text:
Pan Am Flight 103
Memorial Held To Mark 25th Anniversary Of Lockerbie Bombing
Saturday marked the 25th anniversary of the bombing of Pan Am Flight 103 over Lockerbie, Scotland. Two hundred and seventy people were killed in the terror attack.
Investigation Continues 25 Years After Lockerbie Bombing
On December 21, 1988, the 747 bound from London Heathrow to JFK Airport exploded and fell out of the sky over Lockerbie, Scotland.
Man Convicted Of Bombing Pan-Am Flight 103 Dies At Home
A New Jersey woman whose daughter was killed in the 1988 Lockerbie bombing says the death of the only person ever convicted in the case should not be used as an excuse to end any ongoing investigations into who planned and carried out the blast.
NY Sculptor Seeks Home For Tribute To Victims Of Pan Am Flight 103 Terror Bombing
Suse Lowenstein, who lives in Montauk, N.Y., on the far eastern tip of Long Island, has the massive sculpture, called "Dark Elegy," on display in her backyard garden.
Tri-State, Nation Reacts To Death Of Libyan Leader Moammar Gadhafi
Officials say Moammar Gadhafi, who ruled Libya for more than four decades, was captured and killed Thursday after his hometown of Sirte fell to revolutionary forces.
Bert Ammerman, Brother Of Pan Am Flight 103 Victim, Finds Relief In Gadhafi's Death
As reports of Moammar Gadhafi's death flooded the airwaves Thursday, Bert Ammerman took a moment to reflect.
Susan Cohen, Whose Daughter Was Killed In Pan Am 103 Bombing, Reacts To Report Of Gadhafi's Death
Gadhafi was alleged to be behind the bombing of Pan Am flight 103 back in 1988. The 747 exploded over Lockerbie, Scotland, killing 259 people on board and 11 on the ground.
Relatives Of Lockerbie Victims Set To Marry
Two New Jersey natives united in tragedy are getting married.
Doctor: Experts Agreed On Lockerbie Bomber Health
A cancer specialist who advised Scotland's government over the release of the Lockerbie bomber on Thursday defended the assessment of medical experts that the prisoner had only three months to live.


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The Immune System and
Infectious Diseases
Vertebrates Developed the Immune System to Deal with Pathogenic
Microorganisms, Malignant Cells, and Macromolecules
The immune system orchestrates a potent defense that consists of the produc-
tion of specific antibody molecules and lymphocytes capable of reacting with and
inactivating foreign agents, either directly or indirectly through the involvement
of molecular and cellular inflammatory processes. The importance of the immune
system to our survival in the face of the wide variety of disease-causing agents is
tragically demonstrated by the devastating consequences of the immunological
impairment of acquired immune deficiency syndrome (AIDS) and of congenital
immunological deficiencies such as severe combined immunodeficiency (SCID)
in infants. On the other hand, the enormous power of the immune system as a
protection against pathogenic agents carries with it the price that the action of the
system may lead to or exacerbate a series of immunological diseases, including
systemic lupus erythematosus, rheumatoid arthritis, and type I diabetes (juvenile
The immune system is composed mainly of lymphocytes and macrophages.
The cells of the immune system are found in the blood and lymph, where they are
in a recirculating pool, and in the spleen, lymph nodes, and lymphoid tissues
associated with the gastrointestinal tract, the brochopulmonary tree, and mucosal
surfaces. Lymphocytes and macrophages develop in the thymus and the bone
Although each cell type in the immune system has a major role to play, it is
the lymphocytes that form the unique elements of the system since they display
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the antigenic specificity that is the hallmark of immunity. Lymphocytes are of
two major types, B cells and T cells. B cells are the antecedents of antibody-
producing cells, whereas T cells have their major effects in regulating the level of
activity of the immune system and in mediating cellular effecter mechanisms of
immunity, such as destroying virus-infected cells and tumor cells.
The study of the immune system has proven to be of great importance in
efforts to understand and to regulate immune responses, both to enhance the
system's protective actions against microbes and tumor cells and to control its
actions in the development of autoimmune diseases and other disorders with
immunological components. In addition, the cells of the immune system are
valuable in the study of many aspects of normal biology of mammalian cells since
they are easily accessible, have been extensively characterized, and can be easily
Specificity of the Immune Response
Perhaps the Most Remarkable Aspect of the Immune System Is Its Specificity
Each of us has the capacity to make a specific immune response to a vast
array of foreign macromolecules: The body develops antibody molecules specific
for structures (antigenic determinants called epitopes) on the foreign agent and
produces B and T lymphocytes that bear membrane receptors specific for these
epitopes. We now recognize that the capacity of the immune system to respond to
millions of different foreign antigens depends on the existence of an internal
universe of distinct lymphocytes, each capable of mounting an immune response
against only one set of structurally related antigens.
The capacity of individual lymphocytes to respond to only a single set of
molecules is coupled with a rapid and selective increase in the number of these
lymphocytes as a result of the introduction of the specific antigen (Figure 7-1~.
This increase results in the formation of clones of specific lymphocytes, a prop-
erty that led to the designation of the clonal selection theory to describe the
concept that the enormous specificity of the immune response is achieved by the
antigen-mediated selection of individual cells (or clones of cells), each with but a
single specificity. Selected clones not only increase in number, but also differen-
tiate into antibody-producing cells (B cells) or into active regulatory cells or killer
cells (T cells). Such selection of B cells and the parallel process of T-cell se-
lection forms the basis of protective immune responses.
The capacity of the immune system to make B-cell and T-cell responses to
virtually any foreign substance is based on unique mechanisms that allow the
assemblage of genes for the extremely large number of alternative forms of
antibodies and receptors. Recent progress in the application of molecular biologi-
cal techniques to the study of lymphocytes has led to a solution of this central
biological problem. In order to understand the molecular mechanisms respon
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rl I I I
1 1 1 1 1
Antibody 3
proliferation and
Antibody 99
FIGURE 7-1 Lymphocytes undergo antigen-independent diversification and antigen-dependent
growth and differentiation. Lymphocyte precursors develop into mature lymphocytes through an
antigen-independent process that involves rearrangements of genes for the variable regions of im-
munoglobulins (for B cells) or for the variable regions of T-cell receptors (for T cells). As a result of
this antigen-independent diversification, each lymphocyte expresses a distinctive receptor on its
surface. In the example shown, a series of different B cells (expressing receptors designated 1, 2, ....
n) are exposed to an antigen. Two of these (3 and 99) have receptors that can bind to determinants on
the antigen, and, as a result, they are stimulated to divide and to differentiate into cells that secrete
antibody. That antibody has the same specificity as the receptor, hence, the antibodies are designated
antibodies 3 and 99. A similar situation exists for T-cell responses, except that the T cell recognizes
a complex of antigen and a class I or class II major histocompatibility molecule and that the T cell
does not secrete antibody. T cells mediate their functions as a result of receptor-mediated activation.
[Adapted fran I. ~ Weissman et al., Essential Concepts in Immunology (Benjamin/Cummings,
Menlo Park, Calif., 1978), figure 3-1]
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sible for the generation of the large number of distinctive antibodies and recep-
tors, a review of He salient feature of the structure of these molecules is neces-
sary. Furthermore, the consideration of the structure of these antibodies, known
as immunoglobulin (Ig), and of the related B- and T-cell receptors is important in
its own right since they represent a majority of biological recognition systems.
Antibody Molecules and B-Cell Receptors Are Proteins Called Immunoglobulins
Although Ig exists in several distinct forms, termed classes, these molecules
have a common structural organization consisting of a unit that is a dimer of a
heavy (H) chain and a light (L) chain pair Q;igure 7-2~. The H chain contains four
or five segments, or domains, each of approximately 110 amino acids, whereas
the L chain consists of two such domains. Each H-chain-L-chain pair forms an
antigen-binding site, which has elements of both the H- and L-chain amino-
terminal domains. Indeed, the amino-terminal domains of the H and L chains
from different antibodies differ structurally from one another, an observation that
is consistent with the fact that the binding site of each antibody is different. Thus,
these domains of the H and L chains are designated the variable (V) regions (VH
and Vat ). The variability of the V regions is concentrated into three segments of
each chain, designated hypervanable regions, which contain the amino acids that
actually make contact with the aniigenic determinant in the binding of antibody to
FIGURE 7-2 A schematic drawing of an antibody molecule. Each molecule is composed of two
identical light (L) chains and two identical heavy (H) chains. Me antigen-binding sites are formed by
a complex of both H and L chains. [Reproduced, with permission, from P. H. Raven and G. B.
Johnson, Biology (Times Mirror/Mosby, St. Louis, 1989), figure 52-18B]
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The remaining (carboxy-terminal) portions of the H and L chains are the
constant (C) regions (CH and CL)- The CH portion of the Ig molecule determines
its biological function. Indeed, Ig exists in a series of distinct classes (IgM, IgD,
IgG, IgA, IgE), each of which has a distinct CH region and distinctive functional
The structural basis of antibody-epitope binding has recently been clarified
by determining the crystal structure of antigen-antibody complexes. This struc-
ture graphically illustrates the areas of contact of antibody with antigen (Plates 4
and 5~. More extensive structural analysis of antibody-antigen interactions may
allow the development of a technology to improve the specificity and affinity of
monoclonal antibodies.
Receptors of B cells are Ig molecules that have combining sites identical to
the antibodies that these cells will secrete upon antigenic stimulation. The
receptor and the antibodies differ in that the receptor is a membrane protein, with
a specialized carboxy-terminal region of its H chain that anchors it in the cell
membrane, whereas the antibody (Figure 7-2) is a secreted soluble protein. These
alternative forms of the same molecule are produced through alternative RNA
splicing, which produces distinct H-chain messenger RNAs (mRNAs) for secre-
tory and membrane Ig.
T-Cell Receptor Molecules Are Heterodirneric Ig-like Molecules
Most T cells express receptors composed of a and ,3 chains; others express
receptors composed of ~ and ~ chains. T-cell receptor polypeptide chains have
amino acid sequence homologies to Ig H and L chains. The a and ,8 chains,
which have been studied most extensively, have amino-terminal variable regions
and carboxy-terminal constant regions.
