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ScienceWeek
SCIENCE-WEEK
A Weekly Email Digest of the News of Science
A journal devoted to the improvement of communication
between the scientific disciplines, and between scientists,
science educators, and science policy-makers.
August 24, 2001 -- Vol. 5 Number 34
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The full area of ignorance is not mapped: we are
at present only exploring its fringes.
-- J.D. Bernal (1901-1971)
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Section 1
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Contents of this Issue (Full reports in Section 2):
1. Transcription Factors and Cell Signaling
2. The Hemophilias
3. Brain Imaging of Migraine Auras
4. On RNA Polymerase
5. Internet Misinformation About Illegal Drugs
6. Neurological Basis of Awareness of Space
7. Synthesis of Organofluorine Compounds
8. Electrons and Phonons in Superconductivity
9. Cosmic Molecular Hydrogen
10. Apparent End of World Population Growth
11. Design of Synthetic Iron Reservoirs
12. Communication Between Non-Contacting Macromolecules
13. In Focus: On Isaac Newton
14. SW Archive: Is US Health Care Really the Best in the World?
15. Sources
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Section 2
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1. TRANSCRIPTION FACTORS AND CELL SIGNALING
"Transcription" is the process by which the genetic information
in DNA is converted into RNA, and transcription factors are a
class of DNA-binding proteins that regulate RNA transcription.
In this context, a "growth factor" is any specific substance
that must be present in a culture medium for multiplication of
the cultured cells to occur. Certain growth factors have been
identified as cytokine proteins (peptide hormones) that stimulate
the growth and division of target cells by binding to cell
membrane receptors.
G-proteins are a family of signal-coupling proteins that act
as intermediaries between activated cell receptors and effectors,
for example, the transduction of hormonal signals from the cell
surface to the cell interior. The G-protein is apparently
embedded in the cell membrane with parts exposed on the outside
surface and inside surface. The outside moiety is activated by
the first messenger, and the inside moiety activates the second
messenger, the G-protein thus acting as a trans-membrane signal
transducer.
... ... Lewis C. Cantley (Harvard University, US) discusses
transcription factors in intracellular signaling pathways. Once
receptors in the plasma membrane of cells become activated
through binding with their ligands (e.g., hormones or growth
factors), the binding initiates a cascade of signals that are
transmitted to the nucleus of the cell where they switch on the
expression of specific genes ("target genes"). In many of these
signal transduction pathways, there is a key transcription factor
ordinarily "trapped" in the cell cytoplasm that becomes modified
as a consequence of the activation of the hormone or growth
factor receptor. The modified transcription factor is then free
to escape from the cytoplasm and enter the cell nucleus, where it
activates target genes. The signaling events that lead from
receptor activation of the cell surface to the release of the
transcription factor into the nucleus are still poorly understood
for certain families of transcription factors. Santagata et al
(2001) now present evidence for a new signaling pathway in which
the apparent transcription factor "tubby" is released from its
association with plasma membrane phosphtidylinositol and moves to
the cell nucleus. A defective version of tubby has been
implicated in mature-onset obesity. Tubby is apparently clipped
from the plasma membrane by the enzyme phospholipase C-beta,
which hydrolyzes phosphatidylinositol lipids following activation
of G-protein coupled hormone receptors.
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SCI 2001 292:2019,2041
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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2. THE HEMOPHILIAS
The clotting of blood involves several enzymes and molecules
known as coagulation (clotting) factors. Most of these factors
are synthesized in the liver and released into blood plasma.
Clotting is a complex process in which coagulation factors
activate each other. Once the process is initiated, there occurs
a cascade of reactions that acts in a positive feedback manner to
form a large quantity of product. There are 12 clotting factors,
denoted by Roman numerals, with no factor VI. Factors VIII and IX
are known as antihemophilic factors. Factor VIII concentrates are
made by culling the factor from plasma of a very large number of
donors, and between 1982 and 1985 most such factor VIII
preparations were contaminated with HIV, the virus that causes
AIDS, and most hemophiliacs who used the products at that time
became infected with AIDS.
... ... P.M. Mannucci and E.G. Tuddenham (University of Milan,
IT) discuss the medical biology of the hemophilias. Of the
various types of hemophilia, the most common are due to an
inherited deficiency of factor VIII or factor IX. The genes for
these blood coagulation factors lie on the X chromosome, and when
mutated, they cause the X-linked recessive traits hemophilia A
and B. Since these disorders are X-linked, they usually occur in
males. The infected boy usually has inherited the mutant gene
from his carrier mother, but approximately 30 percent of cases
arise from a spontaneous mutation, and in such instances there is
no family history of hemophilia. The incidence of hemophilia A is
1 in 5000 male live births, and that of hemophilia B 1 in 30,000.
In contrast, a deficiency or dysfunction of the adhesive
glycoprotein "von Willebrand factor" causes the most frequent
bleeding disorder (von Willebrand's disease), which may affect 1
in 1000 cases. Hemophilia is well known for its effect on the
royal houses of Europe. Queen Victoria, a clinically normal
carrier of the defective gene, had one son (Leopold) who had
hemophilia, and two daughters (Alice and Beatrice) who were
carriers, and who in turn transmitted the disease to the Russian,
Prussian, and Spanish royal families. Since the two X-linked
hemophilias are clinically indistinguishable and none of the
descendants of Queen Victoria who were known to be affected are
now alive (the last one, Waldemar, died in 1945), we may never
known which type of hemophilia they had. Victoria's great-great
granddaughter Olympia, from the Spanish branch, had a son (Paul
Alexander) who died in childhood of a "blood" disorder, and she
may therefore be the last surviving carrier of the defective
gene.
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NEJM 2001 344:1773
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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3. BRAIN IMAGING OF MIGRAINE AURAS
The term "migraine" refers to an attack of a unilateral severe
headache with pulsating, throbbing pain, often coupled with
nausea and vomiting. Estimates of the prevalence of people
experiencing more than occasional migraine in the US range from
12 million to 24 million. The syndrome is 3 times more common in
women than in men, and is believed to involve the
neurotransmitter serotonin (5-hydroxytryptamine). A migraine
attack is often associated with an "aura" that may precede the
attack by more than an hour or may be concurrent with the attack.
The aura is a transient neurologic visual, somatosensory, motor,
or language deficit, with most persons reporting visual auras
that include flashing lights and scintillating zigzag shapes.
The term "cortical spreading depression" refers to a
decrease of electrical activity in the cerebral cortex that
begins in one region and slowly spreads throughout the entire
cortex. The phenomenon was first observed in the cerebral cortex
of mammals in the 1950s.
Functional magnetic resonance imaging (fMRI) is a technique
based on the fact that oxyhemoglobin, the oxygen-carrying form of
hemoglobin, has a different magnetic resonance signal than
deoxyhemoglobin, the oxygen-depleted form of hemoglobin.
Activated brain areas utilize more oxygen, which transiently
decreases the levels of oxyhemoglobin and increases the levels of
deoxyhemoglobin, and within seconds the brain microvasculature
responds to the local change by increasing the flow of
oxygen-rich blood into the active area. This local response thus
leads to an increase in the oxyhemoglobin- deoxyhemoglobin ratio,
which forms the basis for the fMRI signal in this technique.
Because of its high spatial resolution (millimeters) and high
temporal resolution (seconds) compared to other imaging
techniques, fMRI is now the technology of choice for studies of
the functional architecture of the human brain.
... ... N. Hadjikhani et al (Harvard University, US) report on
mechanisms of migraine aura revealed by functional magnetic
resonance imaging in human visual cortex. Cortical spreading
depression has been suggested to underlie migraine visual auras.
Using functional MRI with near-continuous recording during visual
auras in 3 subjects, the authors observed blood oxygenation
level-dependent signal changes that show at least eight
characteristics of cortical spreading depression time-locked to
percept/onset of the aura. The authors suggest their results
strongly indicate that an electrophysiological event such as
cortical spreading depression generates the aura in human visual
cortex.
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PNAS 2001 98:4687
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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4. ON RNA POLYMERASE
The central event in the process by which genetic information in
DNA is converted into RNA (transcription) is the RNA-polymerase-
catalyzed conversion of the sequence code of the template strand
of a gene into a complementary RNA transcript. RNA polymerases
are found in all living cells, with one type found in prokaryotes
(cells without a cell nucleus and other membrane-bound
organelles), and 3 types of RNA polymerase found in eukaryotes
(cells with a cell nucleus).
