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ScienceWeek
SCIENCE-WEEK
A Weekly Digest of the News of Science
June 26, 1998
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As in mathematics, so in natural philosophy,
the investigation of difficult things by the
method of analysis ought ever to precede the
method of composition. This analysis consists
in making experiments and observations, and
in drawing general conclusions from them by
induction, and admitting of no objections
against the conclusions but such as are taken
from experiments, or other certain truths.
-- Isaac Newton (1642-1727)
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Contents of This Issue:
1. On Science, Politics, and Asteroids
2. Evolution of Cosmic Structure: Largest Simulation to Date
3. An Argument for a Lightweight Universe
4. Connection Topology: Dynamics of "Small-World" Networks
5. On the Thermodynamic Hypothesis of Protein Folding
6. On the Neurobiology of Depression
7. Environmental Pollution: Frog Deformities and Human Hazard
8. Anti-Tuberculosis Drug Resistance 1994-1997
9. Low Level Asbestos Exposure: Dangerous or Not Dangerous?
10. Wetterhahn Laboratory Poisoning Case: Final Medical Report
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1. ON SCIENCE, POLITICS, AND ASTEROIDS
It is not often that a leading science journal invites a leading
science-fiction writer to present a lead essay in its pages. But
there are many scientists at work today who made their first
youthful contact with the adventurous aspects of science in the
novels of Arthur C. Clarke. Now 81 years old and Chancellor of
the University of Moratuwa (LK), Clarke was trained as a
scientist and originated the idea of satellite communication in a
scientific article in 1945. In a recent essay in the journal
*Science*, Clarke makes the following points: 1) For more than a
century, science and its occasionally ugly sister technology have
been the chief driving forces shaping our world. They decide the
kinds of futures that are possible. Human wisdom must decide
which are desirable. Clarke says it is "truly appalling" that so
few of our politicians have any scientific or engineering
background. 2) Clarke says, "I have encountered a few
'creationists' and because they were usually nice, intelligent
people, I have been unable to decide whether they were *really*
mad or only pretending to be mad. If I was a religious person, I
would consider creationism nothing less than blasphemy. Do its
adherents imagine that God is a cosmic hoaxer who has created the
whole vast fossil record for the sole purpose of misleading
humankind?" 3) Clarke says the scientific establishment has only
slowly understood that the history of this planet, and perhaps of
civilization itself, has been modified in important ways by
physical impacts from space, and he proposes that we embark on a
serious study of the probability of comet or asteroid impactors
on the planet Earth. 4) Concerning energy production from new
sources, Clarke says his guess is that large scale industrial
application will begin around the turn of the century -- "at
which point one can imagine the end of the fossil-fuel-nuclear
age, making concerns about global warming irrelevant, as oil-and-
coal-burning systems are phased out."
QY: Arthur C. Clarke, 25 Barnes Place, Colombo 7, LK.
(Science 5 Jun 98 280:1532) (Science-Week 26 Jun 98)
2. EVOLUTION OF COSMIC STRUCTURE: LARGEST SIMULATION TO DATE
One of the important problems in cosmology is to explain the
present structure of the universe, and the evolution of that
structure from the primordial material that came into existence
following the Big Bang. Computer simulations are a significant
part of this research, the idea essentially to calculate from
first principles the properties of a model based on a particular
set of assumptions, compare the results of the calculations with
what is observed in the real universe, and thus, temporarily,
confirm or deny the usefulness of the assumptions that form the
basis of the model. This is the paradigm for most theoretical
model construction in all the sciences, and as a method it is
nothing unique to cosmology. In cosmology, however, the number of
interacting entities is enormous. A new simulation effort was
recently reported, evidently the largest simulation of cosmic
structure to date, the new effort involving consideration of a
simulated cosmos of a billion entities, each of which is
equivalent to about 10 galaxies. The work was carried out at the
Max Planck Institute for Astrophysics (Garching, DE), using a
512-processor Cray supercomputer, and reported at the end of last
month at a cosmology meeting in Paris by Jorg Colberg (MPI-
Astrophysics Garching, DE). The work was also presented a week
ago at the American Astronomical Society San Diego (US) meeting
by August Evrard (University of Michigan, US). This is apparently
the first simulation of how gravity could have gathered post-Big
Bang ripples into large meta-galactic structures -- walls,
clumps, filaments of galaxies -- filling all of space. Some
astro-physicists are saying this work marks a turning point in
numerical cosmology, and they expect this model universe to be a
powerful tool for interpreting data from large surveys of the
real sky. This simulation omits factors other than gravity, such
as pressure and radiation, that also govern galaxy formation. The
calculations have involved two different models, one a model
based on a mass density sufficient to stop cosmic expansion, and
the other (called the "lambda" model) based on a light-mass
universe that will expand forever. Apparently, it is the lambda
model that is producing structures more in agreement with
observations, although both models have difficulty accounting for
some of the more massive and distant galaxy clusters seen in the
real sky.
QY: Joseph Glanz (science_editors@aaas.org)
(Science 5 Jun 98 280:1522) (Science-Week 26 Jun 98)
3. AN ARGUMENT FOR A LIGHTWEIGHT UNIVERSE
As mentioned in the previous report, a fundamental question in
cosmology is whether the expansion of the universe will continue
indefinitely (an open universe) or eventually cease (a closed
universe). According to the current analytical framework used to
describe the universe, the answer to this question depends on the
mass density of the universe. If the mass density is below a
certain calculated value, the "critical density", there is not
enough mass to provide the gravitational attractions necessary to
slow and halt the expansion. This critical density is equal to
1.9 x 10^(-29)H^(2) grams per cubic centimeter, which is
equivalent to approximately 10 protons per cubic meter. The (H)
indicated is the Hubble constant, the rate at which the expansion
velocity of the universe changes with distance. Often used is a
derived constant Omega(sub m), which is expressed in units of the
critical density, so that a value of Omega(sub m) = 1 means the
mass density is the critical density. The standard models of the
initial expansion of the universe (*inflation), as well as
general arguments not dependent on ad hoc adjustments of
cosmological parameters, predict a flat universe with the
critical density needed to just halt its expansion. But at the
present time, only a small fraction of the critical density has
been detected, even when all the unseen dark matter in galaxy
halos and clusters of galaxies is included. There is apparently
no reliable indication that most of the matter needed for closing
the universe does in fact exist. ... ... Bahcall and Fan
(Princeton University, US) present an analysis of the problem of
cosmic mass density. They propose that several independent
measures, especially those using the largest bound systems known
-- clusters of galaxies -- all indicate that the mass density of
the universe is insufficient to halt the expansion. They also
propose that a new method involving the evolution of the number
density of clusters with time provides the most powerful
indication so far that the universe has a subcritical density.