The Molecular Genetic Basis of Immunoglobulin and T-Cell Receptor
Diversification Relies on DNA Translocation Events
Understanding the structure of Ig molecules and B- and T-cell receptors gives
us a basis for considering the genetic mechanisms that develop the information
necessary for encoding the vast array of distinct antibodies and receptors. The VH
domain of Ig molecules is coded for by three independent genes, VH, D, and JH,
which are separated from one another in germ-line DNA, but which are brought
together in B cells by translocation events to form a VHDJH single gene.
The germ line contains a large number (200 to 1,500) of distinct VH genes, 12
D genes, and 4 active JH genes. Since these genes may be chosen randomly for
assembly into a VHDJH gene and since products of each may contribute to the
combining specificity of the resultant VH domain, the number of functionally
different H chains that can be generated by simple combinatorial association may
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be in excess of 104. A similar assembly of distinct genetic elements leads to
formation of the gene for the V' domain. The process by which the VH and V,
genes are assembled and coupled with random pairing of H and L chains, could
lead to the development of more than 108 distinct H and L pairs. In addition to
these mechanisms for creation of diversity, Ig genes undergo somatic hypermuta-
tion in the course of B-cell responses to antigen, leading to a further enlargement
in the number of distinct Ig genes that the immune system can generate. Thus,
through the use of a substantial (but not enormous) amount of genetic informa-
tion, the immune system creates an almost limitless array of distinct Ig molecules.
The processes involved in diversifying T-cell receptors resemble those de-
scnbed for Ig molecules, except that little or no somatic mutation seems to occur.
Although this limits the number of distinct T-cell receptor genes that may form
when compared with the number of Ig genes, the number of possible T-cell-
receptor genes is still very large.
B Lymphocytes
B Cells Undergo an Ordered Set of Developmental Processes as They Develop
from Hematopoietic Progenitor Cells
The B lymphocytes are derived from precursors in hematopoietic tissue.
These progenitor cells develop into pre-B cells, which lack membrane receptors
and thus are insensitive to antigenic stimulation. It is within the pre-B cells that
the translocation events occur through which VRJHCH and the V~J, Cat genes are
assembled and in which their products, the H and L chains, pair with one another
to form intact Ig molecules. Once this has occurred, Ig is expressed on the
membrane; the cell now has a receptor capable of recognizing a foreign (or selfl
antigen. The processes through which the individual Ig genes are activated and
through which the rearrangements are controlled are currently under intense
investigation. The Ig genetic system provides an outstanding opportunity to
obtain basic information about the general process of genetic control. Indeed, one
of the best-characterized systems of tissue-specific genetic enhancers is that of the
Ig H-chain genes.
Binding of antigen to membrane Ig receptors on immature B cells may
eliminate or desensitize these cells. This would lead to the functional deletion of
those B cells that bear receptors specific for endogenous antigens present on the
tissues or in the extracellular fluids of the individual (self- or auto-antigens) and
thus should prevent the maturation of B cells specific for self-antigens. The
elimination of autoreactive B cells would thus lead to a state of immunological
tolerance in the B-cell population. However, the elimination of such autoreactive
B cells seems to be incomplete. Indeed, the production of antibodies that can bind
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to autoantigens is more common than formerly believed. The study of the biology
of tolerance induction and of autoantibody production is important because many
human diseases seem to be caused or exacerbated by autoantibodies and related
autoimmune processes. For example, antibodies to autologous antigens have a
serious effect in systemic lupus erythematosus, in which antibodies to DNA cause
severe kidney disease through deposition of antigen-antibody complexes in the
The immature state of B cells, in which they appear to be uniquely suscep-
tible to induced tolerance, is marked by the expression on their surface of recep-
tors of the IgM class only. These B cells mature further and acquire surface IgD
in addition to IgM. IgM and IgD have the same VH and Via regions and thus have
identical antigenic specificity, although their constant regions differ and presuma-
bly mediate distinct functions. However, no convincing explanation of the
functional difference in IgM and IgD has yet been brought forth. Nonetheless,
coincident with the acquisition of IgD by the maturing B cell are the development
of a resistance to the induction of experimental tolerance and the development of
a heightened ability to become activated and to become antibody-secreting cells,
which suggest that IgD may play an important role in these processes.
Receptor Cross-Linkage Mediates B-Cell Activation
B-cell activation in response to antigenic stimulation seems to follow one of
two activation pathways; these alternatives may reflect the existence of two
distinct types of antigenic substances. Many biologically important antigenic
molecules (termed type II antigens) have multiple copies of the same epitope;
principal among them are the capsular polysaccharides of many pathogenic bacte-
ria. The multiple copies of the same epitope cross-link the receptors on the
surface of specific B cells. Such receptor cross-linkage causes rapid biochemical
changes within the cell, which set in motion the process through which the cell is
stimulated to enter the cell cycle and divide. The earliest event that has been
detected is the activation of the inositol phospholipid metabolic pathway. Initial
progress in delineating the biochemical events that control B-cell activation raises
the possibility that drugs may be developed that can selectively control the
process of B-cell (and T-cell) activation and which for this reason may be of
therapeutic value.
B-cell activation through receptor cross-linkage also leads to the activation of
the c-fos and c-myc cellular proto-oncogenes. These genes and their products,
when properly regulated, play a key role in the cellular activation process. Their
deregulated action seems to influence the deregulated growth of malignant cells,
with c-myc being implicated in certain B-cell tumors.
Among the important tasks that lie ahead are (1) the identification of the
membrane molecules through which Ig signals the activation of inositol phospho
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lipid metabolic pathways to initiate the intracellular signaling process and (2) the
detailed description of the molecular events that occur as a result of the activation
of this signaling pathway. Particularly important will be the identification of the
proteins that are phosphorylated in the course of B-cell activation and the deline
ation of the functions these proteins mediate in the response of the cell.
B-Cell Activation Can Also Occur Through Cognate T-Cell-B-Cell Interaction
Many of the most important antigenic substances against which the immune
system must respond have no more than one copy of any individual epitope.
These molecules include proteins having many different epitopes but no repetitive
elements. since all the receptors on an individual lymphocyte have the same
binding specificity, such antigens cannot cause receptor cross-linkage. Thus, they
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OPPOItTUNITIES IN BIOLOGY
fail to initiate the set of metabolic activation steps described above. Such antigens
can activate B cells only through an indirect mechanism that requires the intimate
participation of T cells in cognate T-cell-B-cell interactions. For this reason, such
antigens are designated T-dependent antigens. In cognate B-cell activation, the B
cell binds antigen through its membrane receptors, but this binding, in and of
itself, results in no intracellular signal. A portion of these bound antigenic
molecules are taken into the cell by endocytosis, where they are fragmented by
proteolytic digestion. Some of the resultant peptides are resumed to the surface of
the cell as a complex with a cellular membrane protein, generally a class II major
histocompatibility complex (MHC) molecule. The association of antigen-derived
peptides and class II molecules is based on the specific binding of the antigen by
the class II molecule. Receptors of helper T cells are specific for a complex of
peptide and class II molecule, rather than for the peptide alone. Thus, helper T
cells that have receptors specific for the particular complex formed on the surface
of a B cell will bind to that B cell, an event that activates the T cell. In turn, such
T cells locally activate B cells either by signal transduction through B-cell surface
molecules involved in the T-cell-B-cell interaction or through the secretion of
soluble lymphokines such as interleukin4 alma, interleukin-2 (IL-2), and inter-
feron y.
The Activation and Proliferation of B Lymphocytes Is a Prelude to Their
Dif/7erentiaiion into Antibody-Secreting Cells
The T-cell-derived lymphokines, including IL-S and the B-cell differentia-
tion factor IL-6, direct the development of B cells into antibody-secreting cells.
The recent purification and molecular cloning of both IL-5 and IL-6 should make
possible a more precise understanding of control of antibody secretion in the near
future. Within the B cell, the differentiation events associated with the develop-
ment of a B cell into an antibody-secreting cell include a change in the processing
of mRNA for Ig H chains. The resting B cell processes the bulk of its H-chain
mRNA to produce a membrane form of Ig, in which the H chain has a hydropho-
bic region near the carboxy-terminal portion of the molecule. This hydrophobic
region, which spans the cell membrane, and the additional "cytoplasmic tail" of
the H chain are encoded in distinct exons in the gene for the H chain. In the
antibody-producing cell, an alternative mRNA-processing mechanism leads to
the production of an H chain that is identical to that found in the resting B cell
except that it lacks the transmembrane and cytoplasmic regions. This H chain
interacts with L chains to form a secretory protein rather than a membrane protein.
An Important Differentiation Event in the Physiology of Antibody Production
Is the "Switch" in Expression of Ig Class by B Cells
As has been described, each Ig class seems to play a distinct role in the
immune response. Cells producing IgG (there are four subclasses of IgG), IgA,
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and IgE derive from precursors that initially express IgM or both IgM and IgD on
their membranes. The molecular basis of this switching event seems to involve
the translocation of an assembled VHDJH gene from its position proximal to the
gene for the constant region of the pH chain (C~) to a comparable position
proximal to a Cat, Car, or Ca gene. ILL and otherrT-cell-derived lymphokines
direct switching to distinct Ig classes. The clarification of the physiological
mechanisms controlling class switching both in vitro and in viva is of great
importance because of the different functions of antibodies of different classes.
T Cells
T Cells Recognize a Noncovalent Complex Consisting of an Antigen-Derived
Peptide and a Class I or Class II MHC Molecule
In contrast to B cells, whose receptors recognize epitopes on soluble mole-
cules, T cells recognize a noncovalent complex consisting of an antigen-derived
peptide and an MHC molecule. The noncovalent complexes that T cells recog-
nize form in and are displayed on the surface of cells with which the T cells
interact. Thus, T-cell recognition of an antigen occurs only in intimate associa-
tion with other cell types, which act as antigen-presenting cells. The subset of T
cells that are principally involved in the stimulation of antibody synthesis and of
cellular immunity (helper T cells) generally recognize antigen-derived peptides
associated with class II MHC molecules, and thus can interact only with those
antigen-presenting cells that express class II molecules. The expression of class II
molecules is largely limited to B cells, macrophages, dendritic cells, and special-
ized endothelial cells in the thymus. Under conditions of immunologically
induced inflammation, however, class II molecules may be found on other cell
types. These cells may thus acquire the capacity to interact with and present
antigen to helper T cells. In general, those T cells which co-recognize antigen
with class II molecules have a surface molecule designated CD4, which may play
an important auxiliary role in the T-cell recognition process. Furthermore, it has
recently been established that CD4 is the cell-surface receptor for the human
immunodeficiency virus (HIV), the virus that causes AIDS. The entry of HIV
into cells depends on its binding to CD4, and those cells that express CD4 are
susceptible to infection with HIV. This role of CD4 in cellular infection by HIV
suggests that strategies to prevent infection by interrupting the binding of the
virus to its receptor should be explored seriously. Structural studies of the
interaction of CD4 with both HIV and with its natural ligand, the class II mole-
cule, may prove to be of great importance in limiting the spread of HIV.
