·
1700BC
Earliest evidence of diagnostic medicine
in
·
180 In his
Methodus Medendo,
Greek physician Galen devises a system of
medicine that will influence medical thinking for over a thousand years
·
980-1037 Avicenna writes The Canons of Medicine,
becomes principal European medical text until 1650
·
1493–1541 Swiss
physician Philippus Aureolus
Paracelsus rejects the prevalent
medical belief of his time that physical illnesses are caused by an imbalance
of the body's four "humors" (melancholic, choleric, sanguine, and
phlegmatic). He proposes instead that the body is weakened by external
conditions and toxic agents, and may be treated with a number of chemical
remedies. Although influenced by contemporary mysticism and the occult,
Paracelsus' medical observations lay the foundation
for modern diagnostic methods.
·
1618 William Harvey describes the circulation
of the blood
·
1659 The syringe is developed in
·
1778 Franz Mesmer
uses hypnotism.
·
1796 Smallpox vaccination using cowpox is
developed by Dr. Edward Jenner
·
1842 Crawford Long uses first anesthetic
(ether). 1846 W. T. Morton uses ether as anesthetic
·
1861 Louis Pasteur's theory of germs proposed. 1885 Pasteur develops a vaccine for rabies. He also develops pasteurization, the heat treatment of
food to prevent contamination by bacteria, and vaccines for cattle, sheep, and
chicken.
·
1865 Joseph Lister begins antiseptic surgery
·
1865 Claude Bernard's classic on scientific
method, An Introduction to the Study of Experimental Medicine, is published. Bernard's first
important work was on the functions of the pancreas gland. A second
investigation - perhaps his most famous was on the glycogenic function of the
liver; in the course of this he was led to the conclusion, which throws light
on the causation of diabetes mellitus. Milieu intérieur,
internal environment, was the original concept of Bernard that led to the
concept of homeostasis.
·
1882 In
·
1895 Wilhelm Roentgen discovers x-rays.
Already in 1896 several hospitals had x-ray facilities, and x-ray photographs
were ruled as acceptable evidence in courts in
·
1899 Aspirin
is first marketed
·
1900 Sigmund Freud’s The Interpretation of Dreams. 1917 Freud’s Introduction to Psychoanalysis.
·
Walter Cannon, professor of physiology at Harvard, first described the concept of homeostasis. 1915 Cannon describes the “fight or flight” response of the
sympathetic nervous system. 1932 He publishes an account of his
theory of homeostasis in The Wisdom of
the Body. He also developed the barium swallow (Upper GI X-ray series).
·
1918
Worldwide influenza epidemic strikes; by 1920, nearly 20 million are dead. In
·
1921 Dr. Frederick Banting, with Charles Best and J.J.R. Macleod, isolated insulin
·
1927
Herman Blumgart, a
·
1928 Penicillin, 1st antibiotic. Dr.
Alexander Fleming notices mold inhibits Staph aureus from growing, mold identified as Penicillium,
later extracts penicillin
·
1944 Kidney dialysis is invented in the
·
1954 Dr. Jonas Salk develops the polio vaccine
·
1954 The
first successful human organ transplant:
Drs. Joseph Murray and J. Hartwell Harrison transplanted a kidney to a patient
from his twin brother.
·
1960 The
first heart pacemaker is made in the
·
1963 Michael E. De Bakey
implants artificial heart in
human for first time at
·
1967 Dr. Christiaan Barnard performs the first successful heart transplant in
·
1977
Scientists at Genentech (Boyer and Swanson) report
using genetically-engineered bacteria containing human insulin gene to produce
insulin. Later the first recombinant
human insulin (Humulin) is sold by Eli Lilly
(insulin was previously made from bovine pancreatic extracts)
·
1977 The
Magnetic Resonance Imaging (MRI)
scanner is developed by Raymond Damadian
·
1978 Birth
of the first child conceived by in vitro
fertilization (
·
1980
Smallpox is declared eradicated
·
1981 AIDS
(Acquired Immunodeficiency Syndrome) is first described. 1983 HIV virus is identified. 1987
AZT, the first HIV antiviral is developed.
·
1982 First
artificial heart implanted at the
University of Utah Medical Center
Clinical Trials
·
Clinical trials (synonyms: clinical studies, research protocol)
evaluate new drugs, medical devices, or other interventions (e.g. procedures)
on patients in strictly scientifically controlled settings
·
Trials may be designed to assess the safety and efficacy
of an experimental therapy, to assess whether the new intervention is better
than standard therapy, or to compare the efficacy of two standard interventions.
·
Clinical trials are required for
regulatory authority approval of new treatment, i.e. the US Food and Drug
Administration, Health
·
The trial objectives and design are usually documented in
a clinical trial protocol.
·
Clinical trials must involve the informed consent of participating human subjects.
·
All interventional studies must be approved by an ethics
committee (in the
·
In the
Study design
·
The randomized
controlled trial (RCT) provides the most compelling evidence of a causal
relationship between the treatment and the effect
o Each study subject is
randomly assigned to receive either the subject treatments or control arm
(another treatment or placebo)
o RCTs may be double-blinded,
single-blinded, or nonblinded
depending on whether either subject or experimenter know which arm the subject
is enrolled in
·
Observational studies, such as the cohort study and the
case-control study provide less compelling evidence than the randomized
controlled trial.
·
These are fundamental distinctions in evidence-based
medicine.
·
Size: Small clinical trials may be "sponsored"
by single physicians or a small group of physicians, and are designed to test
simple questions. Other clinical trials require large numbers of participants
followed over long periods of time, and the trial sponsor is more likely to be
a commercial company or a government, or other academic, research body. It is
sometimes necessary to organize multicenter trials,
which may be international.
Phases
·
Pharmaceutical clinical trials are commonly classified
into four phases
·
Phase I trials consist of a
small (20-80) group of healthy volunteers designed to assess the safety,
tolerability, pharmacokinetics, and pharmacodynamics
of a therapy. These trials are almost always conducted in an inpatient clinic,
where the subject can be observed by full-time medical staff. The subject is
usually observed until several half-lives of the drug have passed. Phase I
trials also normally include dose-ranging studies so that doses for clinical
use can be refined. The tested range of doses will usually be a small fraction
of the dose that causes harm in animal testing. Phase
I trials most often include healthy volunteers, however there are some
circumstances when patients are used, such as with oncology (cancer) and HIV
drug trials. In Phase I trials of new cancer drugs, for example, patients with
advanced cancer are used. These trials are usually offered to patients who have
had other types of therapy and who have few, if any, other treatment choices.
·
Phase II trials are performed on
larger groups (20-300) and are designed to assess clinical efficacy of the
therapy; as well as to continue Phase I assessments in a larger group of
volunteers and patients. The development process for a new drug commonly fails
during Phase II trials due to the discovery of poor efficacy or toxic effects.
·
Phase III studies are randomized
controlled trials on large patient groups (300–3,000 or more depending upon the
condition) and compare the efficacy of the new therapy with current 'Gold
Standard' treatment. Phase III trials are the most expensive, time-consuming
and difficult trials to design and run. Once a drug has proven satisfactory
over Phase III trials, the information makes up the "regulatory
submission" that is provided for review to various regulatory authorities
in different countries.