The authors suggest that various techniques reveal a consistent
picture of a lightweight universe with only 20 to 30 percent of
the critical density, and thus the universe may expand forever.
QY: Neta A. Bahcall (neta@astro.princeton.edu)
(Proc. Natl. Acad. Sci. US 26 May 98 95:5956)
(Science-Week 26 Jun 98)
-------------------
Related Background:
... ... *inflation: The inflationary model, first proposed by
Alan Guth in 1980, involves the idea that quantum fluctuations in
the time period 10exp(-35) to 10exp(-32) seconds following the
Big Bang were quickly amplified into large density variations
during the "inflationary" 10exp(50) expansion of the universe in
that time frame.
-------------------
Related Background:
COSMOLOGY: OPEN, CLOSED, OR FLAT UNIVERSE?
Marc Kamionkowski (Columbia University, US) reviews current
research in cosmology, making the following points: 1) Determin-
ation of the geometry of the universe has been a central goal of
cosmology ever since Hubble discovered its expansion 75 years
ago. 2) The central question is whether the universe is a multi-
dimensional equivalent of a 2-dimensional surface ("flat"), a
sphere ("closed"), or a saddle ("open"). The geometry, in the
context of current theory and observations, determines whether
the universe will expand forever or eventually collapse. 3) Until
now, most astronomers have pursued the geometry by attempting to
measure the mass density of the universe. According to general
relativity, if the density is equal to, larger than, or smaller
than a critical density fixed by the expansion rate, then the
universe is flat, open, or closed, respectively. 4) Another
possibility is to look directly at the predicted observational
effects of a curved (open or closed) universe versus a flat
universe, and in particular at the angular power spectrum of the
cosmic microwave background. The authors suggest that in the near
future a new generation of experiments will provide substantial
advances in these observations, enabling more definitive
statements about the geometry of the universe, and that these
results will in turn provide clues to the new particle physics
required to understand the inflation phase following the Big Bang
origin of the universe.
QY: Marc Kamionkowski (kamion@phys.columbia.edu)
(Science 29 May 98 280:1397) (Science-Week 19 Jun 98)
4. CONNECTION TOPOLOGY: DYNAMICS OF "SMALL-WORLD" NETWORKS
Watts and Strogatz (Cornell University, US) present an analysis
of what they call "small-world" networks, connectivity regimes in
which connections between entities are neither completely regular
nor completely random. Networks of coupled dynamical systems have
been used to model biological oscillators, semiconductor junction
arrays, excitable media, neural networks, spatial games, genetic
control networks, and many self-organizing systems. Ordinarily,
the connection topology is assumed to be either completely
regular or completely random, but many biological, technological,
and social networks lie somewhere between these two extremes. The
authors explored simple models of networks that can be tuned
through the middle ground: networks that can be "rewired" to
introduce increasing amounts of disorder. They report that such
"small-world" systems can be highly clustered, like regular
lattices, yet have small characteristic path lengths, like random
graphs. (In their model, the parameter "characteristic path
length" is essentially an inverse measure of connection
randomness. In a friendship network, for example, a low
characteristic path length represents the constraint that each
individual has only a few friends.) The significance of this
research is that models of dynamical systems with small-world
coupling apparently display enhanced signal-propagation speed,
computational power, and synchronizability. The authors suggest
that although small-world architecture has not received much
attention, it may be widespread in biological, social, and man-
made systems, often with important dynamical consequences.
QY: Duncan J. Watts (djw24@columbia.edu)
(Nature 4 Jun 98 393:440) (Science-Week 26 Jun 98)
5. ON THE THERMODYNAMIC HYPOTHESIS OF PROTEIN FOLDING
Proteins are macromolecules that assume specific high-order
configurations, with each type of protein molecule folding into
the specific configuration necessary for its function. There are
two central aspects of this folding: it occurs extremely rapidly,
on the order of milliseconds to minutes after first synthesis of
the polymer, and the final configuration achieved is always
identical for each type of protein. Thus, protein A rapidly folds
into the protein A-conformation, and protein B rapidly folds into
the protein B-conformation. The question is how does this happen?
What are the variables that control these events? Experimental
techniques in the study of protein folding often involve
"denaturation" and "renaturation" of proteins in vitro.
Denaturation is the elimination of the folding of a protein by
changing ambient conditions such as temperature and pH, and
renaturation is the refolding of the protein molecule into the
native state following restoration of the original ambient
conditions. ... ... Govindarajan and Goldstein (University of
Michigan, US) present a theoretical analysis of current ideas
concerning protein folding. In 1969, C. Levinthal pointed out
that it is impossible for an unfolded protein to find the native
state (its final configuration) by randomly searching through the
entire space of possible conformations. This led Levinthal to
postulate that a protein must follow a specific path to the final
configuration, and therefore folding must be under kinetic
control (i.e., under the control of a specific sequence of
reactions). According to Levinthal, if the final folded state
turned out to be one of lowest configurational energy, it would
be a consequence of the biological evolution of specific chemical
reaction sequences ("kinetic control"), and not of physical
chemistry and the laws of thermodynamics ("thermodynamic
control"). In contrast to this idea of Levinthal, C. Anfinsen in
1973 concluded from the results of his numerous denaturation-
renaturation experiments that the native state of the protein is
indeed the global minimum of free energy, a conjecture that he
called the "thermodynamic hypothesis" of protein folding. The
debate between these two viewpoints of kinetic control and
thermodynamic control has continued for more than two decades,
with numerous experimentalists and theoreticians investigating
whether proteins reach their global free energy minimum in a
pathway-independent manner under thermodynamic control, or
whether the protein molecule follows a specific pathway to a
possibly local free energy minimum under kinetic control.
Govindarajan and Goldstein now report an exploration of the
validity of the thermodynamic hypothesis of protein folding by
simulation of the evolution of protein sequences, investigating
whether what is proposed by the thermodynamic hypothesis could
result through the process of protein evolution, the approach
involving certain assumptions concerning the effects of random
mutations on protein evolution. The authors report that their
results suggest that even if protein folding is under kinetic
control, a specific kinetic sequence will evolve so that the
native state of the protein molecule is most often the state of
minimum free energy. They point out that one consequence of this
is that theoretical methods that predict protein structure by
means of algorithms and search strategies not apparently
available to the protein itself may still be relevant as long as
the model produces an eventual state of minimum free energy.