... ... Aaron Klug (Medical Research Council, UK) discusses RNA
polymerase II (RNA polymerase b). This multi-subunit enzyme is
the central enzyme of gene expression in eukaryotes. It reads the
sequence of one strand of the DNA double helix (the "template
strand"), and in so doing synthesizes messenger RNA, which is
then translated into protein. RNA polymerase II of yeast has 10
subunits and a molecular weight of 0.4 megadaltons. Recent
crystallography by P. Cramer et al (2001) reveals the enzyme in
two states: an open form and a partly closed form. These forms
differ mainly in the position of a massive 50-kilodalton region
of the enzyme called the "clamp", which is thought to close over
the DNA molecule as it enters the enzyme. A group of protein
loops at the base of the clamp appears to act as a set of pivots
for DNA movement. As anticipated from electron microscopy and
cross-linking experiments, the DNA-RNA hybrid is bound in the
cleft between the two large subunits, but makes a right-angle
bend at the active center. The moving DNA-RNA hybrid, as it were,
comes to a "wall" and then runs up against it, so that the
nucleic acids exit the enzyme from its top and back. The
synthesized RNA strand spun off by the enzyme runs through a
groove and exits under the region called the "lid".
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SCI 2001 292:1844,1863,1876
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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Related Background:
ON THE ORGANIZATION OF REPLICATION AND TRANSCRIPTION
In the study of living organisms, the term "replication" refers
in general to the duplication of the organism and in particular
to the duplication of the genome of the organism, a genome that
except in certain viruses consists of DNA. In the particular
sense, therefore, replication refers to duplication of the DNA
molecule. The term "transcription" refers to the process by which
genetic information in DNA is converted into RNA, i.e., the
production of an RNA molecule from a DNA molecule template. Both
processes, replication and transcription, involve the activity of
specific polymerization catalysts (enzymes) called "polymerases".
DNA polymerases catalyze the formation of DNA polymers, either
from DNA templates, or in certain special viruses, from RNA
templates; and RNA polymerases catalyze the formation of RNA
polymers from DNA templates. One general question that
immediately arises is whether these polymerases are mobile or
fixed: in other words, does the polymerase track along the
template, or is the polymerase relatively fixed and the template
pulled into the polymerase entity for the reading of the
sequence? ... ... Peter R. Cook (University of Oxford, UK)
presents an extensive review of current research concerning the
organization of replication and transcription, the author making
the following points:
1) Models for replication and transcription often display
polymerases that track like locomotives along their DNA
templates. However, recent evidence supports an alternative model
in which DNA and RNA polymerases are immobilized by attachment to
larger structures, where they reel in their templates and extrude
newly made nucleic acids. These polymerases apparently do not act
independently, but they are concentrated in discrete "factories",
where they work together on many different templates.
2) The evidence for DNA polymerases being fixed is indirect
and of four general types: a) theoretical evidence suggests how
attached DNA polymerases might be coordinately controlled; b)
some activities are immobilized during reactions in vitro; c)
active DNA polymerases and nascent DNA resist detachment from the
cell substructure; d) newly made DNA is concentrated in discrete
foci, implying that the polymerases are not free to track. The
same evidence supports the idea that active polymerases are
grouped together. As a result, many researchers now accept that
DNA polymerases are fixed in factories which are assembled and
disassembled during various phases of the *cell cycle.
3) The idea that RNA polymerases are fixed is less widely
accepted, but the evidence is of the same four types listed
above, and the author suggests that RNA polymerases are also
fixed.
4) The author suggests that life forms concentrate molecules
so that those molecules can react together, and that by
extension, it might be expected that the polymerases responsible
for the vital processes of replication and transcription would be
concentrated within the cell in specific locations.
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SCI 1999 284:1790
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Text Notes:
... ... *cell cycle: The term "cell cycle" refers to the ordered
sequence of phases through which a cell passes from one mitotic
(i.e., replicating) cell division to the next.
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Related Background:
EVIDENCE FOR A FACTORY MODEL OF DNA REPLICATION
For all organisms, the production of viable progeny depends on
the faithful replication of DNA by the enzyme DNA polymerase,
which incorporates nucleoside triphosphates into a DNA chain.
This enzyme is actually a multi-enzyme complex that takes
different forms in *prokaryotes and *eukaryotes. Two general
models have been proposed for DNA replication. In one model, DNA
polymerase moves along the template DNA (like a train on a
track); in the other model, the polymerase is stationary (like a
factory), and the template DNA is pulled through.
... ... K.P. Lemon and A.D. Grossman present the results of a
study to distinguish between the two models. The authors report
they visualized DNA polymerase of the bacterium *Bacillus
subtilis in living cells by the creation of a *fusion protein
containing the DNA polymerase catalytic subunit (PolC) and green
fluorescent protein (GFP). The authors report the PolC-GFP entity
was found localized at discrete intracellular positions,
predominantly at or near mid-cell, rather than being distributed
randomly. The authors propose their results suggest that the
polymerase is anchored in place, thus supporting the model in
which the DNA template moves through polymerase.
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SCI 1998 282:1516
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Text Notes:
... ... *prokaryotes: In general, cells without a cell nucleus
and other membrane-bound organelles.
... ... *eukaryotes: In general, cells with a cell nucleus and
other membrane-bound organelles.
... ... *Bacillus subtilis: The genus Bacillus is a group of
free-living rod-shaped bacteria, some species of which produce
antibiotics. The genome of B. subtilis has been completely
sequenced.
... ... *fusion protein: In this context, a "fusion protein" is a
protein that results from the fusion of two genes. The essential
idea here is the fusion of the gene for DNA polymerase with the
gene for the green fluorescent protein, so that when and where
the new DNA polymerase-fluorescent protein is expressed it can be
located by its fluorescent moiety.
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SCIENCE-WEEK http://scienceweek.com 25Dec98
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Related Background:
MOLECULAR BIOLOGY: AN INTEGRATED TRANSCRIPTION COMPLEX MODEL
In molecular biology, transcription is the process by which
genetic information in DNA is converted into RNA. The central
event in transcription is the *RNA-polymerase-catalyzed
conversion of the sequence code of the template strand of a gene
into a complementary RNA transcript. This RNA may in turn be
translated into a protein, or the RNA may instead serve a
structural or regulatory role, or the RNA may form the genome of
an *RNA virus. Formation of an RNA transcript has traditionally
been divided into 3 sequential stages, called *initiation,
*elongation, and *termination, and all are subject to regulatory
control. ... ... In a review of transcription, Peter H. von
Hippel (University of Oregon, US) presents what is termed "an
integrated model of the transcription complex", and the author
makes the following points: 1) Recent findings now allow the
development of an integrated model of the thermodynamic, kinetic,
and structural properties of the transcription complex in the
elongation, termination, and editing phases of transcript
formation. 2) Concerning the 3 traditional sequential stages, it
may now be more appropriate to divide the overall process into
two major phases: a) activation and transcript initiation, and b)
transcript elongation, with the latter including termination
(transcript release) and editing (transcript shortening and
resynthesis with increased fidelity. 3) The author suggests the
new model provides an operational framework for placing known
facts and can be extended and modified to incorporate new
advances. 4) The most complete information about transcriptional
mechanisms and their control continues to come from the bacterium
Escherichia coli system, upon which most of the explicit
descriptions in the author's model are based. The transcription
machinery of higher organisms, despite its greater inherent
complexity, appears to use many of the same general principles,
and thus the lessons of E. coli continue to be relevant. In
conclusion, the author points out the following problems in
current research in this area: 1) We do not yet know the
molecular structure of any multi-subunit RNA polymerase. 2) We do
not know the exact path taken through the polymerase by the DNA
and RNA framework of the transcription complex. 3) We do not know
how various *transcription factors change the rates of movement
or the stability properties of the transcription complex. 3) We
do not know how these changes are further modulated by the local
sequences of the template and non-template DNA and the nascent
transcript.
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(SCI 1998 281:660) (SW 28 Aug 98)
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Related Background:
... ... *RNA polymerase: RNA polymerase is an enzyme that
polymerizes ribonucleoside triphosphates into RNA in the order
dictated by a DNA or RNA template. RNA polymerases are found in
all living cells, with one type found in prokaryotes (cells
without a cell nucleus and other membrane-bound organelles), and
3 types found in eukaryotes (cells with a cell nucleus).
... ... *RNA virus: Viruses either have an RNA genome or a DNA
genome, with the respective nucleic acid core single stranded or
double stranded, depending on the viral species. In general, RNA
viruses are subdivided into 3 types, depending on the details of
the virus-host cell viral replication process.
... ... *initiation: In this context, this is the stage that
begins when RNA polymerase binds to the double-stranded DNA
molecule and incorporates the first nucleotide(s).
... ... *elongation: In this context, the phase during which the
RNA polymerase moves along the DNA template and extends the
growing RNA chain by adding one nucleotide at a time.