·
Phase IV trials involve the
post-launch safety surveillance of a drug to detect any rare or long-term
adverse effects over a much larger patient population and timescale than was
possible during the initial clinical trials. Such adverse effects detected by
Phase IV trials may result in the withdrawal or restriction of a drug - recent
examples include cerivastatin (Baycol
and Lipobay), troglitazone
(Rezulin) and rofecoxib (Vioxx).
o
Vioxx was approved in 1999.
In 2004, Merck voluntarily withdrew rofecoxib from
the market because of concerns about increased risk of heart attack and stroke
associated with long-term, high-dosage use. Rofecoxib
was one of the most widely used drugs ever to be withdrawn from the market with
sales revenue of US$2.5 billion
·
An Investigational Device Exemption (IDE)
allows the investigational device to be used in a clinical study in order to
collect safety and effectiveness data required to support a Premarket
Approval (PMA) application or a Premarket Notification
[510(k)] submission to the FDA. IDEs also include
clinical evaluation of certain modifications or new intended uses of already
marketed devices. All clinical evaluations of investigational devices, unless
exempt, must have an approved IDE before the study is initiated. It also
requires IRB approval, informed consent, labelling
“for investigational use only, and monitoring and reporting of results.
·
Links: www.clinicaltrials.gov
·
Evidence-based medicine (EBM) is an attempt to more
uniformly apply the scientific method to medical practice.
·
With a high-tech
health-care system that costs the nation $2 trillion a year, there is little or
no evidence that widely used treatments for many diseases, from cardiovascular
diseased to back pain to prostate cancer, actually work better than various
cheaper alternatives.
·
Using
"evidence-based medicine" (a term he coined), Dr. David Eddy, a heart
surgeon turned mathematician and health-care economist, showed that the annual
chest X-ray was worthless, doctors had little clue about the success rate of
procedures such as surgery for enlarged prostates, and the practice of
preventing women from giving birth vaginally if they had previously had a
cesarean was traced to the recommendation of one doctor. He cites a figure that
only 15% of what doctors do is backed by hard evidence.
o As a consultant on Blue Cross's insurance coverage
decisions, Eddy testified on the insurer's behalf in high-profile court cases,
such as bone marrow transplants for breast cancer. Women and doctors demanded
the treatment, even though there was no evidence it
saved lives. Insurers who refused coverage usually lost in court. When clinical
trials were actually done, they showed that the treatment, costing from $50,000
to $150,000, didn't work.
o Eddy uses computer simulations to run virtual
clinical trials.
·
Up to one-third
of clinical studies lead to conclusions that are later overturned, according to
a recent paper in JAMA. Difficulties are highlighted by an eight-year study of
low-fat diets that cost upward of $400 million. Most subjects failed to stick
to the low-fat regimen, making it tough to draw conclusions. In addition, the
study failed to take stock of different kinds of fats, some of which are now
known to have beneficial effects. Many trials fall into similar traps.
·
In 1993, the
federal government's Agency for Health Care Policy & Research convened a
panel to develop guidelines for back surgery. A prominent back surgeon protested
to Congress, and lawmakers slashed funding for the agency.
·
In studies where
one group of patients hears the full story while other patients simply receive
their doctors' instructions, a key difference emerges. The well-informed
patients opt for more invasive, aggressive approaches 23% less often, on
average, than the other group. In some cases, the drop is much bigger -- 50% to
60%.
·
Systematic reviews of randomized, double-blind,
placebo-controlled trials are generally regarded as the highest level of medical
evidence by evidence-based medicine professionals.
o A systematic review is a
summary of the healthcare literature that uses explicit methods to perform a
literature search and critical appraisal of individual studies to identify the
valid and applicable evidence, and then uses appropriate techniques to combine
these valid studies. Most are are based on an
explicit quantitative meta-analysis of available data
o The best-known source of
systematic reviews of is the Cochrane Collaboration, a group of over 6,000
health care specialists. Cochrane
reviews, based on explicit meta-analyses, are published in the Cochrane
Database of Systematic Reviews section of the Cochrane Library.
·
Clinical guidelines briefly identify, summarize
and evaluate the best evidence and most current data about treatments’
effectiveness, risk/benefit and cost-effectiveness in order to standardize care
and improve the quality of care. They are usually published by professional
associations or governmental agencies. They arose in the
·
Professor Archie Cochrane, a Scottish epidemiologist
through his advocacy caused increasing acceptance of the concepts behind
evidence-based practice. Cochrane's work was honoured
through the naming of the Cochrane Centres and
the Cochrane Collaboration, founded in 1993. The explicit methodologies used to
determine "best evidence" were largely
established by the
·
In contrast, patient testimonials, case reports, and even
expert opinion have little value as proof because of the placebo effect, the
biases inherent in observation and reporting of cases, difficulties in
ascertaining who is an expert, and more.
·
The concept of number needed to treat (NNT) is
increasingly part of evidence-based medicine. NNT is a numerical indicator of
the effectiveness of a therapy. For example, an NNT of 4 means if 4 patients
are treated, only one would respond. An NNT of 2 or 3 indicates that a
treatment is quite effective, but an NNT of 20 to 40 can still be considered
clinically effective.
·
Randomized
trials ended the use of some common treatments: the use of bone marrow
transplant in breast cancer, use of antiarrythmics (flecainide, ecainide) after MI,
many inotropics (except digoxin)
used for heart failure, liberal blood transfusions, and hormone replacement
therapy for decreasing heart disease
·
Criticisms: EBM applies to populations, not necessarily
to individuals. Even if several top-quality studies are available, questions
always remain about how far, and to which populations, their results are "generalizable". In The limits of evidence-based medicine,
Tonelli argues that "the knowledge gained from
clinical research does not directly answer the primary clinical question of
what is best for the patient at hand." Tonelli
suggests that proponents of evidence-based medicine discount the value of clinical
experience.
o In some cases, such as
in open-heart surgery, conducting randomized controlled trials would be
unethical, although observational studies are designed to address these
problems to some degree.
o In managed healthcare
systems, evidence-based guidelines have been used as a basis for denying
insurance coverage for some treatments which are held by the physicians
involved to be effective, but of which randomized
controlled trials have not yet been published.
Levels of Evidence
Systems to stratify evidence by quality have been developed, such as this
one by the U.S. Preventive Services Task Force:
·
Level I: Evidence obtained from at least one properly
designed randomized controlled trial.
·
Level II-1: Evidence obtained from well-designed
controlled trials without randomization.
·
Level II-2: Evidence obtained from well-designed cohort
or case-control analytic studies, preferably from more than one center or
research group.
·
Level II-3: Evidence obtained from multiple time series
with or without the intervention. Dramatic results in uncontrolled trials might
also be regarded as this type of evidence.
·
Level III: Opinions of respected authorities, based on
clinical experience, descriptive studies, or reports of expert committees.