QY: Richard A. Goldstein (richardg@umich.edu)
(Proc. Natl. Acad. Sci. US 12 May 98 95:5545)
(Science-Week 26 Jun 98)
-------------------
Related Background:
ON SIMULATED EVOLUTION AND PROTEIN FOLDING
Proteins are polymers consisting of long chains of amino acid
residues, but that is only the beginning of their functional
chemistry. In biological systems, proteins assume various complex
high-order configurations ("folding"), and it is these
configurations that usually determine the roles of proteins as
biochemical entities in the biological system. An important goal
of molecular biology is to understand the structural and
functional features of proteins, in particular the mechanisms
responsible for specific protein folding. The "bioinformatics"
approach is based on the idea of recognition and identification
in a protein of a new sequence of amino acids similar or
identical to other sequences in other proteins for which
structure and function are known. But this approach encounters
difficulties because of a lack of understanding of what features
of sequences have evolved to encode stability and fast folding in
proteins, and a lack of understanding of which features are
functional and which features are adventitious. Better
understanding of general principles that govern kinetics and
thermodynamics of protein folding can help to reveal the
signatures of protein sequences that are related to folding.
... ... Mirny et al (3 authors at Harvard University, US) report
a study of sequences of fast-folding model proteins 48 residues
long, the sequences generated by an "evolution-like selection"
toward fast folding. They report that such fast folding model
proteins exhibit a specific folding mechanism in which all
transition state conformations share a smaller subset of common
contacts (folding nucleus). The authors suggest their results and
analysis imply that for each protein structure there is a small
number of positions that are most crucial for fast folding into
that structure. Protein sequences that fold fast into that
structure may have evolved by placing into those strategic
folding-nucleus positions amino acids that provide stabilization
of the folding-nucleus.
QY: Eugene I. Shakhnovich (shakhnov@chemistry.harvard.edu)
(Proc. Natl. Acad. Sci. US 28 Apr 98 95:4976)
(Science-Week 12 Jun 98)
-------------------
Related Background:
BROWNIAN DYNAMICS SIMULATIONS OF PROTEIN FOLDING
Protein folding occurs on a time scale ranging from milliseconds
to minutes for a majority of proteins. Computer simulation of
protein folding, from a random configuration to the native
structure, is nontrivial due to the large disparity between the
simulation and folding time scales. In order to overcome this
limitation, simple models with idealized protein subdomains,
e.g., the diffusion-collision model, have gained some popularity.
The diffusion-collision protein-folding mechanism postulates the
early-stage formation of fluctuating quasiparticles (micro-
domains), which may be incipient secondary structures (alpha-
helices and beta-sheets) or hydrophobic clusters. These micro-
domains move via diffusion, and their coalescence leads to the
formation of folded proteins. Thus, the diffusion-collision model
reduces the complexity of the folding process from a consider-
ation of individual amino acids to that of the properties of a
few microdomains and their interactions. ... ... Rojnuckarin et
al (3 authors at 2 installations, US) present an analysis of the
folding of a 4-helix protein bundle within the framework of a
diffusion-collision model. Even with the simplifying assumptions
of a diffusion-collision model, a direct application of standard
Brownian dynamics methods would consume 10,000 processor-years on
current supercomputers. The authors circumvented this difficulty
by invoking a special Brownian dynamics simulation. They report
that a coarse-grained (i.e., crude) model of the 4-helix bundle
can be simulated in several days on current supercomputers, and
that such simulations yield folding times that are in the range
of time scales observed in experiments.
QY: Sangtae Kim (kim01@aa.WL.com)
(Proc. Natl. Acad. Sci. US 14 Apr 98 95:4288)
(Science-Week 15 May 98)
-------------------
Related Background:
A MODEL FOR BETA-HAIRPIN FOLDING IN PROTEINS
To be biologically active, proteins must adopt specific tertiary
configurations, a specific "folding". Although many natural
proteins spontaneously refold once they have been forced to
unfold, synthetic proteins are often produced in an insoluble
unfolded state and are thus inactive and useless until correctly
folded. One important aspect of protein folding is the kinetic
process, the rate at which folding occurs. Were a single
conformation to be found by random searching of all the possible
conformations, the number of years required would range from
10^(7) to 10^(66). In actuality, protein folding occurs on the
scale of microseconds, so there is clearly much yet to be learned
about these macromolecules. Probabilistic analysis of the
kinetics and energetics of a system of entities can be made
within the framework of the theory of statistical mechanics, and
the application of this theory is an important part of current
research into protein folding. In general, protein chains fold
into alpha-helices or beta-sheet structures, and the minimal
beta-structural element is the "beta-hairpin", a turning of the
polypeptide chain that has the shape of a hairpin. As far as
experimental methods are concerned, analysis of folding kinetics
in response to temperature variation is one of the key experi-
mental procedures, and there are now sophisticated methods for
temperature control provided by the coupling of computers and
laser physics. One such method is laser "temperature jump"
spectroscopy, which involves jump-heating (jump-discontinuity
heating) of a small volume of aqueous solution in a short time
domain coupled with spectroscopy in some part of the electro-
magnetic spectrum. Munoz et al (4 authors: National Institutes of
Health, US) used a nanosecond laser temperature jump apparatus
coupled with laser fluorescence excitation to study the kinetics
of folding of a protein beta-hairpin consisting of 16 amino acid
residues, and they report that folding of the beta-hairpin occurs
at 6 microseconds at room temperature, which is 30 times slower
than alpha-helix formation. The authors offer a statistical
mechanical model that provides a structural explanation for their
observations.