... ... *termination: In this context, the stage in which RNA
synthesis ends and the RNA polymerase complex disassembles from
the transcription unit.
... ... *transcription factors: Regulatory proteins that
determine the efficiency with which RNA polymerases bind to DNA
promoter regions during transcription. A "promoter" is a type of
control element, approximately 100 bases long, found in the
genome associated with various genes.
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SCIENCE-WEEK http://scienceweek.com 28Aug99
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Related Background:
STRUCTURAL ANALYSIS OF DNA-POLYMERASE ACTIVITY
DNA polymerases, of which there are several types, are enzymes
that specifically assemble deoxyribonucleoside triphosphates (DNA
nucleotides) into DNA strands in the order dictated by a temp-
late. In addition to the template, a fragment of RNA or DNA must
be annealed to the template as a primer, the catalyzed polymer
synthesis then consisting of additions to one end of that primer.
A critical aspect of DNA polymerase activity is that the template
is copied with high fidelity, but the precise mechanism by which
nucleotides are in sequence correctly incorporated in the copy is
not yet known.
... ... Kiefer et al (4 authors at 2 installations, US) report
high resolution crystal structures (1.8 angstroms) of a
thermostable bacterial (Bacillus stearothermophilus) DNA
polymerase (type I) fragment, the fragment bound with DNA primer
templates at the active polymerase site, and the complex
retaining catalytic activity and allowing direct observation of
the products of several rounds of nucleotide incorporation. The
polymerase also retains its ability to discriminate between
correctly and incorrectly paired nucleotides in the crystal. The
authors suggest their procedure makes possible snapshots of
successive polymerase complexes, and that the structures provide
the most detailed view of any polymerase DNA complexes yet
determined.
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(NAT 15 Jan 98) (SW 30 Jan 98)
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Related Background:
MECHANISM OF RNA POLYMERASE NUCLEOSOME TRANSCRIPTION
... RNA polymerase type III is specific to transfer RNA (tRNA)
and ribosomal RNA (rRNA). Transfer RNA is a class of small RNA
molecules that transfer individual amino acids to a growing
polypeptide chain during protein synthesis, and ribosomal RNA is
a class of RNA molecules that have an important role in the
structure of ribosomes, the large molecular entities that carry
out protein synthesis in all cells. All the RNA polymerases are
large and complex molecules with molecular weights of
approximately 500,000 daltons. Nucleosomes are higher order
structures of eukaryotic chromosomal DNA, the structures composed
of coils of the DNA double helix around a complex of 8 small
basic proteins called histones. Studitsky et al (4 authors at 2
installations, US) report that the large yeast RNA polymerase III
transcribes through a single nucleosome, with direct internal
nucleosome transfer in which histones never leave the DNA
template. The authors suggest their results show that a
eukaryotic polymerase is capable of transcribing through a
nucleosome without displacing it from the template, and that this
ability may reflect a property of importance for the
transcription process in vivo.
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Gary Felsenfeld, National Institutes of Health, US
(SCI 12 Dec 97) (SW 2 Jan 98)
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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5. INTERNET MISINFORMATION ABOUT ILLEGAL DRUGS
Ecstasy (3,4-methylenedioxymethamphetamine; MMDA) is one of the
most widespread illegal psychoactive drugs in the US,
particularly among teenagers and young adults. The drug is a
"designer drug", combining the effects of amphetamines and
lysergic acid diethylamide (LSD). In high doses, Ecstasy
depletes brain monoamine neurotransmitters, with a serotonin
depletion that may last for months and which appears due to
degeneration of serotonin axon terminals. One of the common
effects of the drug is a trance-like state in which religious
ideation and complete surrender occupy almost the entire field
of consciousness. Otherwise, the effect is primarily a
heightened sense of self-awareness and euphoria that may be
extreme. The drug has been called a "recreational drug", and it
has also been advocated as an adjunct to psychotherapy. But as a
psychoactive drug, Ecstasy is quite dangerous, a common
"date-rape" drug, and a cause of many deaths due to overdosage
or extreme side-effects in certain individuals, including acute
renal failure, convulsions, and spontaneous intracerebral
hemorrhage.
E.W. Boyer et al (Harvard University, US) discuss websites
offering misinformation about illicit drugs, such as Ecstasy and
gamma-hydroxybutyric acid. Such "partisan" websites are easily
identified by common search engines if one uses the names of
illegal substances as search terms. With some web pages viewed
more than 160,000 times per day, partisan sites are apparently
effective in reaching adolescents and young adults. In a recent
study, 24 percent of college students used the Internet to obtain
information on illicit substances, and 27 percent of Internet-
using college students reported that Internet use increased the
likelihood that they would use drugs. The authors tabulate
information about the following websites (and others):
a) www.erowid.org: Describes the illicit use of over 200
substances in over 4000 pages, is visited more than 160,000 times
per day, and describes detailed protocols for the use of illicit
substances.
b) www.dancesafe.org: Promotes "non-abstentionist" drug-
related health and safety information. Offers to test pills to
identify those that do not contain Ecstasy.
c) www.ecstasy.org: Contains a question and answer section
with replies from "experts", some of whom are physicians.
The authors state that every partisan website visited made
"potentially harmful recommendations for the management of the
adverse effects of illicit drugs." The authors point out that the
output and traffic of partisan websites far exceed the output and
traffic of anti-drug government websites.
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NEJM 2001 345:469
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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Related Background:
OXYCONTIN NOW A STREET NARCOTIC
The psychological effects of opium may have been known to
the ancient Sumerians of 5000 years ago, but the first undisputed
reference to poppy juice occurs in the writings of Theophrastus
in the 3rd century BC. The word "opium" is apparently derived
from the Greek word for "juice", and the drug is derived from the
juice of the poppy plant, Papaver somniferam. By the 17th century
AD, opium was well-established as a medicinal and narcotic.
Opium contains more than 20 distinct alkaloids, with pure
morphine first isolated in 1806. Codeine was discovered in 1832,
papaverine in 1848, and by the middle of the 19th century, pure
alkaloids rather than crude opium were in widespread use as
medicinals.
In the US, opioid abuse was common as a consequence of the
unrestricted availability of opium until the early years of the
20th century, and apparently also as a consequence of the influx
of opium-smoking immigrants from Asia (who had originally been
introduced to opium by Europeans).
The term "opiates" refers to drugs derived from opium, and
includes morphine, codeine, and a wide variety of semisynthetic
congeners derived from these substances and from thebaine,
another component of opium. The term "opioid" is more inclusive,
referring to all drugs with morphine-like activity, as well as to
naturally occurring and synthetic opioid peptides. The term
"endorphin" is a generic term referring to the three families of
endogenous opioid peptides: the enkephalins, the dynorphins, and
the beta-endorphins.
The term "narcotic" is derived from the Greek word for
"stupor", and at one time referred to any drug that induced
sleep. The word gradually came to be used for strong opiate
analgesics, and now the term "narcotic" is used in a legal
context to refer to a wide variety of abused substances, many of
which are not opioids. This report concerns the marketed drug
OxyContin, the brand name (sold by Purdue Pharma) of a form of
oxycodone hydrochloride (dihydrohydroxycodeinone), which is most
definitely an opioid. Oxycodone is also widely used in
combination with aspirin in the form of Percodan or in
combination with acetaminophen in the form of Percocet. Another
form is Roxicodone. Purdue Pharma's OxyContin is therefore not
the only marketed drug containing oxycodone.
Various opioids are widely used in the US for the treatment
of moderate to severe pain, and although all such drugs are
considered to be "controlled substances", the degree of "control"
apparently varies according to who is writing prescriptions.
The central nervous system actions of oxycodone are
qualitatively similar to those of morphine, with the most
prominent actions involving the central nervous system and organs
composed of smooth muscles. Oxycodone is similar to codeine and
methadone in that it retains at least half of its analgesic
activity when administered orally. Oral potency of oxycodone is
high: 50 milligrams of oxycodone administered orally is
equivalent to 10 milligrams of intramuscularly administered
morphine. Oxycodone tablets come in 20, 40, and 80 milligram
forms. Oxycodone is known to have the capacity to produce
morphine-type drug dependence: repeated use characteristically
produces tolerance for the drug, physical dependence, and strong
craving for higher concentrations. An addiction to oxycodone, in
fact, is not much different than a heroin addiction. "Heroin",
which is the opium derivative diacetylmorphine, is manufactured
outside the US and smuggled into the US for sale and
distribution. Oxycodone, which is another opium derivative, is
manufactured, sold, and distributed inside the US with no
smuggling necessary.