·
Links: National Guideline Clearinghouse, Guidelines International Network, Cochrane Library
·
Biologics or biologic therapies are a new class of
drugs produced through genetic manipulation.
o They can be made only by
a living system and have large, complex molecular structures. They are mostly
produced using cell culture.
o They include standard
single molecule drugs, as well as antibodies and vaccines.
o Biologics include Alefacept
(Amevive), Etanercept (Enbrel), Adalimumab (Humira), Infliximab (Remicade®) and Raptiva. These act
as immunosuppressants by blocking the inflammation
causing action of TNF-alpha. These drugs have only recently begun to receive approval
by the US FDA
·
An example of pharmacogenomics in
diagnostics is the use of multigene analysis to
predict the need for chemotherapy in certain breast cancers.
·
Knowledge of a patient’s genetic makeup can sometimes help avoid
adverse drug reactions, as a study earlier this year showed for warfarin
·
In drug development, genomics can already salvage a drug that
might otherwise be abandoned, as demonstrated by gefitinib,
which has little benefit for the majority of those with lung cancer but may
prove lifesaving in the sizable minority with a specific genotype
Stem Cells
·
Stem cells are cells that retain the ability to renew themselves
through cell division and can differentiate
into a wide range of specialized cell types.
·
The two broad categories of mammalian stem cells exist: embryonic
stem cells, derived from blastocysts, and adult
stem cells, which are found in adult tissues.
Embryonic Stem Cells
·
Embryonic stem cell lines (ES cell lines) are cultures of
cells derived from the inner cell mass (ICM) of a blastocyst.
o A blastocyst
is an early stage embryo - approximately 4 to 5 days old in humans and
consisting of 50-150 cells.
o ES cells are pluripotent, and give rise during development to
all derivatives of the three primary germ layers: ectoderm, endoderm and
mesoderm, or into any of the more than 200 cell types of the adult body.
o When given no stimuli
for differentiation, ES cells will continue to divide in vitro and each
daughter cell will remain pluripotent.
o Embryonic stem cell
research is particularly controversial because, with the present state of
technology, starting a stem cell line requires the destruction of a human
embryo and/or therapeutic cloning. Most researchers use embryos that were
created but not used in in vitro fertility treatments
which are slated to be destroyed, or stored indefinitely.
o Researchers at Advanced
Cell Technology of Worcester, Mass., succeeded in obtaining stem cells from
mouse embryos without killing them. If this technique and its reliability are
improved, it would alleviate many of the ethical problems related to embryonic
stem cell research
o The patents covering
much work on human embryonic stem cells are owned by the Wisconsin Alumni
Research Foundation (WARF). WARF does not charge academics to study human stem
cells but does charge commercial users. WARF sold Geron
Corp. exclusive rights to work on human stem cells but later sued Geron Corp. to recover some of the previously sold rights.
·
In the European Union, stem cell research using the human
embryo is permitted in
·
2001
President Bush announced that federal money could go to researchers working on
existing ESC lines but no new lines could be created using federal funds.
·
In the wake
of Bush's order, Harvard used private funding to develop about 100 new
cell lines from fertility-clinic embryos, which it shares with researchers
around the world.
·
2006 The
U.S. House of Representatives and Senate pass legislation expanding federal
support for embryonic stem cell research.
It is vetoed by President Bush.
Somatic Cell Transfer
·
Stem cells can
be custom-made by inserting a patient's skin cell into a hollowed human egg.
Any resulting therapies would not run the risk of immune rejection. Drawbacks:
The process has not yet been successfully completed with human cells, and it
requires an enormous amount of fresh human eggs, which are difficult to obtain
·
2006
Harvard researchers announced this summer that they would develop new cell
lines through somatic cell nuclear transfer, or therapeutic cloning. In this
process, a cell from a patient with diabetes, for instance, is inserted into an
unfertilized egg whose nucleus has been removed; then it is prodded into
growing in a petri dish for a few days until its stem
cells can be harvested. Unlike fertility-clinic embryos, these cells would
match the patient's DNA, so the body would be less likely to reject a transplant
derived from them. The only people who claim to have succeeded in creating
human-stem-cell lines through nuclear transfer were the South Korean
researchers who turned out to be frauds.
·
In "altered
nuclear transfer," the gene CDX2 is removed before the cell is fused with
the egg. That would ensure that the embryo lives only long enough to produce
stem cells and then dies.
·
No human ESCs have been differentiated reliably enough that they
could be safely transplanted into people, although animal studies with human
cells are under way.
·
Geron claims it is close
to filing for permission to conduct the first human trials relying on ESC-based
therapy. It is using stem cells to create oligodendroglial
progenitor cells, which produce neurons and provide myelin insulation for the
long fingers that extend out from the body of a nerve cell. Lanza's
group is also close to filing for FDA permission to begin clinical trials on
three cell-based therapies: one for macular degeneration, one for repairing
heart muscle and another for regenerating damaged skin.
·
Lorenz Studer at Memorial Sloan-Kettering Cancer Center in New
York City has been able to differentiate ESCs into
just about every cell type affected by Parkinson's disease and has transplanted
them into rats and improved their mobility. Next, he plans to inject the cells
into monkeys.
Umbilical Cord & Placental Stem
Cells
·
Umbilical cord
and placental cells have proved more valuable than scientists initially hoped.
Although about 90% of cord-blood stem cells are precursors for blood and immune
cells, the remaining 10% give rise to liver, heart-muscle and brain cells and
more. Over the past five years, cord-blood transplants have become an
increasingly popular alternative to bone-marrow transplants for blood disorders,
particularly when a bone-marrow match can't be found.
Adult Stem Cells
·
Adult stem cells are undifferentiated cells
found throughout the body that divide to replenish dying cells and regenerate
damaged tissues. They are self-renewing (able to replicate) and multipotent (able to produce different cell types)
·
Signaling pathways
1.
Bmi-1: The transcriptional repressor Bmi-1 is one of the Polycomb-group proteins that was
discovered as a common oncogene activated in lymphoma and later shown to
specifically regulate HSCs and neural stem cells.
2.
Notch: The Notch pathway has now been demonstrated for several
cell types including haematopoietic, neural and
mammary stem cells.
3.
Sonic hedgehog and Wnt:These developmental pathways are also
strongly implicated as stem cell regulators
·
Plasticity: Under special
conditions tissue-specific adult stem cells can generate a whole spectrum of
cell types of other tissues, even crossing germ layers. This phenomenon is
referred to as stem cell transdifferentiation or
plasticity. It can be induced by modifying the growth medium when stem cells
are cultured in vitro or transplanting them to an organ of the body
different from the one they were originally isolated from.
·
They exist in
many major tissues, including the blood, skin and brain. They can be coaxed to
produce more cells of a specific lineage and do not have to be extracted from
embryos Drawbacks: They can generate only a limited number of cell types, and
they are difficult to grow in culture
·
Adipose
derived adult stem cells (ASCs) have been isolated
from human fat. They are similar in many ways to mesenchymal
stem cells (MSCs) derived from bone marrow. However,
it is possible to isolate many more cells from adipose tissue and the harvest
procedure (liposucion) is less painful than the
harvest of bone marrow. Human ASCs have been shown to
differentiate in the lab into bone, cartilage, fat, muscle, and might be able
to differentiate into neurons. Studies in animals suggest that ASCs might be able to repair significant bony defects and ASCs have been recently used to successfully repair a large
cranial defect in a human patient.