QY: Victor Munoz
(Nature 13 Nov 97) (Science-Week 5 Dec 97)
-------------------
Related Background:
A SYNTHETIC OLIGOMER THAT MIMICS PROTEIN FOLDING
The existence of helical folding in polymers such as proteins and
nucleic acids is of extreme importance in biological systems, but
biological polymers are not the only polymers to assume such
special folding arrangements. Beta-peptides, for example, non-
biological polymers synthesized from beta amino acids, form
helices stabilized by hydrogen bonds. Now Jeffrey S. Moore et al
(University of Illinois Urbana-Champaign, US) report that syn-
thetic oligomers with an all-carbon backbone, linear phenyl-
acetylenes with ester-substituted benzene rings linked to one
another by acetylene groups, spontaneously fold into a stable
helical configuration in acetonitrile, and that this apparently
involves a "solvophobic" mechanism similar to the hydrophobic
collapse model of protein folding in water. In both systems, the
phenylacetylene oligomers and biological proteins, hydrophobic
groups associate to form a compact structure that excludes the
solvent. The phenylacetylene oligomers have longitudinal cavities
that might be used for binding metals and other reactive species.
The authors also suggest such systems could be used in the design
and construction of synthetic enzymes.
QY: J. S. Moore, Univ. Illinois Urbana-Champaign, Chemistry (217)
333-0722 (Science 19 Sep 97) (Science-Week 3 Oct 97)
-------------------
Related Background:
PROTEIN-FOLDING MECHANISMS IN PROKARYOTES VS. EUKARYOTES
In biological systems, proteins are the molecules that do most of
the biological work, and the various proteins are the ultimate
expression of the genome of any organism. As polymers, proteins
are similar to the polymers known to polymer chemists, but the
chemical activities of proteins (and their biological functions)
depend mostly on higher-order folding into specific configur-
ations rather than on quasi-crystalline backbone arrays, as is
often the case in non-biological polymer chemistry. It is these
specific configurations that are responsible for the important
specificity and high catalytic power of the proteins that are
enzymes. The configurations, in turn, are an ultimate result of
amino acid sequences which form the backbone of proteins,
sequences which are not simple, as are the backbone sequences of
most non-biological polymers, but are specific, cryptic (coded),
and heterogenous. It is now recognized that complex proteins
usually have more than one folding domain, each involving a
sequence of 100 to 300 amino acids. The entire folding
architecture of a complex protein must be precisely constructed
in order for protein functionality to exist. Which provokes the
question of how the specific folding of particular proteins is
ensured by the biological system. The answer is evident for
simple proteins in vitro: the final configuration is
predetermined by the amino acid sequence, there being a single
energetically favored configuration that will always be attained
at equilibrium. This is Anfinsen's Rule, first proposed by the
protein biochemist C. B. Anfinsen more than 30 years ago. In
vivo, however, and particularly for complicated proteins, the
situation is more involved. This week W. J. Netzer and F. U.
Hartl (Sloan Kettering Cancer Center, NY US; Max Planck Inst.
Biochemistry, Martinsried DE) report an analysis of the
differences between protein folding in prokaryotes (organisms,
such as bacteria, without membrane-bound organelles such as the
nucleus) and eukaryotes (organisms with membrane-bound
organelles). Perhaps the most interesting difference is that in
prokaryotes protein folding is delayed until translation (final
synthesis by the ribosome) is completed (post-translational
folding), while in eukaryotes folding of each protein domain
occurs as each domain is translated (co-translational folding).
One result is that new prokaryote proteins can often be
misfolded. There are helper proteins at work in both prokaryotes
and eukaryotes to chaperon the proteins to their final
configurations, but there is still more possibility for errors in
the prokaryotes. One important consequence of this analysis is
that when bacteria are genetically engineered to synthesize human
protein for clinical use, the susceptibility of prokaryote
protein synthesis to folding errors must be considered.
(Nature 24 Jul 97) (Science-Week 8 Aug 97)
6. ON THE NEUROBIOLOGY OF DEPRESSION
Charles B. Nemeroff (Emory University, US), in a review of the
neurobiology of depression, makes the following points: 1) It is
estimated that 5 to 12 percent of men and 10 to 20 percent of
women in the US will suffer from a major depressive episode
sometime in their life. Approximately half of these individuals
will become depressed more than once, and up to 10 percent will
experience manic phases in addition to depressive phases, a
condition known as manic-depressive illness or bipolar disorder.
2) As many as 15 percent of those who suffer from depression or
bipolar disorder commit suicide each year. In 1996, the US
Centers for Disease Control and Prevention listed suicide as the
9th leading cause of death in the US, taking the lives of 30,862
people. Most experts believe this number is a gross under-
estimate. 3) The search for the biological underpinnings of
depression is intensifying, and emerging findings promise to
yield better therapies. 4) The mind does not exist without the
brain. Considerable evidence indicates that regardless of the
initial triggers, the final common pathways to depression involve
biochemical changes in the brain, and it is these changes that
ultimately give rise to deep sadness and the other salient
characteristics of depression 5) Biochemical abnormalities that
are prominent in some depressions may differ from those
predominating in others. 6) There has been no success in
identifying specific genes involved in depression, perhaps
because any genetic predisposition to depression may involve
several genes, each of which makes only a small and hard-to-
detect contribution. 7) Many cases of depression apparently stem
at least in part from disturbances in brain circuits that convey
signals via certain neurotransmitters of the *monoamine class
(e.g., norepinephrine). 8) There is mounting evidence that
chronic overactivity of the hormonal system known as the
hypothalamic-pituitary-adrenal axis in response to stress, in
particular the overproduction of *corticotropin-releasing factor,
contributes to depression. 9) The author proposes a stress-
diasthesis model of mood disorders, the model involving an
interaction between experience (stress) and inborn predisposition
(diasthesis).
QY: Charles B. Nemeroff, Emory University 404-727-5660.
(Scientific American June 1998) (Science-Week 26 Jun 98)
-------------------
Related Background:
... ... *monoamine: The monoamines in this context are a class of
neurotransmitters that includes 3 catecholamines (dopamine,
norepinephrine, epinephrine), an indoleamine (serotonin), a
quaternary amine (acetylcholine), and an ethylamine (histamine).
... ... *corticotropin-releasing factor (CRF): This is a 41-amino
acid hypothalamic polypeptide discovered in 1981, and the
evidence indicates it is a major physiological regulator of the
pituitary-adrenal axis. It controls release of various hormones
from the anterior pituitary. There is considerable evidence that
CRF is also a neurotransmitter in brain areas outside the
hypothalamus. It apparently mediates neuroendocrine, autonomic,
and behavioral responses to stress, and there is evidence that
CRF-containing neurons play a role in the pathophysiology of
anxiety disorders.
