17 April 2013

ProMED: RICIN


RICIN - USA: (WASHINGTON, DC) LETTERS
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Date: Wed 17 Apr 2013
Source: Chicago Tribune, Reuters report [edited]
<http://www.chicagotribune.com/news/sns-rt-us-usa-obama-letterbre93g0ou-20130417,0,2770928.story>


A letter addressed to President Barack Obama contained a substance
that preliminarily tested positive for the deadly poison ricin,
authorities said on Wed 17 Apr 2013.

News that the letter to Obama was being investigated came as a flurry
of other reports of suspicious letters and a package caused the
evacuation of parts of 2 Senate buildings and set nerves in Washington
on edge.

The letter contained "a granular substance that preliminarily tested
positive for ricin," an FBI statement said. But the statement added:
"There is no indication of a connection to the attack in Boston,"
where 3 people were killed in bombings at the Boston Marathon on
Monday [15 Apr 2013].

The USA Secret Service said the letter to Obama was received at a mail
screening facility on Tue 16 Apr 2013. The mail facility that received
the letter was not located near the White House itself, Secret Service
spokesman Edwin Donovan said in a statement. "The Secret Service is
working closely with the US Capitol Police and the FBI in this
investigation," Donovan said.

Parts of the Russell and Hart Senate office buildings were cleared
while officials investigated suspicious letters and a package, a
Capitol Police spokesman said.

CNN read a statement from a spokesman to Senator Richard Shelby,
saying that Capitol Police were investigating a suspicious package
that had been delivered to their office.

Senator Carl Levin said one of his Michigan regional offices had
received a suspicious-looking letter, but it was not opened.
Authorities are investigating, Levin said in a statement.

On Tue 17 Apr 2013, USA authorities intercepted a letter sent to
Mississippi Senator Roger Wicker that preliminary tests showed
contained the deadly poison ricin.

[Byline: Susan Cornwell]

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Communicated by:
ProMED-mail
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[ProMED-mail awaits more information regarding the presumed ricin.

The following is extracted (citations removed) from: Lutwick LI,
Gradon J, Zellen J: Category B Biotoxins. In Lutwick LI, Lutwick SM
(eds), Beyond Anthrax: Bioterror - The Weaponization of Infectious
Diseases. Springer-Humana, New York, 2009, New York, pp. 181-206:

"Ricin is found in castor beans from the plant _Ricinus communis_ and
is a residual product of the production of castor oil. The oil has
applications as a purgative, an engine lubricant, and as a component
of brake and hydraulic fluid. The industry is no longer active in the
United States but the oil is produced in large quantities in other
areas of the world. Importantly, the oil, if properly prepared, does
not contain the toxin.

"One million tons of castor beans are used each year for producing the
oil. The waste mash from the oil production process can have as much
as 5 percent ricin by weight and is easily and inexpensively isolated
via a simple process in a low technology setting using materials
easily obtainable. Ricin is easily prepared in liquid or crystalline
forms or as a readily aerosolized, lyophilized powder. The toxin is
stable and can be poisonous in its native form in the beans.

"Ricin is a 66 kD [kiloDalton] globular protein with a toxic mode of
action of inhibiting protein synthesis in eukaryotic cells. The
mechanism is due to the enzymatic removal of a single adenine residue
from (amino acid 4324) close to the 3-prime end of 28S ribosomal RNA.
The removal prevents elongation factor-2 from binding. Structurally it
is made up of 2 approximately equal molecular weight subunits, the A
and B chains, linked by a disulfide bond. The B chain facilitates
binding to cell surfaces and entry into the cell through binding to
terminal galactose moieties of cellular membrane glycolipids and
glycoproteins.

"The clinical presentation of ricin poisoning depends on whether the
exposure is parenteral, inhaled, or ingested. In mice, the dose found
to be lethal to 50 percent (LD50) of animals was found to be 3-5
microg/kg in inhalation or intravenous exposures and 20-25 microg/kg
in intraperitoneal, subcutaneous, or intragastric administration. The
time to death in the mice was 60 hours for inhalation, 90 hours for
intravenous, and 80-100 hours for the other exposures. It is important
to note that there is a variation of as much as 2 logarithms
[100-fold] in the microg/kg dose of ricin between animals, with the
horse seeming to be the most sensitive and the frog and chicken the
least.

"The 1st symptoms of toxicity generally occur 6-12 hours after
exposure but can occur as early as 3 hours. This is longer than many
of the chemical agents affecting the lung and more rapid than
infectious agents. In humans, as seemed to have occurred in the Georgi
Markov assassination, multiorgan failure occurred with a prominently
elevated white blood cell count. [Markov was a Bulgarian communist
defector who was killed in London in 2003 by a ricin pellet injected
into his leg from a modified umbrella point -- see
<http://edition.cnn.com/2003/WORLD/europe/01/07/terror.poison.bulgarian/index.html>.]

"As a weapon of bioterrorism, ricin would most likely be dispersed as
an aerosol although contamination of food and water supplies is also
feasible. Although easily obtained, massive quantities of toxin are
necessary to create a large scale effect. Because signs and symptoms
are non-specific, detection of an attack would require a high index of
suspicion based on clinical and epidemiologic factors. The finding of
a geographic cluster of patients with acute lung injury should arouse
suspicion of an attack via an aerosolized agent, although the list of
potential culprits is extensive and includes chemical as well as
biologic agents. Ricin cases do not exhibit mediastinitis, as with
anthrax, and they do not demonstrate any response to antibiotic
therapy as would be expected with an infectious etiology. Pulmonary
edema may develop one to 3 days after ricin exposure, in contrast to
staphylococcal enterotoxin B or phosgene where time to development of
pulmonary edema is 12 and 6 hours respectively.

