jr wrote:
< Are you suggesting nebulizing for SARS or not?>
The anwser is YES.However, it must be remembered that Experimental Research in
NO has shown that one-third are non-responders.
POSITING:
In nasal airways, continuous production of NO
- indicated by presence of gas in nasally derived air
- In Kartagener's syndrome, pts lack NO in nasal air & have severe problems
with
recurrent airway infection
POSITING:
In this study, we identify the epithelium in paranasal sinuses as a major site
of NO production and suggest a role for airway-derived NO in primary host
defence.
POSITING
# The concentration of NO in normal paranasal sinuses
; greatly exceed those that are bacteriostatic to S.aureus
- indicating a role for NO in sinus host defense
sterility of the sinuses (compared to nasal mucosa)
- explained by the differences in epithelial NO production
NO produced in the sinuses will continuously enter the nasal cavity
and have biological effects in more distal parts of the airways following
inhalation
-> sinus-derived NO ; affect pulmonary blood flow or act in an 'aerocrine'
fashion (participate in the first line of defence against airbone infectious
agents)
Airway-derived NO ; have an alternative or complementary role in host difense
- increase ciliary beat frequency in bovine respiratory epithelium
- apical location of airway NOS (cilia are anchored to the same area of cell)
Nitric Oxide
High Nitric Oxide Production in Human Paranasal Sinuses
J.O.N. Lundberg, T. Farkas-Szallasi, E. Weitzberg, J. Rinder et al
Summarized by Jeong Hoon Oh, MD
Nature Medicine, Vol. 1, No. 4, April 1995
Physiological role of the human paranasal sinuses ; several theories, but enigma
Paranasal sinuses - generally sterile in healthy subjects
* mech. of sterility ; not fully understood
- ciliary activity & secretory Ig with intact ostium : cleansing of the sinus
ostium
0.5% of all common colds - complicated by sinusitis
Nitric Oxide (NO) : produced in mammalian cells by NO synthase (NOS)
* substrate ; amino acid L-arginine
* 3 isoforms of human NOSs cloned : neuronal, endothelial & inducible NOS
- neuronal & endothelial NOS ; constitutively expressed & produce low level of
NO
( activity is dependent on Ca influx )
- inducible NOS ; expressed only after induction by certain cytokines or by
bacterial lipopolysaccharide
( not dependent on Ca influx )
( susceptible to glucocorticosteroid - suppressed )
- All isoforms are blocked by L-arginine analogues (ex. N-nitro-L-arginine
methyl ester (L-NAME))
Role of NO in host defence
- implied when produced in large quantities by an inducible NOS
- involved in mouse macrophage-mediated killing of a variety of pathogens
- antiviral properties
* The origin & role of NO of healthy subjects ; not known
POSITING:
In nasal airways, continuous production of NO
- indicated by presence of gas in nasally derived air
- In Kartagener's syndrome, pts lack NO in nasal air & have severe problems
with
recurrent airway infection
POSITING:
In this study, we identify the epithelium in paranasal sinuses as a major site
of NO production and suggest a role for airway-derived NO in primary host
defence.
Methods
Measurement of NO in sinus & nasal air
in 5 healthy subjects (ages 29-41, 4 males)
; after topical anesth.
