Table of contents :
vital procedures and finally reintroduction into the same (or
another)
living organism.
is one of the most important performance parameters of blood
pumps.
Humans
can clear total doses of up to 14 g of free plasma hemoglobin per
day
if
their renal function is normal. Free plasma hemoglobin of up to
130
mg/dL
may be bound to form hemoglobin-haptoglobin complexes in vivo.
Therefore,
if the plasma hemoglobin level exceeds this value, hemoglobinuria
occurs
and leads to organ failure. Currently, comparive in vitro
evaluations
of
the reported hemolysis effects are difficult due to the lack of
uniformity
of the test methods used. In the literature, 3 types of formulas
are
accepted
as indices of hemolysis. In order to avoid confusion, they are
classified
as :
and/or heart
surgery
(cava veins => aorta bypass).
It is a pulmonary technology capable of facilitated gas
exchange in the
blood, thereby bypassing the alveolar-capillary interface.
It consists
of the application of intermediate-term cardiopulmonary
bypass for the
treatment of potentially reversible heart and/or lung
failure in the
neonate,
child, and adult. Applications in the neonate include congenital
diaphragmatic
hernia (CDH),
pulmonary
arterial
hypertension,
meconium
aspiration
syndrome (MAS),
and pre- and post-operative congenital heart
surgery
support. In the older child, myocarditis,
infections,
and respiratory
failure
(RSV
and ARDS)
are the most frequent indications, in addition to
peri-operative
cardiac
surgical support. ECMO can provide this delivery without
causing the
iatrogenic
damage associated with high mechanical ventilation
pressures, high
fraction
of inspired oxygen, or high doses of inotropic
medications. Though
practitioners
use a multitude of other, more "conventional," therapies
for neonatal
respiratory
failure, only ECMO has been proven in a randomized,
controlled,
clinical
trial to improve both mortality and morbidity among
neonates. The use
of
inhaled nitric oxide (iNO) reduces the necessity for ECMO
in newborns
and
infants with acute hypoxemic respiratory failure.
|
|
|
|
|
| cellulose diacetate (hollow fiber) | Plasmaflo-AP05H (Asahi Medical, Tokyo, Japan) |
|
|
| Plasmaflo-AP05 (Asahi Medical) |
|
|
|
| polypropylene (hollow fiber) | Fenwal CPS-10 (Baxter, Deerfield, IL, USA) |
|
|
| Hemaplex-BT900 (Dideco, Mirrandola, MO, USA) |
|
|
|
| Curesis M82 (Organon Teknika, Durham, NC, USA) |
|
|
|
| polypropylene (flat plate) | Centry TPE (Cobe, Lakewood, CO, USA) |
|
|
| polysulfone (hollow fiber) | Sulflux-FS (Kaneka, New York, NY, USA) |
|
|
| polymethylmethacrylate (hollow fiber) | Plasmax-PS05 (Toray, Tokyo, Japan) |
|
|
or albumin or colloid solution (plasma
exchange
(PE))
if they are not replaced with IVIg
with or without polyneuropathy
recipient
=> hyperviscosity
syndrome
and acute
renal
failure
(ARF))
presensitization-associated
recurrent focal
segmental
glomerulosclerosis (FSGS)rejection
: PE removes mercaptans, GABA, phenolic acid,
aromatic amino acids,
liver
regeneration factors, cerebral activity inhibitors,
sodium, potassium,
and ATP. Survival ranges from 18.0ref-30.0ref-33.3ref-37.5ref-66.7%ref
with polyneuropathy
and mainly decrease PV about 20-30% each session.
Probably, the
existing
empirical approach to planning TPE-treatment in hyper-PV
causes a
little
overdose of this therapy. Only one TPE-session is required
to normalize
PV when it is < 2.2 mPas, whereas a maximum
are observed
: ethylene vinyl alcohol and acrylic copolymers may
cause mild adverse
reaction in some patients taking ACEI
or Waldenstrom's
disease.
To prevent plugging reverse rinse of the secondary PF is
carried. DFPP
is most commonly performed in Japan, but very rarely
initiated in the
USA.|
|
|
|
|
|
| ethylene vinyl alcohol | Evalfux 2A (Kuraray, Osaka, Japan) |
|
|
IgG, IgA |
| Evalfux 3A (Kuraray) |
|
|
cytokines | |
| Evalfux 4A (Kuraray) |
|
|
IgM, LDL | |
| Evalfux 5A / lipofilter (Kuraray) |
|
|
LDL-C | |
| versapor acrylic copolymer | Cryoglobulin filter (Pall Gelman, Ann Arbor, MI, USA) |
|
|
cryoproteins |
| cellulose diacetate | Plasmaflo-AP06M (Asahi, Tokyo, Japan) |
|
|
cryoproteins |
(plugging is frequent and requires multiple
backwashing during the
procedures)
(best results at 4°C)
columns removes IgG
pheresis by
and heterozygous who with documented, symptomatic CAD
Table 1: Currently available adsorber devices for
autoimmune diseases
in Europe.
| Selesorb | IM-TR 350, IM-PH 350 | Prosorba | Immunosorba | Ig-Therasorb | Miro | |
| Company | Kaneka, Wiesbaden, Germany | Asahi-Medical, Japan (DIAMED, Köln) | Fresenius, St. Wendel, Germany | Fresenius, St. Wendel, Germany | Plasmaselect, Teterow, Germany | Fresenius, St. Wendel, Germany |
| Adsorber | Dextran-sulphate | Tryptophan, Phenylalanin | Protein A | Protein A | Polyclonal sheep anti-human Ig | C1q-Ligand |
| Matrix | Polyvinylalcohol | Silica | Sepharose | Sepharose | Polyacrylate | |
| Volume | 150 ml | 350 ml | 300 ml | 62.5 ml | 300 ml | 300 ml |
| Priming volume | 1000 ml (2 columns) | 300 ml | 72,5 ml | 290 ml | ||
| Capacity | N/A | 3 l Plasma: 15 nmol anti-ACh-AK (=2.2 g IgG) | 557 mg IgG/Adsorber | 1,2 g IgG/Adsorber | 4 g IgG/Adsorber | 400 mg Immune complexes/ Adsorber |
| Specificity | Anti-ds DNA antibodies, lipids, fibrinogen, immunoglobulins and others | Immunoglobulins, fibrinogen and others | IgG, IgA, IgM | IgG, IgA, IgM | IgG, IgA, IgM | C1q-CIC, C1q-antibodies, anti-phospholipid abs, ibrinogen |
| Preservative | Steam | Steam | 0.1% Thiomersal in buffer pH 7,0 | |||
| Plasma Volume | > 2.5 l | 2 l | 60 - 100 l | > 120 l | 3.5 l | |
| Regeneration | Yes, during one session | No | No | Yes | Yes | No |
| Storage Period | 3 years | 3 years | 18 months | 18 months | ||
| Costs (EUR) | 1,000.00 per adsorber | 650.00 per adsorber | 1,000.00 per adsorber | 10,000.00 per pair | 15,000.00 per pair | 1,900 per adsorber |
,
hemolytic
anemia,
Staphylococcusspp.
