June 25, 1999
Preface
The following document was sent as three email letters to the parent and contains (a) my initial searching for possibilities in the child's and family's medical history and the child's laboratory data, and (b) factors that led me towards focusing upon Kp and hEc, as outlined in other pages in this report. Fortunately, the child had had a number of tests, and some have been repeated, enabling slight variations to be seen as such and helping call attention to significant values that had not changed -- eg, Klebsiella pneumoniae (4+) and hemolytic Escherichia coli (4+) (Kp, hEc; by Great Smokies Lab) -- a significance I had not realized early in my analysis nor had I anticipated when Michael's packet of materials arrived in the mail. A list of his lab tests is presented as reference 7 hereinbelow. He has had many tests, and data therefrom potentiated thorough analyses, resulting in Dr. Stephanie Cave's helpful therapy and my report as presented in these several webpages. This document but one of several delineating aspects of Michael's medical history and lab data and my analysis thereof. The entire batch of reports can be read or downloaded from:
Among many interesting features, note the Michael's IAG reading is very below the reference range, thereby making him an example that not all autism-spectrum children have elevated IAG. Furthermore, a vitamin-levels screen (6.24.99) provides at least one clue that may be linked to his the fact that his IAG is well below reference range, for niacinamide is a byproduct on pathways leading to IAG. When I was perusing Paul Shattock's work in late 1997 and early 1998, I noticed in a reference text about porphyria that elevated IAG might correspond with low niacinamide, thus providing an possible basis for why many autism-spectrum kids have elevated IAG and why many appear to respond well to niacin supplements. Without having researched this point in regard to Michael's data, we note that he has elevated niacinamide and very low IAG (as well as elevated biotin), which suggests focusing some additional research upon these interrelated metabolic pathways. In other words, why his IAG below range remains to be determined and would seem to reflect an alteration in the various metabolic pathways leading to IAG. This is a most complex topic that includes intestinal bacteria as well as aspects of niacin and serotonin metabolism. A fine chart of pathways leading to IAG and niacinamide is in the Porphyria chapter in Scriver's "Metabolic and Molecular Bases of Inherited Disease" (1994). The following material represents preliminary and gradually refined observations and was presented as three emails to the parent as an indication of what I had considered enroute to focusing upon Kp and hEC and their possible translocation from the Michael's intestines, with neurologic and other atypicalities as possible sequelae.Email 1: initial wonderings
Dear Parent,
Here are some responses to various aspects delineated in your medical history
summaries. My reactions will be very preliminary, a considering of possible
significances, clues towards understanding etiology and (perhaps) possible
treatments for Michael.
Parent: Birth weight (9 lb 2oz); all developmental milestones reached ahead
of schedule.
T: I sense the long-shot possibilities of mild cytokines imbalance resulting
in (i) above average weight, and/or (ii) extra dendtritic branching, and/or
(iii) impaired neurotypical pruning of dendrites. The above average weight and
somewhat lengthened gestation time (terminated at 39 weeks) prompts me to keep
in mind the possibility that something subtly atypical may have been occurring
in utero.
{Parent later responsed about two theories of gestational
timing, ie, 38 weeks or 40 weeks.}
Parent: Shortly after his first birthday, ...he had stopped talking
altogether, except for an occasional "mama". Eye contact and interaction
diminished rapidly thereafter, as did appropriate toy play.
T: Language, sociality, and eye contact have neural substrates within the
temporal lobe. In fact, Rolls et al have documented central-amygdaloid neurons
specifically responsive to eye contact. That temporal-lobe traits were being
affected brings to mind Herpes simplex virus (HSV), because of its known
affinity for the temporal lobe and because HSV can be within the CNS of
individuals having no peripheral signs or symptoms of significant HSV. However,
the loss of appropriate toy play suggests the possibility of a more generalized
subclinical encephalitis (an enterovirus?; Rotbart et al) and/or hypoperfusion
resulting from vascular inflammation along the blood brain barrier in regions
supplying blood to the temporal lobes and frontal areas involved in imaginative
play.
