Cells are
divided into two major groups, the prokaryotes and eukaryotes,
based on whether they have nuclei. Attention is also paid to the
types of membranes they contain and the complexity of their genetic
material. Eukaryotic cells have nuclei.
PROKARYOTIC
CELLS
(BACTERIA
INCLUDING MYCOPLASMAS, CHLAMYDIA AND RICKETTSIAE)
Prokaryotes
are cells that live and reproduce independently. The term prokaryote
is made up of "pro" meaning "before" and"
karyon" meaning "nucleus"). Prokaryotes lack a
nucleus.
BACTERIA.
Bacteria do
not contain a nucleus but the genetic material (DNA) is concentrated
in a central region of the cell known as the nucleoid (not surrounded
by membrane). In later bacteria there is a cell wall composed
mainly of peptidoglycan, a polymer of N acetyl glucosamine and
its lactyl ether N acetyl neuramic acid with peptide chains bound
to the lactyl group. Variations in this basic structure have been
described for a number of bacterial genera.
MYCOPLASMAS
This group
of organisms termed prokaryotes is larger than viruses and smaller
than other bacteria. They lack cell walls (which larger bacteria
possess), have very small genomes and require cholesterol for
cell membrane function and growth and are strictly dependent upon
host cells.
Although it
has been difficult to grow them in agar, (without cells), the
addition of rich nutrients has made this possible.
There are
more than 100 known mycoplasmas.
They are found
in normal mammals, including human beings are very widespread
and under some circumstances some specific mycoplasmas can cause
disease.
Mycoplasma
pneumoniae
Are important
in childhood and adult pneumonias (including tracheobronchitis,
sore throats, myringitis and cervical lymph node enlargement.
Mycoplasma
hominis (and ureaplasma urealyticum).
These inhabit
the urogenital tract, and may be pathogenic, causing urethritis
and pelvic inflammatory disease.
Mycoplasma
genitalium (described recently)
This is also
a cause of similar urogenital infections.
Mycoplasma
fermentans.
Until recently
these organisms have been detected without evidence of pathological
consequences.
South Australian
laboratories only test serology for M pneumoniae.
Professor
Garth Nicolson from Houston in Texas has attributed Gulf War Syndrome
and Chronic Fatigue Syndrome to these organisms and the interactions
that they induce in the host.
He and members
of his research team continue to unravel evidence that they are
important in chronic fatigue syndromes and perhaps in other disorders.
Mycoplasmas
certainly are ongoing candidates for causing this sort of pathology,
and may well be able to elude immune mechanisms.
So far there
are not many publications that throw light on Professor Nicolson's
work.
One that is
notable is from Nijs and De Meirleir from Brussels in Belgium.
They describe
evidence for mycoplasma infected CFS patients having elevated
RNAse L -ratios compared to non-infected controls. (See later)
Mycoplasmas
can also produce superantigens
Mycoplasmas
can act as polyclonal T cell and B cell activators and some can
trigger macrophages in vitro.
It appears
that the innate immune system has learned during evolution to
react to the lipid moieties by inflammation, thus alerting the
immune system, whereas the microbes have evolved tactics to evade
a specific immune response by varying their antigens.
Lipoproteins
and lipopeptides are likely to be the main causative agents of
inflammatory reactions to mycoplasmas. This may be relevant in
the context of mycoplasmas as arthritogenic pathogens and their
association with AIDS.
Monocyte derived
elastase can cleave 83kDa RNAseL thus causing deregulation of
the anti viral pathway.
These authors
describe a 37kDa product, which is present in large amounts, and
also a depletion of the 83kDa form.
It is quite
possible that particular people have higher burdens of mycoplasmas
than others do.
We need to
be quite clear that help will come when we can define the difference
between resident mycoplasmas in normal people and some sort of
pathological consequences in some people with higher mycoplasma
loads.
Mycoplasma
pneumoniae uses specific long chain sialo oligo saccharides at
host-cell surface as receptors. (See also in the glyco protein
section).
Autoantibodies
can be a response to I antigen in this molecule on bronchial epithelium
or on red cells. This is a factor in the cold agglutinins found
in acute infection, and may be a part of other immunological changes.
One thing
coming out of the Newcastle work is the possibility that there
are different lipid patterns and in the case of mycoplasmas the
possibility of very low serum cholesterol levels.
This raises
two interesting questions!
How do pathogens
alter lipid homeostasis?
How do lipids
alter pathogen responses?
CHLAMYDIAE
( recenty renamed chlamydophila)
Chlamydiae
are also obligate intracellular parasites possessing RNA and DNA,
a cell wall and ribosomes similar to gram negative bacteria. They
also lack a discrete nucleus.
Chlamydia
pneumoniae can cause upper respiratory tract infection and pneumonia.
Particular
attention has been paid to its presence in some 18-70% of coronary
artery plaques and more recently in a connection to bronchial
asthma.
Chlamydia
trachomatis causes a corneal disease (trachoma) and genital infection,
as well as triggering Reiter's syndrome (perhaps in genetically
vulnerable individuals).
In pelvic
inflammatory disease in USA, Chlamydia trachomatis has been found
in endometrium and fallopian tubes in up to 50% of cases.
So far chlamydiae
have not been implicated in chronic fatigue syndromes, but Dr
David Wheldon, Microbiologist of Bedford,UK, believes that they
may play important roles in diseases such as multiple sclerosis.
(http://www.davidwheldon.co.uk/peer-review.html
)
MORE ABOUT
BACTERIA
Larger bacteria
are a specific kind of organism where the cell membrane is surrounded
by a specific cell wall.
This is another
difference from eukaryotes, and is relevant to one role of some
antibiotics.)
STAINING
CHARACTERISTICS
Routinely
microbiologists stain bacterial preparations.
For example,
the Gram stain allows separation of gram positive from gram negative
organisms.
Other names
are given in relation to some of the in vitro actions of organisms
or their products.
GRAM POSITIVE
BACTERIA
Cell walls
of gram positive bacterial contain teichoic acids which are phosphate
linked polymers of ribitol or glycerol that can have additional
compounds linked to available side groups.
The various
substituents of teichoic acid are often responsible for the biological
and immunological properties associated with disease due to pathogenic
gram positive bacteria.
Most pathogenic
gram positive bacteria have additional extracellular structures.
These include surface polysaccharides such as the group antigens
of streptococci, capsular polysaccharides and surface proteins
and polypeptides.
GRAM NEGATIVE
BACTERIA
Gram negative
bacteria have a similar cytoplasmic membrane and peptidoglycan
layer somewhat reduced compared with gram positive organisms.
They are characterized by outer membrane that is covalently linked
to the tetra peptides of the peptidoglycan layer by lipoprotein.
The outer
layer of the outer membrane contains the lipopolysaccharide constituent
which includes also special proteins which are important to the
function of the gram negative organisms.
Some specific
things that bacteria do include colonization of host surfaces
and depending on the organism, invasion of tissue with sometimes
specific tissue tropism.
I return to
microbiological products to give some examples.
Exotoxins
Some bacteria
produce exotoxins, for example diphtheria, botulism and tetanus.