infection and thrombosis at the site of venous access,
allergic
reactions
leading to anaphylaxis
and activation of coagulation, complement, and fibrinolytic
cascades,
and
aggregation of platelets. Systemic
arterial
hypotension
during plasma exchange is aggravated by the concomitant
administration
of ACEI.
During the course of plasma therapy, patients are
anticoagulated
beacuse
of the loss of platelets and clotting factors removed with
plasma. In
the
absence of liver dysfunction, clotting factors in the
circulation
return
to normal within 24 hours.
: sickle cell crises with suspected target organ damage
or before major
surgery
: sickle cell crises with priapism
(side effects : thrombocytopenia, protamine-induced systemic
arterial
hypotension)
(high costs),
possibly through reduction in high concentrations of
these toxins.
Although
MARS has been shown to be useful in FHF, its clinical
efficacy in
subfulminant
hepatic failure and less severe forms of acute liver
failure (ALF)
remains
uncertain. The current literature also suggests that it
may be
beneficial
to treat cases of acute-on-chronic liver failure
(AoCLF). Developed by
Teraklin AG of Germany, is the best known extracorporal
liver dialysis
system and has existed for approximately ten years. It
consists of two
separate dialysis circuits. The first circuit consists
of human serum
albumin,
is in contact with the patient's blood through a
semipermeable membrane
and has two special filters to clean the albumin after
it has absorbed
toxins from the patient's blood. The second circuit
consists of a
hemodialysis
machine and is used to clean the albumin in the first
circuit, before
it
is recirculated to the semipermeable membrane in contact
with the
patient's
blood. The MARS system can remove a number of toxins,
including
ammonia,
bile acids, bilirubin, copper, iron and phenols. MARS
development
started
at the University of Rostock in Germany. It has 510 (k)
approval from
the
Food and Drug Administration (FDA) for drug overdoses
and poisoning as
of June 2005 and is available in the USA since the end
of 2005.
Canada's
first MARS unit arrived at the Toronto General Hospital
in 2005.,
possibly through reduction in high concentrations of these
toxins.
Although
MARS has been shown to be useful in FHF, its clinical
efficacy in
subfulminant
hepatic failure and less severe forms of acute liver
failure (ALF)
remains
uncertain. The current literature also suggests that it
may be
beneficial
to treat cases of acute-on-chronic liver failure (AoCLF)
(subclavian catheter or internal jugular catheter),
which has direct
access
to the heart. Using these access sometimes tend to have
problems like
blocked
catheter from clots or infection at the insertion site.
Therefore,
extra
care has to be taken with temporary access.
and cephalic
vein
at the wrist. Patency = 90% after 1 year, 75%
after 4 years
and the cephalic
vein,
with patency = 70% after 2 years
and the basilic
vein,
with patency = 70% after 2 years
and femoral
vein.
and the saphenous
vein),
but
are of second choice due to higher incidence of
thrombosis,
infections
and reduced depurative efficiency
– antidecubital vein
– femoral
vein
or greater saphenous
vein
or the Dialock system for pediatric patients
or concomitant sepsis)
into and removed from the peritoneal cavity as either a
continuous (2 L
/ 4 hr) or an intermittent procedure. It has effectiveness
similar to
hemofiltration.
The dialyzing hyperosmotic solution (Dianeal (PD-2))
contains:,
expecially in diabetic patients,
loss of endogenous protein and amino acids, retroperitoneal
fibrosis,
hyperglycemia
and hypertriglyceridemia
(dialyzing hyperosmotic solution often is glucose- or amino
acid-rich
and
some pass into liver via portal circulation)
has consistently been associated with a reduced mortality rate
in
kidney
dialysis patients due to the cholesterol-lowering effects of
systemic
inflammation
and malnutrition, 2 common complications of dialysis. When
dialysis
patients
don't have inflammation or malnutrition, hypercholesterolemia
predicts
a progressively higher risk deathref
=> renal
clear
cell
carcinoma.
Other transport activities were also observed in these devices
and
included
active bicarbonate transport, which was decreased with
acetazolamide, a
carbonic
anhydrase II
inhibitor, active glucose transport, which was suppressed with
phlorizin,
a specific inhibitor of the sodium-dependent
glucose transporters (SGLTs),
and p-aminohippurate (PAH) secretion, which was
diminished with
the SLC22A6 /
anion transporter
inhibitor probenecid. A variety of differentiated metabolic
functions
was
also demonstrated in the RAD. Intraluminal glutathione
breakdown and
its
constituent amino acid uptake were suppressed with the
irreversible
inhibitor
of g-glutamyl
transpeptidase acivicin; ammonia
production was present and incremented with declines in
perfusion pH.
Finally,
endocrinological activity with conversion of
25-hydroxy(OH)-vitamin D3
to 1,25-(OH)2 vitD3 was
demonstrated in the RAD.
This conversion activity was up-regulated with parathyroid
hormone and
down-regulated with increasing inorganic phosphate levels,
which are
well-defined
physiological regulators of this process in vivoref.
It demonstrates metabolic, immunologic and endocrine activity
with
systemic
effects in patients with acute
renal
failure (ARF)
and multiorgan failure
(MOF)ref1,
ref2,
ref3
: it ameliorates cardiac and vascular dysfunction, alters
systemic
cytokine
abnormalities, and improves survival time in a large animal
model of
Gram-negative
septic shockref1,
ref2,
ref3.