{At this point in my initial analysis, nothing was certain or
probable. I'm just scanning for mechanisms that we might link to
traits and substrates and perhaps to diagnostic signs.}
That Michael has benefitted from a gf/cf diet and has numerous food intolerances
indicates changed intestinal permeability, which can be induced by various
pathogens, some of which "hit and run" (eg, C. difficile), some of which can
induce intestinal damage and then migrate intraneuronally (eg, HSV), and some
can linger within intestinal tissue even as they spread into other tissues (eg,
EBV, CMV, HHV6). Furthermore, if a child has increased permeability and an
extended period of altered intestinal flora, then he or she is at risk for
additional pathogen translocations and sequelae therefrom.
In the materials you sent there is some contradiction regarding fungal
colonization. In the paragraph about Stephanie Cave, MD, (one of the child's
physicians) you mention "He (Michael) has been on and off various therapies --
...nystatin, diflucan..." and later you write "there has really not been an
overwhelming Candida problem..."
{Later in my analysis, I learned that the lack of Candida problem
probably reflects the presence of intestinal Klebsiella pneumoniae,
which is known to inhibit Candida (citations provided in another
Michael-report webpage).
Were you to have mentioned persistent Candida, that would have been easier to
address, eg, as a sign of an enduring Th2 shift. That he does not have
persistent Candida suggests that gastrointestinal cell mediated immunity *may*
(overall) be functioning fairly well, although that does not preclude antigen-
specific anergy towards other pathogens (eg, Kp and hEc).
Such pathogen-specific tolerance has been documented in some cases of chronic
active H. pylori and can occur if a pathogen gained access to the gi-tract too
early in the neonatal/early-infant period when the newborn's gastrointestinal
immunity is learning to differentiate self from not-self, friend from pathogen.
Vancomycin and Flagyl have also been tried, suggesting to me a parental effort
to ease gastrointestinal problems, which may also reflect an earlier infection
(eg, CMV) that prepared the intestinal tissues for subsequent colonization.
That ivIg did not seem to have a beneficial effect is important, even as the
significance of that finding may be hard to uncover. You did not say, "ivIg had
no beneficial effect', but did say that Kane's protocol and FGF2 have produced
the most significant improvements.
As you know, autism parents spend much time evaluating and treating a child's
gastrointestinal problems. This is well and good, and some interventions help
wonderfully (eg, gf/cf diets) for some kids. However, my hunch is that, in many
autism-spectrum kids, intestinal permeability issues tend to be secondary
factors reflecting other pathogens that induced the increased permeability and
that may still remain within the child, not necessarily within intestinal tissue
(eg, HSV, CMV, HHV6, et cetera). Alternatively, some children do seem to have
inherent or acquired inabilities to process certain dietary substances; and that
Michael improved greatly since starting Pat Kane's electrolyte and fatty acid
correction (3.4.99) is very important
{Later in my analysis, as citations will show, the improvements
induced by fatty acid modulation *may* have been improving his
macrophage function against Kp and hEc; citations in other documents
of this report.}
That you report those improvements as "in expressive language, interaction/eye
contact, and attention" suggests four pathways:
a. delivery of nutrients to brain tissue
b. removal of troublesome nutrients and peptides
c. alterations in vascular tone and/or inflammation within portions
of the bbb.
d. increased killing of etiologically significant pathogen(s) and,
thereby, diminishing the endotoxins or exotoxins therefrom.
You also describe improvements in response to FGF2 (begun 4.19.99). As a result,
separating Kane-therapy effects from Aguillar-FGF2 is now difficult. Note that
I keep in mind we are considering a real child with real parents, ie, not a
theoretically perfect experimental design, so if two things are working and we
can't quite figure out what's doing what, then at least Good for Michael!
Improvements are important.
I do wonder if the oral-tactile hypersensitivity might be related to FGF2.
[Writing here from memory:] Oral tissue is somewhat like intestinal tissue in
that many cells have a high rate of renewability and thus may be more likely to
experience excessive mitogenic stimulation from FGF2 (but this is just
speculation...?...)
That Michael experienced a regression soon after his MMR/HepB vaccinations
suggests either (i) Michael has one of the rare HLA alleles Susan Owens has
recently presented in regard to HepB reactions, and/or (ii) a pre-existing
infection was present within neurons and/or within locales of the bbb (and/or
possibly within the intestinal tract).
Interferon gamma has been documented as the primary cytokine generated in
response to the MMR; IFNg can increase both intestinal and bbb permeability, and
increases MHC presentation within neurons, and alters MHC presentation in other
cell types. Thus, if a child has a significant chronic active (subclinical)
infection at the time of MMR, tissue damage may ensue.