·
Mammary
stem cells play an important role in carcinogenesis of the breast. Mammary stem cells
have been isolated from human and mouse tissue as well as from cell lines
derived from the mammary gland.
·
Neural
stem cells.
- The existence of
stem cells in the adult brain has been postulated following the discovery
that the process of neurogenesis, birth of new neurons, continues into
adulthood in rats. It has since been shown that new neurons are generated
in adult mice, songbirds and primates, including humans.
- Normally adult neurogenesis is restricted to the subventricular zone, which lines the lateral
ventricles of the brain, and the dentate
gyrus of the hippocampus. Although the
generation of new neurons in the hippocampus is well established, the
presence of true self-renewing stem cells there has been debated. Under
certain circumstances, such as following tissue damage in ischemia, neurogenesis can be induced in other brain regions,
including the neocortex.
- Neural stem cells
are commonly cultured in vitro as so called neurospheres
- floating heterogeneous aggregates of cells, containing a large
proportion of stem cells. They can be propagated for extended periods of
time and differentiated into both neuronal and glia cells, and therefore
behave as stem cells. However, some recent studies suggest that
this behaviour is induced by the culture
conditions in progenitor cells, the progeny of stem cell division that
normally undergo a strictly limited number of replication cycles in
vivo. Furthermore, neurosphere-derived cells
do not behave as stem cells when transplanted back into the brain.
- Neural stem cells
share many properties with haematopoietic stem
cells (HSCs). Remarkably, when injected into the
blood, neurosphere-derived cells differentiate
into various cell types of the immune system. Cells that resemble neural
stem cells have been found in the bone marrow, the home of HSCs. It has been suggested that new neurons in the
dentate gyrus arise from circulating HCSs. Indeed, newborn cells first appear in the
dentate in the heavily vascularised subgranular zone immediately adjacent to
blood vessels.
·
Olfactory adult stem cells
have been successfully harvested from the human olfactory mucosa
cells. These cells appear to have the same ability as embryonic stem cells in
giving rise to many different cell types but have the advantage that they can
be obtained from all individuals, even older people who might be most in need
to stem cell therapies. They can be harvested with ease in contrast to neural
stem cells
·
Adult stem cells are often present in only minute
quantities and can therefore be difficult to isolate and purify. Depending on
the stem cell type, they can be multiplied in-vitro to therapeutic
numbers. Generally though, adult stem cells do not self-renew as effectively as
embryonic stem cells. This is especially true of hematopoietic
stem cells.
·
Dr. Shinya
Yamanaka of
·
Researchers in
Stem Cell History
·
1960s - Joseph Altman and Gopal Das present evidence of adult neurogenesis,
ongoing stem cell activity in the brain; their reports contradict Cajal's "no new neurons" dogma and are largely
ignored
·
1963 - McCulloch and Till illustrate the presence of
self-renewing cells in mouse bone marrow
·
1968 - Bone marrow transplant between two siblings
successfully treats SCID
·
1969 - The first human in vitro fertilization
is accomplished
·
1978 - Haematopoietic stem cells
are discovered in human umbilical cord blood
·
1981 - Mouse embryonic stem cells are derived from the inner
cell mass
·
1992 - Neural stem cells are cultured in vitro as neurospheres
·
1995 - President Bill Clinton signs into law the Dickey
Amendment which prohibited Federally appropriated
funds to be used for research where human embryos would be either created or
destroyed.
·
1997 - Leukemia is shown to originate from a haematopoietic stem cell, the first direct evidence for
cancer stem cells
·
1998 - James Thomson and coworkers derive the first human
embryonic stem cell line at the University of Wisconsin-Madison.
·
2000s - Several reports of adult stem cell plasticity are
published
·
2004 -
·
2004-2005 - Korean researcher Hwang Woo-Suk
claims to have created several human embryonic stem cell lines from unfertilised human oocytes. The
lines are later shown to be fabricated.
·
2001-2006 - President George W. Bush endorses the Congress
in providing limited federal funding for embryonic stem cell research totalling approximately $100 million. At the same time, he
also enacts laws that restrict federally funded stem cell research on embryonic
stem cells to the already derived but dwindling cell lines. Bush also endorsed
funding for a total of $250 million dollars for research on adult and animal
stem cells. In 2006 President Bush vetoed H.R. 810 (Stem Cell Research
Enhancement Act) that would have reversed the Clinton-era law which made it
illegal for Federal money to be used for research where stem cells are derived
from the destruction of an embryo.
·
2007 - Scientists report discovery of a new type of stem cell
in amniotic fluid. This may potentially provide an alternative to embryonic
stem cells for use in research and therapy.
Stem Cell Therapy
·
2004 A team of Korean
researchers reported that they had transplanted umbilical cord stem cells into
a patient suffering from a spinal cord
injury who had been unable to stand for 19 years,
afterwards regained the ability to walk.
·
2005 Researchers at the
University of Wisconsin-Madison differentiated human blastocyst
stem cells into neural stem cells, then into the beginnings of motor neurons,
and finally into spinal motor neuron cells. The newly generated motor neurons
exhibited electrical activity, the signature action of neuron.
·
Researchers at Columbia-Presbyterian found that injecting
bone-marrow stem cells into mice which had had heart attacks induced resulted in an improvement of 33 percent in
the functioning of the heart and damaged tissue had regrown
by 68 percent.
·
Since 2003, researchers have successfully transplanted retinal stem cells into damaged eyes to
restore vision. Using embryonic stem cells, scientists are able to grow a thin
sheet of totipotent stem cells in the laboratory.
When these sheets are transplanted over the damaged retina, the stem cells
stimulate renewed repair, eventually restoring vision. In June of 2005
researchers at the Queen Victoria Hospital of Sussex, England were able to
restore the sight of forty patients using the same technique using adult stem
cells obtained from the patient, a relative, or even a cadaver.
·
Cancer kills
about 7 million people worldwide every year.
·
Neoplasia occurs when cells divide
and proliferate uncontrollably, forming a mass (tumor) and disrupting normal
cells and tissues.
- Tumors are any mass occurring in the body, and may be
benign or malignant (cancer)
- Benign tumors do not spread to other parts of the
body or invade other tissues, and they are rarely a threat to life unless
they extrinsically compress vital structures. Malignant tumors can invade
normal tissue, spread to distant locations (metastasize) and become life-threatening.
·
Hippocrates described several kinds of cancers. He called
benign tumours oncos,
Greek for swelling, and malignant tumours carcinos, Greek for crab. He later added the suffix -oma, Greek for swelling, giving the name carcinoma.
·
Many forms of cancer are associated with exposure to environmental factors such as tobacco
smoke, radiation, alcohol, carcinogenic chemicals and certain viruses
·
Most forms of cancer are "sporadic", and have
no basis in heredity. There are, however, a number of recognised
syndromes of cancer with a hereditary component, often a defective tumor
suppressor allele, such as p53.
·
Cancers are classified by the type of cell that resembles
the tumor and, therefore, the tissue presumed to be the origin of the tumor.