7. ENVIRONMENTAL POLLUTION: FROG DEFORMITIES AND HUMAN HAZARD
One of the fundamental problems in dealing with human health
hazards concerns the decision when to act. Is it the best policy
to wait for definitive evidence, or is it the best policy to act
immediately in response to suggestive evidence? And what if there
is no evidence, but significant public pressure as a result of
public misinformation and ignorance of science? For the past 3
years, there has been mounting evidence that the incidence of
deformities in frogs in almost all parts of the US has risen
markedly. The numbers are serious enough to have aroused the
concern of government agencies, wildlife organizations, and
research biologists. There is hardly any disagreement concerning
the rising number of deformities. The disagreement concerns the
cause, and at this time the cause is a puzzle. Of consequence,
perhaps, is the fact that one of the leading journals of the
chemical industry, *Chemical and Engineering News*, recently
devoted a lead article to the subject. Journalist Bette Hileman
makes the following points: 1) Most research on the puzzle now
focuses on the hypothesis that chemicals in pond water, either
synthetic or natural, are inducing the malformations by
perturbing frog development. The malformations include extra hind
legs, legs with extra parts, legs with missing parts, entire
missing legs, bizarre skin webbings, and missing eyes. 2) The
major hypothesis is that chemicals are causing the deformities by
attaching to retinoid receptors and disrupting the retinoid
signaling pathway. Retinoids, which include the powerful hormone
retinoic acid, regulate limb development in all vertebrates,
including humans. 3) But the retinoid theory is not the only
chemical theory. Also under investigation is the idea that
organophosphate insecticides are responsible. And a non-chemical
hypothesis still considered is that increased ultraviolet light
from ozone depletion could be contributing to the deformities. 4)
James G. Burkhart, head of frog research at the US National
Institute of Environmental Health Sciences, says: "If chemicals
in water are the cause, and if those substances are found in
drinking water at high enough levels to affect human development,
then they would, of course, present a danger to humans."
Meanwhile, the puzzle of increasing frog deformities remains
unsolved.
QY: Bette Hileman (edit_cen@acs.org)
(Chem. & Eng. News 25 May 98) (Science-Week 26 Jun 98)
8. ANTI-TUBERCULOSIS DRUG RESISTANCE 1994-1997
In the past 50 years, the proliferation of anti-microbial agents
for use in humans and animals has placed enormous selective
pressure on microorganisms. Drug resistance in patients with
Mycobacterium tuberculosis infection became apparent soon after
the introduction of effective antituberculosis agents in the
1940s, but it was not until the early 1990s, when outbreaks of
multidrug-resistant tuberculosis were reported in patients with
human immunodeficiency virus (HIV) infection in the US and
Europe, that the problem received international attention.
... ... Pablos-Mendez et al (12 authors at 7 installations, US FR
CA NL KR and the World Health Organization) report a study of
the
prevalence of resistance to 4 first-line drugs (isoniazid,
rifampin, ethambutol, streptomycin) in 35 countries participating
in an international collaborative study of the problem between
1994 and 1997. Among patients with no prior treatment, a median
of 9.9 percent of M. tuberculosis strains were resistant to at
least one drug. The prevalence of primary multidrug resistance
(resistance to at least isoniazid and rifampin) in this group was
1.4 percent. Among patients with histories of treatment for one
month or less, the prevalence of resistance to any of the four
drugs was 36 percent, and the prevalence of multidrug resistance
was 13 percent. Particularly high prevalences of multidrug
resistance were found in the former Soviet Union, Asia, the
Dominican Republic, and Argentina. The authors conclude that
resistance to antituberculosis drugs exists in all 35 countries
and regions surveyed, and they suggest that it is a global
problem. In an editorial in the same issue of the journal, D.E.
Snider and K.G. Castro (Centers for Disease Control, US) warn
that a greater commitment by the developed countries is needed
"if we are to ward off what could become a global health
disaster."
QY: Ariel Pablos-Mendez, Columbia University (US) 212-854-1754.
QY: Dixie E. Snyder, Centers for Disease Control and Prevention,
Atlanta, GA 30333 US.
(New England J. Med. 4 Jun 98 338:1641,1689)
(Science-Week 26 Jun 98)
-------------------
Related Background:
ON THE PROBLEM OF MULTI-DRUG MICROBIAL RESISTANCE
S. Levy (Tufts University, US) reviews the problem of multi-drug
resistant microbes. Antibiotic resistance, initially a problem in
hospitals and developing countries, today affects the world at
large. Some strains of disease-causing bacteria in the US may now
be untreatable: the vancomycin-resistant enterococcus,
Mycobacterium tuberculosis, Pseudomonas aeruginosa, and
Acinetobacter baumanii. The author proposes 5 principles
underlying the problem: 1) Given sufficient time and drug use,
antibiotic resistance will emerge. 2) Resistance is progressive,
evolving from low levels through intermediate to high levels. 3)
Organisms that are resistant to one drug are likely to become
resistant to others. 4) Once resistance appears, it is likely to
decline slowly, if at all. 5) The use of antibiotics by one
person affects others in the extended as well as immediate
environment.
QY: Stuart B. Levy, Tufts Univ. School of Medicine 617-636-6639
(New England J. Med. 7 May 98 338:1377) (Science-Week 15 May 98)
-------------------
Related Background:
VIRULENCE OF ANTIBIOTIC RESISTANT SALMONELLA
Bjorkman et al (3 authors at 2 installations, SE) report a study
of the virulence of antibiotic resistant Salmonella typhimurium.
During the last decade there has been an alarming increase in the
appearance of antibiotic-resistant bacteria as a result of an
increased use of antibiotics combined with the exceptional
ability of bacteria to develop resistance. One strategy to
reverse this development is to decrease the use of antibiotics to
promote the disappearance of the resistant bacteria present in
human and environmental reservoirs. Implicit in this reasoning is
that mutated resistant bacteria will be less viable in an
antibiotic-free environment. An associated question is whether
resistant bacteria with reduced or no virulence might accumulate
compensating mutations that restore fitness and virulence without
loss of resistance. In this study, the authors examined the
fitness of S. typhimurium in mice, and their results indicate
that most resistant mutants are less virulent than the wild type,
but that the avirulent mutants rapidly accumulate various types
of compensating mutations that restore virulence to wild-type
levels without loss of high-level resistance. The authors suggest
that if their results are general and apply to other medically
relevant pathogens, then the strategy of getting rid of
antibiotic resistant bacteria by a decreased use of antibiotics
may not be successful.