Oral motor planning problems suggest possible involvment of the insular cortex,
which is implicated in aphasia and also receives input from gastrointestinal
tissue.
Parent: Abdomen -- has been large ("Ethiopian belly") since 1 year old.
T: I'm under the impression that if the protruding abdomen is entirely due
to food allergy, then a long period of abstinence reduces the distension.
However, some pathogens are associated with "Ethiopian belly" (search for
"distended abdomen" in PubMed).
His stimming has remained even as the aforementioned improvements (Kane's
protocol, FGF2) have materialized.
Parent: Diarrhea has been a problem since about 1.5 years of age. It actually
got worse from ages 2.5 to 3.5, and continued up until his first secretin
infusion. It has been only an occasional problem since then.
T: His diarrhea was alleviated prior to his starting Pat Kane's protocol,
which therefore was enacted in a child with a gut at least starting to heal.
That diarrhea remains "only an occasional problem since then" suggests that an
underlying pathogen (and perhaps an anergy/tolerance tendency) may still be
present.
T: That Michael's father had an adverse HepB reaction is consistent with (i)
excessive (immune-impairing) stress at the time of the vaccination, and/or (ii)
an underlying immune impairment (possibly infectious-acquired, possibly a rare
HLA allele).
Father's CFS in response to HebB vaccine is consistent with many cases
identified by Dr. Hyde. His talk at the Bethesda NIDS conference conveyed that
the HepB vaccination impairs immunity for a while (as can measles or measles
vaccination), thereby allowing other infections to dig-in more deeply, manifest
more significantly.
I find myself wondering if ongoing chronic active infection associated with
CFS (i) may have led to viral shedding that impacted Michael as a chronic active
infection with early-exposure anergy and/or (ii) may have predisposed Michael's
father to a higher viral load when acquiring and responding to additional
infections to which we all are exposed from time to time. Note that I'm not
suggesting this as a likelihood, but am keeping it in mind as a possibility,
noting also that such infections tend to become somewhat familial.
Email 2: lots of data
Evaluation of Michael's Lab-data
{Note that the email did not comment on each and every aspect of
Michael's lab data -- which are very extensive. A person purchasing
such data seldom knows which aspects will provide clues, which not.
Here are some highlights from Michael's data.}
...6.3.99 Cell count and hemoglobin values offer clues:
Lymphocyte # 4214 r 2000-8000
RBC 4.84 r 4.0-4.9 nearly erythrocytosis
Hemoglobin 14.10 r 10.50-12.70
Iron, total 125 r 25-115
hematocrit 43.90 r 31.70-37.70
MCH 29.13 r 24.10-28.40
MCHC 32.12 r 31.90-35.10
MCV 90.70 r 72.70-83.60
MPV (platelet V) 9.09 r 7.10-9.30
Platelet # 294 r 204-405
{Platelets contain no hemoglobin, participate in
coagulation, aka thrombocytes.}
WBC: 8.60 r 5.50-16.50
{low side of average, despite monocytosis}
Monocyte count 1204. r 0-800 monocytosis
Eosinophil # 688 r 20-650
Basophils # 86 r 0-200
Neutrophil # 2408 r 1500-8500 towards low
Michael has mildly excessive iron and mildly excessive hemoglobin; his mean
corpuscular hemoglobin is slightly high, even as (i) his mean corpuscular
hemoglobin concentration is towards the low end of reference range, and (ii) his
mean corpuscular volume is elevated despite mean platelet volume being nicely
centered within reference range. What cells have increased volume?
{The iron-related findings may have signficance in various ways,
perhaps even to pathways leading to Michael's atypically *low* IAG
levels.}
Is Michael on the verge of anemia despite elevated iron and elevated hemoglobin?
Do these markers reflect aytpical intestinal phenomena and/or a dysregulated
bone-marrow processes?
{Please, internet readers, remember that this document reflects my
initial ponderings in regard to Michael's data and med history; 'twas
a time to consider various possibilities, not to notice absolute
truths, easy diagnoses, etc.}
Without ruling out intestinal participation, the presence of monocytosis and
slightly elevated eosinophils and upper ref range RBCs suggests that bone marrow
may become a focus of concern.