Also pathogenic gut organisms can produce enterotoxins.
Most people
are familiar with the fact that some staphylococci can produce
a toxin associated with what is called 'toxic shock syndrome'.
The lipid
A portion of gram negative lipo-polysaccharide has potent biological
activities capable of producing severe illness, particularly in
the circumstance of gram negative bacteraemia. This effect appears
to be mediated by production (from mononuclear cells) of IL-1,
TNF alpha and perhaps IL-6.
RICKETTSIAE
Since September
and October 2001, I have been checking my CFS patients for rickettsial
infection.
The results
suggest that Dr Cecile Jadin in Johannesburg, South Africa is
identifying an important connection to some of the cases of this
crippling condition.
It seems that
she has found some 3.600 patients with chronic fatigue, fibromyalgia
and related conditions, who test positive for rickettsial serology.
I am therefore
expanding the section on rickettsiae.
The evolutionary
history of rickettsiae is particularly interesting.
Phylogenetic
data suggests that mitochondria originated from a family of alpha-proteobacteria
called rickettsiales.
This high
ranked taxon consists of exceptionally obligate intracellular
endosymbiants of eukaryotic cells. The family includes rickettsiaceae
and rickettsia-like endosymbiants.
A long term
mutualistic relationship between these intracellular bacteria
with a pro-eukaryotic line of cells appears to have given rise
to eukaryotes where 80% of cell energy is derived from the mitochondria.
The invader must have lost many of it's dispensable genes, and
logically it was so integrated with the eukaryote that it joined,
that when much later multicellular systems evolved immune systems
it behaved as self and evoked no immune response, and as well
conserved and evolved it's DNA.
Mitochondrial
DNA is transmitted from generation to generation through the maternal
cytoplasm in the ovum, since any small remnants of sperm mitochondrial
DNA is lost as the sperm enters the egg.
This old organism
has thus become the eukaryote's main energy source and includes
the evolution of carrier proteins to exchange respiration derived
ATP for host metabolites.
Hackstadt
has written a good summary of the history of rickettsiae.
Well, what
of the rickettsiae which we now know as pathogens?
Pathogenic
Rickettsiae
They seem
to range from organisms that cause very severe and even fatal
diseases (Typhus Fever and Rocky Mountain Spotted Fever) to moderately
disabling and less severe chronic disease states.
Some may be
benign under most circumstances. (Or in particular hosts)
This is a
family of gram-negative coccobacilli and short bacilli that grow
strictly in eukaryotic cells.
That remote
origin some 1.5 to 2 billion years ago has led to a stream of
intracellular organisms in birds, reptiles, and mammals that may
have very variable consequences for the host cells.
The cell provides
a rich source of nutrients and rickettsiae have developed a number
of special mechanisms to transport nucleotides and nucleotide
sugars.
They express
an ATP translocase, enabling them to obtain stored energy and
depriving the host cell of that energy
There seem
to be points in the degree of proliferation where cells can be
more seriously damaged, and this is different in Typhus (proliferation
within the cell and at a certain stage cell lysis), compared with
Spotted fever group rickettsiae where organisms spread rapidly
from cell to cell via actin-based motility, without cell lysis
(Hackstadt)
Rickettsiae
tend to be transmitted by insect or tick vectors.
It is likely
that the arthropod vectors are particularly important in the natural
maintenance of the pathogenic rickettsiae.
In the models
of disease, which I am using in this paper, exploration of the
co-evolution of host-pathogen relationships is central.
In this regard,
efficient pathogen replication and endurance or maintenance are
important as is transstadial and trans ovarial transmission (in
the arthropod vector).
I want to
emphasize that rickettsiae can cause both acute and chronic diseases.
The latter however has scant documentation.
Clearly they
are recognized by immune cells, and can evoke T cell activation
as well as B cell antibody production.
Some of the
diseases are very severe (eg Rocky Mountain Spotted Fever) caused
by R rickettsii.
Rickettsial
antigens
These organisms
possess two major immunodominant surface exposed proteins, called
outer membrane proteins (rOMP A and B)
rOMP A functions
as an adhesin for the host cell, and rOMP B shares genetic sequences
and limited antigens with other Spotted Fever and Typhus group
rickettsiae.
DH Walker
and colleagues have been studying mechanisms of pathogenicity
for many years. (Currently in Galveston, Texas, USA)
Rocky Mountain
Spotted Fever is an important diagnostic condition in the Americas.
We are less
sure of the full range and associations of the ongoing presence
in cells of various rickettsiae.
Attention
is being directed at exactly how the immune system deals with
intracellular organisms.
Classification.
Spotted
Fever Group
Rocky Mountain
Spotted Fever, (R rickettsii) Vectors: various ticks
This is a
severe rickettsial disease, documented in 48 of the states of
the USA, Canada, Mexico, Costa Rica, Panama, Colombia and Brazil.
After inoculation
by the tick bite, it spreads lymphohaemotogenously throughout
the body, attaches to endothelial cells, escapes from the phagosomes
and replicates intracellularly. Its spread from cell to cell involves
polar polymerisation of the host cell's actin. It also invades
vascular smooth muscle cells.
The pathological
consequence is mainly increased vascular permeability with local
oedema, ischaemia and hypovolaemia.
Thrombi are
usually limited, but 30-50% of cases develop thrombocytopenia.
If undiagnosed
and untreated, the mortality can be 20-25%.
Serological
positivity by indirect immunofluorescence is very specific, but
may not happen early enough, so that the only useful test in the
acute phase is skin biopsy of the an area of rash, with immunohistological
studies.
Readers can
look at the various clinical presentations and differential diagnoses
in medical textbooks.
Mediterranean
Spotted Fever, (R conorii) Vectors: several ticks
This is found
in the Mediterranean area, Southern Europe, Africa, and south
west and south central Asia.
In Spain 58.6%
of dogs tested had antibodies to R conorii. (Herrero and colleagues),
while in Zimbabwe and South Africa, 34% and 19% of domestic cats
tested positive for the same antibodies. (Matthewman et al)
It has varied
from very severe forms to milder diseases.
Fever, rash
and a lesion at the site of the tick bite are common.
Rickettsialpox,
(R akari) Vector:
mites
Found in USA,
Ukraine and Slovenia
A lesion
at the site of the mite bite is followed by local lymph node enlargement,
fever, headache myalgia and usually a maculopapular rash.
Queensland
Tick Typhus (R australis) Vectors: ticks
Found in
Queensland, Australia and along the eastern seaboard of Australia.
Flinders
Island Spotted Fever
(R honei) Vectors: ticks
Found in
Flinders Island in Bass Strait, between Australian Mainland and
Tasmania, but recently in South Australia
In 2003-3,Dr
Stephen Graves has isolated R Honei from 3 patients with a febrile
illness, typical spotted fever type rashes, cough and abnormal
liver function tests, admitted to Flinders Medical Centre in South
Australia.
This is the
first confirmation of R honei on mainland Australia.
Australian
Tick Typhus
(R marmionii) Vector not established
Found in
a similar case south of Adelaide with acute spotted fever like
illness, and subsequently in cases in Queensland, Australia) The
gene sequence is different from other spotted fever rickettsiae.
