks, cut away as much as is necessary, but don't pull it off. Clothing may sometimes be removed by sprinkling with water or oil. Do not expose the surface of the burn or scald to the air. Cover as quickly as possible with flour or vaseline and wrap a cloth about it wet with a solution of water and common baking soda. If the clothing is afire, force the person to lie down immediately, wrap him in a blanket or other piece of cloth, preferably of woolen. Do not allow him to run around or expose himself to a draught. Fire may be extinguished by slapping the burning parts with a cloth, or throwing water upon the person, but the wrapping process is better, because it immediately smothers the fire, and water is not always available. Slight scalds or burns may be relieved by the application of a solution made of a pint of water with one teaspoonful of baking soda or saleratus. Apply with a piece of lint, and then cover the burn or scald with absorbent cotton, held in place by a bandage. If the burn or scald is severe, apply sweet oil, olive oil, vaseline, or the white of an egg. If these are not handy, cover the spot with starch or use damp earth. Burns caused by lye, and other alkaline chemicals, should be covered with water, then with vinegar, and then treated as those by fire. Burns caused by acids and vitrol should be soaked with water and thoroughly washed with soda (saleratus) or lime water. Chalk or tooth powder may be used when saleratus is not available. Carbolic acid burns may be treated with strong alcohol.
- 55. Burns of the mouth or throat coming from the drinking of hot fluids, may be treated by taking oil or the white of an egg into the mouth and allowing it to run into the throat if the throat is affected. Vinegar should be used for burns in the mouth coming from caustic potash and ammonia. If the burn is serious, summon the doctor. Burns caused by gunpowder should be treated the same as are ordinary burns. Shock or Collapse Shock or collapse frequently occurs after serious accidents. It can be foretold generally, because the skin is cool and clammy, and it is usually accompanied with vomiting or rapid pulse, irregular breathing, or sighing, and the eyelids may be heavy, the pupils dilated, and the mind is not active. Insensibility frequently accompanies a shock. Send for a surgeon or doctor immediately. Place the patient in a warm bed, if possible, cover him with blankets, and allow his head to lie low. Remove all clothing, cutting it to save time. Wrap bandages around wounds or broken bones. Hot cloths, or hot water bags, or a hot brick wrapped in cloth should be applied to the region of the heart, the pit of the stomach, and the feet. If wet cloths are used, wring them out frequently in hot water and re-apply them. It is not necessary to use heat sufficient to burn the skin. Under no circumstances apply heat to the head. If possible, force the patient to drink hot water, hot tea, hot coffee, or hot milk. Malted milk is excellent, but it should be hot. Whisky and other alcoholic liquor should not be given, except by the advice of a doctor. Half a teaspoonful of aromatic spirits of ammonia in water may be given every 15 minutes for four doses, but not more. Stimulants should not be given after the patient begins to recover. Vomiting may be stopped or relieved by administering a little brandy mixed with cracked ice. If the skull is injured or there is concussion of the brain, with or without the appearance of apoplexy or severe breathing, do not administer a stimulant. Sleeplessness.—Insomnia rapidly lowers the vital forces. It is due to several causes, including mental worry, indigestion, physical overexercise, and functional or organic diseases. Insomnia may be considered a natural warning of coming ailment. The cause should be located, and a good physician should be consulted. Sleep is encouraged by exercise in the open air and by taking hot drinks just before retiring. Hot malted milk is excellent; but solid food should not be taken just before retiring. Mild gymnastic exercise may be taken before an open window, but drugs should never be administered without the advice of a physician. Snake Bite.—Do not waste valuable time to kill the snake. If the bite is venomous, rip open the clothing so that the wound will be exposed. Tie a handkerchief or rope
- 56. around the arm or leg, above the bite. It should be drawn so tight that the circulation will be stopped or retarded. The use of a stick or pencil will assist in giving pressure. With a knife, open the holes made by the snake's fangs and cut around the wound liberally, being careful not to sever an artery. Let the blood run freely. Poison is sometimes removed by sucking a wound, but one should not do this if his lips are chapped or bleeding. The wound should be washed with soda solution and large doses of whisky or brandy should be administered. Call a surgeon immediately. Sore Throat.—Sore throat may be merely local or be a forerunner of diphtheria. Better consult a physician. Sprains.