Hemodialysis and hemofiltration have been important
technologies in
saving
the lives of patients with ARF and CRF by clearing small
solutes from
plasma
and thereby preventing death from acidemia, hyperkalemia,
volume
overload,
and uremia. These therapeutic approaches, however, are still
suboptimal,
as patients with ARF have mortality rates exceeding 50%, and
patients
with
end-stage
renal
diseases (ESRD)
have, on average, a life expectancy of 4-5 years. The
preeminent cause
of death in patients with ARF is the development of sepsis or
the
systemic
inflammatory response syndrome with resulting systemic
vasodilation,
hypotension,
ischemic injury to solid organs, multi-organ failure, and
death. This
vasodilation
is due to persistent and excessive pro-inflammation.
Similarly, the
reduced
survival times of patients with ESRD on chronic dialysis have
been
associated
with a persistent and chronic systemic pro-inflammatory state.
The loss
of renal tubule cell mass acutely in acute tubule necrosis and
chronically
in ESRD results in an immunologically dysregulated state
leading to
excessive
pro-inflammationref1,
ref2.
sandwiched between artificial plates or capillaries. The
problem is
deciding
which liver functions are the most important and shouyld be
carried out
by the BAL bioreactor. Biosynthetic capacity is perhaps the
least
essential
because most proteins synthetised by the liver can be given
exogenously
to patients. The generation and detoxification of ammonia is
undoubtedly
important. Although an increase in ammonia in the blood is
toxic to the
CNS, reduction of ammonia levels per se is not
sufficient to alleviate
this toxicity. The enormous scale-up required to use BAL
devices
clinically
is problematic : at least 1010 hepatocytes in a
BAL bioreactor
would be needed to support a patient's failing liver.
Sinusoidal
endothelial
cells can be expanded to achieve that number. A good vitality
of
hepatocytes
is maintained for 2-3 weeks, but functions decrease.
Encapsulation of
hepatocytes
with calcium or sodim alginate gel could reduce immunogenicity
and
reduce
immune-mediated cytolysis. Freezing and thawing and
hepatocytes could
store
the material for long times. Modular extracorporeal liver
support (MELS)
systems combine biologic liver support with artificial
detoxification
technologyref.
),
could
potentially provide and alternative source of human
hepatocytes.
Although the differentiation of bone marrow derived stem
cells into
hepatocytes
has been demonstrated in vivo, it has not been achieved in
vitro as
yet.
However, liver-derived hamatopoietic cells can give rise
to cells that
resemble bile duct epithelial cells. Embryonic stem
(ES) cells
offer
another valuable option, particularly as human ES cell
lines are now
available.
in the treatment of infertilityref
to induce hypogonadotropic hypogonadism 2 weeks before
ovarian
stimulation| GnRH analogue (GnRHa) |
|
|
|
|
| GnRH agonist | ||||
| nonapeptides | ||||
| leuprorelin | S.C. | 500-1000 mg/d | ? | yes |
| I.M. depot | 3.75-7.5 mg/mo | ? | yes | |
| buserelin | S.C. | 100-500 mg/d |
|
|
| I.N. | 300-400, 3-4 times daily | yes | ||
| goserelin | S.C. implant | 3.6 mg/mo | ? | seldom |
| histrelin | S.C. | 100 mg/d | ? | no |
| decapeptides | ||||
| nafarelin | I.N. | 200-400 mg 2/d | ? | yes |
| triptorelin | S.C. | 100-500 mg/d | 50 mg/d | yes |
| I.M. depot | 3.75 mg/mo | ? | no | |
| GnRH antagonist | ||||
| cetrotide | S.C. | single dose | 2 mg/injection | yes |
| S.C. | multiple dose | 0.25 mg/d | yes | |
| orgalutran | S.C. | multiple dose | 0.25 mg/d | yes |
-induced
ovulation
may be responsible : melatonin levels naturally
cycle in response to
light
and dark. Until recently it was thought that
melatonin acted only
through
the pituitary gland in the brain (this gland is
"switched off" during
IVF
treatment because it controls a woman's own hormone
production,
preventing
any activity which could interfere with treatment
which artificially
stimulates
the ovaries to release an egg), but there are also
melatonin receptors
throughout the reproductive system : the hormone may
act directly on
reproductive
tissues to make women more fertile in lighter
months. If you look at
the
animal world, it's biologically better for offspring
to be born in
spring,
so they then get 6-8 months winter comes to develop
: the same pattern
had historically been seen in natural human
reproduction, but it was
less
obvious now because people had more control over
deciding when they
tried
for a baby, and could use contraception to prevent
conception. It has
been
observed that there is a seasonal variation, but it
has been thought it
might be linked to warmer temperatures in summer
months.
monitoring of follicular growth (size and
number) :
eventually endocrine
monitoring of [17b-estradiol]plasma-assisted
pick-up
under general or local anesthesia and 36 hrs
after
administration
of hCG : on average, of 100 oocytes prelevated (within
10-30'), 90 are
mature and can be surgelated (egg
cryopreservation). Doctors are still figuring
out how to do
this reliably
without the formation of damaging ice crystals within
the eggs, and
there
have been fewer than 100 live births using this
method. 40 survive
treatment
but 4 are damaged. At least 2 US companies, however,
already offer
women
the chance to freeze their oocytes. Of the remaining
36 eggs, 17 are
fertilized
(due to high H2O content the cell membrane
becomes stiffer and
fertilization has to be accomplished by
microinjection) and only 2
undergo
a correct implantation giving start to normal
pregnancies. On average,
3.5 pregnancies are obtained every 100 oocytes
prelevated. The average
likelihood of becoming pregnant after one IVF attempt
is roughly
20-30%,
and this drops off with age. Doctors have been
searching for a way to
distinguish
eggs with a high chance of IVF success based on the
their shape, genes
or metabolism, but long telomeres could be the secret
of success : eggs
with an average telomere length shorter than around
6,300 DNA units
never
produce a pregnancy
patient about to undergo chemotherapy and froze it at
-196° C. 6 years
later, they thawed 15 fingernail-long strips and grafted
them under the
woman's abdominal skin using a local anaesthetic (they
feel like beads
under the skin) : transplanting the ovarian tissue back
into the
patients
is also difficult and there is the danger that the
tissue may contain
cancerous
cells, but putting the transplant beneath the skin of
the abdomen
reduces
the health risks and it can be easily removed if
necessary. 3 months
later,
the woman's hormones prompted the tissue to start making
eggs, which
the
doctors boosted with fertility drugs. Over 8 months they
collected 20
mature
eggs with a needle and mixed 8 of them with sperm for
IVF : 2 eggs went
on to form embryos in culture. One was implanted in the
woman, but it
did
not lead to pregnancyref.