The following general categories are usually accepted:
o
Carcinoma: malignant tumors
derived from epithelial cells. This group represent
the most common cancers, including the common forms of breast, prostate, lung
and colon cancer.
o
Lymphoma and Leukemia: malignant tumors
derived from blood and bone marrow cells
o
Sarcoma: malignant tumors
derived from connective tissue, or mesenchymal cells
o
Mesothelioma: tumors derived from the mesothelial
cells lining the peritoneum and the pleura.
o
Glioma: tumors derived from glia, the
most common type of brain cell
o
Germinoma: tumors derived from germ cells, normally found in the testicle
and ovary
o
Choriocarcinoma: malignant tumors derived from the placenta
·
The age of peak incidence of cancer in children occurs
during the first year of life. Leukemia (usually ALL) is the most common infant
malignancy (30%), followed by the central nervous system cancers and neuroblastoma. The remainder consists of Wilms' tumor, lymphomas, rhabdomyosarcoma
(arising from muscle), retinoblastoma, osteosarcoma
and
·
Cancer tissue has a distinctive appearance under the
microscope. Among the distinguishing traits are: a large number of dividing
cells, variation in nuclear size and shape, variation in cell size and shape,
loss of specialized cell features, loss of normal tissue organization, and a
poorly defined tumor boundary.
- Immunohistochemistry and other molecular methods may characterize
specific markers on tumor cells, which may aid in diagnosis and prognosis.
- Dysplasia is an abnormal
type of excessive cell proliferation characterized by loss of normal
tissue arrangement and cell structure. Often such cells revert to normal
behavior, but occasionally, they gradually become malignant
Carcinogenesis
·
The unregulated growth that characterizes cancer is
caused by damage to DNA, resulting
in mutations to genes that encode
for proteins controlling cell division.
·
Many mutation events may be required to transform a
normal cell into a malignant cell.
·
Mutations can be caused
by chemicals or physical agents called carcinogens,
by close exposure to radiation, or
by certain viruses that can insert
their DNA into the human genome.
·
Some carcinogens also appear to work through non-mutagenic pathways that affect the
level of transcription of certain
genes without causing genetic mutation.
·
Some carcinogens are not mutagens, for example alcohol
and estrogen. These are thought to promote cancers through their stimulating
effect on the rate of cell mitosis, increasing the likelihood of a genetic
mistake.
·
Viruses are responsible for 15% of human cancers. The
main viruses associated with human cancers are human papillomavirus,
hepatitis B virus, Epstein-Barr virus, and human T-lymphotropic
virus.
·
Mutations can also occur spontaneously, and may be passed down from one generation to the
next as a result of mutations within germ
lines.
- Chromosomal
translocations, such as the
·
Proto-oncogenes are genes which promote cell growth and
cell division, and tumor suppressor genes discourage cell growth, or
temporarily halt cell division in order to carry out DNA repair. Typically, a
series of several mutations to these genes are required before a normal cell
transforms into a cancer cell.
·
Proto-oncogenes promote cell growth
through a variety of ways. Many can produce hormones which encourage mitosis.
Some are involved in the signal transduction system and signal receptors in
cells, thus controlling the sensitivity to such hormones. When proto-oncogenes
are mutated they become oncogenes.
·
Tumor suppressor genes code for proteins
that suppress mitosis and cell growth.
- Generally tumor
suppressors are transcription factors that are activated by cellular
stress or DNA damage. Tumor suppressors include the p53 protein, which is a transcription factor activated by many
cellular stressors including hypoxia and ultraviolet radiation damage
·
Knudson’s “Two-Hit”
hypothesis is that mutations in both types of genes are required for cancer to occur.
It is only when enough proto-oncogenes have mutated into oncogenes, and enough
tumor suppressor genes deactivated or damaged, that the signals for cell growth
overwhelm the signals to regulate it, that cell growth quickly spirals out of
control.
- Knudson’s two hit
model has recently been challenged by several investigators. Inactivation
of one allele of some tumor suppressor genes is sufficient to cause
tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a
number of experimental approaches. Tumors caused by haploinsufficiency
usually have a later age of onset when compared with those by a two hit
process
·
Since the late
1980s, researchers have focused on the theory that cancer emerges when a
specific handful of genes in a single cell are faulty, through some combination
of inheritance and "random mutation". Ever since then the
cancer-research community has focused intensely on finding specific oncogenes believed to be involved in
each form of cancer. The vast majority of funding continues to back oncogene
research.
·
In the 1990s
Lawrence Loeb proposed that cancer
emerges only a cell becomes "genetically
unstable" so that mutations occur in large numbers of their genes on a
regular basis, and the chances of one of these unstable cells' hitting a gene
sequence needed to become cancerous increases. A large study of the mutant
genes in breast and colorectal tumors underscores how flawed the
handful-of-oncogenes approach is: the study found that 189 different genes are
frequently mutated in these tumors, and that any given
tumor cell has an average of 90 mutated genes.
·
Only a dozen or
so labs focus on Theodor Boveri's
chromosome scrambling as a key to
understanding cancer.
Cancer Stem Cells
·
Cancer stem cell hypothesis states that tumors arise from
cells that have properties of adult stem cells, particularly the abilities to
self-renew and differentiate into multiple cell types, and that these cells
persist in tumors as a distinct population that likely causes disease relapse
and metastasis.
·
However, it is debated whether such cells represent a
minority. If most cells of the tumor are endowed with stem cell properties
there is no incentive to focusing on a specific subpopulation.
·
The first conclusive evidence for cancer stem cells was
published in 1997 in Nature Medicine. Bonnet and Dick isolated a subpopulation
of leukaemic cells that express a specific surface
marker CD34, but lacks the CD38 marker. The authors
established that the CD34+/CD38- subpopulation is capable
of initiating tumors in mice.
·
The existance of leukaemic stem cells prompted further research into other
types of cancer. Cancer stem cells have recently been identified in several solid
tumours, including breast cancer, brain cancer and
colon cancers.
Angiogenesis
·
Tumors induce blood vessel growth (angiogenesis) by
secreting various growth factors (e.g. Vascular Endothelial Growth Factor or
VEGF). Growth factors, such as bFGF and VEGF can
induce capillary growth into the tumor, which supply required nutrients and/or
carry away waste products
·
Evidence now suggests that the blood vessel in a given
solid tumor may in fact be mosaic vessels, comprised of endothelial cells and
tumor cells. This mosaicity allows for substantial
shedding of tumor cells into the vasculature.
·
Angiogenesis-based tumor therapy relies
angiogenesis inhibitors like angiostatin, endostatin and tumstatin.
o
Dr. Judah Folkman, who coined
the word "anti-angiogenesis," was the first to identify stopping
angiogenesis as a strategy for attacking cancerous tumors.
o
The 1st FDA-approved therapy targeted at angiogenesis in
cancer came on the market in the
Metastasis
·
Metastasis is defined as the stage in which cancer cells
are transported through the bloodstream or lymphatic system to implant in
distant sites in the body
Cancer
Treatment
·
A number of different screening tests have been
developed.
o
Breast cancer screening can be done by breast
self-examination. Screening by regular mammograms detects tumors even earlier
than self-examination, and many countries use it to systematically screen all
middle-aged women.
o
Colorectal cancer can be detected through fecal occult
blood testing and colonoscopy, which reduces both colon cancer incidence and
mortality, presumably through the detection and removal of pre-malignant
polyps.
o
Cervical cytology testing (using the Pap smear) leads to
the identification and excision of precancerous lesions. Over time, such
testing has been followed by a dramatic reduction of cervical cancer incidence
and mortality.
o
Testicular self-examination is recommended for men
beginning at the age of 15 years to detect testicular cancer.
o
Prostate cancer can be screened for by a digital rectal
exam along with prostate specific antigen (PSA) blood testing.