A second subset of T cells is able to lyse antigen-bearing target cells, such as
virus-infected or tumor cells. These T cells are generally referred to as killer cells.
Killer T cells mainly recognize antigen in association with a different group of
MHC molecules, class I molecules. In contrast to the expression of class II
molecules, most tissues express class I molecules on the surface of their constitu
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ent cells. Thus, virtually any cell type would be susceptible to the cytotoxic action
of a killer T cell if the cell expressed the complex consisting of antigen and the
class I MHC molecule recognized by the receptors of the killer cell. T cells that
co-recognize antigen with class I molecules express CD8 rather than CD4 on their
membrane. CD8 molecules seem to function in a manner generally similar to
CD4 molecules, but they are not receptors for HIV. The tendency for CD4 to be
expressed on helper T cells and for CD8 to be expressed on killer cells and on T
cell that suppress immune responses (suppressor T cells) makes the enumeration
of the relative number of CD4- and CD8-positive cells a useful first step in the
assessment of the relative state of the immune system in individual patients.
The MHC Molecules Play a Key Role in Several Aspects of Immunity and in the
Rejection of Organ and Tissue Grafts
The MHC is a complex of genes located on the short arm of the sixth
chromosome in humans. This gene complex contains genes for both class I and
class II MHC molecules. Class I molecules are highly polymorphic membrane-
spanning glycoproteins with a molecular weight of approximately 45,000. They
exist on the membrane in association with a 12,000-dalton polypeptide, desig-
nated ,B2-microglobulin. The genes for both the class I polypeptide and )2-
microglobulin are homologous with Ig and are members of the immunoglobulin
supergene family. The class I molecules have three extracellular domains, each
encoded by an individual exon. The two most external domains display substan-
tial structural polymorphism, so that many different allelic forms of each class I
gene exist and individual allelic forms have multiple differences from one an-
other. These allelic differences are recognized by the immune system, and the
responses to the allelic polymorphisms of class I and class II molecules are
principally, but not solely, responsible for the rejection of grafts.
Class II molecules are heterodimers of two chains, designated a and if, both
of which are encoded in the MHC. In the human, there are four sets of these
Helper T cells usually recognize complexes of antigen-derived peptides and
class II molecules, whereas killer T cells usually co-recognize antigens and class I
MHC molecules. These complexes are formed by noncovalent interaction be-
tween the MHC molecule and the antigen-derived peptides. Moreover, distinct
polymorphic forms of class I and class II molecules are associated with the
capacity to respond to specific antigens; this polymorphism correlates, at least in
part, with the capacity of the MHC molecules to bind peptides derived from those
antigens. The association of distinct human leukocyte antigen types with suscep-
tibility to diseases such as non-insulin-dependent diabetes mellitus may reflect the
capacity of complexes of antigen and specific MHC molecules to give rise to
immune responses that destroy the tissues upon which such complexes appear.
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vaccine targets will depend on their variability in the parasite population and the
presence of alternative pathways for invasion.
Spread in the Host
When microbes enter into tissues beyond the epithelial surfaces, they are
transported into the lymphatic system, where they are presented to the immune
system. This interaction may limit the infection or may disseminate it to regional
lymph nodes and eventually to the blood. Some microorganisms invade blood
vessel walls and enter the blood directly. Spread through the blood can be rapid
and can result in generalized infection.
A Number of Pathogenic Bacterial Species Can Penetrate and Grow
Intracellularly Within Host Cells
Intracellular bacteria resist host immune mechanisms essentially by hiding
within host cells. Vascular circulation of host cells infected in this manner can
then disseminate the bacteria further into the lymph and blood, which in turn seed
other organs and tissues of the host.
Some bacteria and protozoa gain entry into the host cell cytoplasm passively
by being phagocytosed by macrophages. Once inside the phagocytic cells, these
organisms evade the intracellular killing activity of the macrophage by mecha-
nisms that include resistance to lysosomal microbicidal activity, inhibition of
phagolysosomal fusion, or simple escape from the confinement of the lysosomal
vacuoles and multiplication free in the cytoplasm of the host cell.
Other bacteria induce their own uptake by phagocytic cells such as epithelial
and endothelial cells. The microbial gene products that mediate the binding to
host cells and that trigger the endocytic uptake of bacteria have been partially
characterized by genetic methods (gene cloning and mutagenesis).
Microbes Can Spread Through Local Extension into Neighboring Tissues and
Through Peripheral Nerves
For microbes that do not enter the bloodstream or peripheral nerves, spread
may occur by extension to adjacent cells or release into fluids on body surfaces.
Nonspecific host defenses and local anatomical features may play central roles in
limiting infection. The spread of bacteria from local sites is enhanced by spread-
ing factors, particularly enzymes. But whether these enzymes play additional
roles in the pathogenesis of bacterial disease remains obscure. Viral spread by
successive infection of adjacent cells is best illustrated with viral infections of the
skin (warts and vaccinia).
OCR for page 224
An alternative route of spread is through peripheral nerves. Certain viruses
(rabies and herpes simplex) and toxins (tetanus and diphtheria) spread from the
periphery of the body to the central nervous system through nerves. The exact
neural pathway and the microbial determinants remain undefined. For neuro-
tropic reoviruses, the viral attachment protein is responsible for allowing the
neurotropic strain to enter peripheral nerves, whereupon subsequent movement
takes place in the fast axonal transport system (see Chapter 4~.
The specific microbial and host factors that determine the capacity of the
microbe to spread and choose one or another pathway in the host are poorly
defined. The initial battle between the host and the parasite takes place in lymph
nodes and results in either a virulent or nonvirulent outcome. Virulent bacteria
entering a lymph node often kill macrophages or resist being taken up by them,
produce products that dilate blood vessels and affect inflammatory cells, and
produce substances that allow the bacteria to continue to divide and spread.
Similarly, some viruses resist macrophage destruction and thus have the capacity
to replicate, rather than be destroyed in macrophages or lymphocytes. These
viruses can then spread within the host as part of the cells' normal migration.
Whereas viruses including those that are relatively avirulent spread with rela-
tive ease through the host via the bloodstream, most bacteria, fungi, and protozoa
are blocked from spread by lymphatics. Understanding the factors that determine
whether a microorganism can evade the filtering action of the lymph nodes is a
goal of major importance.
After Entering the Blood, Microbes Are Efficiently Transported
Through the Body
Although most bacteria or fungi do not regularly invade the blood, many
viruses, rickettsiae, and protozoa do. These microbes may be carried in several
compartments: free in plasma, in leukocytic-associated compartments (mononu-
clear phagocytes), and in erythrocytic-associated compartments. Removal of
microbes from the blood may be efficient. Since the reticuloendothelial system
with its population of fixed macrophages is heavily concentrated in the liver and
spleen, most clearance occurs at these sites. Infected leukocytes may also be
trapped at these organs, which would help to arrest infection. Transient bacter-
emia or viremia are thus usually of little consequence. But, when host resistance
is impaired or when especially virulent microbes circulate, a sustained viremia or
septicemia may occur.
The liver is the main organ responsible for clearing foreign particles, includ-
ing bacteria, from the blood. Studies of virulent strains of bacteria may shed light
on the mechanisms by which pathogenic organisms escape being recognized by
hepatic lectins and hence being cleared from the blood during bacteremia or
OCR for page 224
The blood may also deliver microbes to distant organs. The blood-tissue
junction plays a central, albeit poorly defined, role in determining spread into an
organ. For a microbe to enter an organ, it must first bind to the surface of the
endothelium of the blood vessel, usually in capillaries. It must then reach the
tissue by moving through breaks or leaks in the vessel wall, growing through the
wall, or being carried passively in association with some structure (or cell)
passing through the wall. Our ability to study this phase of the infectious cycle
has improved dramatically in recent years with the development of methods to
culture blood vessels and to study the interaction of microbes with endothelial
Interactions of Viruses with the Host Cell
Viruses Exist Either as an Extracellular Virion Particle or as Intracellular
Forms Undergoing Replication
For inactivation of a virus, the infectious virus particle must be neutralized by
antibodies or its replication must be inhibited within the host cell. To be therapeu-
tically useful, any agent that inhibits replication must specifically affect a viral
replication process and not the host cell.
Once a virus has bound to the cell receptor molecule, the virion must cross
the plasma membrane to enter the host cell. Nucleocapsids of some lipid-
enveloped viruses cross the plasma membrane by direct fusion of the lipid
envelope with the cell plasma membrane. Nucleocapsids of other types of viruses
cross the membrane into the cytoplasm after being taken into endocytotic ves-
icles. Once inside the host cell, the viral genome is transported to its cellular site
of replication-often the nucleus for DNA viruses and the cytoplasm for RNA
viruses. One of the next events is the synthesis of viral mRNA if the viral genome
cannot be used directly for translation. With some DNA viruses, host-cell
enzymes produce the viral mRNA. For other viral genomes, such as double- or
single-stranded RNA genomes, no cell enzymes exist that can transcribe the
genomes into mRNA. Therefore, these viruses encode a transcriptase enzyme,
which is often encapsidated in the virion. After viral proteins are translated, the
input viral genome is amplified or replicated and progeny virions are assembled.
Any of these viral-specific stages of replication are potential targets for antiviral
Cellular Molecules or Structures May Be Appropriated by Viruses and Modif ed
to a New Form for the Replication of the Virus
If the virus utilizes a host-cell component for its own replication or inacti-
vates a host-cell function to promote its replication process, injury to the cell can
OCR for page 224
result. For example, poliovirus inactivates one of the host-cell translational
initiation factors during its replication cycle. This inactivation is believed to favor
the translation of viral mRNAs, but it is also one of the factors that eventually
leads to cell death and lysis. Similarly, DNA viruses such as herpes simplex
utilize parts of the cell's nuclear transcription and DNA replication apparatus for
their replication, and they inhibit these cell processes. Herpes simplex virus may
even utilize preexisting nuclear sites of cell DNA synthesis as sites for assembly
of viral DNA replication complexes. Such perturbations of the host cell may lead
to the gross pathological changes in the cell known as cytopathic effect.