This is not surprising in IVF treatment, where the
chances of
successful
implantation are 20-30% at best : Oktay is trying once
more to produce
a pregnancy in the same woman and he is about to start
the procedure on
others. Once the technique is improved, doctors say it
may offer hope
to
cancer patients or others whose ovaries are affected by
disease or
drugs.
Some of these patients have already banked their ovarian
tissue. In
1997,
the Belgian woman Ouarda Touirat was diagnosed with
stage IV Hodgkin's
lymphoma
- cancer of the lymph system that had spread to other
organs. 5 tissue
samples, about 12-15 mm (0.5-0.6 of an inch) long and 5
mm (0.2 of an
inch)
wide, were taken from her left ovary. 4 of the samples
were cut into 70
small cubes while the other was left uncut; all were
frozen in liquid
nitrogen
at -196 C (-320 F). Touirat then underwent a powerful
course of seven
anti-cancer
drugs over six months which caused her periods to end,
and this was
followed
by a course of radiotherapy. Tests confirmed that both
her ovaries had
failed. In 2003, after her recovery from cancer, the
stored tissue was
thawed and reimplanted in the pelvic region, tucked into
a niche next
to
the right ovary, which like the remains of the left
ovary had
atrophied.
A week later, a network of tiny blood vessels could be
seen around the
implanted tissue, a good sign that it had been accepted.
5 months
later,
the patient started to resume her menstrual cycle and
after 11 months
she
conceived. She became pregnant by natural means, not by
IVF. They
observed
a developing egg in the graft, but none in the two
ovaries, just before
the woman fell pregnant. On Sep 23, 2004 at the
Cliniques
Universitaires
Saint-Luc in Brussels, > 7 years after slices of
ovary were
placed in storage
to give her the chance of motherhood after cancer
therapy, 32-year-old
Touirat gave birth to a healthy 3.72-kg (8.2-pound) girl
named Tamararef.
Oktay believes the pregnancy could have resulted if one
of the woman's
ovaries survived the chemotherapy and produced eggs on
its own : few
women
who have chemotherapy for Hodgkin's lymphoma, as this
woman did, are
completely
sterilised by the treatment
in which tumour cells might be reintroduced with the graft
and any
children
born from the technique might be somehow different,
although animal
experiments
suggest that offspring should be normal. Over the last few
years,
Oktay's
group have grafted pieces of thawed ovarian tissue on to
women's
ovaries
or arms, and showed that the tissue resumes making eggs
and live
embryos.
increases if a woman has had IVF. And the risk is
even greater if
the eggs come from a non-relative. 61 pregnancies resulted
from egg
donation
were compared with a control group of standard IVF
pregnancies, in
which
the eggs come from the woman who wants to get pregnant.
Hypertension
attributable
to the pregnancy struck 12.5% of women in the first group,
as opposed
to
3.7% of those who had the more common procedure. But the
researchers
discovered
another striking difference in the group receiving donated
eggs: the
risk
of high blood pressure increased by more than fivefold in
cases where a
woman had received an egg from a unrelated person, but
only twofold
when
the egg came from a sibling. The researchers have yet to
prove why eggs
from unrelated donors make complications more likely, but
they believe
the answer lies in how the immune system reacts to the
developing
fetus.
The presence of foreign proteins on these eggs could
trigger an
abnormal
response in the patient's immune system leading to
hypertension. The
immune
system could be to blame. Some people believe an immune
response
against
cells in the uterus might lead to the release of reactive
oxygen
molecules
in the blood, which could damage the blood vessel cells
that protect
against
hypertension. But there is still much debate over the
issue. Their
findings
should encourage sisters to consider donating eggs.
Donation from a
sibling
would improve the outcome both in terms of the well-being
of the
pregnant
mother and the health of the baby
,
which are able to give rise to almost every tissue in the
body, would
be
removed and nurtured in the lab with molecules that
encourage them to
develop
into either sperm or eggs. The resulting cells could be
fused with the
sperm or egg of the other partner by fertilization, and the
embryo
could
then be implanted. Such a technique would do away with a lot
of the
objections
to reproductive cloning infertile couples with defective
eggs or sperm
for whom current ARTs do not work.-assisted
direct
insemination of a preovulatory follicle in women with at
least
one
patent fallopian tube and controlled ovarian stimulation.-assisted
pick-up
and then placed, together with a sample of semen, in a
transcervically
catheterised uterie tube
by mechanical or local application of a zona
solvent like
acid or
enzymes using microneedle to inject the material
of early cleaved embryo by partial slicing by means of
micromanipulation
before replacement so as to improve chances
of
eventual
hatching
to provide an access through which sperm can more easily
gain path to
the
egg
: zygote
intra-Fallopian
transfer
(ZIFT) : echographic pick-up + IVF+
laparoscopic delayed transfer of a maximum of 3 zygotes in
the fimbrial
end of one healthy fallopian tube => natural tubal
transport of
embryos
to the uterus. Better nidation rates than gamete
intra-Fallopian
transfer (GIFT).-assisted
pick-up;
after IVF
the zygote
is then placed in a transcervically catheterised uterine
tube
: fertilization
in
vitro and embryo transfer (FIVET / IVF-ET)
: nidation occurs in 15-20%. Despite both doctors and
patients widely
believe
that placing several embryos into the womb during
treatment boosts the
chances of pregnancy, the pregnancy rate after
transferring 1 embryo is
just as high as that after transferring 2. In January
2003, Swedish
health
authorities banned the transfer or > 1 embryo at a time
except
in exceptional
circumstances : the rate of pregnancies after the
legislation was just
as high as it was before (around 33% were successful).