QY: Dan I. Andersson (dan.andersson@smi.ki.se)
(Proc. Natl. Acad. Sci. US 31 Mar 98 95:3949)
(Science-Week 8 May 98)
-------------------
Related Background:
EMERGENCE OF MULTIDRUG-RESISTANT SALMONELLA IN THE US
Strains of salmonella that are resistant to antimicrobial agents
have become a worldwide health problem, with a distinct strain of
Salmonella enterica serotype typhimurium becoming a major cause
of illness in humans and animals in Europe, especially in the UK.
Glynn et al (6 authors at 2 installations, US) report an analysis
of data collected in the US by local and state health departments
and public health laboratories between 1979 and 1996 in national
surveys of the antimicrobial-drug resistance of salmonella. The 5
drugs involved were ampicillin, chloramphenicol, streptomycin,
sulfonamides, and tetracycline. The authors report that the
prevalence of S. typhimurium resistance to the 5 antibiotics
increased from 0.6% in 1979-1980 to 34% in 1996, and they
conclude that multi-drug resistant S. typhimurium has become a
widespread pathogen in the US. The authors suggest that more
prudent use of antimicrobial agents in farm animals and more
effective disease prevention on farms are necessary to reduce the
dissemination of this bacterial mutant and to slow the emergence
of resistance to additional antimicrobial agents in this and
other strains of salmonella.
QY: M. Kathleen Glynn, Centers for Disease Control and
Prevention, Atlanta, GA 30333 US.
(New England J. Med. 7 May 98 338:1333) (Science-Week 8 May 98)
-------------------
Related Background:
ON THE RESISTANCE OF BACTERIA TO ANTIBIOTICS
S. Levy (Tufts University, US), in a review of recent
developments in antibiotic resistance, notes that strains of at
least 3 pathogenic bacterial species -- Enterococcus faecalis,
Mycobacterium tuberculosis, Pseudomonas aeruginosa -- have
already developed resistance to every one of the 100 antibiotic
drugs in use by clinicians. Levy says a change in attitudes of
the public and clinicians concerning the overuse of antibiotics
is badly needed, and that a reversal of increasing bacterial
resistance to antibiotics, as well as increasing resistance of
parasites, fungi, and viruses to antimicrobials and antivirals,
will require a new global awareness of the broad consequences of
anti-pathogen drug usage.
QY: Stuart B. Levy, Tufts Univ. School of Medicine 617-636-6571
(Scientific American March 1998) (Science-Week 20 Feb 98)
-------------------
Related Background:
STUDIES SHOW MARKED INCREASE IN DRUG RESISTANCE OF MICROBES
Widespread use of antibiotics continues to force the evolution of
strains of pathogens resistant to the drugs. For example, the
incidence in the U.S. of microbes resistant to penicillin has
increased fourfold since 1994. At the May 19th International
Conference of the American Lung Association and American Thoracic
Society in San Francisco, researchers from the State University
of New York (Buffalo NY US) and the University of Iowa College of
Medicine (Iowa City IA US) found the increase in resistance of
Streptococcus pneumoniae, a common cause of respiratory
infections, to be dramatic. 10.5% of the samples were highly
resistant to antibiotics and 24.9% moderately resistant. In 1994,
those figures stood at only 3.2% and 14.1%, respectively. In the
Southeastern part of the U.S., 41% of the samples were found to
be resistant. The researchers suggest that the medical community
must be on the watch for rapidly developing epidemics caused by
antibiotic resistant strains of pathogens, and that antibiotics
themselves should be administered only when necessary if we are
to slow down the evolution of these resistant microbes.
(UPI 19 May 97)
-------------------
Related Background:
APPEARANCE OF A STAPHYLOCOCCUS STRAIN RESISTANT TO VANCOMYCIN
Staphylococcus aureus is a common pathogenic bacterium in
hospitals, and causes thousands of often fatal infections each
year. Vancomycin is an antibiotic of last resort, which is used
when all other antibiotics fail. Now the first case has appeared
in Japan of a 4 year old boy infected with a strain of
Staphylococcus aureus resistant to vancomycin. Health experts
tsay it is only a matter of time before the pathogen reaches U.S.
hospitals. Fred Tenover, laboratory chief of the U.S. Center for
Disease Control Hospital Infections Branch says, "The strain is
marching up the ladder of resistance... It is not a cause for
panic, but it is a cause for concern." (UPI 28 May 97)
-------------------
Related Background:
REDUCED ANTIBIOTIC USAGE LOWERS BACTERIAL RESISTANCE
To understand the mechanism of the worldwide increase in
bacterial resistance to antibiotics one need only consider that
for all biological organisms most chemical aspects are more or
less displayed as a Gaussian distribution, the so-called "normal"
or "bell-shaped" curve. What this means in the context of
applying an antibiotic to a population of a particular bacterial
species is that something like 10% or 15% of the population will
show much lower than average resistance to the drug, about 60%
will have close to the average resistance to the drug, and about
10% to 15% will show above average resistance to the drug, all
because of the way the chemistry responsible for resistance to
the drug is distributed in the population. These numbers are
variable from one species of bacteria to another, and they also
vary with the antibiotic used, but the general idea is the same.
The result of all of this is that if we use an antibiotic against
a specific bacterial population, those members of the population
that have superior resistance to the antibiotic will survive to
reproduce their genome, most of the others will be killed, and
before long we will have on our hands populations of that species
which are more or less totally resistant to the antibiotic. This
is nothing more than a concrete instance of the idea of
"selection pressure" in evolution. In 1946 about 90% of
Staphylococcus aureus (a common and dangerous pathogen bacterium)
in hospitals were killed by the antibiotic penicillin, which
first became widely available at about that time. By only 6 years
later, 75% of S. aureus caught and cultured in hospitals were
resistant to penicillin, and by the 1970s, 90% of S. aureus,
whether in hospitals or in the community, were resistant to the
drug. There are similar stories concerning other bacterial
species and other drugs, the worst scenarios evidently occurring
in hospitals; but one cannot fault hospitals, because in both
hospitals and the community antibiotics have been routinely
needlessly administered and/or over-administered, with a
consequent selection pressure that produces antibiotic-resistant
pathogens. Can the process be reversed? There may still be some
hope against bacterial species which are not already over-
whelmingly resistant. This week Helena Seppala et al (about 100
authors in FI) report that in Finland, after an organized
nationwide reduction in the use of macrolide antibiotics
(macrolides are large-ring molecules with many functional side
groups) for outpatient therapy, the resistance of group A
streptococci to the common antibiotic erythromycin dropped by
half from 16.5 per cent in 1992 to 8.5 per cent in 1996. In an
editorial in the New England Journal of Medicine, Morton N.