In a recent article, Paul Tough points out that these days
the only street narcotic for sale in many small US towns is
OxyContin, the tablets of which users crush to disable its
patented time-release mechanism, the powder then snorted or
injected for a powerful and immediate opiate high. Legally,
OxyContin is sold only by prescription for the treatment of
chronic pain, but in practice the drug is immediately available
everywhere for cash in small towns in the US. The going rate for
OxyContin is apparently one dollar a milligram, or $40 for a 40-
milligram pill. Oxycodone is the only active ingredient of
OxyContin, and the "oxy buzz", as it is called, is produced by
the opiate composition.
Paul Tough points out that until very recently, OxyContin
abuse was considered a regional problem, labeled "hillbilly
heroin", and confined to areas far from US population centers.
However, this year abuse of OxyContin has apparently started to
move away from its backwoods origins and into metropolitan areas
on the East Coast, into the Deep South and parts of the
Southwest, and into suburban communities throughout the Eastern
US. In Miami-Dade county, there have been 11 overdose deaths so
far this year in which oxycodone was the probable cause,
according to the county medical examiner. There have been 11 more
overdose deaths in Philadelphia, according to the medical
examiner there. Police in the Connecticut city of Bridgeport
recently arrested a local doctor for prescribing tens of
thousands of OxyContin tablets to patients, apparently often
without any medical examination at all. Police in Boston say that
more than a dozen suburban pharmacies have been held up by a gang
of young men looking for OxyContin.
Purdue Pharma has recently announced plans to modify the
time-release mechanism in OxyContin tablets to make the mechanism
secure even with tablet-crushing, but the modification is
expected not to be in place for at least 3 years. Meanwhile,
government statistics indicate that as of 1999, 221,000 people in
the US have abused OxyContin, which apparently is currently
prescribed to 1 million patients, with revenues in the year 2000
to Purdue Pharma from this drug at $1.14 billion. In the year
2000, physicians in the US wrote more than 6.5 million
prescriptions for OxyContin, making the drug the 18th best-
selling prescription drug in the US (as measured by retail sales)
and the No. 1 opioid painkiller.
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Paul Tough: NYT 2001 29 July
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PRAXIS 13 Aug 01 http://www.scienceweek.com/praxis/
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Related Background:
MOLECULAR AND CELLULAR BASIS OF DRUG ADDICTION
There is a paradigm well known to all neurobiologists, but not so
well known, or not known at all, to others. The paradigm goes
like this: 1) All human behavior results from activity of the
human nervous system. 2) The activity of the human nervous system
is highly dependent upon its chemistry. 3) The introduction of
exogenous chemicals into the human nervous system can cause an
alteration of its activity, a disruption of its activity, or a
complete and chaotic breakdown of its activity, the entire
spectrum ranging from reversible or irreversible minor mood
alterations to extreme and violent psychotic states. Truly, most
"psychoactive" drugs, as they are called, are the equivalent of
the proverbial monkey wrench tossed blindly into the innards of a
working machine. Thus drug addiction is a chronic and pervasive
social problem, an acute personal psychiatric problem, and a
biological scientific problem of considerable urgency. Eric J.
Nestler and George K. Aghajanian (Yale University, US), reviewing
current research on the cell biology of drug addiction, emphasize
that drug addiction is the result of adaptations in specific
brain neurons, that research must focus on the cellular types of
adaptations, and that further research must identify the specific
genes that contribute to individual differences in vulnerability
to addiction.
-----------
E. Nestler: SCI 1997 3 Oct
SW 1997 24 Oct
-------------------
Related Background:
DRUG ADDICTION AND THE GLUTAMATE NEUROTRANSMITTER
Dopamine is an important neurotransmitter in the human brain, and
it has been implicated in several serious behavioral pathologies.
There is a dopamine hypothesis of depression, a dopamine
hypothesis of schizophrenia, and dopamine has also been
implicated in the reinforcing effects of psychostimulant drugs of
abuse such as cocaine and amphetamine. Another neurotransmitter,
glutamate, is a major excitatory amino acid neurotransmitter
accounting for an estimated 40 percent of all nerve signals in
the human brain, and involved in phenomena such as neural
development, learning, and memory formation. Glutamate is
ordinarily released under close cellular biochemical control and
reuptake, and in excess amounts it is an intense excitant of
nerve cells and potentially toxic. Glutamate is suspected as an
important contributor to the pathogenesis of a number of
neurodegenerative disorders, including amyotrophic lateral
sclerosis and parkinsonian dementia. The glutamate receptor is
the molecular site that mediates the actions of glutamate
neurotransmitters, and this receptor has been a focus of
intensive research and has been differentiated into N-methyl D-
aspartate (NMDA), kainate, and quisqualate subtypes. Neurons that
release glutamate are called "glutamatergic", and they have been
located in many important areas of the human brain. Until the
past few years, the study of the neurobiological basis of drug
addiction has focused on dopamine, but there is apparent growing
interest in the involvement of glutamate as a key
neurotransmitter. This was the focus of a recent meeting (May
3-5, 1998) at the US National Institutes of Health in Rockville,
Maryland (US), at which evidence was presented that blockade of
glutamate transmission prevents behavioral sensitization in rats
to repeated doses of amphetamine or cocaine. Behavioral
sensitization, also called "reverse tolerance", is the
development of increased sensitivity to the effects of drugs such
as pyschostimulants, and its occurrence in animals is considered
a prime model for human drug abuse. The idea that glutamate
biochemistry and neurophysiology may play a key role in human
drug addiction is apparently exciting many researchers in the
field.
-----------
Ingrid Wickelgren: SCI 1998 280:2045
SW 17 Jul 98
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PRAXIS 13 Aug 01 http://www.scienceweek.com/praxis/
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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6. NEUROLOGICAL BASIS OF AWARENESS OF SPACE
H-O. Karnath et al (University of Tubingen, NL) discuss human
brain localization for spatial awareness. The current
understanding of spatial behavior as dependent on parietal lobe
function is largely based on the belief that "spatial neglect" in
humans (a lack of awareness of space on the side of the body
contralateral to a brain injury) is typically associated with
lesions of the posterior parietal lobe. However, in monkeys, this
disorder is observed after lesions of the superior temporal
cortex, a puzzling discrepancy between the species. The authors
report that contrary to the widely accepted view, the superior
temporal cortex is the neural substrate of spatial neglect in
humans, as it is in monkeys. But unlike in the monkey brain,
spatial awareness in humans is a function largely confined to the
right superior temporal cortex, a location topographically
reminiscent of that for language on the left. Thus, the decisive
phylogenetic transition from monkey to human brain seems to be a
restriction of a formerly bilateral function to the right side,
rather than a shift from the temporal to the parietal lobe. The
authors suggest the speculation that this lateralization of
spatial awareness parallels the emergence of an elaborate
representation for language on the left side.
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NAT 2001 411:950
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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Related Background:
NEUROBIOLOGY: ON LOCALIZATION OF FUNCTION IN THE HUMAN BRAIN
For more than 200 years, neurobiologists have been concerned
with the general problem of what is called "localization of
function" in the human brain. That there is considerable
localization of function is indisputable: there are brain regions
involved with specific primary inputs such as vision, audition,
taste, etc., brain regions for specific primary outputs to
various muscle systems, and brain regions for speech and the
understanding of language. The still unclear aspects concern
anatomical localization of other so-called "higher faculties",
e.g., learning, memory, perceptual analysis, motivations, various
other cognitive abilities, etc.
Classical studies of localization of function in the human
brain essentially began with Franz Joseph Gall (1758-1828), who
postulated that the shape of the human brain, especially its
convolutions, was related to "mental capacity", and that
different parts of the brain were involved with different parts
of the human body. This latter proposal concerning the relation
between different parts of the brain and different parts of the
body was essentially a correct view. But Gall also believed he
could correlate the shape of the human brain with various
emotional and temperamental qualities, and that the shape of the
brain, particularly its convolutions, could be deduced from the
irregularities existing in the topology of the overlying skull.
Thus began the 19th century pseudoscience of "phrenology", a
quackery that postulated that various human character traits
could be identified by literally feeling bumps on the head. The
public adored the idea, and so-called "phrenologists" continued
to bamboozle the public long after Gall was dead. What started as
a useful view that correlated brain anatomy with function, ended
in a popular pseudoscience that still had the public confused and
misled 100 years later.
The next most important figure in this field was Pierre Paul
Broca (1824-1880), a neurosurgeon who in 1861 discovered the
motor area of the brain responsible for speech, and who studied a
series of patients with traumatic injuries in this area. As a
result of Broca's work, the idea that at least certain brain
functions are localized was put on a firm scientific footing, and
a long history of research by clinical neurologists attempting to
correlate traumatic brain injury to loss of specific brain
function began. Beginning in the 1950s, evidence from localized
electrophysiological studies was added to the data resulting from
studies of traumatic brain injury, and in the 1990s an entirely
new set of data from functional magnetic resonance imaging of
the human brain in action became available to researchers
studying localization of brain function. This field is now
intensely active and of signal importance in neurology and
cognitive science. But the human brain is profoundly complex, and
there are still more questions than answers about how things get
done in this 1400-gram mass of tissue that makes us what we are.