However, the
frequency
of twin pregnancies fell from 23% to < 6% (transferring
a single
embryo
can still result in twins if 1 embryo splits naturally
into 2). 2
studies
from US fertility clinics mirrored the Swedish results.
When otherwise
healthy women were offered the choice of having one embryo
implanted
instead
of 2, pregnancy rates remained just as high (over 70%).
Researchers
hope
that the data, which echo that emerging from a number of
other studies,
will encourage more clinics to favour single embryo
transfers. In women
under 36 years of age, transferring one fresh embryo and
then, if
needed,
1 frozen-and-thawed embryo dramatically reduces the rate
of multiple
births
while achieving a rate of live births that is not
substantially lower
than
the rate that is achievable with a double-embryo transferref.
In women aged > 37 years, or with previous experience
of failed
IVF, however,
it may still make sense to transfer more than one embryo.
The risk of
multiple
births is much lower in these groups. Many countries other
than Sweden
are already encouraging a limit to the number of embryos
transferred.
In
September 2004, the ASRM released new guidelines advising
USA clinics
to
transfer < 2 embryos to women < 35. However, one of
the
biggest obstacles
to the widespread adoption of single embryo transfer is
that patients
in
the USA and many other countries pay for their own
treatment, which
often
costs over $10,000 for a single IVF cycle. Wanting to
maximize their
chances
of success, patients tend to favour the transfer of
multiple embryos in
each cycle; and clinics support the practice because they
believe it
will
increase the pregnancy rates, which they publish to
attract patients.
To
overcome this perception, there is a need to educate
patients about the
new data and about the health risks associated with twins
(sHLA-G) (secreted by embryos and thought to
help them
survive after
implantation) in supernatants of individually cultured
46-h embryos is
a potentially valuable indicator of 'embryo
competency' and IVF
outcome.
Of women aged under 39 whose embryos pumped out
above-average levels of
HLA-G, 71% became pregnant. Of women whose embryos
made below-average
amounts
of HLA-G, only 22% fell pregnant. The pregnancy rate
for women over 39
was lower overall, but high HLA-G embryos still fared
betterref.
Anyway one criticism is that although the team
measured HLA-G produced
by each embryo, they implanted 2-3 embryos into the
uterus at a time,
so
they cannot prove that the high HLA-G embryos were the
ones that
implanted.
Earlier studies have hinted that embryos making HLA-G
divide faster and
are better able to implant. By selecting specific
embryos for transfer
based on their individual sHLA-G expression, pregnancy
and implantation
rates can be maximized while the number of embryos
transferred can be
reduced,
thereby minimizing the incidence of high-order
multiple pregnancies
to be carried out at the University College Hospital
in London. Up to 4
couples will be approved
to be carried out at the University College Hospital
in London. 4
couples
were be approved, including Angela Donovan. Women
already are allowed
to
screen for retinoblastoma 11 weeks into pregnancy
and abort affected
foetusesref
: hematopoietic
stem
cells (HSC) transplantation
from umbilical cord blood or bone marrow from the
newborn will be used
to treat disease in an older brother or sister.,
the first child in Britain, and among only 5 in the
world, to receive a
successful transplant from a sibling born to help
cure their illness.
His
parents, Michelle and Jayson, received initial
treatment, including
IVF,
from the Assisted Reproduction and Gynaecology
Centre, in London. But a
ruling by Britain's Human Fertilisation and
Embryology Authority (HFEA)
forbiddiong PGD meant the couple were forced to turn
to a clinic in
Chicago
to complete the procedure. In 2002, two 3-day-old
embryos were
implanted
in Mrs Whitaker. In June 2003, she gave birth to
Jamie, a perfect
genetic
match for his brother. It meant stem cells from the
baby's umbilical
cord
could be used to treat Charlie. The transplant was
practiced in July
2004
at Sheffield Children's Hospital and in October
tests on Charlie's bone
marrow have produced very promising results..
The perfect match Jodie Fletcher born on
August 2005,
the disease that affects their 5-years old son Zain
Hashmi.
However,
the Hashmis have not yet conceived such a child, and
currently face a
second
legal challenge to the HFEA's decision, by the
pro-life group Comment
on
Reproductive Ethics (CORE). The family hoped that
umbilical cord blood
would cure Zain, who needs painful blood
transfusions every 3-4 weeks
and
drugs from a drip for 12 hours, 5 nights a week.
After 6 attempts and
several
miscarriages the couple have yet to have a baby.
With time running out
for Mrs Hasmi, 40, they believe their best chance
lies in a donor. The
UK's highest court gave the go ahead for the
creation of "saviour
siblings"
to give umbilical cord, blood, or bone marrow to try
to save the life
of
a brother or sister. 5 judges in the House of Lords
unanimously ruled
that
the law that set up the HEFA gives the authority the
power to licence,
alone or separately, both PGD and tissue typing on
embryos used in
treatment
for IVF. The ruling, upholding an appeal court
judgment in April 2003,
removes all doubt for Raj and Shahana Hashmi, who
have been trying to
produce
a sibling with the same tissue type as their son
Zain, aged 6, who was
born with thalassaemia major. The couple, from
Leeds, have so
far
had 6 unsuccessful attempts at IVF, but each time
they either failed to
produce an embryo of the right tissue type or the
pregnancy ended in a
miscarriage. The case was taken to the House of
Lords by Josephine
Quintavalle
and her campaigning group, Comment on Reproductive
Ethics (CORE), who
argued
that the HEFA had no power to licence the creation
of a baby to save
the
life of another. The arguments hinged on the wording
of the Human
Fertilisation
and Embryology Act 1990. Lawyers for Mrs
Quintavalle, who had won her
case
in the high court before the judge's ruling was
overturned by the
appeal
courtref,
argued in the House of Lords that the act's wording
allowed the
authority
to licence preimplantation genetic diagnosis but not
tissue typing. But
the law lords decided that the authority's
discretion was wide enough
even
to allow the selection of an embryo's
characteristics on social
grounds,
although it was unlikely that such a licence would
be granted. Lord
Hoffmann
said that the technique of taking a single cell from
an embryo and
testing
it for genetic disorders and tissue compatibility
was "a way to save
the
Hashmi family from having to play dice with
conception. He noted that
parliament
had said nothing about, for example, sex selection.