Swartz (Massachusetts General Hospital, Boston US) calls this "an
impressive example of how an enlightened national policy on
antibiotic use can become an effective public health measure."
QY: H. S. Seppala, Antimicrobial Research Laboratory, PO Box 57,
20521 Turku, FI.
(New England J. Med. 14 Aug 97)
-------------------
Related Background:
NEW MULTI-DRUG RESISTANCE OF PLAGUE PATHOGEN
Plague, also called bubonic plague or "Black Death", is a disease
with a notorious history. It is caused by the bacillus Yersinia
pestis, which infects wild rodents. The bubonic variant of the
disease is transmitted to humans from rodents by the bite of an
infected flea. Human to human transmission occurs by inhalation
of respiratory droplets spread by the cough of patients with
plague who have developed pulmonary lesions, and the result of
this is "primary pneumonic plague", which differs from "bubonic
plague" in that bubonic plague affects the lymph nodes, among
other tissues (producing "buboes", lymph node swellings). The
last plague pandemic began in Hong Kong in 1894 and spread
throughout the world. Plague still exists as an endemic disease
in many parts of the world, including the southwestern U.S.
Prevention of plague is based on rodent control, and the use of
insect repellents to minimize flea bites. Early treatment after
infection with the antibiotics streptomycin, chloramphenicol, or
tetracycline reduces mortality to less than 5%. Nevertheless,
plague is now considered a reemerging disease, with recent
epidemics in a number of countries after an absence of as much as
3 decades. The incidence of the disease has also been spreading
in the U.S. Now Marc Galimand et al (World Health Organization
and the Pasteur Institute, FR) report high-level resistance of Y.
pestis in a clinical isolate in Madagascar to multiple
antibiotics, including resistance to all the drugs recommended
for plague prophylaxis and therapy. The resistant genes are
apparently carried by a plasmid that can conjugate to other Y.
pestis isolates. So this pathogen species, heretofore considered
universally susceptible to antibiotics, is now exhibiting high
and spreadable resistance to these drugs. Epidemiologists are
alarmed and are urging an international effort to deal with the
problem.
QY: Elisabeth Carniel, Institut Pasteur, 28 rue du Dr. Roux,
75724 Paris CEDEX 15, FR.
(New England J. Med. 4 Sep 97)
-------------------
Related Background:
APPARENT IRREVERSIBILITY OF BACTERIAL ANTIBIOTIC RESISTANCE
At a recent meeting of the European Society for Evolutionary
Biology (Arnhem NL), several research groups have apparently
independently confirmed the unhappy news that bacteria that have
mutated to exhibit resistance to specific antibiotics do not
evolve susceptible strains when they are no longer exposed to
these antibiotics. Bruce Levin and Bassam Tomah (Emory Univers-
ity, US) report that 25% of bacteria sampled from infant diapers
are strains of E. coli still resistant to the antibiotic strepto-
mycin, which has been rarely used during the past 30 years.
Richard Lenski (Michigan State University, US) has independently
shown that after 20,000 generations in the absence of strepto-
mycin, E. coli still carries the gene that confers resistance to
the antibiotic. The consensus is apparently that a compensatory
mutation has occurred, a mutation that compensates for the loss
of fitness produced by the gene that confers antibiotic
resistance, and which results in long-term survival of the
resistant strain. Levin suggests the same kind of compensatory
mutations "will almost certainly be found in other resistant
bacteria." The implication is that the evolutionary development
of bacterial resistance to antibiotics will not be reversed by
reducing the use of these antibiotics, which means the effective-
ness of these antibiotics is essentially irreversibly lost.
QY: B. Levin, Emory Univ., Population Genetics (404) 727-5660.
(Science 24 Oct 97)
9. LOW LEVEL ASBESTOS EXPOSURE: DANGEROUS OR NOT DANGEROUS?
Asbestos is a commercially relevant group of strong, ductile, and
fire-resistant mineral fibers. These properties, which differ
among different mineralogic types of asbestos, strongly affect
its in vivo persistence and toxicity. Chrysotile asbestos
constitutes approximately 99 percent of airborne asbestos fibers
in the general environment. Heavy industrial exposure to asbestos
causes lung cancer and mesothelioma (a cancer of one of the
layers of cells lining various body cavities), but it is not
clear whether much lower environmental exposure to asbestos also
causes these cancers. Various regulatory agencies have estimated
the risk of cancer from low asbestos exposure by extrapolating
from the data for high asbestos exposure.
... ... Camus et al (3 authors at 3 installations, CA) tested the
prediction model used by the US Environmental Protection Agency
(EPA), by examining the predicted risk of asbestos-induced lung
cancer in a population of women with relatively high levels of
nonoccupational exposure to asbestos. Mortality among women in 2
chrysotile-asbestos mining areas of the province of Quebec (CA)
was compared with mortality among women in 60 control areas. The
EPA model, applied to the measured asbestos concentrations in the
local air, predicts approximately 75 excess deaths from lung
cancer in the mining-area population. The authors report their
study indicates between 0 and 6.5 excess deaths from lung cancer
in the population (relative risk = 1.0). The authors conclude
they found no measurable excess risk of death due to lung cancer
among women in two chrysotile-asbestos mining regions, and that
the EPA model overestimated the risk of asbestos-induced lung
cancer by at least a factor of 10. In an editorial rebuttal to
this paper, P.J. Landrigan (Mount Sinai School of Medicine New
York, US) makes the following points: 1) All forms of asbestos
are carcinogenic. All have been shown in clinical, epidemiologic,
and laboratory studies to be fully capable of causing lung
cancer, mesothelioma, and the full range of asbestos-related
diseases. All forms appear to be equipotent in the capacity to
cause cancer of the lung. 2) The most plausible explanation of
the low mortality from lung cancer observed in the Camus et al
study is that the women in the mining areas were exposed to an
asbestos aerosol in which many particles were too large to reach
their lungs. Previous studies have indeed established that the
risk of cancer in the mining and milling industry is much lower
than that in the industries that process and use asbestos, such
as textile manufacture and insulation. In mining and milling,
many large asbestos particles are suspended in the air, and they
tend not to reach the pulmonary alveoli as efficiently as small
particles. Thus, air sampling based on light microscopy in the
mining environment produces a spuriously high estimate of true
alveolar exposure. 3) Landrigan says: "Camus et al go beyond
their data when they assert, without qualification, that the
EPA's model overestimates the risk of lung cancer among persons
with nonoccupational exposure to asbestos by at least a factor of
10. The EPA's current regulatory controls embody a level of
caution commensurate with the hazard." 4) Chrysotile-asbestos is
still indisputably a human carcinogen, and this is also true for
Canadian chrysotile. Camus et al did, in fact, find the risk of
lung cancer associated with residence in the asbestos mining
areas to be more than 7 times that in non-mining areas
(standardized mortality ratio = 7.63). Landrigan concludes:
"Assertions that chrysotile can be used without risk in
developing nations are contrary to fact and extremely dangerous."