(This name
acknowledges 40 years of work on Q fever done by Professor Barrie
Marmion, and particularly his evidence of a post Q fever variety
of chronic fatigue syndrome.)
This information
alerts Australian doctors to be aware of rickettsial diseases
in Australia.
North Asia
Tick Typhus(R
sibirica) Vectors: ticks
African Tick-bite
fever (R africae) Vector ticks
This is present
in South Africa, Zimbabwe, Tanzania, and Guadeloupe in the Caribbean
Typhus
Fever Group
Epidemic
Typhus, (R prowazekii) Vectors: human lice
This has a
world wide distribution.
Unlike other
arthropod vectors, the louse does not pass the organisms to it's
offspring.
This is a
severe illness coming about one week after inoculation, manifesting
as high fever, prostration, severe headache, cough and myalgia.
A rash is
usually prominent. Twelve percent have neurological involvement.
There is a
fascinating recrudescent, mild form of epidemic typhus (Brill-Zinsser
Disease) occurring years after the acute disease, possibly relating
to a decrease in immune function. It is a good example of the
capacity of these organisms ability to survive, presumably in
a dormant form, for very many years.
Murine
Typhus,
(2 types)(R typhi) Vectors: fleas (usually rat fleas)
Worldwide
in distribution.
The animal
reservoir is the rat and transmission by bite of infected rat
fleas involves the scratching of the bite contaminated by the
flea faeces.
Aerosolised
flea faeces are also suspected to play a part. (Circumstantial
evidence suggest this may be inhaled, without there being a flea
bite)
Incubation
period is 8-16 days.
Headache,
myalgia, arthralgia, malaise, nausea and fever occur, often with
some rash. Thirty five % of patients develop a hacking cough.
Laboratory
tests can reveal anaemia, leucopenia (early) and leucocytosis
(later), thrombocytopenia, abnormal liver and kidney function.
With lung
involvement some patients can require intensive care.
The illness
is often milder in children.
Interest has
also arisen in a variety of rickettsia called R felis, transmitted
by cat and opossum fleas.
Scrub Typhus
Group
Scrub Typhus
(R. (renamed Orientia)(tsutsugamushi) Regarded as a different
group, because of different cell wall characteristics and genetic
makeup. Vectors: mites in chigger (larval) form.
This is found
in Asia, Australia, New Guinea and Pacific Islands (principally
in tropical regions)
It is a of
variable severity involving fever, headache, myalgia, cough and
gastrointestinal symptoms, and regional lymphadenopathy near the
bite.
The limited
descriptions I provide here are to illustrate the best documented
varieties of acute rickettsial diseases.
There are
at least 30 different strains of rickettsiae, and classification
as well as exploration of pathologies relating to them is still
unfolding.
According
to current evidence, R australis, R felis, R honei and R marmionii
are known to occur in Australia. Historically Typhus fever has
also occurred in Australia, and Dr Stephen Graves has recently
confirmed a case in Melbourne.
Although I
have spelled out some material on Rocky Mountain spotted fever
for world wide readers, it has never been found in Australia.
Q Fever
The other
related but distinctly different example is Q fever, where the
organism has been named Coxiella burnetii and is known for its
ability to survive for long periods outside of the reservoir or
any vector.
This latter
organism is also known for it's high level of infectiousness.
It seems to be one which does not need an insect vector to transmit
it.
That does
not exclude the possibility that close contact with pet animals
may not some times result in inhalation or swallowing of insect
vector faecal pathogens or shed viruses.
Avoiding unduly
close oral contact with animals and their fomites would seem to
be prudent.
It has been
reported that in the town of Roma in Queensland that 1/3 of the
population test positive for Q fever serology.
Up to 10%
of Q fever cases emerge with post Q fever fatigue, and these tend
to have raised levels of IL6. Professor Marmion found the organisms
in the bone marrow of this group of patients.
The HLA haplotypes
of this group appear to be DRB1*11.
We can see
this as an example of the various expressions of a disease in
different individuals.
Cecile Jadin,
a Belgian doctor now working in South Africa, has written an important
document about connection between rickettsial diseases and CFS
as well as fibromyalgia syndromes.
In her book
"A Disease called Fatigue", Dr Jadin describes the high
probability that many Rickettsial diseases are transmissible by
breathing, swallowing or contamination of abrasions or cuts by
organisms.
The science
of this is in need of better validation.
The evidence
is strong that doctors should be vigilant in checking for this
disease, and also that post infection fatigue is one of the important
possibilities.
Prof Andrew
Lloyd at U of NSW is following some of these cases in a prospective
study.
Can Rickettsiae
result in chronic illness?
Rickettsiae
have many attributes, which make them a likely candidate for persistence
and causation of chronic fatigue syndrome/fibromyalgia syndromes.
The intracellular
location means they can adversely affect cell metabolism, such
as scavenging ATP. They are also not so susceptible to immune
system activity except the degree to which T cell and macrophage
activity can evoke particular cytokine responses.
Phospholipase
A2 (PLA2) activity evoked by the typhus group rickettsiae causes
haemolysis in vitro, and may mediate entry into the host cells,
as well as escape from the phagosome.
Walker is
interested in this phagosomal escape.
With both
Typhus and the Spotted fever group, the PLA2 may contribute to
cell injury by increasing free arachidonic acid being susceptible
to oxidation and the production of inflammatory prostaglandins.
This has therapeutic
implications, since a PLA2 inhibitor (bromophenacyl bromide) decreased
cell injury and inhibited the release of free fatty acids. (Walker
et al)
Quercetin
inhibits the same enzyme.
Rickettsiae
(eg R.prowazekii) can be included in a group of intracellular
pathogens which possess specialized secretion systems which they
use to subvert host defences.
The class
called typeIV have homology to the conjugal transfer systems of
naturally occurring plasmids, and use them to export toxins.
Other organisms
that have these systems are Legionella pneumophila, Coxiella burnetii
and Brucella abortus. (Sexton & Vogel)
Study of microbial
genomes provides insights about their survival in host cells.
Reductive
evolution has led to dispensing of genes which cover overlapping
pathways but high priorities for genes which lead to more effective
immune system evasion. (R prowazekii has a genome less than a
third the size of E Coli.) (Palmer)
Intracellular
pathogens can target macrophages, and increase the production
of certain cytokines such as interleukin10.
The survival
of organisms inside the macrophage, an antigen processing cell,
is helped sinceIL10 is a potent immune suppressive factor (Red
path et al)
IL10 can down
regulate inflammatory cytokines.
Rickettsiae
cause vasculitis, which seems to vary in degree in different family
members.
The endothelial
cell is a primary target for R conorii and George et al found
increased levels of circulating endothelial cell (EC) and EC fragments,
plasma thrombomodulin and von Willebrand factor in 12 patients
with Mediterranean Spotted Fever.
These levels
fell progressively with successful treatment.
Intracellular
pathogens may also make a neurotoxin.
Rickettsiae
certainly make toxins (eg haemolysins) but there is very little
literature on this.
There is evidence
of a gene in R typhi, which codes for a haemolysin.