·
Diagnosis usually requires the histologic
examination of tissue by a pathologist. This tissue is obtained by biopsy or
surgical removal.
·
Once diagnosed, cancer is usually treated with a
combination of surgery, chemotherapy and radiotherapy.
·
In addition to removal of the primary tumor, surgery is
often necessary for staging, e.g.
determining the extent of the disease and whether it has metastasized to
regional lymph nodes. Staging is a major determinant of prognosis and of the
need for adjuvant therapy.
·
Adjuvant chemotherapy given
following (as an adjunct to) surgery or radiation. Neoadjuvant chemotherapy is given prior to other treatments.
·
Palliative treatment is given to
control the symptoms of cancer, not to treat the cancer primarily.
Chemotherapy
·
Chemotherapy is the treatment of cancer with drugs ("anticancer drugs")
that can destroy cancer cells.
·
Most chemotherapeutic
drugs work by impairing mitosis (cell division). Most forms of chemotherapy
target all rapidly dividing cells and are not specific for cancer cells. Hence,
chemotherapy has the potential to harm healthy tissue, especially those tissues
that have a high replacement rate (e.g. intestinal lining, hair, blood cells).
As a result, gastrointentinal disturbances, hair loss
(allopecia), and low blood counts are common side
effects.
o
Low white blood cell counts (neutropenia)
can be treated with synthetic granulocyte-colony stimulating factor (G-CSF),
e.g. filgrastim, lenograstim,
Neupogen, Neulasta
o
Some studies and patient groups claim that the use of cannabinoids derived from marijuana during chemotherapy
greatly reduces the associated nausea and vomiting, and enables the patient to
eat. Some synthetic derivatives of the active substance in marijuana (Tetrahydrocannabinol or THC) such as Marinol
may be practical for this application. Natural marijuana, known as medical
cannabis is also used and recommended by some oncologists, though its use is
regulated and not everywhere legal
·
During World War II, people exposed to mustard gas were
later found to have very low white blood cell counts. It was reasoned that an
agent that damaged the rapidly growing white blood cells might have a similar
effect on cancer. Therefore, in the 1940s, several patients with advanced
lymphomas were given the drug intravenously. Their improvement, although
temporary, was remarkable. That experience led researchers to look for other substances
that might have similar effects against cancer.
·
The majority of chemotherapeutic drugs can be divided in
to: alkylating agents, antimetabolites,
anthracyclines, plant alkaloids, topoisomerase
inhibitors, monoclonal antibodies, and other antitumour
agents. All of these drugs affect cell division or DNA synthesis and function
in some way.
o
Alkylating agents add alkyl groups to DNA. Examples: nitrogen mustards (cyclophosphamide), nitrosoureas (carmustine, BCNU), platinum compounds (cisplatin,
carboplatin)
§
Nitrogen mustards may also be used for chemical
warfare.
o
Anti-metabolites masquerade as purines or pyrimidines, the
building blocks of DNA, to prevent DNA and RNA synthesis. Due to their
efficiency, these drugs are the most widely used cytostatics.
o
Plant alkaloids block cell division by
preventing microtubule function. They are derived from the Madagascar
periwinkle (see bioprospecting). Examples: vinca
alkaloids (vincristine, vinblastine)
and taxanes (paclitaxel)
o
Topoisomerase inhibitors interfere with both transcription and replication
of DNA by upsetting proper DNA supercoiling.
Examples: irinotecan, topotecan,
etoposide
§
Podophyllotoxin is a plant-derived
compound used to produce two cytostatic drugs, etoposide and teniposide. They
prevent the cell from entering the G1 and S phases. The exact mechanism of its
action still has to be elucidated. The substance has been primarily obtained
from the American Mayapple.
o
Some newer agents don't directly interfere with DNA,
including the tyrosine kinase inhibitors which
directly target (targeted therapy) a molecular
abnormality in certain cancers
o
Some drugs may be used which modulate tumor cell behaviour without directly attacking those cells, for
example hormone treatments
§
Prostate cancer is often sensitive to finasteride,
an agent that blocks the conversion of testosterone to dihydrotestosterone.
§
Breast cancer cells often highly express the estrogen
and/or progesterone receptor. Inhibiting the production (with aromatase inhibitors) or action (with tamoxifen)
of these hormones can often be used as an adjunct to therapy.
·
The treatment of some Leukaemias
and Lymphomas requires the use of high-dose chemotherapy, and Total Body
Irradiation. This treatment ablates the bone marrow, and hence the body's
ability to repopulate the blood. For this reason, bone marrow, or peripheral
blood stem cell harvesting is carried out before the therapy, to enable
"rescue" after the treatment has been given. This is known as
autologous transplantation. Alternatively, bone marrow may be transplanted from
a Matched Unrelated Donor
o
Although
once a common treatment, randomized studies found that autologous bone marrow
transplant did not improve overall survival for patients with breast cancer
Radiation Therapy
·
Radiation therapy (also called radiotherapy, X-ray
therapy, or irradiation) is the use of ionizing radiation to kill cancer cells
and shrink tumors.
·
Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or
internally via brachytherapy.
·
The effects of radiation therapy are localized and
confined to the region being treated. Radiation therapy injures or destroys
cells in the area being treated (the "target tissue") by damaging
their genetic material, making it impossible for these cells to continue to
grow and divide.
·
Although radiation damages both cancer cells and normal
cells, most normal cells can recover from the effects of radiation and function
properly. The goal of radiation therapy is to damage as many cancer cells as
possible, while limiting harm to nearby healthy tissue. Hence, it is given in
many fractions (or treatment
sessions), allowing healthy tissue to recover between fractions
·
Targeted
therapy blocks the growth of cancer
cells by interfering with specific targeted molecules needed for growth,
rather than by simply interfering with all rapidly dividing cells. Targeted
cancer therapies may be more effective and less harmful to normal cells.
·
The main
categories of targeted therapy are small molecules and monoclonal
antibodies
Small Molecules
·
Small molecule
drugs generally include signal transduction inhibitors` (tyrosine kinase inhibitors) which block the signal transduction
pathways of growth factor receptors
·
Imatinib mesylate
(Gleevec) is approved for chronic myelogenous
leukemia, gastrointestinal stromal tumor and some
other types of cancer. Gefitinib (Iressa)
targets the epidermal growth factor receptor (EGFR) tyrosine kinase and is approved in the
Immunotherapy
·
Cancer Immunotherapy be
either through immunization of the
patient, in which case the patient's own immune system is trained to recognize
tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in
which case the patient's immune system is recruited to destroy tumor cells by
the therapeutic antibodies.