QY: Michel Camus, Institut Armand-Frappier, 531 Boul. des
Prairies, Laval, QC H7V 4Z3, CA.
QY: Philip J. Landrigan, Mount Sinai School of Medicine, New
York, NY 10029 US.
(New England J. Med. 28 May 98 338:1565,1618)
(Science-Week 26 Jun 98)
10. WETTERHAHN LABORATORY POISONING CASE: FINAL MEDICAL REPORT
In the spring of 1997, the science community, and in particular
the chemistry community, was saddened to learn of the tragic
death of Karen E. Wetterhahn, age 48, a professor of chemistry
(Dartmouth College, US) and a noted researcher on the effects of
heavy metals in biological systems. Wetterhahn died of
dimethylmercury poisoning as the result of the accidental
spillage of a few drops of the chemical on her latex glove-
covered hand. The accident occurred on August 14, 1996, and the
poisoning produced progressive destruction of Wetterhahn's
nervous system, until she finally died 10 months later. Before
she lapsed into a vegetative state, Karen Wetterhahn requested
that her case be presented to the general medical community, to
scientists working with mercury, and to toxicologists, in the
hope of improving the recognition, treatment, and prevention of
future cases of mercury poisoning. The full medical case report
of the illness, death, and autopsy of Karen E. Wetterhahn has now
been published. Nierenberg et al (9 authors at 2 installations,
US), the authors of the report, make the following points: 1)
Dimethylmercury is lethal at a dose of approximately 400 mg of
mercury (equivalent to a few drops, or approximately 5 mg per
kilogram of body weight. It is classified as a "supertoxic"
chemical. 2) Records suggest that Wetterhahn handled dimethyl-
mercury on only one day, while wearing latex gloves and working
under a ventilated hood designed to prevent exposure to chemical
fumes. She had delayed but ultimately fatal neurotoxic effects
similar to those caused by methylmercury compounds, and this case
illustrates the potent toxicity of dimethylmercury and the need
for additional safety precautions if it is to be used in any
scientific research. 2) Five months after the accident, on
January 20, 1997, Wetterhahn was admitted to the university
medical center with a 5 day history of progressive deterioration
in balance, gait, and speech. She had lost 15 lb over a period of
2 months, and had experienced several brief episodes of nausea,
diarrhea, and abdominal discomfort. 3) Wetterhahn recalled that
in August 1996, while transferring liquid dimethylmercury from a
container to a capillary tube, she spilled several drops from the
tip of the pipette onto the back of her gloved hand. She reported
that she had cleaned up the spill and then removed the protective
gloves. (The date of the accident was established from her
notebooks and other laboratory data to be August 14, 1996.) 4) On
February 6th, 22 days after the first neurologic symptoms
developed (and 176 days after exposure), Wetterhahn became
unresponsive to all visual, verbal, and light-touch stimuli. 5)
The authors report they could find only 3 previously reported
cases of poisoning with dimethylmercury, all of which were fatal,
and that equally bleak outcomes had been reported in patients
with severe methylmercury poisoning. In view of the dismal
prognosis, and after more than 3 months of aggressive treatment
and support, Wetterhahn's advance directives were followed, and
she died peacefully on June 8, 1998, 298 days after exposure. 6)
Some anatomical findings from the autopsy report: "The cortex of
the cerebral hemispheres was diffusely thinned, to 3 mm. The
visual cortex around the calcarine fissure was grossly gliotic,
as was the superior surface of the superior temporal gyri. The
cerebellum showed diffuse atrophy of both vermal and hemispheric
folia. Microscopical study showed extensive neuronal loss and
gliosis bilaterally within the primary visual and auditory
cortices, with milder loss of neurons and gliosis in the motor
and sensory cortices. There was widespread loss of cerebellar
granular-cell neurons, Purkinje cells, and basket-cell neurons,
with evidence of loss of parallel fibers in the molecular
layer... An extensive high mercury content was found in the
frontal lobe and visual cortex, liver, and kidney cortex. The
mercury content of the brain was approximately 6 times that of
whole blood at the time of death... 7) The authors conclude:
"Dimethylmercury appears to be so dangerous that scientists
should use less toxic mercury compounds whenever possible. Since
dimethylmercury is a "supertoxic" chemical that can quickly
permeate common latex gloves and form a toxic vapor after a
spill, its synthesis, transportation, and use by scientists
should be kept to a minimum, and it should be handled only with
extreme caution and with the use of rigorous protective
measures."
QY: David W. Nierenberg, Dartmouth-Hitchcock Medical Center,
Hinman Box 7506, Lebanon, NH 03756 US.
(New England J. Med. 4 Jun 98 338:1672)
(Science-Week 26 Jun 98)
-------------------
Related Background:
DEATH OF PROMINENT CHEMIST PROMPTS CALL FOR CHANGE IN NMR METHODS
The international chemistry community was shocked recently by the
death of Karen E. Wetterhahn, age 48, Professor of Chemistry at
Dartmouth College (NH US). Wetterhahn was a well-known authority
on the effects of heavy metals on biological systems. Ten months
ago, in the course of calibrating a nuclear magnetic resonance
(NMR) apparatus with the standard dimethylmercury, Wetterhahn
accidentally spilled a few drops of the substance on her latex-
covered hand. Unexpectedly, the substance penetrated the glove,
and within a few months the first neurological symptoms of
mercury poisoning appeared. She died on June 8th. John Winn, head
of the Dartmouth Chemistry Department, and others, have now
called for the chemical community to establish an NMR standard
safer than dimethylmercury. (Chemical & Engineering News 16 Jun
97) (Science-Week 26 Jun 97)
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