—Most sprains are serious, and a doctor should be called at once, but before he arrives the following simple treatment may be applied. Sprains twist and tear the ligaments and may rupture the small blood vessels. The flow of blood may be checked by application of cold or heat or by pressure. If the ankle or foot is sprained, wrap a folded towel tightly around the part sprained and then apply moist heat and elevate the leg. Immerse the foot in water as hot as can be borne and keep on adding hot water for about 20 minutes, so that the temperature may not be lowered; then apply a bandage, but continue the bathing treatment. Cold applications may be used instead of hot water, and should be applied by dipping cloths in ice water frequently, and wrapping them about the parts injured. Stings of Poisonous Insects or of scorpions, centipedes, etc., should be treated with hartshorn, ammonia, after which cold water or cracked ice should be applied. Do not fail to call a surgeon or doctor. If the sting remains in the wound, remove it either by pressure on the skin or with a knife. The stings of common insects, such as mosquitoes, ants, etc., should be treated with a weak solution of ammonia, salt water, or a cloth wet with water in which a teaspoonful of baking soda to a pint of water is dissolved, may be bound on it. Suffocation.—Always summon a physician. Place the patient in the air, remove all tight clothing about the neck and chest, and apply artificial respiration. Apply hot water in bottles to the body. Put mustard plasters above the heart, on the soles of his feet, and on his wrists. When the patient shows signs of recovering, give mild stimulants. If the patient is in a close room, open the windows and all of the doors. In rescue work do not open windows, but smash out all of the glass. In entering a room full of smoke, cover the mouth with a handkerchief wet with water or vinegar and water. Crawl on the floor, as the smoke is less dense near the floor. The rescuer should attach a rope to himself, so he can be pulled from his dangerous position. Sunstroke.—Indications of sunstroke or heat prostration are a slow but full pulse, very labored breathing, and the skin is hot and dry, the face usually red, and the person affected is unconscious. Remove the sufferer to a shady place, and be sure to loosen his collar and clothing, if tight. Raise the head and shoulders. The head, face, and chest should be drenched with cold water, and if it is very hot use cracked
- 57. ice. In ordinary cases of heat prostration, the patient is not unconscious, the skin is pale and clammy, and the breathing is not normal. Force the patient to lie on his back with his head level with his body, and loosen all tight clothing. Apply heat to the extremities, and cold to head. The patient should not be allowed to drink too much water. Give him hot drinks, and apply heat to the spine and feet. Under no circumstances administer alcoholic stimulants. Always send for a physician. Temperature of the Body.—The normal body temperature is 98.4 degrees Fahrenheit. When it is higher, the patient is supposed to have a fever. Temperature usually rises in the afternoon, being one degree higher than in the first part of the night or in the early morning. It gradually falls from midnight to six or seven o'clock in the morning. The temperature of a child frequently rises two degrees from slight causes. Every family should carry a clinical thermometer. Bodily temperature should be taken by holding it in the mouth under the tongue for two minutes. Temperature under 101° indicates a slight fever; under 103° a moderate fever; under 105° a high fever. When the temperature rises two or three degrees above normal, send for a doctor at once. Temperature of the Sick-Room.—Sixty-eight degrees Fahrenheit is a good average temperature for the sick-room. In certain diseases the average temperature may be lower, and for throat or chest affections it should be higher. When the patient is being washed or dressed, the temperature should be kept at about 70°. Toothache.—If the nerve is exposed, or nearly so, toothache may be cured by placing in the cavity a small piece of cotton soaked in creosote or oil of cloves. If it continues, consult a dentist. Transporting the Wounded.—Great care should be taken, because the slightest carelessness is likely to cause intense suffering. A four-handed seat may be made by two persons, the hands of each one clasping one of the wrists of the other, and two ordinary men can easily carry a person of average weight. A stretcher will carry the patient in a horizontal position if the persons carrying it place their hands under it. A stretcher may be made of boards, over which are placed coats or shawls, or a blanket may be fastened to two stout poles; if no poles are handy, a shawl tightly held by two persons will do, but great care should be taken to keep it tight. A window shutter is generally available. The sufferer should be very carefully placed upon the stretcher, and had better be lifted by several persons, by two at least. The bearers of the stretcher should not keep step, the opposite feet should be put forward at the same time to prevent the swaying of the stretcher and the rolling of the patient. Never carry the stretcher on the shoulders. Carry the patient feet foremost, except when going up hill. In case of a fractured thigh or leg, carry the patient head first when going down hill. Ventilation.—The sick-room should never be without fresh air. Impure and close air breeds disease and encourages illness. Fresh air should be introduced constantly and steadily. The windows may be lowered at the top or patented ventilators used.