The term "cortex" (cerebral cortex), in this context, refers
to the thin surface layering of nerve cells of the brain, the
region only several millimeters thick but covering all of the
brain surface. This is the part of the central nervous system
most intimately involved with the so-called "higher faculties",
although the cortex generally operates in concert with other
parts of the brain. The structure is primitive in lower mammals,
and is found progressively more pronounced and with greater
surface area in primates and man. Many contemporary
neurobiologists who study the brain emphasize precise "mapping"
of the cerebral cortex into "areas" associated with specific
functions.
... ... Jonathan C. Horton (University of California San
Francisco, US) presents an essay on localization of function in
the human brain, the author making the following points:
1) Given the limitations of histology, researchers often
designate areas in brain cortex by topography. For example, any
region that contains its own representation of the visual world
qualifies for "area" status. Unfortunately, topographic order in
other than primary visual areas ("higher" visual areas) is often
too crude to provide a reliable definition of boundaries. Another
limitation is that topography may not be meaningful outside
sensory and motor cortices. The author asks: "What constitutes
topography in regions concerned with language, motivation, or
personality?"
2) The author points out that relentless experimental
efforts and a battery of technical advances have provided us with
better maps of the brain. But much of the cortex stubbornly
refuses to be mapped, and the author suggests it is worth
questioning the assumption that the cerebral cortex consists of a
finite number of areas with sharp borders. An alternative is that
only certain regions -- mostly motor and sensory cortex -- are
organized in this way. Other regions might be diffuse fields
separated by gradual transitions in function, properties, and
connections. As Broca said in 1861: "Although I believe in the
principle of localization, I have asked and still ask myself
within what limits this principle can be applied." The author
(Horton) concludes: "For brain cartographers, the last frontier
is in their heads."
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NAT 2000 406:565
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SCIENCE-WEEK http://scienceweek.com 1Sep00
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7. SYNTHESIS OF ORGANOFLUORINE COMPOUNDS
A.G. Myers et al (Harvard University, US) discuss the synthesis
of organofluorine compounds. The identification of potassium
fluoroacetate as the toxic principle of the South African plant
Dichapetalum cymosum in 1943 by J.S. Marais is often regarded as
an important early discovery that directed attention to the
potential of fluorine substitution to profoundly influence the
biological activity of organic molecules. Fried and Sabo (1954)
reported the synthesis of 9alpha-fluorohydrocortisone acetate and
showed that it exhibited glucocorticoid activity 11 times greater
than that of the corresponding hydrocarbon (cortisol acetate).
The enhanced activity has been attributed to the lower pK(sub-
alpha) of the 11beta-hydroxyl group and its increased ability to
donate a hydrogen bond, as well as its increased resistance to
metabolic inactivation by oxidation. Fried's discovery led to the
development of at least six commercial antiinflammatory agents.
More importantly, his demonstration of the extraordinary
potential of fluorine substitution to alter and enhance the
pharmacological properties of organic molecules became the basis
of a powerful strategy for synthetic drug development in the
pharmaceutical industry.
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JACS 2001 123:7207
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8. ELECTRONS AND SUPERCONDUCTIVITY
Philip B. Allen (State University of New York Stony Brook, US)
discusses the basis of high-temperature superconductivity. Copper
oxides are still by a factor of 3 the highest-temperature
superconductors known. Superconductivity requires the binding of
electrons in pairs, but the binding force in these
"unconventional" materials remains unknown. Following the
discovery of superconductivity in 1911, the mechanism of
superconductivity remained a mystery for almost half a century.
Then, in 1957, the Bardeen, Cooper, and Schrieffer (BCS) theory
introduced a new form of quantum coherence into physics, one
involving a quantum "pair field" or "pair wavefunction"
representing an attractive interaction between electrons.
Normally, electrons are considered to repel each other because
they carry the same charge sign. So how, in a superconducting
state, do electrons attract each other and pair up? Bardeen,
Cooper, and Schrieffer, building on earlier theories and
experiments, identified the source of the attraction as an
"indirect" interaction in which one electron alters a vibration
of the material lattice (the alteration considered as a "phonon")
and the other electron feels the alteration. The interaction
causing conventional superconductivity is thus the electron-
phonon interaction. The interaction mechanism of high-temperature
("unconventional") superconductors remains unknown.
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NAT 2001 412:494
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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Related Background:
SUPERCONDUCTIVITY: ON 50 YEARS OF THEORY
The current general theory of superconductivity is based on
several ideas:
1) The interaction between particles involves the exchange
of energy quanta.
2) The interaction between electrons in a material can under
certain conditions produce an effective "coupling" between
electrons, and when this occurs, the material may exhibit
superconductivity -- the flow of electrons without resistance.
3) The interaction and effective coupling between electrons
in a material can take various forms, involving various types of
energy quanta, depending on the material and on conditions, and
thus producing the various types of superconductivity.
In this context, a "heavy-fermion" system is one in which
electrons acquire very large effective masses, often hundreds of
times that of a free electron [*Note #1].
... ... Piers Coleman (Rutgers University, US) presents a
commentary on current research in superconductivity, the author
making the following points concerning the history of theory in
this field:
1) In the late 1950s, John Bardeen (1908-1991), Leon N.
Cooper, and John R. Schrieffer demonstrated that
superconductivity involves the formation of bound pairs of
electrons, called "Cooper pairs". Their theory (BCS theory)
argued that the electron pairs were "glued together" by small
deformations (phonons) in the crystal lattice, the deformations
accompanying the motions of electrons. But although phonons had
been implicated in superconductivity many years before BCS
theory, it was not until the 1960s that it became possible to
definitively identify phonons as the "glue" (the interaction
energy quanta) in conventional superconductivity.
2) In the early 1960s, G. Eliashberg demonstrated that the
electron-pairing forces created by phonons could be incorporated
into BCS theory using a set of equations that now bear his name.
It turns out that the exchange of phonons between the electrons
in a Cooper pair produces tiny harmonics in the energy
distributions of the electrons, and these harmonics can be
detected experimentally. In the late 1960s, W.L. McMillan and
J.M. Rowell experimentally confirmed the long-suspected role of
phonons in conventional superconductors, and demonstrated that
the Eliashberg refinement of BCS theory was accurate to
approximately 1 percent.
3) The 1970s and 1980s led to the discovery of
superconductivity in two new unconventional classes of materials,
the heavy-fermion and high-temperature superconductors.
Conventional superconductivity is suppressed by the tiniest
concentration of magnetic atoms, but the unconventional
superconductors contain a dense array of magnetic atoms, which
appear to be actively involved in electron pairing. This has led
physicists to consider a new kind of magnetically mediated
superconductivity in which the quanta that glue electrons into
pairs are derived from magnetic fluctuations. In many kinds of
unconventional superconductors, it appears that the glue that
binds electrons together exists only as a fleeting entity, rather
than as a well-defined excitation.
-----------
NAT 2001 410:320)
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Text Notes:
... ... *Note #1: Fermions (electrons, protons, neutrons) are
particles that obey the Pauli exclusion principle: i.e., no two
fermions of the same kind can occupy the same quantum state.
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SCIENCE-WEEK http://scienceweek.com 29Jun01
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Related Background:
ON THE DISCOVERY OF HIGH TEMPERATURE SUPERCONDUCTIVITY
One of the operating tenets of 20th century "big science" is that
important breakthroughs in science can be more or less engineered
if appropriate conditions are constructed and appropriate
individual researchers placed in those conditions. When this
approach produces a success, the various bureaucrats who support
the idea feel reaffirmed; when various counter-examples to the
approach occur, it is the turn of the doubters to feel
reaffirmed. A cogent instance of a counter-example was provided
in 1986 by the Bednorz-Mueller discovery of high-temperature
superconductivity -- a discovery of signal importance in
experimental physics made by two relatively unknown researchers
working in what can be characterized as a backwater and poorly-
equipped laboratory. Not only was the discovery of high-
temperature superconductivity totally unexpected by the
international physics community, but the discovery of the
phenomenon by outsiders under "little science" conditions caused
a degree of shock in the science policy system. Ordinary
superconductivity is a property of many metals, alloys, and
chemical compounds at temperatures near absolute zero, at which
temperatures (their "critical temperatures") their electrical
resistivity vanishes and they become strongly diamagnetic.