Vasculotoxic
and neurotoxic substances seem most likely.
The claim
about neurotoxin is an interesting one, since such a toxin has
been identified in borreliosis, and accounts for muscle pain,
stiffness and spasm.
In a few it
seems to produce a” stiff-man syndrome". It would be
interesting to test all future cases of the "stiff-man syndrome"
for rickettsiae, and those who have been ill since being in other
countries, for borrelia serology.
In my literature
search I could not find evidence for a neurotoxic rickettsial
product, but there is very good evidence for neurological abnormalities
in acute and chronic rickettsiosis.
Some may reflect
vasculitis, and or cytokine abnormalities.
The cerebral
perfusion abnormalities found in CFS sufferers on SPECT scanning
by Drs Reynold Casse, Richard Burnet, and Richard Kwiatek in Adelaide
may relate to these pathological changes, local neurone injury,
or to autonomic instability.
Here in South
Australia, I have recently started testing my CFS/fibromyalgia
patients for rickettsial serology and am finding more than 60%
are positive for the spotted fever/typhus fever group,
(I am also
evaluating controls without fatigue.)
I have (by
2005) 702 cases tested for rickettsial serology.
Of these
644 have CFS or FMS by conventional criteria.
Only 5 of
the persons deemed to have no fatigue like symptoms tested positive
(2 at
1/128 and
3 art 1/256)
If we break
them down by titre 20 are +ve at 1/1024,
59 are
+ve at 1/512
159 are
+ve at 1/256
126 are
+ve at 1/128
Dr S Graves
of the Australian Rickettsial Reference Laboratory thinks that
the 1/256 or greater are probably true positives and 1/128 are
impossible to interpret.
I am aware
of 427/822 CFS patients with positive serology tested by other
SA doctors.
This work
will need to be clarified as the Geelong based Australian Rickettsial
Reference Laboratory does its routine serology against the whole
organism and doesn't report the separate IgG and IgM antibodies.
A discussion
with Dr Geoffrey Higgins (IMVS) reveals that controls that are
blood donors have a low rate of positives and all are low titre.
(Approximately 6% of a series of 90 donors)
Three positives
are the mothers of sero positive CFS patients. Both are fatigued,
but may not fill the international criteria of CFS.
There is documented
clustering of CFS and related disorders in published literature)
(Drs Paul Cheney, and Trevor Marshall)
The antibodies
to cell wall antigens of rickettsiae cross react to other members
of the group (eg all of the spotted fever group and typhus group)
we need to know whether there are other organisms which can give
rise to positive rickettsial serology.
We intend
to explore this further by checking for rickettsial DNA by PCR,
and by culture from the buffy coat of blood collected in EDTA
tubes.
I have now
found positive PCRs for rickettsiae in 2 chronic fatigue patients.
One was from
knee tissue and one in a removed lipoma. Both had serology positive
at 1/256
If these organisms
are like coxiella (Q fever) or like borrelia (Lyme disease) they
may be difficult to find outside of tissue biopsies.
We will also
try to do control and blinded studies to assess the prevalence
of Rickettsial disease in the South Australian community.
So far it
appears that in South Australia, the serological test distinguishes
the CFS sufferers from other people, suggesting that there is
a distinctive form of chronic rickettsiosis in SA. It may emerge
that the clinical illness often has a mild beginning.
The clinical
profile would make the spotted fever members most likely.
We do not
know why these people are testing positive, and what this implies
about past or present rickettsial disease.
I will spell
out the desirable therapy for rickettsial disease in the section
on management.
We do not
know why a subgroup appear to respond promptly to one or more
courses of antibiotics, why some relapse and others show little
response or get worse despite multiple courses.
Until we have
a reliable PCR or successful culture techniques available to us
in South Australia, we will continue to fly blind.
By this I
mean that the evidence is indirect and the reason for the symptoms
unclear.
Other tick-borne
infections
Lyme disease
This fascinating
disease covers a spectrum of clinical presentations as well as
illustrating how the discovery of an infective agent can be overlooked
for many years until a much more thorough exploration leads to
indirect, then direct evidence of its presence.
Lyme is a
city in Connecticut, USA, located in an area where the local fauna
include a white-footed variety of mice, local foxes, and white
tailed deer.
(Interestingly,
white tailed deer have recently been found to suffer from a prion
disease akin to bovine specific encephalomyelitis)
A tick called
Ixodes scapularis carries the organism from animal to animal.
This tick
exists in three stages
(1) A 6
legged larva, which hatches in midsummer and seeks hosts such
as the mice, then growing until it falls off, remaining dormant
through winter.
(2) In spring
it moults, emerging as an 8-legged nymph, which can attach to
small mammals or human being who happen to come by. The nymph
is the main vector for human Lyme disease.
3) It becomes
much larger as it feeds, and again falls off, lying dormant
until the next summer when it moults and becomes the adult 8
legged tick usually biting passing white tailed deer. These
adult ticks have a sexual life synchronized within their feeding.
The male is stimulated to make large numbers of sperm, as the
female makes thousand of eggs, and the copulation gives rise
to eggs, which are probably borrelia free.
Thus the reinfection
from the hosts is important in the life cycles of the germs.
Borrelia burgdorferi,
the causative organism organism is a fastidious microaerophilic
spirochaete, which has many immunogenic proteins.
It has a slender
spiral organism with a single chromosome carrying 853 genes.
Within the
non-nucleoid area of the organism are plasmids carrying a further
430 genes.
In its usual
form there is a double-layered cell wall.
The outer
wall is coated with a protective "slime" of carbohydrate
composition.
From the cytoplasm
flagellae protrude through the inner wall and wrap themselves
within the space between the inner and outer walls.
Flagellae
contain a protein named flagellin.
Borrelia burgdorferi
is not the only borrelia, but it possesses one chromosome with
910,725 base pairs constituting 853 genes, and at least 17 plasmids
with 533,000 base pairs and 430 genes.
These organisms
use glucose in anaerobic ways and not the pentose phosphate pathway.
They can’t
synthesize fatty acids, and derive amino acids, fatty acids and
co-factors from host cells.
Some of the
plasmid genes are replicas of chromosomal genes.
Some code
for immunogenic proteins (peptidoglycans) while others control
attachment mechanisms.
Outer surface
proteins called OSP A and B are expressed in the tick intestines
and OSP C is upregulated as the germ traverses the tick salivary
gland.
These antigens
are recognized by the mammalian hosts.
The significance
of evolutionary changes has been recognized in both hosts and
vectors as well as in the bacteria.
As with rickettsiae
there has almost certainly been some reductive evolution involving
loss of genes due to adaptation to the use of host cell mechanisms.
There are
fascinating pathogenic mechanisms which reveal to us how our old
ideas of mechanism have been too limited.
Human plasminogen
and urokinase type plasminogen activator are bound to the spirochaete
surface leading to plasmin production.
The organism
has some tropism to skin, neural, and A-V nodal cells, and joint
components, with ability to persist in these sites.
Borrelia burgdorferi
adheres to host integrin receptors in extracellular matrices,
and to vitronectin, fibronectin and matrix glycosaminoglycans,
as well as heat shock proteins.