The only reasonable
inference is that parliament intended to leave the
matter to the
authority
to decideref
if the fetal Rh blood type is positive. Although the
incidence of
severe
RhD alloimmunization has decreased with prophylactic
anti-D
immunoglobulin
administration during and after pregnancy,
sensitization still occurs
in
a small group of women. In such women, Rh disease
will continue to be
significant
problem and for their babies who may be affected.
Preimplantation
genetic
diagnosis (PGD) may be utilized to avoid
materno-fetal blood group
incompatibility
in an RhD-sensitized woman. Biopsy of a single cell
from early
cleavage-stage
embryos screening for RhD-negative embryos allows
the transfer of only
RhD-negative embryo(s) into the uterus. This avoids
any complications
related
to haemolytic disease of the fetus and newborn. This
article describes
the first reported case of an unaffected pregnancy
using PGD for Rh
disease.
IVF and embryo transfer resulted in a clinical
pregnancy and the birth
of a healthy girl in November 2003, confirmed to be
blood type RhD
negative,
to a couple who had previously had one child
severely affected by Rh
disease.
PGD in couples with a heterozygous RhD-positive male
partner provides
an
option for avoiding haemolytic disease of the
newborn in RhD
alloimmunized
mothersref
used to detect chromosome copy number, the greatest
inherent risk of
misdiagnosis
is due to chromosomal mosaicism--ie, the co-existence
of aneuploid and
diploid cells in one embryo. This situation has been
shown to affect,
on
average, at least 50% of cleavage-stage embryos in
numerous studies
worldwide
that used FISH, molecular analysis (comparative
genomic hybridisation),
and karyotyping. For single-gene and chromosomal
cases, the easiest way
to increase accuracy is to analyse 2 independent cells
: an acceptable
pregnancy rate (15% versus 27%) can still be achieved
despite a policy
of taking 2 cells from embryos consisting of at least
6 cells
than conventional IVF patients
due to simultaneous transfer of 3-4 embryos in FIVET
(20-30% vs. 1%) The rate of multiple gestations after in vitro
fertilization
is 26.4% in Europeref
and 35.3% in the USAref,
as compared with 1.1% after natural conception. Adverse
outcomes
associated
with high-order gestations include serious perinatal morbidity
and
mortality
and long-term disabilities (Crowther CA. Multiple pregnancies.
In:
James
DK, Steer PJ, Weiner CP, Gonik B, eds. High risk pregnancy:
management
options. 2nd ed. Philadelphia: W.B. Saunders, 2002:129-52)
stage would enhance the likelihood of pregnancy as compared with
the
usual
procedure in which the embryo is transferred at the
single-cleavage
stage
(day 3)ref1,
ref2,
but this suggestion remains controversialref.
The main disadvantage of transferring the embryo at the cleavage
stage
rather than at the blastocyst stage is that the morphologic
criteria
that
govern embryo selection on day 3 are highly subjectiveref
and less accurately reflect the genetic quality (euploidy
status) of
embryos
than do the criteria used on day 5. For example, among women 36
years
of
age or older, 59% of embryos judged as "top quality" on day 3
were
found
to be aneuploid, as compared with 35% of blastocysts judged as
"top
quality"
on day 5ref1,
ref2.
If these findings also apply to women under 36 years of age
(albeit in
a lower proportion)ref,
then selecting only one cleavage-stage embryo for use (even if
it is of
top quality) would increase the chances of transferring a
chromosomally
abnormal embryo. On the other hand, a potential downside to the
use of
blastocyst-stage embryos is that some embryos are not able to
reach the
blastocyst stage in cultureref.
Additional concerns about the use of blastocysts include the
possibilities
of an increased risk of monozygotic twins, an altered sex ratio
of
births,
and epigenetic effects on the embryo. In infertile women under
36 years
of age, those undergoing transfer of a single blastocyst-stage
(day 5)
embryo embryo have a higher rate of pregnancy than those
undergoing
transfer
of a single cleavage-stage (day 3) embryo (P=0.02) . The rate of
delivery
was also significantly higher in this group than in the group
undergoing
transfer of a single cleavage-stage embryo (32.0% vs. 21.6%;
relative
risk,
1.48; 95% confidence interval, 1.04 to 2.11). 2 multiple births
occurred,
both of monozygotic twins, both of which were in the group
undergoing
transfer
of a single cleavage-stage embryoref.
Despite the well-recognized risks associated with multiple
gestations,
many patients still want to have multiple embryos transferred to
enhance
the probability of pregnancyref.
Increasing awareness of the costs and risks of multiple births
has led
the medical community to reduce the number of embryos
transferred. For
single-embryo transfer to be accepted by patients, doctors, and
payors,
however, it must be associated with acceptable pregnancy rates.
One
approach
to optimizing pregnancy rates after single-embryo transfer is to
follow
it with transfer of a frozen–thawed embryo in cases in which the
initial
transfer is not successful. In a previous randomized trial, this
strategy
achieved a rate of live births that was not substantially lower
than
the
rate after transfer of two fresh cleavage-stage (day 2) embryos
(38.8%
vs. 42.9%) and was associated with a dramatic reduction in the
rate of
multiple births (0.8% vs. 33.1%)ref.
However, these results were obtained among women under 36 years
of age
who had at least two good embryos available for transfer and
thus had a
good prognosis, and the plausible difference in rates of live
births
between
the two protocols (on the basis of the 95% confidence interval)
was as
high as 11.6%. For some couples, this difference may not be
acceptable,
particularly given the observation that the stress associated
with in
vitro
fertilization leads many couples to abandon treatment without
proceeding
to a second trial, even if they can afford itref.
Increasing the pregnancy rate in the cycle in which fresh
embryos are
used
would be expected to increase the acceptability of single-embryo
transferref.
The rate of live births after transfer of a single fresh
blastocyst-stage
embryo was similar to that after transfer of two fresh
cleavage-stage
(day
2) embryos in the Scandinavian studyref.24
Smaller
studiesref1,
ref2
have found rates of ongoing pregnancy of up to 60% after
elective
transfer
of a single blastocyst. Similarly, analysis of a
population-based
sample
of 50,819 in vitro fertilization procedures in the
USA in 2001 revealed
that transfer of a single blastocyst-stage embryo resulted in a
live-birth
rate ranging from 31.6 to 39.5% among women 20 through 37 years
of ageref.