·
Monoclonal antibodies are raised against specific
antigens presented on the surfaces of tumors.
o
The antibodies may function by blocking receptors (VEGF,
EGFR), activating complement, or being conjugated to toxins, radioligands, or chemotherapeutic agents
o
Trastuzumab (Herceptin)
is a monoclonal antibody specific for the epidermal growth factor receptor 2
protein (HER2). It received FDA-approval in 1998, and is clinically used for
the treatment of breast cancer. The use of Trastuzumab
is restricted to patients whose tumours over-express
HER-2, as assessed by immunohistochemistry (IHC) and
either chromogenic or fluorescent in situ hybridisation (FISH), as well as numerous PCR-based
methodologies. Amplification or overexpression of
HER-2 is present in 25-30% of breast carcinomas and has been associated with
aggressive tumour phenotype, poor prognosis,
non-responsiveness to hormonal therapy and reduced sensitivity to conventional
chemotherapeutic agents.
·
Dendritic cell based immunotherapy utilizes dendritic
cells to activate a cytotoxic response towards an antigen.
o Dendritic cells, an antigen
presenting cell, are harvested from a patient. These cells are then either
pulsed with an antigen or transfected with a viral
vector. The activated dendritic cells are then placed
back into the patient; these cells then present the antigens to effector cells intitiating a
cytotoxic response.
·
T-cell based
adoptive immunotherapy uses T cells that have a natural or genetically engineered
reactivity to a patients' cancer whixh are expanded in
vitro using a variety of means and then adoptively transferred into a
cancer patient.
o T cells with a natural
occurring reactivity to a patients cancer can be found
in infiltrated in that patients' own tumors. The tumor is harvested, and these
tumor infiltrating lymphocytes (TIL) are expanded in vitro using high
concentrations of interleukin-2 (IL-2), anti-CD3 and allo-reactive
feeders. These T cells are then transferred back into the patient along with
exogenous administration of IL-2.
o In the case of
engineered T cells, T cell receptors (TCR) that have been identified to have
reactivity against tumor associated antigens are cloned into a replication
incompetent virus that is capable of genomic integration. A patient’s own
lymphocytes are exposed to these viruses and then expanded non-specifically or
stimulated using the engineered TCR. The cells are then transferred back into
the patient.
·
Cancer vaccine is used to describe a process whereby a person's immune
system is coaxed into recognizing and destroying malignant cells. A cancer
vaccine is generally considered an immunotherapy, because, unlike prophylactic
vaccines against infectious diseases, a cancer vaccine is not preventive and
must be administered after cancerous cells develop.
o Note that the HPV vaccine is not a cancer vaccine as
described above. It works by preventing infection by the HPV thereby reducing
the occurrence of cervical cancer, not by coaxing the body into recognizing and
destroying malignant cells. Gardasil and Cervarix are preventive (rather than therapeutic) HPV
vaccines, recommended for women 9 to 25 years old.
o A tumour
can have many different types of cells in it, each with different cell-surface
antigens. Furthermore, those cells are derived from the individual with cancer,
and therefore display few if any antigens that are foreign to that individual.
This makes it difficult for the immune system to distinguish the cancer cells
from normal cells.
o Renal cancer and
melanoma are the two cancers with most evidence of causing spontaneous and
effective immune responses, possibly because they often display antigens that
are recognized as foreign. Therefore, many attempts at developing cancer
vaccines are directed against these tumors.
·
2003 Severe acute respiratory syndrome (SARS) causes an epidemic in
·
2003 A
polio epidemic broke out--eventually reaching 17 African and Asian
nations--when Muslim leaders in northern
·
More
than 40 million people worldwide carry HIV, although 95% are never officially
diagnosed HIV-positive. Every 24 hours 15,000 more become infected with the
virus, while 8,000 others die of the resultant AIDS. AIDSVAX, the HIV vaccine,
trials began in 1998-99, in Europe and
·
Commonly known
as mad cow disease, bovine spongiform encephalopathy attacks an animal's nervous
system. People who eat food contaminated with BSE can contract a rare disease
that is nearly always fatal, variant Creutzfeldt-Jakob disease.
·
In the
Vaccinations
Avian Flu
·
Avian flu strains:
o
.png "\"Image:H5n1 spread (with regression).png\"")
H1N1, which caused
"Spanish flu" and currently causes seasonal human flu
o
H2N2, which caused "Asian flu"
o
H3N2, which caused "
o
H5N1, the world's major current pandemic threat
·
"Avian flu" today refers to infection from a
subtype of Influenza A virus, H5N1, which can cause
severe illness in humans. H5N1 infects more species than any previously known
flu virus strain, is deadlier than any previously known flu virus strain.
·
H5N1 is mainly spread by domestic poultry, both through
the movements of infected birds and poultry products and through the use of
infected poultry manure as fertilizer or feed. Infected birds transmit H5N1
through their saliva, nasal secretions, feces and blood. H5N1 remains
infectious for 6 days at 37 °C ( 98.6 °F). Humans with
H5N1 have typically caught it from chickens. Migrating waterfowl carry H5N1,
often without becoming sick. Many species of birds and mammals can be infected
with H5N1, but the role of animals other than poultry and waterfowl as
disease-spreading hosts is unknown.
·
H5N1 first infected humans in the 1990s. Currently, it is
transmitted by contact with infected birds, and has been transmitted from one
person to another only in a few cases. H5N1 flu is therefore not pandemic now
and is not currently capable of causing a pandemic. Only 
if H5N1 mutates into a
form that can be readily transmitted from one person to another could it cause
a pandemic.
·
In the first two months of 2006 H5N1 spread to Africa and
·
60% of humans known to have been infected with the
current Asian strain of H5N1 have died from it
·
In 2003, world-renowned virologist Robert Webster
published an article titled "The world is teetering on the edge of a
pandemic that could kill a large fraction of the human population" in American
Scientist.
·
While the pandemic human influenza viruses of 1957 (H2N2)
and 1968 (H3N2) clearly arose through reassortment
between human and avian viruses, the influenza virus causing the 'Spanish flu'
in 1918 appears to be entirely derived from an avian source.
·
Experts have identified key events (creating new clades, infecting new species, spreading to new areas)
marking the progression of an avian flu virus towards becoming pandemic, and
many of those key events have occurred more rapidly
than expected.
·
Billions of dollars are being spent by at least 12
companies and 17 governments towards developing pre-pandemic influenza vaccines
in 28 different clinical trials. There is no highly effective treatment for
H5N1 flu, but oseltamivir (Tamiflu),
can sometimes inhibit the influenza virus from spreading inside the user's
body. A vaccine will need to be specifically produced by the actual pandemic
flu virus strain.
·
In the Spanish
Influenza pandemic, 50 million to 100 million people worldwide were killed
during about a year in 1918 and 1919. The highly lethal second and third waves
of the 1918 Spanish flu evolved through time into a less virulent and more
transmissible human form. Although the overall fatality rate for the Spanish
Flu was at most 1% to 2% of the population, the lethal waves of the Spanish Flu
are not reported to have emerged with anything like the over-50% case fatality
ratio observed to date in human H5N1 infection.
o
Despite not having originated in
o
In the
o
In 1998, a team from the US Armed Forces Institute of
Pathology (AFIP) recovered samples of the 1918 influenza from the frozen corpse
of a Native Alaskan woman buried in permafrost near
o
During the pandemic of 1918, some military doctors
injected severely afflicted patients with blood or blood plasma from people who
had recovered from the flu. Data collected during that time indicates that the
blood-injection treatment reduced mortality rates by as much as 50 percent.