If the virus stimulates the expression or activity of certain cell gene products
and the cell survives infection, the cell may emerge with an oncogenic, or
cancerous, phenotype. In this case, pan or all of the viral genome becomes
integrated into the cell genome. For example, infection of mouse cells with
simian virus 40 (SV40) leads to a low frequency of transformed cells that retain
part of the SV40 genome and continue to express the large T antigen that interacts
with the host cell to alter its growth controls.
Two other possible outcomes of viral infection are the establishment of a
latent or a persistent infection. In a latent infection, no infectious virus is found in
the cell, but upon reactivation, the viral genome within the cell is replicated and
infectious virus is produced. In a persistent infection, the infected cell survives,
but the cell continuously produces infectious virus at some detectable level.
Cell and Tissue Tropism
A Hallmark of Microbial Infection Is the Localization of Infection in Specific
Tissues or Cells
Localization gives rise to the specific symptom complex of infectious dis-
eases and is perhaps the most characteristic feature of microbe-induced diseases.
The factors determining the localization of microbes in certain tissues their
tropism-have been under intensive investigation. Although we still do not know
the details of all the factors involved, certain aspects of major significance in host-
parasite interaction are emerging. These factors include the presence of cell-
surface receptors recognized by surface structures of microbes, tissue-specific
proteases, and tissue-specific enhancer DNA or other regulatory sequences in the
viral DNA. Although tissue localization has been studied in all classes of
microbes, most of the recent insight into tissue specificity has emerged from
studies with bacteria and viruses; the findings concerning bacterial adhesion have
already been described.
That the specificity of certain viruses (for example, poliovirus) for human
cells results from the interaction between the viral capsid and host-cell receptors
exposed at the cell exterior has been well known since the late l950s. The
OCR for page 224
presence or absence of receptors for viruses on the cells' plasma membrane is of
central importance in initiating infection. For a number of viruses, the attachment
protein on the virus panicle recognizes sugar molecules on host cells as bacterial
lectins do, suggesting that many strategies used by bacteria to colonize and adhere
to host tissues resemble those used by viruses.
The Identification of Receptors for Viruses and Other Microbes Is a Focus of
Biological Research
In addition to receptors containing static acid, considerable progress has been
made in identifying cell-surface proteins that are both physiological receptors and
receptors for viruses. These cell-surface proteins include the acetylcholine recep-
tor for rabies virus, the p-adrenergic receptor for reovirus 3, the T4 lymphocyte
antigen for HIV, and the CR2 receptor for Epstein-Barr virus. Given the central
role of receptors in pathogenesis and tropism, one should stress the importance of
determining receptor identities and characterizing the molecular interactions in-
volved in the binding reactions between virus and host receptor. Although
considerable work is being done on the receptor binding of some viruses (such as
influenza, polio, and HIV), the role of receptors, especially the question of
receptor identity, has been neglected in most other virus systems.
In addition to illuminating microbial pathogenesis, the isolation of receptors
should provide insights into the structure and function of many normal cell
proteins. The possible importance of cell-surface receptors for protozoa is illus-
trated by studies with malaria. Malaria sporozoites attach to liver cells, possibly
in response to specific receptors. Whereas the merozoite responsible for initiating
and perpetuating the erythrocyte stage has a complex surface, the sporozoite has a
dense surface coat protein that contains two regions conserved in all malarial.
These regions may be conserved for binding to liver cells or to mosquito salivary
glands. One of these regions is highly homologous to the soluble human protein
thrombospondin, which cross-links host cells.
Other Determinants of Tissue Tropisms Include Tissue-Specif id Host Enzymes
and Regulatory Factors
The cleavage of viral glycoproteins from an inactive precursor form to an
active product is an important determinant of pathogenicity for myxovirus and
paramyxovirus. The cleavage of viral proteins by tissue-specific proteases is
necessary to the production of infectious virus. The nature of this cleavage
determines whether there will be high titers of virus. Thus, host proteases
probably play a specific role in the organ-specific activation of viral proteins.
Increased research on specific steps in viral replication and the factors regu-
lating those steps will undoubtedly enhance understanding of the molecular
OCR for page 224
biology of viral virulence. In the context of tissue tropism, certain regulatory
factors may be cell- or tissue-specif~c. Thus, for example, enhancer sequences
active only in certain cells could lead to enhanced replication and high titers of
virus in specific cells. Such factors may play an important role in the localization
of viral growth and tissue injury.
How Is Injury Mediated?
Many Infectious Agents Can Multiply in the Host Without Causing
Significant Damage
Infectious diseases are the most important outcomes of multiplication of
microorganisms in the host. Many infectious agents, however, multiply in the
host without causing significant damage. For viruses, this is probably the rule
rather than the exception, even for viruses that are capable of causing disease. For
some viruses, damage at the morphological level may be undetectable, even when
effects on aspects of cell function or secretion may be profound. This type of
effect on the cell, whereby the cell is capable of replicating without any detectable
histological abnormality, but loses a differentiated function, has been termed a
loss of "luxury" functions. Cells that secrete important products for host physiol-
ogy (such as hormones) are especially important in this regard. Thus, disease
production by viruses may not be associated with more than minimal overt
In contrast, when bacteria, fungi, protozoa, or rickettsiae invade tissues, overt
tissue injury, slight or profound, is the rule. Microorganisms may damage cells
directly by replicating in a particular cell, or, in the case of bacteria and fungi, by
exposing cells to toxins that are part of the bacterial cell wall (endotoxin) or that
are released from the replicating microbe (exotoxins).
In addition to the direct injury by microorganisms or their products, the
damage may occur indirectly. The host response itself may lead to pathological
outcomes, which may be relatively nonspecific (as when proteases are released
from macrophages in an inflammatory response that subsequently results in injury
to normal cells) or may result in specific injury from cellular immune responses or
the action of antibodies.
Direct Damage of Cells by Viruses Can Occur in Different Ways
In general, viruses shut down host macromolecular synthesis while modify-
ing the cell to synthesize viral proteins. Cytopathic viruses generally cause cell
death only after they replicate, suggesting that the primary effects of viral infec-
tion involve the cellular synthetic machinery and that later effects on the cell are
secondary. The later effects include, depending on the virus, profound effects on
the cytoskeleton, injury to membrane and leakage of ions, fusion of membranes
OCR for page 224
(resulting in multinucleated giant cells), or damage to lysosomes with release of
lysosomal enzymes.
One of the best-studied viral systems is poliovirus. Poliovirus causes host
protein synthesis to decline and ribosomes to dissociate from host mRNA. Polio
infection inhibits the host by inhibiting the cellular cap-binding complex required
for attachment of "capped" mRNAs to ribosomes. Since polio RNA is uncapped,
unlike cellular mRNA, it is unaffected by the loss of the cap-binding protein.
Other viruses inhibit the host in different ways. For example, inhibition of
host-protein synthesis by mengovirus results from competition between viral and
host mRNAs.
These studies illustrate the feasibility of gaining insights into details of the
molecular basis of viral injury. Undoubtedly, this will be a major focus for the
next decade and will aid in identifying new anoroaches for developing antiviral
, ~, ~
Infection Can Result in Indirect Damage from the Response of the Host
Inflammatory Response. The host response to microbial infection generates
inflammation. This response, clasically resulting in redness, swelling, pain, and
loss of function, may damage the host more than the replicating microbe. The
early inflammatory response has both cellular components (macrophages and
natural killer cells) and humoral components (complement, interferon, and tumor
necrosis factor). The release of proteases from macrophages with injury to
normal tissue (the so-called innocent bystanders) illustrates one way by which
such injury may be mediated.
Hypersensitivity. In addition to early inflammatory reactions, the classic
reactions of hypersensitivity may be involved in microbial immunopathology.
Anaphylactic reactions depend on reactions of antigens with IgE antibodies
attached to mast cells that lead to the release of histamine and heparin from mast
cell granules, and they may be severe enough to lead to urticaria, bronchospasm,
or shock. Helminth parasites induce severe hypereosinophilia, as in tropical
(filarial) pulmonary eosinophilia, in which the toxic contents of the eosinophile
granules are responsible for tissue destruction and resultant pathology.
In the type of hypersensitivity reaction termed antibody-dependent cellular
cytotoxicity, antibody combines with antigen on the surface of the cell and results
in cell lysis through the action of killer lymphocytes, polymorphonuclear leuko-
cytes, or macrophages. This type of reaction may be important in certain viral,
parasitic, and bacterial infections. Although cytotoxic reactions can be shown in
vitro, they need further study to define their role in vivo.