(Diamagnetic substances such as the alkalis and alkaline earth
metals, the halogens, and the noble gases are repelled by magnets
and tend to position themselves at right angles to the magnetic
lines of force.) High-temperature superconductors were unknown
until 1986, but at present there are some known high-temperature
superconductors with critical temperatures greater than 100
kelvins. The accepted theory of ordinary superconductivity
is the Bardeen-Cooper-Schrieffer theory (BCS theory) (1957). At
the present time, a successful theory of high-temperature
superconductivity has not been developed, in spite of a great
deal of effort. Johannes Georg Bednorz (1950- ) and K. Alexander
Mueller (1927- ) shared the Nobel Prize in Physics in 1987 for
their discovery of high-temperature superconductivity in a
ceramic oxide (lanthanum-barium-copper) alloy at 30 kelvins, at
that time the highest superconductivity temperature
ever observed, the work having been carried out at the IBM Zurich
Research Laboratories at Rueschlikon.
... ... Helga Nowotny (Swiss Federal Institute of Technology, CH)
presents an essay on innovation in research and the modern
partnership between basic research and applied science, the
author making the following points:
1) One of the most exciting recent success stories of
science began in September 1986 with the appearance in the
_Zeitschrift fur Physik_ of an article with the cautious title,
"Possible high-T(subc) superconductivity in the Ba-La-Cu-O
system." A few weeks later, the names of the two authors,
Alexander Mueller and Georg Bednorz, and their discovery hit the
front pages of _The New York Times_ and researchers around the
world were caught in an unprecedented frenzy, attempting to
replicate and surpass the findings of the initial breakthrough.
The race for high-temperature superconducting systems was on.
2) The discovery of high-temperature superconductivity was
unexpected in terms of its discoverers, the place of its
discovery, and the scientific ideas involved. It contradicted
conventional wisdom and the expectations of peers and research
administrators. Mueller and Bednorz were outsiders, Mueller a
specialist on perovskites (a type of oxide mineral) and Bednorz a
crystallographer. They benefitted from the novice effect, but
they also enjoyed a degree of autonomy that allowed them to
prepare for the unpredictable. Of the 3 superconductivity
laboratories of IBM, the Rueschlikon laboratory where the two
researchers were based was by far the most modestly equipped. And
the discovery contradicted long-held views, not only overturning
certain established empirical rules concerning superconductivity,
but also unveiling previously unknown phenomena not accounted for
by the classic Bardeen-Cooper-Schrieffer theory.
3) The author points out that even if we knew how to create
conditions under which creativity can flourish, and how to favor
the occurrence of what cannot be planned, the problem remains of
how to turn highly individualistic bursts of scientific
creativity into socially desired techno-scientific outcomes. "For
the most disturbing paradox is this: there has been a relative
decline in the importance of the individual creative act, while
its proliferation is encouraged. Individual scientific creativity
has become a necessary, but no longer sufficient, precondition in
a long, branching sequence of possibilities."
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NAT 1999 401:859
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SCIENCE-WEEK http://scienceweek.com 3Dec99
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9. COSMIC MOLECULAR HYDROGEN
William Klemperer (Harvard University, US) discusses molecular
hydrogen as a cosmic entity. Molecular hydrogen, H(sub2), is the
most abundant chemical species in the Universe. Although it also
the simplest molecule, its electronic states frequently exhibit
surprising complexity, and evidence is emerging that this
complexity may play a key role in astronomical processes
involving molecular hydrogen, with important implications for
cosmic chemical evolution. Atomic hydrogen (H), whose hyperfine
transition at 1420 megahertz initiated atomic and molecular
radioastronomy, pervades the diffuse gaseous matter in galaxies,
but in dense interstellar regions, including the centers of
galaxies, hydrogen is molecular. Unfortunately, the terrestrially
accessible absorption spectrum of molecular hydrogen is weak:
molecular hydrogen can only be observed from the surface of the
Earth if it forms a strongly heated gas, in which case its
vibrational emission is readily observed. Electronic spectra of
molecular hydrogen can be observed by extraterrestrial
observatories. The characteristic features of the electronic
states of molecular hydrogen and its optical response are seem
most prominently in illuminated regions such as diffuse
interstellar clouds or in photon-dominated regions near bright
stars.
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SCI 2001 293:815
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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Related Background:
NO EVIDENCE OF NEARBY GALACTIC OR INTERGALACTIC HYDROGEN RESERVES
Neutral hydrogen gas is the material from which galaxies and
stars are made, and its distribution is therefore of interest.
Also, neutral hydrogen may contribute to the so-called inter-
stellar "dark matter", the existence or non-existence of which
remains one of the fundamental unresolved problems of modern
astronomy, since dark matter has been proposed as the
explanation, among other things, for the calculated masses of
galaxies from gravitation theory being 10 to 100 times the masses
apparent from their luminosities. Since it has been suggested by
a number of astronomers that large reservoirs of neutral hydrogen
are hidden in dark intergalactic clouds or in dim galaxies,
surveys of interstellar neutral hydrogen are of some importance
in this context. Now Martin Zwaan and Ertu Sorar (University of
Groningen, NL; University of Pittsburgh, US) report that an
analysis of data from the 300-meter Arecibo radio telescope in
Puerto Rico, which can detect neutral hydrogen out to 200 million
light years, indicates there is no significant neutral hydrogen
beyond that already known to be associated with known sources --
no significant neutral hydrogen in dark clouds and none in so-
called "low-surface-brightness" or dim galaxies. Assuming the
local universe is not atypical, it will now be difficult to
propose neutral hydrogen as a candidate for a significant
contribution to dark matter, or to propose that protogalactic
"mists" still exist in our vicinity.
-----------
E. Sorar: SCI 29 August 1997)
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SCIENCE-WEEK 12 Sep 1997 http://scienceweek.com
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10. APPARENT END OF WORLD POPULATION GROWTH
W. Lutz et al (International Institute for Applied Systems
Analysis, AT) discuss world population growth. There has been
enormous concern about the consequences of human population
growth for the environment and for social and economic
development. But this growth is likely to come to an end in the
foreseeable future. Improving on earlier methods of probabilistic
forecasting, the authors demonstrate that there is approximately
an 85 percent chance that the world's population will stop
growing before the end of the century. There is a 60 percent
probability the world's population will not exceed 10 billion
people before 2100, and approximately a 15 percent probability
that the world's population at the end of the century will be
lower than it is today. For different regions, the date and size
of the peak population will vary considerably. There is
approximately a 75 percent chance that the peak population of the
European portion of the former USSR has already been reached in
2000, an 88 percent probability that it will be reached by 2025,
and over a 95 percent chance by the end of the century. For the
China region, the probability of reaching a peak within the next
two decades is still low owing to its relatively young age
structure. By 2040, the probability becomes greater than half. In
sub-Saharan Africa, despite the prevalence of HIV, there is a low
probability of peaking before the middle of the century.
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NAT 2001 412:543
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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Related Background:
ON THE PEAKING OF WORLD POPULATION GROWTH
In theory, the growth of a biological population is a geometrical
progression. If the resources necessary for maintaining
organismic viability are infinite, the population growth curve
will be exponential. On the other hand, if vital resources are
limited, growth will follow a sigmoid curve ("S-curve"). Since
limited resources is the usual parameter for real biological
populations, it is the sigmoid curve which is the norm. The early
part of the sigmoid curve, however, the so-called "J" section, is
essentially exponential in character, and if an examined
population is in this phase of its growth, it is often difficult
to determine where the upper bend to a sigmoid shape will occur.
In 1798, the economist Thomas Robert Malthus (1766-1834)
published anonymously his _Essay on Population_, in which he
maintained that since human population growth is a geometric
progression, and any increase in food supply perforce an
arithmetic progression, human population would always outrun the
food supply, and the various known population limiters such as
famine, disease, and war were therefore essential for the
survival of the species. This, of course, created a furor, and in
the second edition of his work in 1803, Malthus suggested that
the moral restraints of delayed marriage and sexual abstinence
might counter the increase in population. Thus did the adjective
"Malthusian" enter the language of social and political
discourse. No matter the validity of the analysis of Malthus, his
idea sparked heated debates throughout the next two centuries,
debates that in one form or another continue today. One major
characteristic of all of these debates has been the lack of
knowledge about when the "J" section of the curve will turn to
form the "S-curve".
... ... Vaclav Smil (University of Manitoba, CA) presents an
essay on the human population growth rate, the author making the
following points:
1) Some time in the first half of the 17th century, after
thousands of years of stagnation or very slow annual growth
amounting to a small fraction of 1 percent, the global population
passed through the "J-bend" of the exponential growth curve and
began its still unfinished ascent.