-> max. antrum puncture with an autoinjector (Sinoject ) through the inferior
meatus
-> a syringe was connected to a catheter placed in the sinus
-> 20ml of air aspirated over a period of 15 sec
-> repeated every minutes for 5 minutes
-> NO measurement performed before & after intrasinus instillation of NOS
inhibitor L-NAME (3.7mM in saline) & as a control D-NAME (3.7 mM in saline)
-> entire sinus was filled with the solution & emptied again after a 10-min
incubation period
; additional experiment
nasal air was aspirated (20ml over a period of 15s) using an occlusive nasal
olive (connected to a syringe & introduced into the vestibulum of the nose)
-> asked to hold breath with mouth closed while the contralateral nostril was
left open
- ( air was forced from one nostril to the other via the nasopharynx )
-> before & after measurement of intranasal administration of a total of 20mlg
L-NAME (14.8mM in saline 5ml) - inhaled as an aerosol through the nose over
10-min period
in 4 pts (56-77 yrs, 3 males) undergoing routine surgery to alleviate orbital
compression due to proptosis
; air was aspirated repeatedly from one max. sinus
in all experiments ; the aspirated air was immediatelt injected into an NO
chemiluminescence analyzer
; NO values remained stable in the syringe for longer than 2 min at widely
varied conc. of NO in air
in 49 healthy non-smoking subjects (age 0-62, 22 male)
measurement of nasal NO concentrations continuously by sampling air (0.7 l
/min)
form one nostril
-> nasal olive was connected directly to the sampling tube of chemiluminescence
analyzer and introduced into one nostril
-> asked to breath through the mouth (contrlateral nostril was left open)
: NO levels in ambient air were less than 4 ppm in all
Immunohistochemical & in situ hybridization studies
Mucosal Bx from maxillary, frontal, or sphenoid sinus in 8 pts after surgical
opening
Nasal Bx from inferior or middle turbinate in all patients
-> specimens incubated with
- monoclonal & polyclonal antibodies raised against fragments of mouse
macrophage NOS, and
- monoclonal antibodies against human neuronal & endothelial NOS
(the mouse macrophage NOS shows 77% identity to human hepatocyte inducible NOS)
-> sections were incubated with fluorescein isothiocyanate-conjugated
anti-mouse
IgG & anti-rabbit IgG antibodies
-> analyzed in microscope
* Control : macrophage NOS antibodies were preincubated with mouse macrophage
lysate for 2 hrs
Results
Sinus and nasal NO concentrations
High concentrarions of NO ; found in sinus air on first aspiration
- in all healthy subjects & in the pts undergoing surgery
Mean sinus NO concentration in healthy subjects (n=5)
: 9.1 ?3.8 ppm
- remained similar during repeated aspirations
-> indicating continuous production
Estimated NO release into one maxillary sinus : 20 nmol /min
Fig. 1
Sinus NO concentrations ;
- not significantly changed by local instillation of control substrate D-NAME
- reduced by NOS inhibitor L-NAME by 78% compared with D-NAME
( * Nasal NO concentrations (1.2 ?0.2ppm) were only reduced by 22% following
nasal inhalation of L-NAME )
Fig. 2
Age-dependency of NO values
- observed when sampling air continuously from one nostril in group of healthy
subjects
- NO levels were increased with age
- low in newborns, and reaching levels similar to those in adults at the age of
10
Fig. 3
* higher sampling flow rate using continuous method (0.7 l/min)
- generally lower NO concentrations than in sampling of air into a syringe
(0.08
l/min)
Tissue expression of NOS
Polyclonal & monoclonal antibodies against mouse macrophage NOS
- staining in the epithelial cells of paranasal sinuses in all biopsies
( strongest in the apical part of the epithelial cells )
- staining always disappeared if the antibodies were preincubated with mouse
macrophage lysate
Patchy staining in nasal epithelium
Monoclonal antibodies against neuronal and endothelial NOS
- did not stain the sinus or nasal epithelium
With in situ mRNA hybridization
; both human hepatocyte NOS probes - labelled the epithelial cells in the sinus
nasal epithelium exhibited a low grain density ( higher than background level )
human neuronal & endothelial NOS probes did not label the epithelium
same probes labelled human brain tissue and vascular tissue
Discussion
large & continuous production of NO in human maxillary sinuses
> conc. of NO in the range of highest permissible atmospheric pollution levels
(25ppm)
NO - originate from the epithelial cells lining the sinus
( since strong NOS immunoreactivity was found apically in those cells.)
- sinus NO values were reduced by local instillation of an NOS inhibitor into
the sinus
in situ hybridization and immunohistochemical studies
: NOS sharing mRNA sequence homology with human hepatocyte inducible NOS
-abundant in normal sinus epithelial cells
bronchial epithelial cells ; express inducible NOS
- in inflammatory conditions
- in vitro after stimulation with certain cytokines
- not under basal conditions
* NO excretion per min. into one single maxillary sinus
- exceeded the total normal NO output from entire lower airways
Sinus NOS : differs from the NOS found in normal lower airway epith.
- shows mRNA sequence homology with human hepatocyte inducible NOS
- produce large amounts of NO
- properties associated with constitutive isoforms of NOS
@ process regulating the expression and activity of sinus NOS- remains to be
studied.