{Gradually, I came to look away from this possibility, because many
of Michael's immune shifts appear to be consistent with effects of
persistently atypical levels of Kp and hEc.}
The WBC portrait offers mixed signals.
...COMPARISON of WBC/RBC data from two tests
10.8.98 Cell count and hemoglobin values offer clues, especially in comparison
to the data from 6.3.99:
*** MVC is increased in report of 6.3.99. What cells are changing?
*** Monocyte count is increasing from mid-range to 150% elevation by 6.3.99.
Here I will present a comparison, with 10.8.99 preceding 6.3.99. Note the
different reference ranges wich *may* be age adjustments (we ought ask the lab).
Nonetheless, several categories suggest significant changes (progression)
between the first and second blood draws. When the same lab-test category is
available, the 10.8.98 test is presented in the line before the 6.3.99 entry.
Two data sets compared, with earlier test listed first. Tests worth watching are
indicated with a single asterisk; tests showing significant change are indicated
with double asterisks:
Lymphocyte count 3774 r 3000-9500
Lymphocyte count 4214 r 2000-8000
Lymphocytes 51 r 46-73 towards L 10.8.98 only
RBC 4.33 r 4.04-4.85
* RBC 4.84 r 4.0-4.9
{nearly erythrocytosis}
* Hemoglobin 12.80 r 11.30-12.30 H
* Hemoglobin 14.10 r 10.50-12.70 H
* Iron, total 111 r 29-91 H
* Iron, total 125 r 25-115 H
** hematocrit 37.10 r 37.0-41.0 towards L
** hematocrit 43.90 r 31.70-37.70 H
MCHemoglobin 29.56 r 25.00-29.00 H
MCH 29.13 r 24.10-28.40 H
MCHConcentration 34.50 r 28.00-32.00 H
MCHC 32.12 r 31.90-35.10
* MCVolume 34.50 r 28.00-32.00 H
* MCV 90.70 r 72.70-83.60 H
MplateletV 9.09 r 7.10-9.30 6.3.99 test only
Platelet # 294 r 204-405 6.3.99 test only
{Platelets aka thrombocytes contain no
hemoglobin, participate in coagulation}
* WBC 7.40 r 6.00-17.00 towards L
* WBC 8.60 r 5.50-16.50 towards L
{low side of average, despite monocytosis}
Monocyte count 592 r 50-1000 midrange
** Monocyte count 1204 r 0-800 monocytosis ***
Eosinophils 5 r 0.0-5.20 towards H 10.8.98 only
* Eosinophil count 370 r 40-650 mid-range
** Eosinophil count 688 r 20-650 H
Basophils 1.00 r 0-2.0 mid-range 10.8.98 only
Basophil count 74 r 0.0-200.0 mid-range low
Basophil count 86 r 0-200 mid-range low
Neutrophils 35.00 r 20-46.00 mid-range 10-8-98 only
Neutrophil count 2590 r 1500-8500 mildly towards low
Neutrophil count 2408 r 1500-8500 mildly towards low
II. B.U.N., Creatinine, Proteins
B.U.N. 14.00 r 3-16 towards H
Creatinine .40 r .50-.80 L
B.U.N./Creatinine ratio 35.00 r 6.0-25.00 H
Albumin 5.00 r 3.5-5.2 towards H
Protein 7.50 r 5.9-7.8 towards H
{BUN values can be increased by renal damage, increased protein
metabolism, etc. Creatinine can be increased by renal damage and by
ascorbic acid intake; but ascorbic acid is reported as low, Great
Plains report for 10.22.98 collection. Low levels also can reflect
kidney damage. I have little experience in kidney med lit.}
That these values are skewed suggests added watchfulness since FGF2 side effects
would seem to include kidney damage. These values were reported for a blood draw
on 6.3.99, ie, prior to Kane's protocol, secretin, and FGF2.