2) During the late 1960s, the relative rate of global
population growth peaked at just over 2 percent per year, the
rate then falling to approximately 1.7 percent by 1990. In the
early 1990s, the natural increase of the global population fell
below 1.5 percent.
3) As with other species, the exponential growth of humanity
will end and the other bend of the growth curve will form,
creating an S-shaped curve -- but neither the onset of the S-bend
nor the eventual maximum population count can be predicted with
great certainty. The author suggests it is highly probable that
we are already beyond the mid-point of the S-curve, and that the
current global total of 6 billion may not double again. The high
variant of the latest (1998) long-range forecast by the United
Nations has the global population growing to no more than 10.7
billion by the year 2050, while the low-growth scenario forecasts
only 7.3 billion people by that year.
4) The medium forecast of the United Nations of a world
population of 8.9 billion by 2050 is based on the assumption that
by the year 2050 total fertilities will be almost universally no
higher than the replacement ratio of 2.1 children per woman,
compared to the current global mean of approximately 2.7. But
this assumption of a reduction in replacement ratio may be wrong,
given that some countries (e.g., Ethiopia and Nigeria) still have
replacement ratios as high as 6 to 7 children per woman.
5) The author concludes: "The world population may, after
all, undergo one more doubling to 12 billion. Even so, we may be
seeing the beginning of the end of the growth of our species.
Children born today may be thinking about their retirement at a
time when the global population count will have stabilized -- or
even begun to decline."
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NAT 1999 401:429
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SW 12 Nov 99
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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11. DESIGN OF SYNTHETIC IRON RESERVOIRS
Y. Hara and M. Akiyama (Tokyo University of Agriculture and
Technology, JP) discuss the chemistry of iron reservoirs in
biological systems. Iron is an essential element for almost all
living organisms, but its availability is limited due to the
formation of insoluble ferric oxide polymers. In response,
organisms have developed efficient systems for iron capture,
storage, and release. In mammals, iron is absorbed from digested
food and carried by transferrin to various locations for
utilization or to ferritin for storage. Microorganisms use
siderophores (low-molecular weight chelating compounds) to
sequester iron from the environment, and siderophore-iron
complexes are transported into cells, where the iron is released.
Description of biological iron transport and storage processes
requires knowledge of iron mobilization by ligand-metal exchange.
In this respect, the design and synthesis of artificial
iron(III)-storing compounds and evaluation of their iron-binding
properties would lead to a better understanding of the intricate
processes of biological iron mobilization. The authors report the
development of a synthetic iron-reservoir model based on
ferrichrome, with a detailed experimental analysis of iron-
chelating properties.
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JACS 2001 123:7247
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SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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Related Background:
MARINE ORGANISMS: ACQUISITION AND USE OF TRANSITION METAL IONS
Metalloproteins comprise a third to a half of all known proteins.
Metals function in catalysis, play structural roles, and activate
biochemical processes. Many essential life processes, including
photosynthesis, respiration, and nitrogen fixation, involve
multi-electron transformations, and the essential steps in all of
these processes are catalyzed by metalloenzymes that contain iron
and other transition metal ions that can exist in multiple
oxidation states.... ... Alison Butler (University of California
Santa Barbara, US) reviews some of the mechanisms by which marine
organisms acquire iron and use other essential metal ions, and
the author makes the following points: 1) Molybdenum is the most
abundant transition metal ion in surface seawater at a
concentration of 100 nM, followed by vanadium at 20 to 35 nM. In
contrast, iron levels in surface seawater are extremely low: 0.02
to 1 nM. 2) Despite its relative scarcity, iron is essential to
marine organisms, and iron levels represent one of the key
limitations in marine ecosystems. 3) Relatively little is known
about marine bioinorganic chemistry, but recent studies are
beginning to unravel some of the mysteries. 4) Marine
microorganisms acquire iron through novel *siderophores, new
siderophore-mediated processes, and other processes. However, in
times of severe iron stress, phytoplankton substitute flavodoxin
for ferrodoxin, replacing the iron-sulfur cluster with an organic
cofactor. The carbonic anhydrases of *diatoms, which have no
homology to other known carbonic anhydrases, are particularly apt
to substitute Co for Zn in the active site, and some even contain
Cd. 5) Iron is arguably the most important transition metal in
the ocean, precisely because of its relatively low abundance. 6)
In addition to phytoplankton, *heterotrophic marine bacteria have
been shown to be limited by the low level of iron in the ocean.
7) In seawater, many of the first-row transition metal ions are
partially or fully complexed by as yet undefined organic ligands.
8) In contrast to the deficit of iron in surface seawater,
vanadium is abundant, and the bioorganic chemistry of vanadium is
diverse. Most marine *tunicates acquire vanadium in large
quantities, but the functional significance of the sequestered
vanadium has eluded researchers since its discovery in seawater
near the turn of the century. The author suggests that detailed
studies into the bioinorganic chemistry of transition metal ions,
together with increased knowledge of the concentration and
speciation of these ions in the oceans, are necessary for a
complete picture of global element cycles involving both
terrestrial and oceanic components.
QY: Alison Butler, Univ. of California Santa Barbara 805-893-8000
(SCI 1998 281:207)
-------------------
Related Background:
... ... *siderophores: Molecular receptors that bind and
transport iron.
... ... *diatoms: Also called bacillariophytes. Microscopic
unicellular eukaryotic algae; differentiated into approximately
10,000 different species.
... ... *heterotrophic: (syn: organotrophic) Refers to organisms
dependent on external sources of organic compounds as a means of
obtaining energy and/or materials.
... ... *tunicates: Also called urochordates. Subphylum of the
chordates, comprising sea squirts and similar forms.
-----------
SCIENCE-WEEK 31 Jul 1998 http://scienceweek.com
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12. COMMUNICATION BETWEEN NON-CONTACTING MACROMOLECULES
J. Voelker et al (State University of New Jersey Rutgers, US)
report a quantitative experimental demonstration of solvent-
mediated communication between noncontacting polymers. The
authors show that changes in the activity of a solvent component
caused by a conformational change in one biopolymer can result in
changes in the physical properties of a second noncontacting
biopolymer present in solution. Specifically, the release of
protons on denaturation of a donor polymer (a 4-stranded DNA
tetraplex) modulates the melting temperature of a non-contacting
accepting polymer (polyadenylate). In addition to such cross-
talk, the authors also demonstrate counter-ion mediated cross-
talk between non-contacting biopolymers. The authors demonstrate
that such "through-solvent" dialogue between biopolymers that do
not directly interact can be used to evaluate association-
dissociation reactions of solvent components (e.g., protons,
sodium ions) with one of the two biopolymers. The authors propose
that such through-solution dialogue is a general property of all
biopolymers, and that as a result, such solvent-mediated cross
talk should be considered when assessing when assessing reactions
of multicomponent systems such as those that exist in essentially
all biological processes.
-----------
PNAS: 2001 98:7694
-----------
SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
-------------------
Related Background:
ON WATER AND THE STRUCTURES OF BIOLOGICAL MOLECULES
A prominent consideration in the minds of biologists who work at
the level of cells and molecules is that water is the most
prevalent chemical substance in all biological systems, and that
interactions of water with other biological molecules,
particularly with biological macromolecules, are not clearly
understood but are probably of considerable significance.
... ... M. Gerstein and M. Levitt present a review of some
aspects of the physical chemistry of water and an account of
their own computer simulations of biological macromolecules in
aqueous solutions. The authors make the following points: 1) At
the present time it is possible to model proteins and their
associated water molecules on a desktop computer in a few days.
Researchers have now simulated the aqueous structures of more
than 50 proteins and nucleic acids. 2) A single water molecule
has an essentially tetrahedral geometry, with an oxygen atom at
the center of the tetrahedron, hydrogen atoms at 2 of the 4
corners, and clouds of negative charges at the other 2 corners.
Reflecting the tetrahedral geometry of water, each molecule in
liquid water often forms 4 hydrogen bonds: 2 hydrogen bonds
between its hydrogens and the oxygen atoms of 2 other water
molecules, and 2 hydrogen bonds between its oxygen atom and the
hydrogens of other water molecules. The necessity of maintaining
a tetrahedral hydrogen-bonded structure gives water an "open"
loosely packed structure compared with that of most other liquids
[*Note #1]. 3) Present computer simulations are able to reproduce
quantitatively many of the bulk properties of water, such as its
average structure, rate of diffusion, and *heat of vaporization.