Tissue Damage Mediated by Immune Complex. Circulating immune com-
plexes are probably common in most viral infections, but they also occur with
OCR for page 224
: ~
~ ~ ~ SLOW VlRUS~ES, PO<::)RIN tJND~ERSTOOD~,
T h e : c a u s a t i v ~ a g e : ~ n t : f o r : : t h e t r a n s m i : s s i ~ b l e � p o n g i f : o r r n ~ : : e n c e p h a l o p a t h i e s ~ : ~ ~ :
(~craoiQ::kL'rL, ~:CrQut~faId:- a to ~ lsQasQ and ~erstmann-~trauss er~svn:- :::
drom~) r ~:mains~ ~a~ mystery.~: ~ ~Possibly~:associated ~are ~mysterious ~ agents ~:
~calied~ sldw~vi~ruses. ~The:�auses~ these diseases chailenge~ our concepts: :
~ of ~:~convent~'ona m'�roo~g:anis~ms s'~nce,~to:~ate, t ~ey~ ,mre~ not ~een~ s ~own~ to :~
::~:~:::co~ain~ RNA :or~:DNA.~: ~: :Infectivibr~de~dved :~from :~:brai:n:~:~ or;:~:lym:pho;id: :tiss~ue~: ;
~ ~ . ~
: :::~ ~homog~:ndtes ~has:~several~unusu~al~biolog~ical :properti~es,:~s:uch~:as:~ex~ptiQnal:
:: ~resistance~ :to i~n:activat~n~ b) :~rmaldehyde~ or~ ty::~ultravio:let~ or~ x-irrad~iation~.~ ::
Attempts~ td ~purify~the ~agent~ ~indicate that ~infe�tivity remains ~associatdd w~h ~ :
~cellular~:me~mbrane fradt~ns~ and thus lacks~homogeneous~ b:~physical~ pro~
Fert'es. ~ ut ,ermore' eve uation ot purn:'catwon~ protoco s 1as~ 3een ~am~pered
~y: t 3e Inamura~ ot assays us: - ~ :o ~quant~: InJ:~'v~7 ~e :recent~ use ot
: the incubation~:period~ ass~ay~ to~ qu:an$~ify:~inf~ctivity:~is ~qui~: and requires fewe:r:~ ~ ::~
animals but. if an:~hina. is less or~cise in discriminating ouantitative: d ffQr-:
en~s.: ~Thus, Wth~because of ths~inaccura~ ot~the essay:: ano tne nonno-:
~:: ~ mogenous~ ph:ysical nature of ~:~ the:~:~agerit, ~ it ~:re:ma~i:ns::~ extremeIy ~ difficult ~ to
i:~: desi:gn ~an :effective ~pu::rif:icat:ion ~::prdto�ol :~r:~th~el::infedtious age:nt.~::~
~: ~:: ~: Recent~ly~ several: research:~:~gro~u~ps ~have~:~patti~ally~: ~pu~rified:::::i~fectivity: o~n
sucrose~ gradients.: ln intectio:us ~fradtions ~: macromolecular:~fibril-like~:: stru:c-:
tures have been visualized with the electron~microscope: ~which raises the
~: :possibilRy tbat ;these: might: be the~ ag~e~nt or :a~ oomponent~ of the: agent.
: Prot:ein con,~nents of these fraction:s we:re :fu:rther purif:ied~: :under denaturing
conditions. Since infectivity was: destroyed in: t:hese procedures, ~ it was
impossible to relate the purified:: prote:ins d~i:rectl~y~ :~to t~he: infectious: agent.
Partial amino acid sequence analysis of th~e mayor polypoptide :obtained
known as prion ~protein,~:has led~to the cloning and sequencing of the:
: com:plementary::DNA~:en:coding the :prioni:prc~tein. Hybridizatio:n experi:ments ~
with these clones: show~d :that ~:prion protei:n: ~mRNA~ was ~ndt :found exclu-~ :
sively in::scrapie-inf~ctdd~ animals, but::: occorred to the same~ e~ctent:in t:he :
tissues of un:inf~ted animals. :Thus, th~e relationship of:the prion protein:
gene and Rs expressed protein to the infectious agents of scrapie and other;
: :
spongiforrn encephalopathie:s is as yet uncertain. : ~ ~
OCR for page 224
THE IMMUNE SYSlEM AND INFE=IOUS DISEASES
parasites and bacteria. Immune complexes may lead to pathological outcomes,
either in the vascular spaces or in tissues.
Autoimmune responses have recently been identified for viral and bacterial
antigens. In such cases, the host responds not only to the microbial antigen but
also to normal host components. A variety of mechanisms for autoimmunity have
been proposed. With our increased capacity to study components of the immune
system as well as to define the individual microbial proteins or components
involved in recognition of the immune system by microbes, we should in the next
several years gain striking insights into the etiology of autoimmune reactions to
Bacterial Toxins Are Studied More as Probesfor Specific Cell Functions Than
They Are for Their Roles in Pathogenesis
Toxic proteins and peptides, which are involved in a wide variety of biologi-
cal phenomena (such as bacterial pathogenesis, attack by venomous insects and
animals, and the toxicity of certain plants), have classically been of interest from a
medical perspective. Microbiologists in the 1880s and 1890s were intrigued by
toxins because they provided a potential explanation of bacterial disease. More-
over, they soon found that repeated injection of sublethal doses of toxins into
animals induced specific resistance to those toxins, a finding that represented the
discovery of humoral immunity. They developed methods of immunization,
which culminated in the mass inoculations and successful immunizations against
diphtheria and tetanus toxoids.
From a biological standpoint, toxins represented little more than curiosities
until recently. Within the past two decades, interest in these substances and the
mechanisms whereby they affect cells of the animal or plant host has revived.
Toxins are excellent probes of important biochemical and cell-biolog~cal proc-
esses; they are interesting from the point of view of structure and functions of
proteins and with respect to the theoretical analysis of microbial host-parasite
interactions and their genetic regulation. Moreover, the progress made in under-
standing toxin structure and mode of action has stimulated new potential applica-
tions in medicine. The coupling of cytotoxic proteins to monoclonal or polyclo-
nal antibodies provides a new approach to chemotherapy for cancer and other
diseases that call for the elimination of a specific class of cells.
Finally, the cumulated knowledge on classical toxins may provide an impor-
tant base of information for understanding yet another aspect of the immune
system, namely cellular immunity. Evidence is increasing that the killing of cells
recognized by the cellular immunity system involves the action of cytotoxic
proteins. Similar molecules may also mediate tissue regression and other onto-
logical phenomena.
OCR for page 224
Persistent Infections
Microbial Persistence Is a Common Sequel to a Large Number of Infections
Persistent infections may be important in the maintenance of microorganisms
in host populations. In certain circumstances they may be activated in immuno-
suppressed patients, and they may be associated with neoplasms. Persistent
infections include those in which the microbe is latent (as in a noninfectious state
in some location in the host) or persistent (as when it multiplies more or less
continuously for long periods of time).
Parasites Are Able to Remain in the Blood Exposed to the Immune System) for
Months to Years
Plasmodium malariae, one of the four human malarial parasites, can persist
in the bloodstream for the life of the host, reinvading new red cells every Free
days. The adult schistosome, a trematode, lives in venules for many years,
copulating and laying eggs that spread the infection and trigger the disease.
Within days after the schistosome enters the host, its tegument becomes resistant
to complement lysis and to cell-mediated killer mechanisms. The African
Dypanosome Trypanosoma gambiense, a flagellate that infects animals and hu-
mans, undergoes antigenic variation to escape destruction by antibody-dependent
complement lysis. Each parasite clone contains multiple genes capable of ex-
pressing antigenically unique surface proteins. The control of expression is not
fully understood, but gene duplication and translocation to an expression site is
one mechanism. The trypanosome continually expresses new surface proteins
from its large repertoire of genes, which are funkier expanded by mutation. The
American trypanosome Trypanosoma cruzi, uses a different evasive maneuver: It
elaborates a molecule similar to a decay-activating factor that speeds the break-
down of a critical complement component and thus may prevent complement-
dependent lysis by the alternative pathway. Despite the many strategies of
parasites, the host does eventually become immune to most parasites. The
challenge to immunologists is to develop vaccine strategies that attack parasites in
susceptible stages or by mechanisms that they cannot resist.
Studies on the Immune System and Infectious Diseases Have Made Enormous
Progress During the Past Decade Because of the Introduction of
Powerful New Technologies
The applications of molecular biology, monoclonal antibodies, flow cytomet-
ric analysis, modern methods of cell culture, and powerful new techniques of
OCR for page 224
protein chemistry have led to many of the insights described in this chapter.
Improvements during the forthcoming decade promise to bring us the solutions to
many of the central unresolved problems of immunology and pathology as well as
to provide a new level of insight to all aspects of cellular biology. Equally, the
central role of the immune system in resistance to infectious diseases, in the
elimination of tumor cells, and in the pathogenesis of many chronic disease makes
it an obvious target for clinical efforts. During the next decade, substantial
emphasis needs to be placed on developing a quantitative understanding of the
contribution of the various components of the immune system to the function of
that system in humans and other animals, both in normal situations and in various
disease states. Such information together with our growing understanding of the
basic cellular and molecular mechanisms of immunity should make possible the
development of new vaccines for the prevention of many of the still-uncon~olled
infectious diseases such as AIDS and malaria and should allow the introduction of
rational therapy for a host of immunologically based disorders.

subset: commoncrawl


text:
Quick Pattern Question
I'm working on a quick knit for a friend and I got stuck on part of the pattern, it says to inc 6 sts evenly across next and then EOR 1 time. [20 sts], coming from 8 stitches.
I'm not sure if this means knit one row while increasing 6, and then knit another row (the end of row) increasins once OR knit 7 more rows increasing on each row. Any input is greatly appreciated! Thanks! |
K one row adding 6 incs. Then one row worked even (no incs...14 sts). Then work another row with 6 incs (20 sts).
EOR means row in between worked even. R1: K (6 incs) (8+6=14) R2: worked even R3: K (6 incs) (14+6=20) HTH, cam |
Thank you so much!
eor = every other row
All times are GMT -4. The time now is 09:18 PM. |
copyright knittinghelp.com


text:
Ramesh, MP and Kalpana, S Shenoy (1988) Wind Speed Data Collected in the Ridge Line Around Talacauvery in Western Ghats During the Interval January - March 1988. Project Report. National Aerospace Laboratories, Bangalore.
Full text available as:PDF - Published Version Restricted to Archive staff only Download (1213Kb) | Request a copy |
This report presents wind speed data collected in the western ghats on the ridge line surrounding Talacauvery (origin of rivercauvery) located in Kodugu district.The data collection was initiated during last week of December 1986. Four data loggers were installed over a span of about 2-3 kilometers. Based on the data collected for one year, data logging was continued in two sites into 1988. One site (Muvalemotte side) has been chosen to set up five WECs each of 110 W. The other site was on the Bramhagiri peak, which has shown a good potential. In this report data for the period January- March 1988 has been reported.
Item Type: | Proj.Doc/Technical Report (Project Report) |
Uncontrolled Keywords: | Wind Data, Microprocessor , EPROM |
Subjects: | RENEWABLE ENERGY > Wind Energy CHEMISTRY AND MATERIALS > Chemistry and Materials (General) |
Division/Department: | Wind Energy Programme, Wind Energy Programme |
Depositing User: | Ms Indrani V |
Date Deposited: | 13 Jan 2012 10:15 |
Last Modified: | 25 Jun 2013 13:27 |
URI: | http://nal-ir.nal.res.in/id/eprint/10217 |
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38 year old man | Cedar Park, TX, USA | Seeking women 30-40 within 40 miles of Austin, TX
hakuna matata
I'm an honest hardworking individual that likes the outdoors..I work as a Project Manager for an architectural firm and after a long week I like to hit the green belt for trail run or a mountain bike ride, I find it's a great to start the weekend. I have an 18 year old daughter that lives in Florida and I'm proud to say she just graduated and is heading off to college . I have found that very few people are morning people....me...mornings are my favorite....if you like mornings, that's a great start! My favorite things to do in my "Cory time" are work on my motorcycle, ride my motorcycle, Mountain Biking. I also like to go camping and not cabin camping or trailer camping....I would much prefer primitive camping. Will add more later...