III. Dysbiosis
Test of 8.3.98
Skewing of Probiotic microflora
Lactobacillus 0+
E. coli 0+
Bifidobacter 4+
Pathogen colonization
Klebsiella pneumoniae 4+
Haemolytic E. coli 4+
Gamma strep 4+
Pseudomonas aeruginosa 1+
{Klebsiella is among the pathogens that can
induce polyclonal immune activation and
therefore may account for why Michael has
several *mildly* elevated antibodies, eg, mumps
at 40/10.}
Test of 10.19.98
Skewing of Probiotic microflora
Lactobacillus 0+
E. coli 4+
Bifidobacter 4+
Pathogen colonization
Klebsiella pneumoniae 4+
Haemolytic E. coli 4+
Gamma strep 4+
Pseudomonas aeruginosa 1+
Test of 2.8.99
Probiotic
Lactobacillus 0+
Bifidobacterium 4+
E. coli 4+
Pathogen colonization
Klebsiella 4+
Haemolytic E. coli 4+
Gamma strep 4+
{At least three Great Smokies reports document
and mention severe bacterial dysbiosis.}
Test of 4.7.99
Probiotic
Lactobacillus 0+ ***
Bifidobacterium 0+ ***
E. coli 0+ ***
Pathogen colonization
Klebsiella 4+
Haemolytic E. coli 4+
Gamma strep 1+
{In retrospect, here writing on June 27, 1999, I note that his
probiotic flora have virtually disappeared. Kp and hEc appear to be
winning; this is not good, especially since damage to intestinal
tissues will continue, thereby making translocation more likely, and
more rapid if already occurring.}
Intestinal colonization may be a major factor in Michael, not only with regard
to diarrhea and food hypersensitivities but also in regard to translocation of
pathogens and/or their toxins, with possible sequelae including kidney and/or
liver damage as well as neurologic impairment. I wonder if there is an
underlying immune impairment that is allowing this dysbiotic colonization of
severe pathogens to be occurring.
HHV6, EBV, and other viruses can colonize the intestinal tract (and impair
immunity) and also can migrate into bone marrow and/or endothelial tissues of
the bbb. Viruses like these are among the mechanisms by which an intestinal
immune impairment could be occurring.
{Remember, at this point I was merely looking at any and
all possibilities that *might*/*could* occur.}
Whereas treating dietary deficiencies is important and would seem to reflect
Michael's dysbiosis, identifying and treating an underlying infection (if any)
would seem to be a more fundamental level of therapeutics. Note, however, that
the parent's sketch of Michael's medical history did not describe results of
ivIg, other than to omit ivIg as an effective therapy for him.
{Later, as I perused the Kp and hEc literatures, I found citations
making clear that ivIg ususally does *not* work against Kp but that
hyper-ivIg specifically made for anti-Kp effect does work. Citations
are in a different one of Michael's reports.}
Again, the fourth stool-microbiology report continues to echo in ways quite
perplexing. I wonder when the vancomycin was given? What lowered the gamma
strep? What lowered the beneficial bacteria? This fourth stool sample was
collected before FGF2 was initiated and a month and four days after starting Dr.
Kane's dietary manipulations. What happened to alter the probiotic bacteria? Are
the Kp, hEc, and/or Pseudomonas increasing and translocating at a higher rate?
Is that why the monocytosis is occurring?
IV. Fecal IgA 56 r 44-183 10.19.98
V. Urinary IAG 1.76 r 4.6-9.5 L ***
{Urinary IAG is elevated in many autistic children,
suggesting that Michael's neurologic deficits place him
into a different subgroup re: etiologic processes.}
{The AAL report mentions that these tests are normalized to
creatinine excretion, which is below range in Michael. I do
not know if AAL's "normalized to creatinine excretion"
remains calibrated for a child whose creatinine is out of
range.}
{Later in this document, low IAG is linked to elevated
niacinamide.}
VI. Subtle skewing of CD4/8/28/38/DR/16/56 data (9.17.97), as determined in a
1997 panel, notably:
elevated platelets
mid-range lymphocytes # and %
towards high # of CD8/CD28
towards high # of CD8/CD38
towards high # of CD8/DR
low % of CD8/CD28
low % of CD8/CD38
low % of CD8/DR
mild skewing of CD16/56 subsets
towards low % of probable NK cells
at low 1/4 regarding # of probable NK cells
{As of 6.26.99, I am crediting these mild shifts to immune
altering effects of Kp and hEc -- even as we are retaining
the possibility of another occult infection (eg, CMV).
Email 3: Focusing upon Kp and hEc
{Gradually, as I returned to the lab data and continued perusing a
variety of medical literature, the etiologically significant
possibilities for Michael increasingly focused upon his persistent
Klebsiella pneumonia and hemolytic Escherichia coli, especially as
med lit revealed many citations consistent with specific aspects of
Michael's med history and lab data -- as described and cited in other
of the webpages in this report.}
Here are my initial responses after browsing Klebsiella pneumoniae literature.