"There are limited data describing the outcome from an inhalation
exposure. In the 1940s, sublethal and accidental exposures were said
to have occurred and were manifest 4-8 hours after exposure with
fever, cough, shortness of breath, and nausea. Studies in rodents
suggest an inhaled ricin aerosol could lead to necrosis of the upper
and lower airway, respiratory distress syndrome and respiratory
failure. Chest x-ray would be expected to show bilateral infiltrates.
In animal studies death occurred in 36 to 72 hours and was dose
dependent. In primates, symptoms and time to death were also dose
related and associated with alveolar flooding, fibropurulent
pneumonia, and necrotizing tracheitis. Death occurred 36 to 48 hours
after challenge following a 8-24 hour preclinical period." - Mod.LL

BMJ: PSA @ 40, 50,& 60 clinically indicated.

Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f2023 (Published 16 April 2013)
Cite this as: BMJ 2013;346:f2023
  1. Andrew J Vickers, attending1,
  2. David Ulmert, research fellow23,
  3. Daniel D Sjoberg, research biostatistician1,
  4. Caroline J Bennette, PhD student4,
  5. Thomas Björk, associate professor3,
  6. Axel Gerdtsson, resident3,
  7. Jonas Manjer, associate professor5,
  8. Peter M Nilsson, professor6,
  9. Anders Dahlin, data manager7,
  10. Anders Bjartell, professor3,
  11. Peter T Scardino, chair2,
  12. Hans Lilja, attending clinical chemist, professor2891011
Author Affiliations
  1. Correspondence to: H Lilja, Memorial Sloan-Kettering Cancer Center, 1275 York Ave (Box 213), New York, NY 10065, USA liljah@mskcc.org
  • Accepted 13 March 2013

Abstract

Objective To determine the association between concentration of prostate specific antigen (PSA) at age 40-55 and subsequent risk of prostate cancer metastasis and mortality in an unscreened population to evaluate when to start screening for prostate cancer and whether rescreening could be risk stratified.
Design Case-control study with 1:3 matching nested within a highly representative population based cohort study.
Setting Malmö Preventive Project, Sweden.
Participants 21 277 Swedish men aged 27-52 (74% of the eligible population) who provided blood at baseline in 1974-84, and 4922 men invited to provide a second sample six years later. Rates of PSA testing remained extremely low during median follow-up of 27 years.
Main outcome measures Metastasis or death from prostate cancer ascertained by review of case notes.
Results Risk of death from prostate cancer was associated with baseline PSA: 44% (95% confidence interval 34% to 53%) of deaths occurred in men with a PSA concentration in the highest 10th of the distribution of concentrations at age 45-49 (≥1.6 µg/L), with a similar proportion for the highest 10th at age 51-55 (≥2.4 µg/L: 44%, 32% to 56%). Although a 25-30 year risk of prostate cancer metastasis could not be ruled out by concentrations below the median at age 45-49 (0.68 µg/L) or 51-55 (0.85 µg/L), the 15 year risk remained low at 0.09% (0.03% to 0.23%) at age 45-49 and 0.28% (0.11% to 0.66%) at age 51-55, suggesting that longer intervals between screening would be appropriate in this group.
Conclusion Measurement of PSA concentration in early midlife can identify a small group of men at increased risk of prostate cancer metastasis several decades later. Careful surveillance is warranted in these men. Given existing data on the risk of death by PSA concentration at age 60, these results suggest that three lifetime PSA tests (mid to late 40s, early 50s, and 60) are probably sufficient for at least half of men.

Introduction

Screening for prostate cancer with the prostate specific antigen (PSA) test became widespread long before the availability of randomised evidence as to its value. There is now evidence that PSA screening is associated with reduced mortality from prostate cancer in men who would not otherwise be screened,1 2 although this comes at considerable harms in terms of the number of men who need to be screened, undergo biopsy, and be treated to prevent one man experiencing prostate cancer metastasis or dying.
That said, PSA screening is not a single intervention and men can be screened in different ways. There is surprisingly little evidence to support many aspects of contemporary screening guidelines. In particular, the age at which screening starts and the frequency of PSA testing is rarely justified in terms of empirical data. Recent evidence has suggested that a single PSA measurement can predict the long term risk of clinically relevant prostate cancer.3 4 5 6 This suggests that a baseline concentration could be used to determine whether a man might benefit from subsequent PSA tests and, if so, when these should be administered.
We used data from the Malmö Preventive Project cohort to develop an evidence based schema for prostate cancer testing. We retrospectively analysed PSA in previously unthawed, archived, anticoagulated blood plasma obtained at baseline from a large highly representative population based cohort of men who had not been screened for PSA and had been followed for 25-30 years. As such, the cohort provides a “natural experiment” for investigating the association between PSA and long term prostate cancer outcomes.
Using this cohort, we previously showed that PSA concentration at age 60 can predict the risk of death from prostate cancer by age 85 (AUC of 0.90). In particular, the 25 year risk of death from prostate cancer in men with PSA below the median (≤1 µg/L) is low (0.2%) and suggests that half of the men at age 60 could be exempt from further screening.7 We determined the risk of metastasis or death from prostate cancer within 25-30 years based on PSA measured close to the time when screening is normally recommended to begin. As there was little screening for prostate cancer in our cohort, these results can be used to determine which men are most likely to benefit from screening.