In germ to
germ contact plasmids may be transferred from one bacterium to
another, and this increases genetic diversity.
In favourable
conditions, Borrelia burgdorferi divides every 8-12 hours.
It can also
develop large cyst like bodies in which small spirochaetes can
develop and then be released.
In variants
called L forms, they may lose the spiral shape, become deficient
in cell wall (hence losing susceptibility to amoxycillin and other
cell wall inhibiting antibiotics) and exhibit reduced activity,
yet still surviving.
Like Coxiella
burnetii (Q fever organism) and rickettsiae, the difficulty in
curing all cases, has been well documented.
Cultures from
blood are almost always negative, but cultures are positive in
tissue specimens from sufferers .Ear lobe blood seems to give
a higher yield of positives.
Dr Lida Mattman
has used special culture methods, very high magnification, dark
ground illumination, special stains, immunofluorescent tests,
and electron microscopy up to 100.000x magnification to see these
bacteria.
Garth Nicolson
has used PCRs to assess borrelia and mycoplasma prevalence in
various disorders including CFS, FMS, Gulf war syndromes and inflammatory
states
From the tick
bite incubation can be 3-32 days.
This infection
can present as
Stage
1
The early
local red skin lesion at the site of the tick bite (this is
called erythema migrans),
Stage
2
A disseminated
infection with severe malaise, fever, severe aching, headache,
stiff neck and fatigue and often secondary annular skin lesions.
There may
also be enlarged lymph nodes, cough and conjunctivitis.
About 15%
have meningitic, encephalitic and neuritic features, and 8%
A-V node or myo-pericarditis. Sometimes mood sleep and memory
disturbances are present.
Stage3
Months after
the onset some 60% of untreated cases develop oligoarticular
arthritis, (for a time in the past, children were diagnosed
erroneously as juvenile rheumatoid arthritis)
Unquestionably
this can also present like a fibromyalgic variety of CFS.
HLA DRB1 *0401
and *0101 alleles may mark a human vulnerability to arthritic
responses.
A neurotoxin
has been identified in borreliosis.
The immune
response to this infection is local (biopsy shows infiltration
with plasma cells and lymphocytes with some vasculitis)
Several detect
weeks may be needed for the specific IgM antibody to rise, with
croprecipitates, and circulating immune complexes eg. IgG rises
later (months)
Cytokines
TNFa, and IL1b are also elevated.
Tissue biopsy
with culture and PCR and enzyme linked immunoabsorbent assay (ELISA)
or Western blot testing may be helpful.
It is claimed
that 15% of patients treated with antibiotics get a Herxheimer
reaction, usually in the first 24 hours of therapy.
A primary
infection due to borrelia contracted in Australia has yet to be
documented.
Chronic cases
need much longer courses of antibiotics
Three of my
patients with CFS who have travelled widely have positive borrelia
serology.
As previously
mentioned there are possibly other borrelia which do not show
up as positive to B burgdorferi serology.
Bartonellosis
The Bartonella
species are tiny gram negative bacilli which can adhere to and
invade mammalian cells. They can come from cat scratches and also
tick bites. (Bartonella henselae) and they too can to produce
chronic fatigue and fibromyalgic syndromes.
Ehrlichiosis.
Ehrlichiae
are small, obligately intracellular bacteria, which can cause
human disease with fever, headache, myalgia, malaise, gastrointestinal
upsets, cough, rash and confusion. Professor Tim Roberts and colleagues
at the University of Newcastle have documented Ehrlichiae in Australian
dogs.
Two of my
patients have positive erhlichial serology.
Babesiosis
This is usually
a tick borne protozoan disease of animals, but can be seen in
USA as a febrile illness, with aching and fatigue.
I feel that
the evidence is strong that infection and its concomitants are
crucial to the on going CFS.
Specific testing
may require particular laboratories, and careful consideration
of the implications of the results.
I re-emphasize
that serology can be inadequate in determining the presence of
these pathogens.
I really think
that CFS is connected to consequences of injury evoked by intracellular
type organisms such as the herpes family of viruses (eg CMV or
a mutated form of CMV and HHV6), mycoplasmas, chlamydiae, rickettsias,
borrelias, ehrlichias and perhaps other organisms, and the body's
responses to these events.
More on
toxins
Medicine has
long recognized toxins as in tetanus, and diphtheria.
I would like
the reader to be aware of research into toxins , both in terms
of local and general effects.
The outbreak
of haemolytic uraemic syndromes after ingestion of particular
pathogenic E Coli ( Contaminants of some meat and metwurst type
products), reminds us of the toxins produced by these strains.
These toxins
are very similar to toxins produced by shigella ( Shiga toxins)
These shiga
toxin-producing Escherichia coli secrete a novel AB5 cytotoxin,
named subtilase cytotoxin (SubAB), which induces vacuole formation
in addition to cytotoxicity in susceptible cells.
Adelaide researchers
have found that these toxins kill cells by inactivating an essential
component in the cell’s endoplasmic reticulum.
Toxins like
those of clostridium difficile are extremely toxic to intestinal
cells, but researchers are now exploring remote locations for
such toxin effects.
Clostridium
difficile toxin B (TcdB) inactivates the small GTPases Rho, Rac
and Cdc42 during intoxication of mammalian cells.
Clostridium
difficile produces three toxins, TcdA, TcdB and CDT. TcdA and
TcdB are single-stranded molecules acting as glucosyltransferases
specific for small GTPases. CDT is an actin specific ADP-ribosylating
binary toxin characteristically composed of two independent components,
enzymatic CDTa (48kDa) and binding CDTb (99kDa).
The prevalence
of binary toxin producing strains is estimated to be from 1.6%
to 5.5% (Rupnik, Grabnar and Geric, 2003)
The ADP-ribosylating
toxins (ADPRTs) are a family of toxins that catalyse the hydrolysis
of NAD and the transfer of the ADP-ribose moiety onto a target.
This family includes many notorious killers, responsible for thousands
of deaths annually including: cholera, enterotoxic Escherichia
coli, whooping cough, diphtheria and a number of clostridial binary
toxins.( Holbourne et al) 2006)
Ritchie Shoemaker
MD of Pocomoke in Maryland, USA writes extensively about toxins.
The organism
behind estuary syndrome (pfiesteria) produces a neurotoxin, and
possibly small molecular weight toxins from some of these organisms
may turn out to explain the majority of these disorders.
I quote Shoemaker,
” Best
defined as causing "chronic, neurotoxin-mediated illness,"
these little understood diseases make people sick by producing
low molecular-weight toxins (aka, "ionophores") that
"hide out" in the body's fat-containing tissues, where
they remain impervious to the germ-fighting "antibodies"
which endlessly patrol the human bloodstream.”
He suggests
toxin-mediated disorders as part of Chronic Lyme Disease, Sick
Building Syndrome, Chronic Fatigue, Chronic Soft Tissue Injury
and several waterborne maladies involving toxin-forming blue-green
algae and one-celled dinoflagellates, including toxin-forming
ciguatera and Pfiesteria.