The success of single-blastocyst transfer will require effective
methods
of cryopreservation of blastocysts. Data are needed to compare
the
rates
of live births (including both births resulting from transfer of
fresh
embryos and those resulting from transfer of frozen–thawed
embryos)
after
transfer of cleavage-stage and blastocyst-stage embryos. A
live-birth
rate
of 11% has been reported after transfer of frozen–thawed
blastocyst-stage
embryos (94 of 857 cycles)ref,
whereas the live-birth rate after transfer of freeze–thawed
cleavage-stage
embryos is approximately 15%. A concern in randomly assigning
patients
to treatment at the time of consultation, before embryologic
data were
available, was that it might lead to a high rate of cancellation
of
transfers
of blastocyst-stage embryos. However, among this population of
women
under
36 years of age who were undergoing a first or second trial of in
vitro
fertilization, cancellation of transfer on day 5 was rare.
Prospective
studies are needed to determine whether blastocyst transfer is
appropriate
in older women or in women with repeated implantation failures.
Recent
dataref1,
ref2,
however, suggest that the number of embryos with two pronuclei
(day 1)
or cleavage-stage embryos may serve as a predictor of the
success of
blastocyst
transfer. An increased risk of monozygotic twins has previously
been
reported
with blastocyst transfer in retrospective studiesref1,
ref2.32,33
There
were no cases of monozygotic twins after single-blastocyst
transfer
in our study, but the study was not powered to assess the risk
of
monozygotic
twins or other potential risks associated with extension of
embryo
culture
to day 5, such as birth defects and long-term health outcomes.
The 2
second-trimester
pregnancy losses in the blastocyst-transfer group, including the
elective
termination owing to anencephaly, may be a cause of concern,
although
the
rates of such complications did not differ significantly between
the
groups.
Larger studies are required to address these issues. The higher
rates
of
ongoing pregnancy and delivery after transfer of a single
blastocyst-stage
embryo than of a single cleavage-stage embryo are probably due
to a
better
selection processref.
Although some genetically abnormal embryos are able to reach the
blastocyst
stage, the risk of aneuploidy in a top-quality blastocyst is
lower than
that in a top-quality cleavage-stage embryoref1,
ref2.
A recent meta-analysis comparing transfer of cleavage-stage and
blastocyst-stage
embryos did not show a difference in favor of the latter embryosref.
However, this analysis included studies involving transfer of
more
cleavage-stage
embryos than blastocyst-stage embryos, and the transfer of more
cleavage-stage
embryos could have compensated for the potentially lower quality
of any
individual cleavage-stage embryo relative to that of a
blastocyst-stage
embryo. In appropriately selected patients (with > 3 good
embryos on day
3), transfer of 2 blastocysts results in a significantly higher
delivery
rate than transfer of two cleavage-stage embryos, but with the
drawback
that almost half of the initial pregnancies involved twinsref
(<37 weeks, 30.3 vs 6.3%) : compared with spontaneously
conceived twins
who were matched for maternal age, IVF twins have an increased
risk of
preterm birth between 32 and 36 weeks of gestation (OR =
1.48), and an
elevated risk of preterm birth at <37 weeks of gestation
when
parity
is also matched for an OR =1.57. There was an increased rate
of
cesarean
delivery among IVF twins (OR = 1.33). There were no
significant
differences
in incidences of perinatal death, low birth weight infants, or
congenital
malformationsref.
(<2500 g, 27.4 vs 4.6%)
(5.4% of all babies in the IVF group (1.39 [1.25-1.54]), and
the rates
of neural-tube
defects
(NTDs)
and oesophageal
atresia
were higher than those in the controls
in the IVF groupref1,
ref2
(1.7), epilepsy
(1.5), congenital
malformations
(1.8) or childhood
cancer
(1.6), but also for asthma
(1.4) or any infection
(1.4).,
Angelman
syndrome
and retinoblastoma
are injected into an animal inducing a myeloma and mAbs are
recovered
from
serum after sacrifice. In such a model it isn't possible to
obtains
MAbs
against intracellular Ags. sometimes when they are injected into
a
species
different from that of the animal above mentioned, they can
become
target
for host Abs (e.g. human anti-mouse activity (HAMA)).
(unproved yet; it could have higher effectiveness)
)
:
).
He aims to produce cloned ES cells using the DNA of
adults with a
genetic
form of MND and then coax these to develop into motor
neurons -- the
long
nerve cells that transmit messages from the brain and
spinal cord to
the
muscles. The eggs they use will not be allowed to grow
beyond 14 days.
Once the stem cells are removed for cell culture, the
remaining cells
will
be destroyed. They will compare the behaviour and
chemical profile of
neurones
with the gene defect to those without
in sheep's milk which can be used in medicines to treat
cystic fibrosis
and emphysema. But the work was put on hold after its
partner Bayer
pulled
the plug on the trials, saying they were too costly. PPL
said on July
15,2003
it was to slaughter up to 3000 genetically modified sheep
at its 2
farms
in Scotland, but had not confirmed how many of the
Whakamaru flock,
made
up of about 3000 genetically modified sheep and 1000
normal sheep, will
be killed.
animals, such as the Tasmanian tiger (Thylacinus
cynocephalus), an Australian marsupial, may prove
more difficult,
but cells frozen under modern conditions might offer a way to
preserve
animals that have more recently become endangered.
Resurrecting a
species
will require more than recreating 1-2 animals. Genetic
diversity,
having
many animals to interbreed, is essential for maintaining a
healthy
population.
Alliance
to Rescue Civilization (ARC) wants to establish a
genetic
Noah's Ark
of sorts or a protected stash of genomes from Earth's wide
array of
species
and individuals. The concept is somewhat similar to the Frozen
Zoo
project,
based at the San Diego Zoo. The difference is this genetic
library
could
one day be used to revive the human species. And it's not just
the ARC
that has pondered such a moon-based bank. Bernard Foing, chief
scientist
with the ESA, said it's an idea that his agency has discussed
for some
time : such a plan is probably decades away and much needs to
happen
before
any such project becomes even remotely possible. Still, every
journey
and
project begins with a single step, and that is where the
Smart-1
orbiter
comes into play.