[a] Most striking feature of lab data: persistent gastrointestinal Klebsiella
pneumoniae comorbid with hemolytic Escherichia coli.
[b] That I am not an expert in Klebsiella pneumoniae literature has shaped my
writings for Michael. I've perused hundreds of abstracts and found some that
appear to be significant and perhaps helpful. My role seems to be that of
organizing Kp and Ec literatures in ways that can call attention to aspects that
may have etiological and/or treatment significance for Michael.
[c] Kp may account for his early gastro problems and is often nosocomial and
is one possibility among many -- eg, CMV and other pathogens. However, Kp and
hEc are repeatedly documented in Michael's Great Smokies Lab tests (now 4 in
number!).
[d] Kp is a polyclonal activator that may account for some of the mildly
elevated antibodies levels, but early exposure to certain pathogens dulls
immunological responses against those pathogen -- eg, CMV (see cd5-iga.htm
paper).
[e] A series of studies in the 1970s describe Kp as inducing impaired memory
as part of Kp's polyclonal-activation effects, (1-4). I ought search for related
studies).
[f] Kp can translocate.
Klebsiella pneumoniae (Kp) and Escherichia coli (Ec) can translocate
from gastrointestinal tissue into mesenteric lymph nodes, peritoneum,
and other tissues, including the brain. (citations in other reports
for Michael)
[g] Kp is associated with distended abdomen but is not the only cause.
Are we looking at a chronic peritoneal infection, which Kp can establish?
[h] Fatty acid changes can alter body's response to Kp.
[i] At least some Kp fragments contain mannose, whereby macrophages identify
and respond to the Kp.
[j] If some of the Kp fragments are reaching a mildly permeable bbb, then some
astrocyte activation may be occurring due to mannose receptors on astrocytes
etc.
[k] Studies could be done to document or rule out possibility of Kp fragments
in blood, ie, assays not just the serology of IgGs holding Kp fragments.
[l] Low anti-CMV antibodies are amgibuous, because CMV can be present in
persons having *no* anti-CMV antibodies (5). And I wonder if EBV and HHV6 might
be the same way, even though perhaps not yet studied in this regard.
However, I find myself thinking away from occult CMV, EBV, and HHV6 because
drastic marrow-related myeloid skewing is not apparent, although some signs of
myeloid skewing are present, and they may reflect a systemic cytokines response
to Michael's chronic active infection by Kp and hEc.
[m] After examining the various Kp and hEc citations presented in other of
Michael's report pages, citation-6 suggests possible (long-shot?) strabismus
connection???, via a bbb/vascular effect due to Kp and improvement due to a
gradual diminishing of Kp fragments in circulation due to more effective anti-Kp
macrophage activity in response to fatty acid manipulation? (cites in the other
report pages).
In closing
I would like to stress that this document (originally sent as three emails) was shared with Michael's parents (and now with others having interest) as a way to illustrate how my perusal of his medical history and lab data began and how it progressed to its current focus upon Kp and hEc, with afterthoughts for further research into his low IAGs and elevated niacinamide. In the days after sharing Michael's report with his parents, I find myself still moving forwards -- eg, into further perusal of his atypically low IAG level. What is that telling us? Is that a dysbiosis/serotonin effect? Is there a subtle metabolic glitch in one of the pre-IAG pathways? Much food for thought... Sincerely, Teresa Binstock Researcher in Developmental and Behavioral Neuroanatomy June 25, 1999Additional report topics
Summary Why Klebsiella pneumonia and hemolytic E. coli have come to demand much attention in this report. (Kp, hEc)
Peritoneal and abdominal Kp and hEc
Neurologic aspects of Kp and hEc
Miscellany regarding Kp and hEc
A series of autism-spectrum research monographs is available by links on a web page: http://www.jorsm.com/~binstock/index.htmReferences
1. Immunology 1978 Sep;35(3):511-8
Competition of the actions of antigen and polyclonal B-cell activator in the
induction and amplification of B-memory cell function.