These newly
mentioned toxin-producers include the following:
--Dinoflagellates,
such as Pfiesteria, ciguatera and chattonella;
--Fungi,
including stachybotrys and fusarium;
--Bacteria,
such as pseudomonas fluorescens;
--Spirochetes,
including Lyme disease-causing borrelia;
--Blue-green
algae, such as rapidly reproducing microcystis and cylindrospermopsis.
I intend to
explore this literature until it is adequately investigated.
In the therapy
section I will write about how we might manage toxin-mediated
diseases, particularly noting the capacity to bind small molecule
toxins in the gut, by cholestyramine and colestipol.
New frontiers
in bacterial ecology.
I have been
in dialogue with Trevor Marshall, Ph D, now in California, and
we are slowly unravelling information about cell wall deficient
and L form bacteria which both evade immune mechanisms and may
evoke unwanted responses.
The theme
is a range of cell wall deficient or L forms of bacteria, which
evade immune mechanisms and evoke either TH1 or TH2 responses.
We perhaps
should look for L forms of bacteria by live blood examinations
at 8-10,000x magnifications, (ear lobe blood) and by special stains
as well as immunofluorescence.
I have 4 DVDs
of a Chicago Workshop/seminar where an absolutely amazing microbiologist,
(Dr Lida Mattman) shows extensive slides of these special stains.
Ear lobe blood
seems to allow better numbers of bacteria to be seen than venous
or finger tip blood.
If white cells
are positive, then PCR for specific organisms could be added.
This is a
theme.
"We
are all here to treat each other well in order to awaken our
best help for each other!"
Activated
macrophages possess the enzyme 1 alpha hydroxylase to turn 25
hydroxy D3 into the 1,25 dihydroxy D3, and Marshall claims that
this aids the survival of the bacteria.
This is illustrated
in the granulomatous disease, sarcoidosis.
Sarcoidosis
It has been
well documented that BALF from Sarcoidosis patients is hyper-reactive
to the presence of bacteria. A recent study by Agerberth, et al,
[4] extensively demonstrated the hyper-reactivity of BALF from
Sarcoidosis patients to the biochemical substances formed by bacteria
(lipopolysaccharides and lipopeptides).
For two decades,
study after study has shown that bacterial lipopolysaccharide
actively stimulates the production of more inflammatory cytokines
from the BALF of Sarcoidosis patients than it does from the BALF
of Controls
Marshall states
that this is very significant in marking a TH1 type immune response
and claims they are responses to these cell wall deficient bacteria
located in macrophages.
See www.marshallprotocol.com
What Marshall
fails to do, is to prove that this situation is true in all cases
of sarcoidosis.
He has not
so far published scientific evidence that the work also applies
to otherTH1 set diseases like Crohn’s disease, rheumatoid
arthritis and some cases of CFS.
However another
fascinating finding is that Marshall finds that the use of olmesartan,
an angiotensin 2-receptor blocker seems to improve some cases
of CFS and sarcoidosis.
Olmesartan
rapidly reduces 1,25 dihydroxy D3 levels.
I mention
this here because this has invited us to look at the interplay
between bacterial evolution and survival mechanisms as well as
the particular immune responses of individuals.
Angiotensin
2 receptor blockers (ARBs) are vasodilators, but A2 receptors
are used by
some organisms as entry points.
Angiotensin
is a vaso-constricting product from liver precursors, but it seems
now clear that it plays a role in some inflammatory states, perhaps
by changes in its receptor, and in the downstream events from
receptor activation.
Marshall suggests
that the A2 receptor may alter with inflammation and at least
one A2R blockers is anti-inflammatory and are definitely able
to stop NF kappa beta activation, thus decreasing transcription
of the TNF alpha gene, and decreasing this inflammatory cytokine.
Another ARB
(telmisartan) is peroxisome proliferation activation receptor
agonist, (it has about one third the PPAR agonist actions of pioglitazone)
and possesses the capacity to up regulate gene activity and decrease
insulin resistance, as well as being anti-inflammatory. Although
telmisartan has been demonstrated to decrease inflammation in
vessel locations, it may not work so well in the TH1 set CFS situation.
Other A2R
blockers have very little PPAR actions.
So why
does olmesartan work best?
Perhaps it
exceeds the others in blocking the inflammatory evoked portion
of the receptor.
Marshall has
computer-generated models of the A2 R receptors and of particular
chemokine receptors
Chemokine
receptors and chemokines play a crucial role in leukocyte recruitment
into inflamed tissue, and he demonstrates that CCR2b receptors
on monocytes can be blocked by olmesartan.
Marshall is
concerned about Herxheimer type reactions when intracellular cell
wall bacteria are killed by the antibiotics listed below, and
he believes that olmesartan can decrease this type of reaction.
THERE ARE
GOOD REASONS WHY WE SHOULD PETITION THE AUSTRALIAN GOVERNMENT
TO ALLOW PFIZER (OR SANKYO) TO BRING THIS SAFE AGENT INTO AUSTRALIA
FOR THIS SPECIFIC PURPOSE!!
Inflammatory
cytokines like TNF alpha and IF gamma down regulate the PPAR
gene.
Minocycline
and azithromycin are better than doxycycline, in dealing with
cell wall deficient bacteria, because of better intra cellular
penetration.
In this situation
dosing we could follow Marshall’s recommendations, and I
will document this in the chapter on therapy.
The dose is
remarkably low, but it may need to be repeated.
Each of these
medications has capacity to decrease matrix metalloproteinase
activity as well.
PROBIOTICS
This term
refers to bacteria in the intestinal tract which not only cause
no harm, but actually protect the intestine, counter pathogenic
bacteria or their products and may even serve to enhance immunity
or protect against auto-immunity or allergy.
Lacto bacilli
are sometimes called probiotics and they may work by adherence
to intestinal cells thus competing with pathogenic bacteria for
attachment. In effect this inhibits some of the pathogenic component.
Benefits of
probiotics.
They may have
the following benefits.
·
Producing natural antimicrobial agents such as hydrogen peroxide,
lactic, formic and acetic acids.
·
Diminishing some toxicity from ammonia, free ammonia nitrogens,
free serum phenols, indole, and indican.
·
Assist in the production of lactase.
·
Assist absorption of nutrients.
·
Specifically decrease activity of Helicobacter Pylori and Candida
Albicans.
·
Protect against enteric rotavirus.
·
Protect excessive cell division in colonic crypts.
·
Relieve constipation and diarrhoea and also inhibit specifically
Salmonella, Shigella, Pseudomonas, Staphylococcus and Klebsiella.
·
Improve acne.
·
Lessen procarcinogens.
Research is
underway to better specify beneficial effects of each kind of
probiotic.
Although
most probiotics used to date have been lactobacilli (acidophilus
and bifidus) there are certainly other probiotics under current
study.
James C Paton
and his colleagues at the University of Adelaide have engineered
a harmless strain of E Coli, so that it carries human cell type
docking sites on its surface, enabling these bacteria to bind
bacterial toxins such as the toxin of the Cholera vibrios.
Laboratory
tests confirmed the high binding capacity and further tests showed
protection of baby mice from cholera if they were pre-treated
with the engineered E Coli.
Another engineered
E coli variant proved to bind Shiga toxins and the toxin produced
by pathogenic E Coli.