In nasal epithelium ; only weak & patchy immunostaining for inducible NOS
minor decrease in nasal NO concentrations upon nasally inhaled L-NAME
-> much of NO found in nasal air ; produced in the paranasal sinuses
nasal NO concentrations will be reduced
- in conditions altering the communication bet. the sinuses & nasal cavity
- in situations where one or several sinuses are filled with fluid or poorly
developed
age-dependent increase in nasal NO levels
: to follow the development and pneumatization of paranasal sinuses
POSITING
# The concentration of NO in normal paranasal sinuses
; greatly exceed those that are bacteriostatic to S.aureus
- indicating a role for NO in sinus host defense
sterility of the sinuses (compared to nasal mucosa)
- explained by the differences in epithelial NO production
NO produced in the sinuses will continuously enter the nasal cavity
and have biological effects in more distal parts of the airways following
inhalation
-> sinus-derived NO ; affect pulmonary blood flow or act in an 'aerocrine'
fashion (participate in the first line of defence against airbone infectious
agents)
Airway-derived NO ; have an alternative or complementary role in host difense
- increase ciliary beat frequency in bovine respiratory epithelium
- apical location of airway NOS (cilia are anchored to the same area of cell)
Excess production of NO - may be pathogenic;
* asthmatic airway epithelia express an inducible NOS
* asthmatics show elevated NO levels in exhaled air
- the production site within the host cell will determine whether the NO has a
damaging effect on the host cell
; in the sinus, the enzyme seems to be located mainly apically in epithelial
cells,
whereas inducible NOS staining in asthmatic epithelium is seen in the cytosol.
-> In sinus epithelial cells, most NO may be released extracellulary,
whereas in asthmatic bronchial epithelium, intracellular NO levels may be high
Conclusion
- There is a continuous and large production of NO in the paranasal sinuses in
healthy subjects.
- An enzyme showing mRNA sequence homology with human hepatocyte inducible NOS,
is constitutively expressed, and located apically in epithelial cells of the
sinuses.
- NO may serve important host defense functions in these enigmatic cavities.
NITRIC OXIDE
Richard A. Robbins, Matthew B. Grigham
summarized by Jeong Hoon Oh, MD
Int J Biochem Cell Bio Vol. 29 No. 6 857-860 1997
Synthesis & Degradation
formed when one of the chemically equivalent guanido groups of the essential
amino acid L-arginine is oxidized by five electrons
- catalyzed by a group of enzymes (nitric oxide synthase(NOS)) & several
co-factors
( only L-arginine is cleaved ( not D-arginine ))
# NOS exist in several isoforms -> variation in NOS activity
* Constitutive NOS (cNOS, Type III NOS) : generally exist in endothelial cells
- constitutively expressed & Calcium-dependent
- cNOS accounts for the baseline production of the small amounts of NO from
endothelial cells
* Brain NOS (bNOS, nNOS, Type I NOS) : predominantly in neural tissue
- constitutively expressed & Calcium-dependent
- produces picomolar amounts of NO
* Inducible form NOS (iNOS, Type II NOS) : detected in a variety of tissues &
organs in addition to vascular endothelium
- not expressed in most tissues, but is induced by bacterial
lipopolysaccharide(LPS) or cytokines (ex. TNF, IL-1, IFN)
- mech. of activation is different to constitutive NOS, but 50% homologous with
cNOS or bNOS at the protein level
- induction-> formation of much larger amounts (>1000-fold) of NO for longer
periods of time
# several co-factors necessary for NOS activity
; flavones(FAD, FMN), tetrahydrobiopterin, NADPH
# major regulator of iNOS activity
; transcriptional regulation of iNOS mRNA
( Nuclear factor -k?appears to play a major role in regulating iNOS
transcription )
# Inhibitors of NOS ; synthetic & naturally occuring
- most inhibitors have substitutions made at the guanido group of arginine
( compete for the active site on NOS with arginine )
; ex. L-N-monomethyl-L-arginine (L-NMMA), L-nitroarginine methyl ester
(L-NAME),
aminoguanidine
Biological Function
# endothelial-dependent control of vascular tone & mediates vascular smooth
muscle relaxation
- by increasing formation of cyclic guanyl monophosphate
# endothelium-independent vascular smooth muscle relaxation in cerebral & other
arteries
# in the brain, act as a neural messenger mediating the action of glutamate
acting at NMDA receptors
-> excess NO accounts for a major portion of the neural damage following strokes
# modulate both acute & chronic inflammatory reactions
- NO may suppress inflammation by reducing lymphocyte activation
# relaxes tracheal muscle and reduces metacholine-induced bronchoconstriction
- There is evidences of NO functions as the neurotransmitter of the inhibitory
non-adrenergic & non-cholinergic bronchodilator response
@ NO is a potent vasodilator and may narrow airways by dilating the bronchial
vessels
- airway blood vessel dilation and edema proposed to account for the airway
obstruction in asthma
# participate in host defense by mediating antimicrobial activity and
cytotoxicity for tumor cells
also increases ciliary beat frequency
Medical Applications
# Excessive production of NO -> hypotention seen in septic shock
( NOS inhibitors result in an increase in blood pressure in septic shock )
# Beneficial during respiratory distress syndrome
- inhalation of NO would improve ventilation-perfusion mismatching by selective
vasodilation of well-ventilated alveoli.