Nakashima I, Yokochi T, Nagase F, Kato N
Using the capsular polysaccharide of Klebsiella pneumoniae (CPS-K) as a
polyclonal B-cell activator (PBA) and sheep red blood cells (SRBC) as a
T-dependent antigen, the correlation of the actions of PBA and T-dependent
antigen on B cells in induction and amplification of immunological memory was
studied. B-memory cell function, as judged by anti-SRBC responsiveness in vitro
of spleen cells of CPS-K, was amplified by the secondary injection of SRBC into
SRBC-primed mice, whereas it was decreased markedly by injection of CPS-K. When
CPS-K was injected simultaneously with, or 1 or 2 days before the secondary
injection of SRBC, B-memory cell function was also decreased markedly. On the
other hand, CPS-K did not inhibit induction of B-memory cell function when
injected simultaneouly with the primary injection of SRBC. However, CPS-K
inhibited induction of B-memory cell function when injected 3 days before the
primary injection of SRBC. The inhibition by CPS-K of amplification of B-memory
cell function in response to SRBC when CPS-K was injected simultaneously with
the secondary injection of SRBC occurred markedly in mice primed with SRBC 8
days or longer before the secondary injection, whereas it was not detectable in
mice primed 3 days before. It is concluded that the CPS-K-mediated signal and
the SRBC-mediated signal act competitively on the same subpopulations of B
cells in induction and amplification of memory, and that the susceptibility of
B cells to the CPS-K-mediated negative signal changes correspondingly with
their maturation stage.
PMID: 359463, UI: 79026228
2. Immunology 1976 Oct;31(4):649-58
Comparative studies on the actions of antigen and polyclonal B-cell activator
in differentiation and proliferation of B-cells and B memory cells.
Nakashima I, Nagase F, Yokochi T, Kojima T, Ohta M, Kato N
Using the capsular polysaccharide of Klebsiella pneumoniae (CPS-K) as a
polyclonal B-cell activator (PBA) and sheep red blood cells (SRBC) as a T
cell-dependent antigen, we compared the ability of PBA and antigen to
differentiate (generate antibody-forming cells, AFC) and proliferate (generate
immunological memory) virgin B cells and B memory cells. In vitro CPS-K induced
the differentiation of IgM virgin B cells, IgM B memory cells and IgG B memory
cells to AFC, as well as or better than SRBC. The differentiation of B memory
cells to AFC by CPS-K did not require the participation of macrophages or T
cells, whereas the action of SRBC depended strictly upon the helper actions of
these cells. The responsiveness to CPS-K and SRBC of normal and antigen-primed
spleen cells as judged by anti-SRBC PFC responses in vitro was markedly
decreased after stimulation of virgin B cells and B memory cells in vivo by
CPS-K injection into normal or primed mice but greatly increased after the
injection of SRBC. The decrease in the responsiveness to CPS-K of spleen cells
from mice treated with CPS-K appeared principally due to exhaustion of the
functions of B cells and B memory cells. From the present data it has been
concluded that the signals required for the differentiation and proliferation
of B cells of B memory cells are different from each other, the signal for
differentiation being provided by either antigen (SRBC) or PBA (CPS-K), while
the signal for proliferation only by antigen.
PMID: 789231, UI: 77027666
3. Jpn J Microbiol 1975 Aug;19(4):277-85
Adjuvant action of capsular polysaccharide of Klebsiella pneumoniae on antibody
response. IV. The roles of antigen and adjuvant for induction of primary and
secondary antibody responses and for development of immunological memory to
bovine serum albumin.
Nakashima I, Kato N
A study was performed to clarify the roles of primary and secondary injections
of antigen and adjuvant (capsular polysaccharide of Klebsiella pneumoniae,
CPS-K) in induction of antibody responses and in the development of
immunological memory in mice to bovine serum albumin (BSA). A primary injection
of BSA alone neither induced significant primary antibody response nor
increased immunological memory for a secondary antibody response but, if
primary injections of BSA and CPS-K were performed simultaneously, high
antibody responses were induced. Moreover, a prior injection of BSA alone or
CPS-K alone decreased the level of primary antibody response and the degree of
increase in memory following the subsequent injection of BSA mixed with CPS-K.
In contrast, a secondary injection of BSA alone into mice once primed with a
mixture of BSA and CPS-K elicited very high secondary type antibody response
and increased secondarily the memory for a tertiary antibody response.