Testing is
needed to exclude any downside of genetically engineered organisms
where molecular mimicry might lead to a few persons developing
strange auto-immune type conditions.
It is possible
that HLA haplotype testing might reveal if any persons have a
higher risk as well as revealing others resistant to these auto-immune
phenomena.
Manufacture
of probiotics is comparatively inexpensive and administration
is simple.
Several specific
probiotics appear to lessen severity of irritable bowel syndrome
symptoms (VSL#3 and E Coli Nissle)
YEASTS
and FUNGI.
These are
rounded cells, which have budding forms (yeasts) or hyphae (moulds)
Candida albicans
is common yeast found in the soil and water and can give mostly
low-grade clinical disorders such as inflammation in the mouth
and vulva. It is more likely to over grow in these sites when
antibiotics change normal flora and also in diabetes, severe renal
disease, and malignancy and immune deficiency syndromes.
In these latter
circumstances systemic invasion may occur.
Despite the
many claims, there is no hard evidence that candida causes chronic
fatigue syndromes.
Nevertheless
it would be foolhardy to disregard clinical experience where people
seem worse when exposed to yeast or who report clinical episodes
of candidal infection.
NEWCASTLE
RESEARCH
Dunstan and
colleagues at the University of Newcastle, (New South Wales) and
the University of Sydney, have been searching for changes in chronic
fatigue syndromes. believe they are able to identify particular
urinary amino acid, organic acid, and metabolite excretion that
they believe correlates with the presence of toxin producing coagulase
negative staphylococci. This research compares CFS sufferers with
healthy medical students.
On behalf
of my patients I would like to thank them for this committed work.
We are fortunate
that some researchers have dared to enter a field of study to
identify whether there are microbial and biochemical changes in
these syndromes.
OTHER BACTERIAL
CHANGES IN CFS.
Coagulase
negative staphylococci can be identified in the anterior nares
(just inside the nostrils), the perineum and other moist body
locations. It appears that there are more isolates in people with
chronic fatigue than in the population at large.
These researchers
have gone on to identify specific toxins alpha, beta, gamma and
importantly delta/“horse” toxin (haemolysin) in these
people. These toxins are haemolysins. The toxins may have effects
at locations which they can reach. The level of such toxins correlate
with pain levels in the subjects studied.
In females
the vulva may also harbour staphylococci.
Other aspects
of staphylococcal colonization include the possibility that these
organisms can make materials called "super antigens"
which are potent activators of immune cells and cytokine production.
More Newcastle
work
URINARY
METABOLITES AS MARKERS.
Specifically
these researchers believe metabolites in the urine of chronic
fatigue sufferers (labelled C.F.S. urinary metabolites CFS UM
27 and 28), and a high urine tyrosine/leucine ratio correlates
with pain in chronic fatigue and also with the presence and magnitude
of coagulase negative staphylococci.
The tyrosine/leucine
ratio is a measure of non-fibrillar protein breakdown and may
be initiated by interleukin 1 (IL1) and tumour necrosis factor
(TNF).
Tyrosine comes
from muscle in catabolic states. It can be recycled by the body.
Of course
some tyrosine may be of dietary origin. (meat)
LINK WITH BACTERIA
Scandinavian
researchers have implicated coagulase negative staphylococcal
materials in chronic fatigue associated pain (and in other chronic
pain syndromes). A possibility is that the above toxins may have
direct or indirect effects on target cells such as muscle cells.
About 40%
of the population carry staphylococci in the anterior nares.
Virtually
all of us have some of these organisms somewhere on or in our
bodies but it may be that a proportion of CFS sufferers are living
with a higher burden of organisms. Perhaps their neutrophils do
not destroy this part of their flora or they have factors conducive
to staphylococcal survival in these sites.
Some 10% of
women have vaginosis a situation where organisms in the vagina
produce mild local changes (including a rather fishy odour) and
these people are an example of a sub group who are living with
some undesirable organisms. This is not necessarily the same group
that carry gram negative staphylococci.
For some who
do have visible lesions there may be reasons for the recurrence
or persistence of infection.
When the neutrophils
of some people who have recurrent pimples and furuncles are tested
against their own staphylococci they fail to kill them but are
effective against other staphylococci. (McDonald)
In vitro,
neutrophils from other people are perfectly able to kill the staphylococci
of the furuncle sufferer. It may be something of this kind that
accounts for the Newcastle findings, but it is likely to be a
different mechanism.
More on
coagulase positive staphylococci.
Because I
recently saw a patient with recurrent anal and peri-rectal abscesses,
I use the following as an example of a comprehensive approach
to dealing with this difficult therapeutic task.
Coagulase
positive staphylococci have not been incriminated a causes of
chronic fatigue syndromes, but the following information is important
to health professionals in grasping the role of microorganisms
in the larger picture of life on earth.
Carriage rates
of coagulase positive staph are a least 30% of healthy adults
with the anterior nares, axillae and vulvo vaginal areas in women
and perineum of both sexes being the common carriage places.
More often
than not abscesses come from that individual’s own flora,
where the organism is an opportunist to such things as blocked
sweat or sebaceous ducts or perianal gland ducts or even a small
tear (e.g. anal region)
Staphylococci
can colonise and invade tissue, attaching to both cells and extra
cellular
matrix materials
and have many ways to evade or counter host defences as well as
damaging
the local tissue. Staphylococci are survivors.
In order to
discover how to tip the balance against them I note the mechanisms
by
which they
cause the injury as follows: -
1.
Adhesion to extra cellular matrix through adhesins. Adhesion
occurs to
fibrinogen,
fibronectin, collagen and elastin.
2.
Genes within the staphylococcus write the code for the production
of
enzymes
such as coagulase which binds to prothrombin and promotes
conversion
of fibrinogen to fibrin. In the meshes of the fibrin, the staphylococcus
is relatively protected from the host mechanisms which try to
destroy it.
Other enzymes
such as hyaluronidase break up hyaluronic acid
molecules
facilitating local spread and a series of other proteases
contribute
to tissue destruction.
3.
Other staphylococcal products include membrane-damaging toxins
such
as alpha,
beta and delta haemolysins and some of these toxins specifically
injure
membranes destroying their integrity. One particular example
is
a leukocidin
acting against polymorphs, monocytes and macrophages
and can
injure mucus membranes and skin.
4.
Staphylococci in colonies elaborate biofilm, which further serves
to
protect
them from host defences.
5.
Staphylococci can produce a catalase which converts hydrogen
peroxide
to oxygen
and water which interferes with oxygen free radicals.
6.
Staphylococci can survive in non dedicated phagocytes and small
colony
variants can also form which are relatively resistant to
cell wall
active antibiotics and also to aminoglycosides and can persist
inside
cells for very long periods of time.
7.
A fascinating part of staphylococci is the existence of super
antigens
which bind
directly (and without prior processing) to MHC class 2
molecules
on the surface on antigen presenting cells, stimulating T cells
and the
release of cytokines IL 1 & 2, tumour necrosis factor alpha
and
interferon
gamma.