# NO levels in exhaled breath are increased in some disorders such as asthma.
In another C Creel communication,
C.Creel reported:
< ..What is puzzling, doctors say, is why the
transferred patient who had been exposed to the virus
didn't show even mild SARS symptoms -- high fever,
difficulty in breathing, dry cough
-- and how he could have spread the virus to the U.S.
visitor but not other patients and nurses.
``It defies imagination as to what happened,''
.... Dr. Alan Bernstein, president of the Canadian
Institutes of Health Research (CIHR), said it is
difficult to build a ''scientific story'' around one such case.
But he said a transmission such as this raises
questions about whether the quarantine should be
raised from 10 days for those who may have been
exposed to the virus and the need for more sensitive testing.
There is no diagnostic test for SARS yet and no
vaccine....
Health officials Wednesday were planning to send
up to a 1,000 people in Whitby, east of Toronto, into
quarantine after 12 patients at dialysis clinic
developed SARS-like symptoms.
Officials are investigating this new possible cluster,
which, if confirmed, would be the Toronto area's third
outbreak of SARS. The first one lasted from mid-March
to mid-April.>
I received an urgent call from a man I met while taking lunch on 28.5.03
near my new relocated clinic. He remembered our lunch conversation when he was
rushing to the hospital for complaints of sudden difficulty in breathing,
throbbing headache , dizziness and weakness. The patient related that he had
recently returned from China. He produced the Alert Card given to him at the
KLIA Malaysia. He is 56, Male and is Chinese. There was no history of Cough,
Fever or any flu-like symptoms when I first examined him. He refused to be
admitted but he had promised me to be admitted if the symptoms persisted.He was
obviously stressed.
He was given:
Colloidal Silver [ 3-5 ppm ] orally and spraying
Noni Whole Plant Extract [ Nitric Oxide Formula
]orally and spraying
Dr. Reckaweg 193 [ Immunogen ]
Green Plus
Distilled Water
[ The whole Noni Plant Extract 10 cc is mixed with 100 cc of
Colloidal Silver [ 3-5 ppm ] for general spraying and nebulization ]
He reported to me the next morning, with no more pain or
tightness over the chest or any respiratory distress or
dis-ease. For the next two weeks he and his family members showed no signs of
any illness and to-date with no complaints of Fever, Cough or any respiratory
distress. All family members were given generous helpings of colloidal silver [
3-5 ppm ]. But he is a very angry man : all his friends had avoided and
boycotted him because he had sojourned and returned from a SARS designated
regio, China.
" The Nose is Smart on the Nitric Oxide Airway Dynamics in the parasinuses "
http://www.academon.com/lib/paper/8091.html
My patient confided in me his feelings and thoughts on the societal boycott
imposed by global health regulations
because he happened to be in the wrong places
and at the wrong time in the course of his international flight and travelling.
There is curiously little mentioning of the role of Nitric Oxide in the
management of SARS.
With regards
Lew
***************************************************************
World Health Organisation has issued a global alert on
Severe Acute Respiratory Syndrome(SARS)
If you have recently visited any of the country / area with recent local
transmission of SARS (as classified by WHO) and within 10 days of your return,
develop high fever above 38°C or above 100.4°F and have one or more respiratory
symptoms including cough, shortness of breath or difficulty in breathing, you
should immediately go to the nearest government hospital and present this card.