Injection of CPS-K simultaneously with or shortly before or after the secondary
injection of BSA did not increase the level of the secondary antibody response
and the degree of the secondary increase in memory. Augmentation of the
secondary antibody response was elicited by simultaneous injection of CPS-K
only when the secondary response was induced inadequately by a suboptimum or
supraoptimum dose of antigen.
PMID: 1104933, UI: 76072763
4. Immunology 1974 Aug;27(2):179-93
Non-specific stimulation of immunoglobulin synthesis in mice by capsular
polysaccharide of Klebsiella pneumoniae.
Nakashima I, Kato N
PMID: 4138825, UI: 75033062
5. Taylor-Wiedeman J et al. Polymorphonuclear cells are not sites of persistence
of human cytomegalovirus in healthy individuals. Journal of General Virology.
74 ( Pt 2):265-8, 1993 Feb.
ab: Polymorphonuclear leukocytes (PMNL) have been shown to harbour human
cytomegalovirus (HCMV) in viraemic patients, but to date PMNL of asymptomatic
healthy subjects have not been examined directly to determine whether this is
a normal site of HCMV persistence. Using the polymerase chain reaction (PCR),
paired DNA samples prepared from adherent peripheral blood mononuclear cells
(PBMC), which are known to be a site of persistence of HCMV, and PMNL of 10
healthy adults were analysed. All of seven individuals who were HCMV
seropositive, and one of three who were seronegative gave a reproducible signal
for HCMV DNA in their adherent PBMC, whereas none of the paired PMNL DNA samples
gave a positive result. The remaining two seronegative subjects showed no HCMV
DNA in either the PBMC or PMNL samples. In every case where PCR for HCMV was
negative, PCR amplification of a control human gene was used to show there was
no inability to amplify the DNA. We conclude that within the leukocyte
population of normal asymptomatic HCMV carriers, PMNL do not appear to harbour
persistent HCMV whereas adherent PBMC in the same subjects are a site of
persistence.
6. Kansenshogaku Zasshi 1995 Sep;69(9):1017-20
[A case of gas-containing liver abscess with multiple metastatic lesions].
[Article in Japanese]
Higashi T, Makino Y, Katsurada K
Department of Emergency Medicine, Osaka Prefectural General Hospital.
A 63-year-old male was admitted to our hospital because of high fever and
delirium. He had been diagnosed as diabetes mellitus five years before but not
treated at all. An abdominal CT scan showed gas-containing abscess in the right
lobe of the liver. Klebsiella pneumoniae and Bacteroides distasonis were
cultured both from the punctured specimen of the abscess and from arterial
blood. Catheter drainage was carried out percutaneously under guidance with
ultrasonography and antibiotics was administered intravenously. He was
diagnosed as purulent meningitis by lumbar puncture on admission and as
endophthalmitis because of swelling of the left eyeball on hospital day 4. CT
scan also showed multiple metastatic lesions in the cerebrum and in the lung.
After three months, he was discharged from the hospital in good condition,
except for loss of vision of the left eye.
PMID: 7594794, UI: 96056832
7. Michael's lab tests and medical history:
A. One of Michael's parents wrote a thorough yet concise medical history that
also included possibly relevant aspects of the mother's and father's and near
relatives' histories.
B. Urinary IAG etc 12.16.98
C. " " 1.11.99
D. Urine organic profile 7.14.97
E. Stool substances eval 5. 7.98
Stool substances eval 10.19.98 *
Stool substances eval 10.22.98 * different labs
F. Red cell lipids eval 10.18.98
G. Urine dysbiosis markers 2. 8.99
H. " " " 3.16.99
I. " " " 4. 7.99
J. Candida immune panel 6. 3.99
K. WBC RBC etc 10. 8.98
WBC RBC etc 6. 3.99
L. stool bacteria 8. 3.98
stool bacteria 10.19.98
stool bacteria 2. 8.99
stool bacteria 4. 7.99
M. Kp sensitivity to antibiotics 8. 3.98
Kp sensitivity to antibiotics 10.19.98
Kp sensitivity to antibiotics 2. 8.99
N. Essential and toxic elements 6.23.97
O. Amino acid analysis 10. 8.98
P. B vitamins eval 6.24.97 ***
{niacinamide high, possible link to his low IAG}
Q. Hair analysis 9.18.97
Hair analysis 12. 1.97
Hair analysis 2.19.98
R. immune panel 9.16.97
immune panel 2. 2.98
immune panel 10. 8.98