- 58. To change the air, open the windows in an adjoining room, and then open the door between the rooms, but the fresh air in the adjoining room should be warm before it is allowed to penetrate the sick-room. By swinging the door back and forth, the air will be fanned in. Do not maintain the erroneous impression that cold air is pure because it is cold, for cold air may be as foul as warm air. Night air is not dangerous. The patient must breathe night air or closed-in day air, and closed-in air rapidly becomes foul. Vomiting.—Lie down and hold small pieces of ice in your mouth. If it continues, consult a physician. Wills.—A will, untechnically speaking, is virtually a bill-of-sale or transfer of property by its owner to those he may designate, but differs from the ordinary bill-of-sale in that there is no consideration mentioned on the part of those who will receive the property, and the will is not operative until the death of the maker of it. No one can execute a will unless he is presumably in his right mind, and knows what he is doing. Nor can a will be made by an idiot or one insane. The will must be signed and witnessed by several witnesses, each witness signing as a witness in the presence of all of the other witnesses. While it would appear that every one has a right to dispose of his property as he chooses, a will is not likely to stand in law if it can be proved that the maker of it was under undue or unfair influence, and, therefore, distributed his property to the prejudice of those who would be entitled to it if no will was made. For example: a will is not likely to hold good if its maker unfairly disowned close legal heirs, like a wife, husband, or children, or bequeathed his property to some institution which it could be shown he probably would not have done had not unfair pressure been brought to bear upon him at the time he made his will. All legal heirs should, as a rule, be mentioned in a will, even though they are given insignificant sums. As the laws differ in the several states, it is suggested that it is better and safer to consult a good lawyer, or one familiar with conditions. Wireless Telegraphy.—The exact date of the discovery or invention of wireless telegraphy is not accurately known. Many scientists discovered it theoretically before Marconi made it practical. Some scientific authorities claim that it was originated by Professor Dolbear, of Massachusetts. In 1899, messages were sent from England to France, and recently an intelligible message was flashed across the Atlantic Ocean. Unscientifically speaking, wireless telegraphy consists of discharging powerful electrical currents into the atmosphere, their vibrations being taken up by the natural electricity in the air, and received by wires placed at an elevation. Practically all sea-going steamers are equipped with wireless telegraphy. Woman's Suffrage.—The first convention in the interest of woman's rights was held July 19, 1808, at Seneca Falls, N. Y. In 1850, a National Woman's Rights Convention was held in Worcester, Mass. From that time woman's suffrage was agitated in America and in England, and many of the leading women of the world strongly advocated it. It is growing rapidly, and is being recognized throughout the