Inform your doctor of your recent travel history and that you wish to be
screened for SARS
, Disease Control Division, Ministry of Health Malaysia,
Level 2, Block A, Health Offices Complex, Jalan Cenderasari, 50590 Kuala
Lumpur, Mataysla
Tel: 03-26946394 · Fax: 03-26946404 · Webslte: http://webjka.dph.gov, my/sars -
19 May2003
To the Doctor
The person presenting this Health Alert Card may have been
exposed to
Severe Acute Respiratory
KLIA
Syndrome (SARS)
MINISTRY OF HEALTH MALAYSIA
[ stamped ]....... while he / she was in an affected
area.
DATE: 27/ 5/03 SARS is a notifiable illness under the
Prevention and Control of Infectious DiseasesAct 1988.
Please notify the nearest Health Office
or
Disease Control Division, Ministry of Health Malaysia,
Level 2, Block A, Health Offices Complex, Jalan Cenderasari, 50590 Kuala Lumpur,
Tel: 03-2694 6394 · Fax: 03-2694 6404
******************************
Toronto doctors baffled how SARS infected U.S. man
By Rajiv Sekhri
TORONTO (Reuters) - Toronto doctors said
Wednesday they were mystified by how the SARS virus
spreads after a U.S. man caught it while visiting a
ward in a Toronto geriatric hospital thought to be
free of the deadly illness.
Infection-control specialists said the baffling
transmission could be the first of its kind in
Toronto. And after teams here battled SARS for three
months, the outbreak also heightens fear and confusion
as they probe 12 new possible SARS cases just east of
the city.
A North Carolina man developed SARS more than a
week after he left Toronto in mid-May. A patient in
the same room the American had visited was later
diagnosed with severe acute respiratory syndrome. The
patient had been transferred to the geriatric hospital
May 15 from a Toronto facility where the
SARS virus had lingered unnoticed for two weeks.
What is puzzling, doctors say, is why the
transferred patient who had been exposed to the virus
didn't show even mild SARS symptoms -- high fever,
difficulty in breathing, dry cough
-- and how he could have spread the virus to the U.S.
visitor but not other patients and nurses.
``It defies imagination as to what happened,''
said Dr.Donald Low, chief of microbiology at Mount
Sinai Hospital in Toronto, who is one of the leaders
in the battle against SARS.
``I think we have to accept the fact that (the
U.S. visitor)got SARS in Toronto and that most likely
he got it in a health-care facility because that is
where he visited, and there happened to be SARS cases
that eventually showed up in the same room,'' Low said
in an interview.
``But we don't feel comfortable putting the whole
story together with what we know about this disease to
date,'' Low said, adding that the SARS outbreak is the
``most unusual and difficult challenge'' he has faced
in his 25 years of combating infectious diseases.
Dr. Alan Bernstein, president of the Canadian
Institutes of Health Research (CIHR), said it is
difficult to build a
''scientific story'' around one such case.
But he said a transmission such as this raises
questions about whether the quarantine should be
raised from 10 days for those who may have been
exposed to the virus and the need for
more sensitive testing.
There is no diagnostic test for SARS yet and no
vaccine.
The disease has killed 33 people in the Toronto
area, the only place outside of Asia hit hard by the
virus, whichoriginated in southern China and has
spread to about 30 countries through travelers.
Health officials Wednesday were planning to send
up to a 1,000 people in Whitby, east of Toronto, into
quarantine after 12 patients at dialysis clinic
developed SARS-like symptoms.
Officials are investigating this new possible cluster,
which, if confirmed, would be the Toronto area's third
outbreak of SARS. The first one lasted from mid-March
to mid-April.
The disease resurfaced in late May, more than a
month after no new case had been reported, crushing
hopes the city had the virus under control.
Doctors are still learning more about the virus
but say more research is needed.
Dr. Bhagirath Singh, scientific director of the
CIHR's Institute of Infection and Immunity, said: ``We
are learning the virus can survive three hours, and
now people believe it can survive up to three days. Do
we have answers? The answer is, no.''
Worldwide, SARS has killed about 780 people and
infected more than 8,400. In the Toronto area, where
more than 4 million people live, there are 64 probable
SARS cases. Twenty three people were in critical
condition Tuesday and another 260 were being
monitored for infection.
--
--------- Original Message ---------
DATE: Mon, 16 Jun 2003 22:31:32
From: jrowl...@nctimes.net
To: silver-list@eskimo.com
Cc:
>Are you suggesting nebulizing for SARS or not?
>jr
>
>
>--
>The silver-list is a moderated forum for discussion of colloidal silver.
>
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>
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>
>
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