Camping , Cooking , Fishing/Hunting , Movies/Videos , Museums and art , Music and concerts
Billiards / Pool, Cycling, Martial arts, Running, Walking / Hiking, Weights / Machines
I exercise 3-4 times per week.
I have Dogs
Him | What he is looking for | |
Appearance | ||
Height: | 5'8" (172cms) | 5'0" (152cms) to 5'8" (172cms) |
Body type: | About average | About average, Athletic and toned |
Eyes: | Blue | No preference |
Hair: | Dark brown | No preference |
Lifestyle | ||
Smoke: | Yes, but trying to quit | No Way, Occasionally, Yes, but trying to quit |
Drink: | Social Drinker | Never, Social Drinker |
Occupation: | Architecture / Interior design | No preference |
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Ethnicity: | White / Caucasian | No preference |
Faith: | I'll tell you later | No preference |
Languages: | English | English |
Education: | Associates degree | Some college, Associates degree, Bachelors degree, Graduate degree |


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English graduate students have organized a November 16-18 conference here about fantasy literature featuring keynote speakers Neil Gaiman, author of the Sandman series of graphic novels, and Jack Zipes, noted UM scholar of fairy tales and folklore. Other featured authors are Patrick Rothfuss, Pamela Dean, Nnedi Okorafor-Mbachu, and many local fantasy writers including MFA alumna Haddayr Copley-Woods.
October 2007 Archives
Put Down the Book and Talk to Someone!
FUSE, the Fellowship of Undergraduate Students of English, invites majors to meet each other in a variety of settings. The mission of FUSE, according to its founding members, is "to connect to the literary pulse of the Twin Cities and provide a dynamic student community for English majors at the University of Minnesota.�
Regular Activity:
*weekly English Study Nights, every Tuesday night, 6pm-9pm at Marrakesh Coffee in Dinkytown, to hash out ideas for the next paper, discuss recently-read books, or just hang out!
For more information on events, study nights, and other activities, students can contact: email@example.com, check out the FUSE website, and "Put down the book and talk to someone!�
The oratorio To Be Certain of the Dawn, by composer Stephen Paulus and Department of English professor Michael Dennis Browne, is nearly sold out for its single performance at Orchestra Hall on Tuesday, February 12, with the Minnesota Orchestra. The orchestra has announced tickets for the dress rehearsal, at 10 am that day. The Minnesota Orchestra debuted the oratorio two years ago at the Basilica of St. Mary and will be recording it for Bis Records after the February performance. Music director and conductor Osmo Vanska talks about the work.
Congratulations to associate professor Andrew Scheil, who received a McKnight Presidential Fellowship. The Fellowship recognizes promising faculty who recently gained tenure and the rank of associate professor. The awards include three years of research support. Scheil is currently on sabbatical with a National Endowment for the Humanities Fellowship.


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On some single-stage, step-down and step-up procedures for comparing three normal means.
Liu, W. (1996) On some single-stage, step-down and step-up procedures for comparing three normal means. Computational Statistics & Data Analysis, 21, (2), 215-227. (doi:10.1016/0167-9473(95)00013-5).
Full text not available from this repository.
The problem of pairwise comparisons of three normal means in the balanced one-way fixed effects anova model is considered. In order to compare the performance of a single-stage procedure, a step-down procedure and a step-up procedure which all strongly control the type I familywise error at the same level, a method of power assessment is proposed. The power function is defined to be the probability of detecting, with correct directional decision, each pair of treatments with mean values at least δ-distance away from each other. The global minimum power is then used as a criterion for comparing the three procedures. Expressions are provided allowing simple computer evaluation of the global minimum power for each of the three procedures. The findings are that the step-down procedure performs better than the step-up procedure, and both step-down and step-up procedures perform substantially better than the single-stage procedure. A table of sample sizes necessary to guarantee certain power levels for each of the three procedures is also given.
Item Type: | Article |
ISSNs: | 0167-9473 (print) |
Related URLs: | |
Subjects: | Q Science > QA Mathematics |
Divisions: | University Structure - Pre August 2011 > School of Mathematics > Statistics |
ePrint ID: | 30083 |
Date Deposited: | 14 Mar 2007 |
Last Modified: | 27 Mar 2014 18:18 |
URI: | http://eprints.soton.ac.uk/id/eprint/30083 |
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Christmas Fruitcake Cookies Mix in a Jar
Layer the following in a quart-size jar: Bake at 350 degrees F for about 10 minutes. Cool on a wire rack and store in a tightly closed container. |
Mixes Home
Jar Recipes
Cookie Mixes Mix Recipes
Bread Mixes
Soup Mixes
Beverage Mixes Bake in a
Jar Recipes Gift Recipes


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Scroll through the page to review your answers. The correct answer is highlighted in green. Your incorrect answers (if any) are highlighted in red. If you'd like to take the test over again, click the reset button at the end of the test.
Define the cost of an algorithm.
True or false: Different implementations of the same algorithm can lead to different efficiency measures.
True or false: Different platforms running the same algorithm always take the same amount of time.
True or false: If an algorithm is run on two very different platforms, it may have a different O() efficiency.
True or false: the data structure a programmer uses in an algorithm can have an effect on an algorithm's efficiency.
Define the real running time of an algorithm.
The efficiency and complexity of an algorithm are measured in ____ because it allows for easy comparisons of similar algorithms.
If a function required 10n 2 +24n 3 +12(nlogn) + 2n steps to run, what would its big-O notation be?
If a function required 5/n + 12/n 3 + 100/(nlogn) steps to run, what would its big-O notation be?
The process of determining the rate of growth of a function is called:
True or false: O(nlogn) < = O(nloglogn)
True or false: If n > m , O(n m) < = O(m n) .
O(c n) is referred to as:
True or false: When comparing two functions, we focus on the limit of the function as n approaches 0.
Word processors often have a "find" function that allows you to search for a word in your text. If the application uses the data as is (i.e. doesn't put it into any sort of new data structure), what search algorithm or structure does it most likely use?
True or false: linear search requires a data set to be sorted.
True or false: Given n pieces of data, the best we can do to search it is O(n) .
True or false: Searching is an important topic in computer science, and new algorithms for it are being devised all the time.
True or false: Linked lists are often searched with a modified binary search method.
True or false: Most people look up a name in a phonebook with a modified linear search algorithm
True or false: The mailman finds your house using a binary search method.
Binary search requires data to be in what order?
True or false: Linked lists allow for random access.
True or false: Arrays allow for random access.
True or false: When doing a linear search, every element in the array or list is always examined.
True or false: When doing a binary search, every element in the array or tree is examined.
True or false: A doubly-linked list would allow for random access whereas a singly-linked list wouldn't.
If you were going to implement a spell checker, which of the following structures might you allocate to hold the words best?
A reversible function is one where for h(x) = y and h -1(y) = x . True or false: a hash function is always a reversible function.
A deletion operation when using linear probing to handle collisions is:
True or false: A hash function can only have one input.
True or false: A hash function usually returns a non-negative integer.
Which of the following rules does NOT make for a good hash function?
True or false: Brute-force string searching and Rabin-Karp string searching are the only known ways to look for a string within another string.
True or false: Binary search would not be considered a brute-force searching method.
True or false: Rabin-Karp works because two strings can never hash to the same value.
True or false: Fingerprinting is a method that often uses hash functions.
True or false: There are cases where Rabin-Karp string searching is actually worse than brute-force string searching.
In modular arithemetic, (amodb + c)modb , is the same as:
True or false: Rabin-Karp string search is always O(M + N) .
Using knowledge you have to throw away a portion of your data set while continuing to search the rest is a technique used in:
Given the following hash function:
int hash(char* str) { int sum = 0; while (*str != '\0') sum += (int) *str++; return sum % 1; }
A algorithm that is O(1) could run slower than which of the following:
True or false: A linked list would also be a good way to store a hash table.
True or false: The ideas behind a hash table require that the data structure used have random access capabilities.
When thoroughly reading this SparkNote, the method you use for going through it most closely resembles which search?
True or false: A binary search requires a binary search tree as the data structure being search.
A hash table lookup on a well implemented hash table using separate chainging can result in which of the following access efficiencies?
True or false: After reading this guide, you're now an expert on basic searching methods.


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Title: | Hudson County |
Description: | This web site contains much useful information about Hudson County or New Jersey, its elected officials and the many services, which the County and its various agencies provide to our citizens. It also contains the names and telephone numbers of the officials in the twelve municipalities, which make up our county, comparable information with respect to our State Legistrative delegation and our representative in the U.S. Congress. |
Keywords: | Hudson County, telephone directory, phone numbers, boards and agencies, citizens names municipalities, City of Bayonne, City of Jersey City, Borough of East Newark, City of Hoboken, City of Union City, Town of Guttenberg, Town of Harrison, Town of Kearny, Town of Secaucus, Town of West New York, Township of North Bergen, Township of Weehawken, |
Category: | Government and Society |
State: |
1 | A J Hudson Company A stocking distributor for pneumatic components and supplies, as well as a builder of custom control panels. | 26 |
2 | Town of Hudson Official site features overview of town services,history and calendar of events. | 27 |
3 | Michael Hudson Photography Gallery specializing in fine art and travel photography; features include image gallery of black and white, hand coloured and colour pictures, including photographs of Great Britain. | 55 |
4 | Hudson Funeral Home and Cremation Services Hudson Funeral Home and Cremation Services is located in Durham and in Granville County, North Carolina. | 46 |
5 | Polos at Hudson Corners Polos at Hudson Corners features 1, 2 and 3 bedroom floorplans, Standard 9' or 10' tray ceilings, An elegant clubhouse with full fitness center, a resort style swimming pool with heated spa, Gourmet Kitchens, Crown molding, Standard vertical and mini blinds and much more. Call or stop by today. | 14 |
6 | County of Monterey Recorder-County Clerk Includes document recording, fees, marriage licenses, birth/death certificates, and fictitious businesses. | 81 |


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April 9th, 2012 at 11:12 am
Live+7 DVR Ratings: 'New Girl' Tops Absolute Ratings Gain, 'Fringe' and 'The Firm' Top % Gains, 'Castle' Tops Total Viewer Gains in Week 27
During week twenty-seven of the 2011-12 broadcast season (March 19, 2012 - March 25, 2012) New Girl topped the rankings for
[Read-More]April 8th, 2012 at 8:27 am
Bubble Watch: 'Supernatural' Likely Renewed; 'Fringe' Still Likely Canceled + 'Best Friends Forever' & 'Scandal'
'Touch' still likely, "Awake" still doomed.