)
was cloned by Professor Ian Wilmut of the Roslin
Institute, Edimburgh, in collaboration with PPL
Therapeutics by fusing a mature cell from the mammary
gland
of a nameless
6-year-old died 3 years before and an egg cell whose nucleus
had been
removed.
From 277 attempts, just 29 blastocysts implanted in the
uterus and she
was the sole living birthref.
The achievement is announced on February 23, 1997. A
mammalian oocyte
is
a huge cell containing perhaps 100,000 mitochondria. The
mature
mammary-gland
cell that was merged with the oocyte was much smaller,
containing
between
2,000 and 5,000 mitochondria. The researchers
could find no mitochondria in cloned sheep that could have
been derived
from the mature cell (all came from the oocyte) : as in
conventional
sexual
reproduction although the recipient oocyte has lost its
nucleus, it
still
retains the capacity to wipe out invading mitochondria. In
1998, some
researchers
suggested that her DNA could have come from an adult stem
cell or from
a fetal cell - Dolly's mother was pregnant when the cell for
the clone
was taken. But DNA fingerprinting of frozen tissue cleared
the argument
up, and re-affirmed Dolly's status as a clone.
and the first and the only named rat clone, is now father to
a litter
of
healthy 2-month-old pupsref.
Genetically modified rats can be produced by other methods,
but their
DNA
is altered at random. Cloning gives added control - specific
genes in
the
donor cell can be altered, added, or removed : genetically
modified,
cloned
rats take longer to make and suffer more ill health. Small
rodents have
been used in medical research for over a century. Mice
gained
popularity
during the 1980s when researchers developed the ability to
manipulate
the
mouse genome at will - resulting in some 5000 GM strains.
,
was made by scientists at Texas A&M University. It is a
genetic
copy
of his donor (skin cells were used), a south Texas buck
considered a
huge
trophy
.
Researchers sucked several nuclei out of developing fly
embryos, and
injected
them into a fertilized fly egg. From over 800 initial
attempts, they
conjured
5 adult insects. But embryonic cells are much easier to
reprogramme
than
adult cells and there are not many close parallels to what's
going on
in
mammalsref
)
ambles on to the world stage today. His birth was a feat of
ingenuity
and
perseverance, but some scientists question the value of the
exercise.
The
Afghan hound puppy has been hidden from the world at the
Seoul National
University in South Korea for the 9 weeks since his birth
from a yellow
Labrador retriever. He bears exactly the same DNA as an
older hound who
lent a few ear cells to the researchers. He's also quite a
survivor,
being
the only one of 1,095 cloned embryos implanted in 123 dogs
to survive
to
healthy puppyhood. Since Dolly the cloned sheep made her
appearance
nearly
a decade ago, the field has not advanced as much as was
expected at
first.
Cloning animals has proven difficult and every species
presents its own
problems. Even when everything seems to be going right, the
majority of
cloned embryos fail because their genes are expressed in
abnormal ways.
For dogs, the main challenge lies in harvesting the eggs.
Canine eggs
leave
the ovary at a very early stage of development and then
mature as they
travel towards the uterus in the oviducts. Harvesting the
eggs at the
point
of ovulation and trying to mature them in a test tube
failed. So the
research
team had to wait and remove the eggs by flushing them out of
the
oviducts
using a custom-made solution. The nucleus of each of
these
egg was removed
and replaced with a nucleus from an ear cell.
Successfully
fused cells
were then implanted in female dogs. The painstaking work was
completed
by the lab of Woo Suk Hwang, the South Korean researcher who
is famous
for creating a cloned human embryo and deriving stem cellsref.
It took a team of about 15 people 2.5 years to produce the
dog, whose
name
'Snuppy' is short for Seoul National University
puppy. The donor
dog belongs to a professor of internal veterinary medicine
at the
university.
The point of bringing Snuppy into the world is to pave the
way for a
line
of dogs that could model certain human illnesses. But
cloning a kennel
of diseased canines is a long way offref.
Future solutions will involve the development of a hormone
treatment
whichmight
induce canine ovulation, or a method for maturing eggs in a
test tube.
Independent evidence from the Seoul National University
Investigation
Committee
has been provided that Snuppy, the one of the pair to
survive, is a
genuine
cloneref1,
ref2.)))))))
: they can live to 11 or 12 years and lung infections are
common in
older
sheep, particularly those housed inside)))
:
gene, which is an important component in breast milk,
were born in east
China’s Shandong Province. Only a few countries are
capable to do this
type of cloning, including UK and Argentina).
Fused
egg cells from hundreds of failed NT attempts in rhesus
monkeys
all
stopped dividing shortly after the first few divisions. The
mitotic
spindles
were disarrayed and the chromosomes on the spindles were
misaligned.
The
daughter cells also contained unequal numbers of
chromosomes. The NT
oocytes
were missing several proteins essential for proper
chromosome
distribution
to daughter cells : NuMA1
needed for spindle pole assembly, as well as 2 motor
proteins, KIFC1
/
HSET and KIF11
/ Eg5. The absence of these proteins was due to their
close
association
with the oocyte DNA : when the DNA was removed from the
oocytes in
preparation
for NT, the proteins were also accidentally removed.
Reinserting the 3
missing proteins into the fused oocytes allows cell division
to proceed
normally. In some animals, such as cows, the cells get their
spindle
machinery
from other sources, such as the cell that is being cloned.
In other
animals,
the spindle and its proteins are not as closely associated
with the
oocyte
DNAref))ref
: attempts to produce the third generation of cloned bulls
were
unsuccessfulref
technology..
It can also be used to confer susceptibility to a given drug
=> genetic
ablation of some cell types in the developed
organism..
Because of the dominant nature of the knockdown, embryonic
phenotypes
could
be directly assessed in embryos completely derived from ES
cells by the
tetraploid aggregation methodRef)
and seroprophylaxis
levels by overexpression of a D-galacturonic
acid
reductase
in gene dose defects
and seroprophylaxis.
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