Host Problems
Crucial to
the host defences are capacities to immobilise and destroy the
organisms and the function of neutrophils, generation of complement
and coating of the organisms by specific antibody play a major
part. Staphylococcal peptidoglycan activates complement and of
course complement punches holes in the staphylococcal cell wall
allowing it to be destroyed.
Antibodies
markedly enhance these actions. Specific defects in the host can
include
inadequate
neutrophil numbers and functions impaired complement generation
and lack of anti staphylococcal antibodies. Rarely people are
deficient in IgG, IgM or IgA.
Professor
Peter McDonald pointed out to me that in people with persistent
staphylococcal infections their own neutrophils are ineffective
in destroying their own staphs but maintain ability to destroy
other peoples staphs. Yet other peoples’ neutrophils can
destroy the patient’s staphs.
Once a fistula
or sinus forms it is a nidus for ongoing infection and co-existence
of other pathogens and there is no shadow of a doubt that its
excision is crucial to recovery.
I may follow
some or all of the following to deal with persistent staphylococcal
infections.
Therapeutic
Preparations
1.
Supplements of Vitamin C of the order of 250mg 6 times a day,
zinc as
zinc amino
acid chelate equivalent to 15mg of elemental zinc per day.
Healthy
function of neutrophils depends on adequate amounts of these
nutrients.
2.
Milk derived substances
(a) Lactoferrin.
This is a series of glycoproteins found in milk and
particularly
in colostrum and kills staphylococci and enteropathogens
while
protecting normal flora. In particular it breaks up biofilm
and
also
renders iron unavailable to iron requiring bacteria.
It also
inactivates candida. The dose would be 200 to 400mg per day.
(b) Lysozymes.
These are antibacterial enzymes that are found in human milk,
but not in usual dairy products.
Recently
scientists have introduced the gene into goats and the transgenic
goat milk exhibits protective effects against some bacteria.
(c). Transfer
factors. These are a series of colostral polypeptides
of about 40
amino
acid sequences which transfer immunity from the mother to
the
Infant
and can be used to transfer immunity to naive subjects. As
well
transfer factors stimulate T natural killer cells and also
down
regulate
auto immunity. The standard dose is up to 6 x 50mg capsules
a
day.
Bovine
transfer factors presumably only provide protection against
organisms which have entered the cow! They do appear to stimulate
T natural killer cells.
(d) Immune
globulins in milk also appear to be helpful.
3.
The regular use of lactobacilli particularly including bifidus
organisms
which support
healthy colonic flora as well as cell function.
4.
Fructooligosaccharides (inulin and similar saccharides) appear
to support the good gut flora.
5. Possibly
the use of Bio-strath elixir, which is derived from plasmolysate
of Saccharomyces cerevisiae. (Evidence base not established)
There may be circumstances where these saccharomyces are contra
indicated.)
6.
In the case of dealing with abscesses.
Probably
a course of clindamycin 150mg 6 hourly in the few days before
the draining
procedure. Clindamycin has good penetration in to walled off
sites,
a property also shared by fucidin.
7.
The use of intra nasal mupirocin (Bactroban) bd for patient
and closest
contacts.
8.
Meticulous washing of the hands after touching the nose and
after
any toileting
is important as is washing all handkerchiefs in
“Napisan”
or similar and even dipping trouser pockets into “Napisan”
and washing
hands after disposal of any tissues.
9.
In some parts of the world anti staphylococcal vaccines have
been
successfully
used to decrease the risk of staphylococcal infections.
10.
Supplements with omega 3 fatty acids such as the use of flax
seed oil and various fish oils.
11.
Use of probiotics. (See earlier)
It is possible
that either mannose or the acetyl mannans from Aloe Vera can interfere
with galacto lectins which are adhesion factors for staphylococci.
The subject
of bacteriophage specific killing of resistant organisms could
bear a lot of fruit in the next decade.
More details
about bacteria are beyond the scope of this introduction
(a) Thus in
bacterial structure and metabolism there exists the possibility
of injury from produced endo and/or exotoxins, cell wall antigens,
and other products which result from an interplay of cells such
as poly morphonuclear leucocytes and the bacteria they destroy.
POSSIBLE
BREAKTHROUGH IN UNDERSTANDING GUT FLORA CHANGES IN CFS.
The intestines
contain some 10 trillion bacterial cells and perhaps 1,000 different
species.
There is increasing
evidence that disturbances in intestinal flora are common with
Western type diets and may play a role in obesity, non-alcoholic
fatty liver disease, irritable bowel syndrome (IBS), inflammatory
bowel diseases(IBD) and even some kinds of cancer. The chemicals
products of intestinal microbes may even contribute to abnormal
brain chemistry.
We have discussed
the intestinal flora where vast numbers of bacteria are ordinarily
non-pathogenic. Indeed evidence supports many protective functions
from this flora.
At present
there is some investigation into the subject of the varieties
of normal and abnormal gut flora.
Henry Butt
of the University of Newcastle NSW has reported that it is very
common for CFS/fibromyalgic subjects to have a low count of E
Coli in faecal flora.
As well counts
of enterococci were high, and this correlated with cognitive dysfunction.
Dr T Hey of
Buckeburg reports that researchers in the virology department
of the Medical College in Hanover, Germany (Breull, Fischer and
Verhagen) have found that >80% of fibromyalgic sufferers carried
bacteriophages which infect and destroy large numbers of E Coli.
The researchers
further claim that with lysis of the coliforms, much lipopolysaccharide
is released with adverse effects on intestinal cells, and also
through absorption, on other body cells.
This could
easily be a cyclic process so that the flora could fluctuate and
the lysis have peak times paralleling the days of worse pain.
It might also
explain why some CFS/fibromyalgia sufferers get adverse reactions
when antibiotics are given.
Butt and colleagues
also report patients with an overgrowth of other aerobes such
as enterococci, streptococci or other unidentified organisms.
It is possible
that gut flora changes are associated with intestinal cell abnormalities
which could alter absorption of required nutrients, and allow
larger molecules to cross the gut lining. (A "leaky gut".)
As well, altered flora could mean abnormal fermentation and its
consequence as well as a deficit in required amino acids. Both
decreased synthesis (eg serine by E coli), and increased intestinal
cell catabolism of needed amino acids could decrease amino acid
availability for other body cells.
In addition
increased excretion of 3-methylhistidine is associated with initiation
of fibrillar muscle protein breakdown (actin and myosin). (Associated
with increased IL1 and IL6.)
3-methyl histidine
cannot be recycled as transfer RNA (tRNA) does not code for methylated
amino acids such as methylated histidine or lysine.
Microbiology
is a field where there is emerging re-evaluation of the roles
of microorganisms in diseases which were not originally thought
of as infective.
This reviewer
of the literature feels that there is a vital need for patients
who have one or more identifiable abnormality to be screened by
the other major world's researchers to discover just how many
abnormalities there really are.
This chapter
has raised my own consciousness of the amazing properties of life
at microbial levels
In this setting,
evolution is a co-evolution and will continue as long as life
exists.
We will do
well to look repeatedly at this interplay of germs and the places
in which they live.
Every city
needs microbiologists who are looking closely for the” hard
to find “bacteria!