4) Biological molecules such as proteins and DNA contain both
hydrophilic and hydrophobic parts arranged in long chains. The 3-
dimensional structures of these molecules are determined by the
way these chains fold into more compact arrangements in which
hydrophilic groups are on the surface where they can interact
with water and hydrophobic groups are buried in the interior away
from water. These local macromolecule solubility considerations
were formulated in 1959 by Walter Kauzman as a "hydrophobic
effect" crucial for protein folding. 4) There are 3 types of
water molecules that must be considered in a computer model of a
biological molecule in aqueous solution: a) the ordered water
surrounding and strongly interacting with the macromolecule; b)
the bulk water beyond the ordered water; and, c) any water
molecules that may be buried within the macromolecule. 5)
Computer simulations of DNA in water have revealed that water
molecules are able to interact with nearly every part of the
double helix of DNA, including the nucleotide base pairs that
constitute the genetic code. In contrast, water is not able to
penetrate deeply into the structure of proteins, whose
hydrophobic regions are arranged on the inside into a close-
fitting core [*Note #2].
-----------
SA 1998 November
-----------
Text Notes:
... ... *Note #1: In hydrated crystal structures, water molecules
generally donate two hydrogen bonds but may accept either one or
two. When water molecules are 3-coordinated (rather than 4-
coordinated as discussed by the authors in their review), the
geometry can be planar or pyramidal. But examples are known of
coordination as low as 2 and as large as 7.
... ... *heat of vaporization: The quantity of energy required to
evaporate 1 mole (or a unit mass) of a liquid at constant
pressure and temperature.
... ... *Note #2: Concerning the interaction of water molecules
with biological molecules, water molecules hydrogen-bonded to the
functional groups of biological molecules are apparently linked
in chains into extended networks, and some researchers have
suggested the *polarizability of these networks provides a
mechanism for long-range recognition between biological molecules
in aqueous solution.
... ... *polarizability: The electric dipole moment induced in a
system (such as an atom or molecule) by an electric field of unit
strength.
-------------------
SCIENCE-WEEK http://scienceweek.com 13Nov98
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13. IN FOCUS: ON ISAAC NEWTON (1642-1727)
"In October 1669, on the retirement of Barrow, [Newton] was
elected Lucasian Professor of Mathematics, a post he held for 26
years. One of the Professor's duties was to 'lecture and expound'
some mathematical discipline of his choice at least once each
week at a prearranged time during the seven months of the
Cambridge academic year... He carried out his minimal lecturing
duties, but, as his secretary Humphrey Newton (no relation)
records many years later: 'So few went to hear him, and fewer
that understood him, that ofttimes he did in a manner, for want
of hearers, read to the walls... he usually stayed about half an
hour; when he had no auditors, he commonly returned in a 4th part
of that time or less.' Humphrey also provides some engaging
personal details: 'His carriage then was very meek, sedate, and
humble... I cannot say I ever saw him laugh but once... I never
knew him to take any recreation or pastime either in riding out
to take the air, walking, bowling, or any other exercise
whatever, thinking all hours lost that was were not spent in his
studies... He very rarely went to dine in the Hall, except on
some public days, and as if he has not been minded, would go very
carelessly, with shoes down at the heels, stockings untied,
surplice on, and his head scarcely combed.' This, however, is not
the whole story. Newton had a circle of personal friends and did
a certain amount of academic entertaining. Humphrey tells us
that, 'when invited to a treat, he used to return it very
handsomely, freely and with much satisfaction to himself.' His
niece, Catherine Conduitt, relates how one of his cronies -- a
lecturer in chemistry -- fell from favor. 'He told a loose story
about a nun, and then Sir Isaac left off all confidence with
him.'"
-----------
Stuart Hollingdale: _Makers of Mathematics_
(Viking Press, New York 1989, p.171)
http://www.amazon.com/exec/obidos/ASIN/0140227326/scienceweek
-----------
SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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14. FROM THE SW ARCHIVE:
IS US HEALTH CARE REALLY THE BEST IN THE WORLD?
In general, the health of a population is "public health", and
public health is for the most part a consequence of both culture
and national policy. The US is one of the major developed
countries on the planet, with what is probably the most developed
scientific enterprise, but is this intense scientific effort
correlated with a comparable high level of health care for the US
population? For the most part, the answer is apparently no.
... ... Barbara Starfield (Johns Hopkins University, US) presents
a commentary on current assessments of US health care, the author
making the following points:
Information concerning deficiencies of US medical care has
been accumulating, although the high cost of the US health care
is apparently tolerated under the assumption that better health
results from more expensive care. The facts are as follows:
1) More than 40 million people in the US have no health
insurance.
2) 20% to 30% of patients in the US receive contraindicated
care.
3) An estimated 44,000 to 98,000 people in the US die each
year as a result of medical errors.
4) According to several studies, the US population does not
have anywhere near the best health in the world. Of 13 countries
in a recent comparison, the US ranks an average of 12th (second
from the bottom) for 16 available health indicators. Countries in
order of average ranking on the health indicators (with first as
best) are Japan, Sweden, Canada, France, Australia, Spain,
Finland, the Netherlands, the UK, Denmark, Belgium, the US, and
Germany. On separate indicators, the rankings of the US are as
follows:
... ... Low birth-weight percentages: 13th (last in ranking)
... ... Neonatal mortality and infant mortality overall: 13th
... ... Postneonatal mortality: 11th
... ... Life expectancy at 1 year for females: 11th
... ... Life expectancy at 1 year for males: 12th
... ... Life expectancy at 15 years: females 10th; males 12th
... ... Life expectancy at 40 years: females 10th; males 9th
... ... Life expectancy at 65 years: females 7th; males 7th
... ... Life expectancy at 80 years: females 3rd; males 3rd
... ... Age-adjusted mortality: 10th
5) The poor performance of the US was recently confirmed by
the World Health Organization, which used different indicators,
the WHO report ranking the US as 15th among 25 industrialized
countries. Although common explanations for the poor performance
of the US in these rankings blame the "bad behavior" of Americans
(e.g., smoking, drinking, violence, etc.), the data comparing
such behavior to the behavior of the people in other countries
indicates otherwise. Concerning the long-existing poor ranking of
the US with regard to infant mortality, this low-ranking is not
the result of the high percentages of low birth-weight and infant
mortality among the US black population, since the international
ranking hardly changes when data for the white population only
are used.
6) The US health care system may contribute to poor health
through its adverse effects. For example, US estimates of the
combined effect of errors and adverse effects that occur because
of *iatrogenic damage include:
... ... 12,000 deaths per year from unnecessary surgery.
... ... 7000 deaths per year from medication errors in hospitals.
... ... 20,000 deaths per year from other errors in hospitals.
... ... 80,000 deaths per year from *nosocomial infections in
hospitals.
... ... 106,000 deaths per year from non-error adverse effects of
medications.
These total to 225,000 deaths per year from iatrogenic
causes, so that iatrogenic cause is the 3rd leading cause of
death in the US, after deaths from heart disease and cancer.
7) The author concludes: "Recognition of the harmful effects
of health care interventions, and the likely possibility that
they account for a substantial proportion of the excess deaths in
the US compared with other comparably industrialized nations,
sheds new light on imperatives for research and health policy.
Alternative explanations for these realities deserve intensive
exploration."
-----------
JAMA 2000 284:483
-----------
Text Notes:
... ... *iatrogenic: In general, this denotes any result produced
by surgery or other treatment. In this context, and in the usual
usage, the term is used for a result that is unwanted and
injurious to the patient (e.g., an infection due to contaminated
surgical instruments).
... ... *nosocomial infections: In general, a nosocomial
infection is any infection acquired by a patient as a result of
entrance into a hospital. It is estimated that some 15 to 20
percent of all hospital workers carry the bacterial pathogen
Staphylococcus aureus on the skin of their hands, and that 60 to
70 percent of all hospital workers carry S. aureus in their
nostrils.
-----------
SW 2000 4 August
-----------
SCIENCE-WEEK 24 Aug 2001 http://scienceweek.com
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15. SOURCES:
AGP: Archives of General Psychiatry
APL: Applied Physics Letters
AS: American Scientist
CEN: Chemical & Engineering News
GD: Genes & Development
GR: Genome Research
ICAR: Icarus
JAAD: Journal of the American Academy of Dermatology
JACS Journal of the American Chemical Society
JAMA: Journal of the American Medical Association
JCE: Journal of Chemical Education
NAT: Nature
NEJM: New England Journal of Medicine
NYT: New York Times
PNAS: Proceedings of the National Academy of Sciences
PRL: Physical Review Letters
PT: Physics Today
SA: Scientific American
SCI: Science
SK: Skeptic
SW: ScienceWeek
TB: The Biochemist
TS: The Scientist
In the text, the affiliation following the author's name is the
affiliation of the lead author. The indication (na) signifies no
known research affiliation.
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