·
H5N1 attacks are especially lethal in young adults,
consistent with the frequent development of a cytokine storm. Very few persons
over 50 years of age have died. Instead, the age-fatality curve of H5N1
resembles that of the 1918 Spanish pandemic flu, and is the opposite of the
mortality curve of seasonal flu strains, which preferentially kills the elderly
and does not kill by cytokine storm.
|
Highly pathogenic H5N1 |
|
|
|
|
|
|
Countries with poultry or wild birds killed by H5N1. |
|
|
Countries with humans, poultry and wild birds killed by H5N1. |
Bioterrorism
·
The intentional
release of anthrax in 2001 underscored the reality of a bioterrorism threat
posed by category A
agents, including smallpox, plague, tularemia, hemorrhagic fevers, and botulinum toxin.
·
The NIH is
developing vaccine candidates for Ebola and smallpox, both currently in
clinical trials.
·
Project BioShield grants support the development of new and improved
medical products to treat category A agents.
Chemicals
·
Even though many
health statistics have been improving over the past few decades, a few
illnesses are rising mysteriously. From the early 1980s through the late 1990s,
autism increased tenfold; from the early 1970s through the mid-1990s, one type
of leukemia was up 62 percent, male birth defects doubled, and childhood brain
cancer was up 40 percent. Some experts suspect a link to the man-made
chemicals. There's little firm evidence.
·
From DDT to PCBs,
the chemical industry has released compounds first and discovered damaging
health effects later. Regulators have often allowed a standard of innocent
until proven guilty.
o
Each year the U.S.
Environmental Protection Agency (EPA) reviews an average of 1,700 new
compounds that industry is seeking to introduce. Yet the 1976 Toxic Substances
Control Act requires that they be tested for any ill effects before approval
only if evidence of potential harm exists—which is seldom the case for new
chemicals. The agency approves about 90 percent of the new compounds without
restrictions. Only a quarter of the 82,000 chemicals in use in the
o
The European Union
last year gave initial approval to a measure called REACH—Registration,
Evaluation, and Authorization of Chemicals—which would require companies to
prove the substances they market or use are safe, or that the benefits outweigh
any risks. The bill, which the chemical industry and the
·
Until recently, no
one had even measured average levels of exposure among large numbers of
Americans. No regulations required it, the tests are expensive, and technology
sensitive enough to measure the tiniest levels didn't exist. In 2005 the
Centers for Disease Control and Prevention (CDC) took a step toward
closing that gap when it released data on 148 substances, from DDT and other
pesticides to metals, PCBs, and plastic ingredients, measured in the blood and
urine of several thousand people. The study said little about health impacts on
the people tested or how they might have encountered the chemicals.
·
PCBs, oily liquids or
solids, can persist in the environment for decades. In animals, they impair
liver function, raise blood lipids, and cause cancers.
o
PCBs were once used
as electrical insulators and heat-exchange fluids in transformers and other
products.
o
Some of the 209
different PCBs chemically resemble dioxins and cause other mischief in lab
animals: reproductive and nervous system damage, as well as developmental
problems.
o
By 1976, the toxicity of PCBs was
unmistakable; the
o
GE has spent 300
million dollars on the cleanup so far, dredging up and disposing of PCBs in the
river sediment under the supervision of the EPA. It is also working to stop the
seepage of PCBs into the river from the factories.
o
Birds and other
wildlife along the
·
Mercury is a neurotoxin that can permanently impair memory, learning centers,
and behavior.
o
Coal-burning power
plants are a major source of mercury, sending it out their stacks into the
atmosphere, where it disperses in the wind, falls in rain, and eventually
washes into lakes, streams, or oceans. There bacteria transform it into a
compound called methylmercury, which moves up the
food chain after plankton absorb it from the water and are eaten by small fish.
Large predatory fish at the top of the marine food chain, like tuna and
swordfish, accumulate the highest concentrations of methylmercury.
o
For people in
northern
·
In 1971 the U.S.
Surgeon General declared that lead
levels of 40 micrograms per deciliter of blood were safe. It's now known that
any detectable lead can cause neurological damage in children, shaving off IQ
points.
·
DDT, the archvillain of Rachel Carson's 1962 classic book Silent
Spring, which launched the modern environmental movement, was once hailed
as a miracle substance because it killed the mosquitoes that carry malaria,
yellow fever, and other scourges. It saved countless lives before it was banned
in much of the world because of its toxicity to wildlife.
Environmental Carcinogens
·
Tobacco smoking is associated
with lung cancer.
·
Exposure to ultraviolet
radiation from the sun can lead to melanoma and other skin malignancies.
·
Breathing asbestos
fibers is associated with mesothelioma, a type of
lung cancer.
·
Aflatoxin, which is produced by
the fungus Aspergillus flavus
growing on stored grains, nuts and peanut butter, can cause liver cancer.
·
Cooking protein-rich food at high temperatures, such as
broiling or barbecuing meats, can lead to the formation of many potent
carcinogens that are comparable to those found in cigarette smoke (i.e., benzo[a]pyrene). Pre-cooking
meats in a microwave oven for 2-3 minutes before broiling can help minimize the
formation of these carcinogens.
·
Hundreds
of chemicals are classified as
carcinogens.
o The fumes of the metals cadmium,
nickel, and chromium are known to cause lung cancer.
o Vinyl chloride from PVC causes liver
sarcomas.
o Exposure to arsenic increases the
risk of skin and lung cancer.
o Ethylene dibromide,
used in scientific experiments as a dye, is considered to be probably
carcinogenic in humans because they are potent carcinogens in animals.
o Benzene, kepone, EDB, asbestos, and the waste rock of oil-shale
mining have all been classified as carcinogenic.
o As far back as the
1930s, industrial and tobacco smoke were identified as sources of dozens of
carcinogens, including benzopyrene, tobacco-specific
nitrosamines, and reactive aldehydes such as
formaldehyde — which is also a hazard in embalming and making plastics. Vinyl
chloride from PVC is also a carcinogen.
·
CERCLA (Superfund) identifies all radionuclides as carcinogens.
Tobacco Smoking
·
Adult smokers
experience a life expectancy reduction on the order of six years. Those smokers
who die as a direct result of their habit--close to half of all smokers--are
victims of a drop in their life expectancy of more than twice that amount. In
the world's affluent nations, smoking is responsible for 4 to 10 percent of all
healthcare spending. However, by dying earlier than their nonsmoking
compatriots, smokers often avoid expensive chronic illnesses associated with
old age. Consequently, a Dutch study concluded that if everyone quit smoking in
the
Fats
Trans Fats
·
Most of the trans fats we eat today are industrially created by partial
hydrogenation of plant oils, which makes fats more stable at room temperature.
·
Consumption of trans fat raises LDL cholesterol and increases the risk of
coronary heart disease.
·
In 2006 the New
York City Board of Health voted to require all city restaurants to stop serving
foods containing artificial trans fat by 2008.
Starbucks announced it would immediately eliminate trans
fats from baked goods in half its company-owned
Revised: 2/13/07
Text
Copyright 2007