- 59. country, although all of the States have not given the vote to women. Under the Constitution of the United States a native-born woman may hold any office, including that of president, even though the women in all of the States cannot vote at the presidential election. The Constitution of the United States does not recognize sex, and in the eye of national law, women have all of the rights of men. Women Voters.—Many of the towns, cities, and States give full franchise to women, while others allow them to vote for only a few officials. Woman's suffrage, or the right to vote, is spreading rapidly, and it is probably only a question of time before she will have full franchise throughout the entire country. There is nothing in the Constitution of the United States to prevent a woman from holding the office of president or vice-president if she was born in this country, and she can hold such offices even though she may not be permitted by State law to vote for them. Wool Industry.—The United States produces about $320,000,000 worth of wool in a year and weaves about 55,500,000 square yards, worth about $40,500,000. World's Largest Steamships.—The Imperator, just placed in commission, is the world's largest vessel. She is 919 feet long, 98 feet beam, and 62 feet deep. The boat deck is 100 feet, and the trunks of the mast 246 feet, above the keel. The funnels are 69 feet long with oval openings, 29 by 18 feet. The rudder alone weighs 90 tons. She is registered at 50,000 tons, with a displacement of 70,000 tons. Displacement represents the weight of the water which is occupied by that part of the hull under water. The ship is a modern floating hotel, containing a grill-room, a tea garden, a veranda café, several ladies' sitting-rooms, a palm garden, a ball- room, a gymnasium, a swimming tank, and other accessories. In the first cabin there are 220 regular bath rooms and showers, including 150 private bath rooms. The staterooms do not contain berths, metal bedsteads being used throughout. The entrance hall is 90 feet wide, and 69 feet long. In addition the vessel carries a drug store, a book store, and a flower shop, and several passenger elevators are maintained. To illuminate the ship there are 9,500 electric lamps. The Roman bath is 65 feet long, and 41 feet wide. The swimming bath is 39 feet long, 21 feet wide, and 9 feet deep. The quadruple turbine engines have 72,000 horse-power and develop an average speed of 22-1/2 knots an hour. One of the immense rotars contains 50,000 blades, and weighs 135 tons. The ship carries a crew of 1,100 persons, a complete fire department, and wireless telegraphy. If the Imperator was set on end, she would be higher than the largest building in the world, which is 750 feet high. The ship has a passenger capacity equal to the population of a large town. Yankee.—This word is said to be a corruption of English or Anglais, pronounced by the Massachusetts Indians, who gave this name to the New England Colonists, Yenghies, Yanghies, Yankees. It was applied to the New Englanders by the British soldiers during the Revolutionary War, and to the Federal soldiers by the Confederates during the Civil War.
- 60. Yankee Doodle.—The origin of Yankee Doodle, perhaps the most famous American national air, is unknown. It is supposed to have been an English tune. At any rate, it was introduced into America by the British troops in 1775.
- 62. INDEX Abbreviations in common use, 1 Accidents, 160 Accidents, electrical, 173 Accidents, how to avoid, 185 Acetylene gas, 2 Acid poisoning, 189 Aconite poisoning, 190 Admitted to the Union, 62 Adventists, 2 Arsenic poisoning, 191 Æolian harp, 3 Afire, clothing, 166 Africa, 40 Age, 3 Agricultural implement industry, 3 Air ship records, 114 Alaska, 3 Alberg tunnel, 59 Algebra, 4 Almanacs, 4 Amazons, 4
- 63. American inventions, 57 Ammonia, 174 Antarctic ocean, 40 Apostles' creed, 4 Apothecaries' weight, 154 Apparent death, 160 April Fools Day, 4 Arbor Day, 5 Arctic ocean, 40 Area of a circle, 24 Area of a square, 26 Area of desert, 41 Area of fertile soil, 41 Area of the base of a square, 26 Area of the earth, 39 Area of the oceans, 40 Area of the United States, 62 Areas of earthquakes, 42 Arithmetic, 5 Arnica, 175 Aromatic spirits of ammonia, 175 Artesian wells, 5 Artificial ice, 5 Arts, seven liberal, 108 Asia, 40
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