[Read-More]April 6th, 2012 at 1:48 pm
Thursday Final Ratings: 'Big Bang Theory', 'American Idol', 'Person of Interest', 'Missing', 'Up All Night' Adjusted Up; 'Scandal' Adjusted Down
Thursday's final ratings.
[Read-More]April 6th, 2012 at 8:35 am
TV Ratings Thursday: 'Big Bang Theory' Tops 'Idol', But Fox Wins Night Full of Season/Series Lows
Fox won the night with adults 18-49, though in head-to-head competition from 8-10p, CBS led Fox.
[Read-More]April 2nd, 2012 at 10:45 am
Live+7 DVR Ratings: "Modern Family' Tops Absolute Ratings Gain; 'Nikita' & 'Ringer' Top % Gains in Week 26
'Modern Family' led absolute ratings gains via DVR by a wide margin.
[Read-More]March 30th, 2012 at 2:10 pm
Thursday Final Ratings: 'American Idol',"The Big Bang Theory', 'Missing' and 'Vampire Diaries' Adjusted Up, 'Rules' and 'Touch' Adjusted Down
Thursday's final ratings.
[Read-More]March 30th, 2012 at 8:37 am
TV Ratings Thursday: 'Big Bang Theory' Doesn't Dent 'Community;' 'Awake,' 'Missing' Keep Sliding, As Most Shows Decline
Fox topped the nights adults 18-49 ratings.
[Read-More]March 26th, 2012 at 10:02 am
Live+7 DVR Ratings: 'The Big Bang Theory' + 'New Girl' Top Absolute Ratings Gains; 'Awake' Tops % Gains in Week 25
XXX led absolute ratings gains via DVR by a wide margin.


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Do you love high speed and big waves! Then Jungle Racers water scooters are made for you. But keep an eye out for unexpected water bombs!
Jungle Racers
Jungle Racers are made for speed-loving daredevils who aren't afraid of getting wet. Great for kids and families.
Jungle Racers is located in Adventure Land, the action-filled paradise for cool kids. Go through the cave and hop onto a spectacular Jungle Racers water scooter for a wild trip across the foaming waves. But watch out for water bombs!
Sharply to starboard, Captain!Onlookers can activate small underwater bombs, sending a jet of water into the air. If you don't want to get dripping wet, you'll have to veer sharply to starboard, Captain!
Worth knowingChildren must be at least 100 cm tall.


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off shore sailing schools advice
Well things have been going pretty good finished the sailing class bought a sunfish and a dolphin to practice our new skills on now we are looking for a sailing school in the Caribbean would prefer one that use's single hull vessel's
would like hear peoples experience's both good a bad would like something for this fall if anyone knows a good place thanks newbie |
re: off shore sailing schools advice
I think that most of the schools use monohulls for their training.
I can recommend Rob Swain Sailing School in the BVI, I took some of their ASA courses a while back and was very satisfied. If you are looking at RYA certified schools you might have to head a bit further than the USVI/BVI, though. |
re: off shore sailing schools advice
I've known more that one to go through training with Off Shore Sailing School in Tortola and they were pleased. I've actually seen one go from absolute zero to a reasonably competent fair weather sailor in a week.
re: off shore sailing schools advice
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| Phone Directory | City Manager | Council Goals
The public is invited to attend all City Council meetings. The Council generally meets the first and third Tuesday of each month in the City Council Chamber on the second floor at City Hall, 1945 E. Jackson Road, Carrollton, Texas 75006. The worksession will begin at 5:45 p.m. with the meeting immediately following. Minutes from each meeting are posted after they are approved by the City Council.
(L-R): Mayor Pro Tem Bob Garza, Councilmember Steve Babick, Deputy Mayor Pro Tem Anthony Wilder, Mayor Matthew Marchant, City Manager Leonard Martin, Councilmember Lisa Sutter, Councilmember Jeff Andonian, Councilmember Kevin Falconer, Councilmember Doug Hrbacek.
The Mayor and Councilmembers from Places 2, 4, and 6 are elected at-large and may reside anywhere in the City of Carrollton. The Councilmembers from Places 1, 3, 5, and 7 are elected at-large, but must reside within the boundaries of their respective Place. To see a detailed boundary map for each Place, select the Place number under the Councilmember's name below. To see a Place boundary map for the entire City of Carrollton, click here.
Matthew Marchant, Mayor Phone: (O) 972-466-3001 (VM) 972-466-3166 Contact Mayor Marchant View Bio
Jeff Andonian, Councilmember Place 1, NORTHEAST Phone: (VM) 972-466-3019 Contact Jeff Andonian View Bio
Anthony Wilder, Deputy Mayor Pro Tem Place 2, AT-LARGE Phone: (VM) 972-466-3232 Contact Anthony Wilder View Bio
Doug Hrbacek, Councilmember Place 3, SOUTHWEST Phone: (VM) 972-466-3598 Contact Doug Hrbacek View Bio
Bob Garza, Mayor Pro Tem Place 4, AT-LARGE Phone: (M) 214-533-8782 (VM) 972-466-3258 Contact Bob Garza View Bio
Kevin Falconer, Councilmember Place 5, NORTHWEST Phone: (H) 972-245-6233 Contact Kevin Falconer View Bio
Steve Babick, Councilmember Place 6, AT-LARGE Phone: (VM) 972-466-3257 (C) 972-896-3568 Contact Steve Babick View Bio
Lisa Sutter, Councilmember Place 7 SOUTHEAST Phone: (VM) 972-466-3087 Contact Lisa Sutter View Bio
The City Council is responsible for establishing City policies, considering City resolutions and ordinances, appointing citizens to various City boards and commissions, adopting the City's Comprehensive Plan and annual budget, and approving or rejecting zoning changes.
The Mayor and City Council welcome input from the citizens and business community regarding the goals and direction of the City government. To send the Mayor and the entire City Council or a particular member of the City Council your comments regarding policy, local legislation or the vision for the City of Carrollton, please click on the contact link below each Councilmember's photo or the general contact link on the left. You can also write the Mayor and City Council at 1945 E. Jackson Road, Carrollton, Texas 75006.
All meetings of the City Council are open to the public. View the upcoming Council meeting agenda. Watch Council meetings on government access cable television. To speak in support or opposition to an item scheduled on the Council agenda, an appearance card located at the entrance of the Council Chambers must be completed. Individuals who do not want to speak on an issue, but wish to register their support or opposition may also submit a card.
Items for consideration by the Council are outlined in an agenda. The sections of this agenda include the consent agenda, resolutions, ordinances, public hearings other business and public forum. The consent agenda consists of operational items and items previously discussed and can be approved by Council with one vote. However, the Council may consider any item separately.
Public hearings are conducted to allow for citizen input before the Council votes on any issue. It allows citizens to speak in favor of, against, or ask questions about matters of substantial community concern. Public notice is given in local newspapers to announce hearing dates.
To speak in support or opposition to an item scheduled for consideration, an appearance card located at the entrance to the Council Chambers must be completed. Individuals who do not want to speak on an issue, but want to register support or opposition should also fill out a card. Each name will be read into the record by the Mayor.
Local Government Organization The City of Carrollton is a Home Rule municipality with a council-manager form of government. The City Council is made up of a mayor and seven councilmembers. All members of the Council are elected at-large and serve three-year staggered terms. They are community volunteers who meet in regular meetings twice a month. The role of the Mayor and City Council is to enact local legislation, provide vision for the future of Carrollton, set policy, and hire a City Manager.
The City Manager, Leonard Martin, is the chief executive officer and is responsible to the Council for the proper administration of all affairs of the City as prescribed by the City Charter or required by the Council.
The City of Carrollton, Texas is not responsible for the content of external sites. Thank you for visiting the City of Carrollton, Texas website.


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To delete a section which you don't want to print, click on the red highlight or red X. To restore the section, click on the green arrow icon in the upper right hand corner of the post.
If you have a Winnie the Pooh fan in your household, here's a highly rated FREE app you may want to download! Just head on over to the iTunes store where you can snag the Winnie the Pooh Wonder and Wander app completely FREE for your iPhone or iPad (Compatible with iPhone 3GS, iPhone 4, iPhone 4S, iPhone 5, iPod touch 3rd generation, iPod touch 4th generation, iPod touch 5th generation, and iPad. Requires iOS 5.0 or later. This app is optimized for iPhone 5.). Plus, check out all the positive reviews! :-)
Enter the fantastical world of the Hundred Acre Wood where Moms, Dads and their Little Ones can interact with Winnie the Pooh and his friends – creating happy fun and sharing whimsical discoveries. Wander through Winnie the Pooh's world – that is full of bright colors, sounds and smackerels of action-reaction elements.
(Thanks, Nicole!)


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Economic Inequalities
Shirley Sicurello 11/28/2011 5:56:46 AM
So well done, both as an image and a social commentary. #1426286Lorna Shutter 11/28/2011 7:10:18 AM
Wow! What an amazing contrast! Love the B&W and the statement this makes! Your clarity and depth are wonderful! A fave for me, Lester! :) #9835085Michelle Alton 11/28/2011 8:23:49 AM
Brilliant capture and presentation, Lester. #9835245Amalia Sylvia Ms Arriaga Salinas 11/29/2011 3:22:23 PM
Fantastic image and title Lester!,JO ANN CLEVELAND 12/14/2011 8:05:52 PM
Congratulations on this outstanding finalist Lester!
jo ann c. #9867173
The Judges at BetterPhoto.com 12/15/2011 8:23:37 AM
Excellent juxtaposition in thought and tonal contrast! #9868560Lester A. Garcia 12/15/2011 10:33:02 PM
SHIRLEY, LORNA, MICHELLE, AMALIA & JO-ANNThank you for your kind remarks.
Am honored with your comment.
Merna L. Nobile 12/16/2011 12:57:45 PM
What could be more important in life than to know in our hearts that in everything we have tried to do, we have done our very best?Lorna Shutter 12/16/2011 1:11:17 PM
CONGRATULATIONS on your well-deserved Finalist Award, Lester!!!!! :) #9871590A rural and an urban landscape in one.
Exif: F Number: 6.3, Exposure Bias Value: -2.00, ExposureTime: 1/320 seconds, Flash: did not fire., ISO: 160, White balance: Auto white balance, FocalLength: 300.00 mm, Model: NIKON D300
Uploaded on 11/28/2011 5:13:20 AM
Camera: Nikon D300 Digital SLR Camera
Copyright for this gallery photo belongs solely to Lester A. Garcia. Images may not be copied, downloaded, or used in any way without the expressed, written permission of the photographer.
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Whew! Such stress and so much physical exertion! The language barrier really hurt you this time, but you guys survived and have moved on to new adventures. I can tell from the photos that this city is not as well maintained as previous places you have visited; the same happens in America, of course, from one city to the next.
Lviv, L'viv, Lvov, Lwow, Lwów, Lwiw, ЛbBiB?
Trip Start
Mar 31, 2011
Trip End
Jul 05, 2011
Where I stayed
The fun began with our night train from Krakow to Lviv. Our compartment was so ridiculously small and had three beds stacked on top of each other. There was barely enough room for our luggage, and all of the bedding looked as though it was from the 1920's. Luckily, we had a really nice roommate named Andre from Portugal, who studied at Cornell and now works for the NIH. Definitely made for some good science conversation. The excitement continued when we reached the border between Poland and Ukraine. The train conductor woke us up to check for our passports, then the Polish border control stamped passports, then the Ukrainian immigrations officers confiscated our passports for a while and returned with them after about 20 minutes (stressful). The whole process took about 2 hours, which is obviously a pretty solid portion of our 6 hour train ride/night of sleep. Needless to say, we slept for about 3 hours in total. The worst part is that we had to take the same train back from Lviv to Krakow, but more on that later.
We arrived in Ukraine at 6 AM, got off the bus in a big hurry, and walked into the bus station. It was seriously like being back in Latin America, but without the language advantage. The Lviv train station in the morning was SO seedy-- there were creepy people everywhere trying to sell us stuff and herd us into their taxis. People were yelling everywhere in Ukrainian, and none of the signs were in English. This was particularly troubling because Ukrainian language uses the Cyrillic alphabet (like Russian), so it was pretty much impossible for us to figure out what to do or where to go. I had to use the bathroom after the train, because the train bathroom was totally appalling. Turns out that the bathroom in the train station was even more horrendous, and it cost money to enter and to use toilet paper! Plus, the toilet was just a hole in the ground with little ridges next to it where you were supposed to put your feet. Blah. After the bathroom ordeal, we decided to go find the hostel and buy our train tickets to Poland at a later time (bad idea).
We wandered around for about 30 minutes trying to find the tram station and get on the tram. Then we got off about 5 stops too early because we had no idea what we were doing, and had to wander around lost for about 2 hours before we found the hostel. Disastrous-- my back will probably never recover. But when we got to the hostel, there was free breakfast waiting for us! Fancy breakfast too-- three eggs and toast with black and red caviar. Caviar is a big deal here. I had never even seen caviar before this trip-- it just doesn't make its way into US cuisine. We met a nice man from California who gave us the low down on Ukraine, which was very helpful. He had been travel ling for over a year-- I already feel like I've been Europe forever and it has been less than 3 weeks. Anyway, he warned us that it might be difficult and time consuming for us to get train tickets, so we decided to cruise then head to the ticket station (different from the train station) to get our tickets back to Poland.
We found out that the ticket station was closed from 2 PM to 3 PM, so we went to Old Town to get our bearings and kill some time. Old Town is very different here than in the Baltics or Poland. The buildings are much older, but no less beautiful. The weather was pretty Grey on Friday (4-15), but the colors were still wonderful. I wish our big cities in the US were this beautiful. We found the train ticket station, and then our troubles really began. We stood in line for almost an hour, just to be told by the lady (in half English, half Ukrainian) that we needed to go to the main bus station to get our tickets. So we decided to try and walk to the train station (stupid), and walked forever before realizing that we were on the wrong road. So we took a tram back, wandered around trying to find the right tram to the train station, failed, then walked down the right road for another 2 miles. After finally finding the station, we stood in line for another eternity to find someone who spoke English, only to find out that our train was sold out of 2nd class berths. All they had available was first class (twice the price) and trains for the next day (not express, so 10 hours instead of 6). The lady at the window sent us to the bus station to ask about a bus, but the ladies at the bus station sent us right back to the train station! We couldn't really tell if there wasn't actually a bus from Lviv to Poland or if they just didn't understand what we were asking. Both seem equally possible. We went back to the same lady at the train station, who got really frustrated with us and sent us upstairs to a different ticket booth where people spoke English. So we had to start the whole process from scratch, but at least this lady was nicer. We decided to just take the 1st class compartment in the night train, especially since the first train ride was so brutal. Dad tried to give her a credit card, but it turned out that they only took cash because most of the transactions are under the table to avoid taxes! Thankfully, there was an ATM downstairs in the train station, so we went downstairs, pulled out a TON of Ukrainian hyrvnias, and headed back upstairs to pay. I took a picture of the Ukrainian money because there was SO much of it-- the exchange rate is 8 hryvnia to 1 US dollar. Needless to say, we are exhausted just from buying the ticket.
So after dropping a bunch of money on train tickets, we wanted a bargain dinner. We went to a little place next to Lviv university and feasted on Ukrainian favs for 8 dollars US. Excellent deal! Then back to the hostel to get some sleep for the first time in 3 days. Our hotel was definitely a party joint where other travelers were trying to meet each other and hang out, so I think Dad was pretty unhappy about the situation. We have definitely not been meeting other travelers-- Dad does not seem to be even slightly interested in being social. Oh well, I'm sure we will meet tons of people once Jenna and Adrienne/Jeremy arrive. And at least we were on the 7th floor, so it was pretty quiet. We are getting pretty good at lugging the backpacks up multiple flights of stairs, but it is still pretty painful.
We woke up at 11:30, which means we missed breakfast by about an hour, which was okay because we illegally stole breakfast the day before. We went to a little cafe for lunch and got a giant feast for about $4 US per person! Traditional Ukrainian food is pretty similar to Russian food-- lots of stuffed pancakes and dumplings, but all of the Ukrainian food is drowning in butter sauce. Excellent! Good thing we are walking literally all day, every day, or this butter might catch up to us.
After lunch, we decided to try and climb up to the "high castle." We climbed up a huge hill to find an old restaurant that we thought was the castle for a while. We were so confused as to how the castle could be so new/boring, but then we walked around the side of the building and found another huge hill to climb! I'm not sure we ever actually found the castle, but we did climb up a thing that looked a bit like a castle turret that had been buried for a long time. Regardless, the views were pretty nice. It was obvious that Ukraine hasn't quite fully capitalized on their tourist attractions yet-- most of them were partially obscured by trees and all of them were tainted with power lines. So expect plenty of trees in front of the focus of my pictures, haha. Also hilarious was the number of women at the top of the hill that were wearing stiletto heels! It was really freaking hard for us to climb the hill, and we were wearing practical shoes and have the advantage of altitude endurance! I would have to be carried up the hill in stilettos. We got really nice pictures from the top, and it gave us a really nice perspective of Lviv. Lviv is about 5 times bigger than I expected it to be. The guidebook makes it sound really small and quaint, and the map in the book is totally minuscule, but it is gigantic!
After the hill, we walked to St. George's Cathedral, which was perched on top of another hill. We trekked up and walked around the grounds for a while, then peeked in for a few minutes to watch the service. It was so beautiful-- there was an entire choir of church boys singing and lots of lit candles and incense. Obviously I couldn't take a picture of it, but it was beautiful. We also got a nice unobstructed view from this hill, and the lighting was much better so that was definitely worth it. On top of clouds, Lviv seems to have a fair amount of air pollution, so the sky was difficult to photograph.
We had dinner at a very popular sushi restaurant near our hotel. Sushi in Ukraine is so cheap! We got a giant plate of various types of sushi-- 38 pieces total-- for about $20 US! And it was the best sushi I've ever had. The restaurant itself was really bizarre. They played the entire Owl City CD almost 3 times while we were there. The song "Fireflies" played twice, and I had some pretty good flashbacks of Jenna dancing around and singing that in our kitchen. Jenna-- it would be so funny/mortifying to do something like that here. If you behave even slightly out of the ordinary, everyone around you glares like you have some horrible disease and you are an embarrassment to society. Manners and propriety seem to be very important here (and in Russia), and you seem to be ostracized more extremely if you step out of line than back in the US. Probably has a lot to do with this region's communist history.Someone we met in the hostel told us that he was using the arm rest at a train station while sitting next to some lady, and her husband came up and hit his arm away because he was using more than his share! Pretty extreme, but at least people know to behave.
We headed back to the hotel to pick up our bags and go back to the train station for the 3rd painful time. At least we knew how to get there, after many trials and tribulations. We were able to sneak into the lounge (which they also charge admission for, just like the bathroom), so our wait for the train was pretty comfortable. Then our train arrived 30 minutes early, so we were able to get comfortable in our first class compartment. First class is so much nicer than second class. We were totally astonished. Our compartment had only 2 beds instead of 3, a private bathroom, a TV, heating and AC, and little toiletries kits! What a huge improvement from our last miserable experience on this train. However, getting out of Ukraine was even harder than getting in. First, Ukrainian immigration checked our passports. Then, Ukrainian customs officers checked our passports again and searched around the compartment for contraband items.Next, Polish immigrations checked our passports. Last, Polish customs searched around our compartment. So we had four interruptions, making sleep basically impossible. At least we were in a nice compartment! So now we are in Krakow again, but more on that later. до побачення!
My Review Of The Place I Stayed
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