204 research outputs found
La difficile equazione sull'identità castellana: recupero e conservazione tra luogo e società
No full textLo studio analizza la problematica edilizia legata al recupero dell’architettura fortificata. In particolare vengono esaminati i rapporti tra valore della permanenza storica e contesto. La possibilità di un futuro recupero della stessa viene valutata nella più generale prospettiva del dibattito culturale attuale
Ulipristal acetate in emergency contraception: mechanism of action
No full textWe would like to discuss the mechanism of action of
ulipristal acetate (UPA, marketed as ellaOne1), an orally
active selective progesterone receptor modulator (SPRM)
licensed for emergency contraception (EC). Each tablet
contains micronized UPA 30 mg (equivalent to unmicronized
UPA 50 mg) [1] and it is effective up to 120 h after
unprotected intercourse.
The developers claim that UPA works by delaying ovulation
and excluding any interference with embryo implantation.
They based this conclusion on four experimental
papers investigating the effects of UPA on ovulation [2] and
on human endometrium [3–5], respectively.
These conclusions are shared by most authoritative international
drug administrations. The USA FDA just adds
that alterations to the endometrium might possibly contribute
to UPA efficacy (http://www.accessdata.fda.gov/
drugsatfda_docs/label/2010/022474s000lbl.pdf), whereas
the European Medicines Agency only mentions ovulatory
delay (http://www.ema.europa.eu/docs/en_GB/document_
library/EPAR_-_Product_Information/human/001027/
WC500023670.pdf). Most respected scientific societies
(http://www.sigo.it/usr_files/home/guidelines.pdf) and
many reviews rely completely on those conclusions [2]
and report that ellaOne1, administered immediately before
ovulation, significantly delays follicular rupture.
However, a careful evaluation of the same studies [2–5]
leads us to question the above statements.
One paper evaluated UPA effects during the fertile
period and stated that UPA can delay follicular rupture
even if given immediately before ovulation [2], a point that
is emphasized in its title.
UPA effects were reported to be highly dependent on
levels of luteinizing hormone (LH) at the time of administration:
before the onset of the LH surge, the ability of UPA
to delay ovulation was 100%; after the onset but prior to the
LH peak, it fell to 78.6%, whereas after the peak, it dropped
to 8.3%.
Moreover, when reporting the interval from UPA intake
to follicular rupture, the authors stated that ‘when UPA
was given at the time of the LH peak, the time elapsed to
rupture was similar to placebo (1.54 0.52 versus
1.31 0.48)’ [2]. This means that when either placebo or
UPA were administered around 2 days before ovulation
their effects were null, which seems the opposite of the
conclusive statement of the paper.
As the fertile days are the 4 to 5 days preceding ovulation
plus the ovulation day itself, we should conclude that
UPA can delay ovulation only when taken in the first fertile
days, whereas in the most fertile days (the pre-ovulatory
day and the 2 days around it) [6], it behaves like a placebo
[2].
In spite of these evident limitations, UPA effectiveness
in preventing pregnancies is very high (80%) and does not
decrease depending on which of the 5 days it is taken after
unprotected intercourse [1,7]. This appears surprising if
we assume that UPA effectiveness is due to an anti-ovulatory
action which decreases as LH levels approach to peak:
we should expect a progressive reduction in its effectiveness
as days elapse.
Besides, we wonder how UPA, if taken after ovulation,
could delay a follicular rupture that may have already
occurred up to 4 days earlier. This suggests that the
effectiveness of UPA relies on other mechanisms, particularly
on its endometrial effects.
Experimental studies conclude that the threshold for
altering endometrial morphology is lower than that
for altering folliculogenesis [3–5]. The inhibitory effect
of UPA acts directly on the endometrial tissue through
its inactivation of progesterone receptors [8] and is
observed even after a single administration of its lowest
dose.
When unmicronized UPA (1–100 mg) was administered
in the mid-follicular phase, a time preceding the fertile
days, all doses inhibited luteal phase endometrial maturation
in a similar way. This effect was long lasting: it was
observed even in the very delayed luteal phases following
the coalescence of a new leading follicle and persisted until
the next menstrual flow [3]. This means that all unprotected
intercourse occurring in that cycle after UPA intake
might end in fertilization but with no chance for implantation.
If unmicronized UPA (10–100 mg) was administered in
the early luteal phase [4], there was always a significant
reduction in endometrial thickness, without effects on
luteal hormones. Moreover, the highest doses, 50 mg –
equivalent to ellaOne1 – and 100 mg, significantly inhibited
the endometrial expression of progesterone-dependent
markers of luteal phase differentiation. Peripheral node
addressins were significantly reduced, which is associated
with implantation failure [9]. The trophoblasts, in fact,
initiate implantation by binding to endometrial addressins
through their own L-selectins [10].
When, at last, unmicronized UPA was administered in
the mid-luteal phase, at single doses of 1–200 mg, the
highest dose consistently induced early endometrial
bleeding. This effect was also observed in 50% of the
women treated with 50 mg, the dose equivalent to
ellaOne1 [5].
Thus, evidence shows that UPA endometrial effects can
interfere with embryo implantation and that the high
efficacy of ellaOne1 in EC is probably a result of these
endometrial effects, rather than the anti-ovulatory effects.
References
1 Glasier, A. et al. (2010) Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and metaanalysis. Lancet 375, 555–562
2 Brache, V. et al. (2010) Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture. Hum. Reprod. 25, 2256–2263
3 Stratton, P. et al. (2000) A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women. Hum. Reprod. 15, 1092–1099
4 Stratton, P. et al. (2010) Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB2914. Fertil. Steril. 93, 2035–2041
5 Passaro, M.D. et al. (2003) Luteal phase dose–response relationships of the antiprogestin CDB-2914 in normally cycling women. Hum. Reprod. 18, 1820–1827
6 Wilcox, A.J. et al. (1995) Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. N. Engl. J. Med. 333, 1517–1521
7 Fine, P. et al. (2010) Ulipristal acetate taken 48–120 hours after intercourse for emergency contraception. Obstet. Gynecol. 115, 257–263
8 Blithe, D.L. et al. (2003) Development of the selective progesterone receptor modulator CDB-2914 for clinical indications. Steroids 68, 1013–1017
9 Foulk, R.A. et al. (2007) Expression of L-selectin ligand MECA-79 as a predictive marker of human uterine receptivity. J. Assist. Reprod. Genet. 24, 316–321
10 Genbacev, O.D. et al. (2003) Trophoblast L-selectin-mediated adhesion at the maternal–fetal interface. Science 299, 405–40
An update on the efficacy and safety of novel anticoagulants for cancer associated thrombosis
No full textIntroduction: Cancer-associated thrombosis (CAT) refers to the most common thromboembolic complication of cancer which is venous thromboembolism (VTE). CAT primary prophylaxis, treatment, and secondary prevention are challenging for the complexity of cancer patients, who exhibit hypercoagulability with concomitant-heightened bleeding risk. Areas covered: In this review, the author examines the role of low molecular weight heparins (LMWH), which have been the standard of care for CAT treatment for many years. Direct oral anticoagulants (DOACS) have practical advantages over subcutaneous LMWH, especially for long-term therapy. The author then discusses the results of two RCTs which separately compared the direct oral factor Xa inhibitors, apixaban or rivaroxaban, with placebo for CAT prophylaxis in ambulatory high-risk cancer patients and found that DOACS reduced VTE but increased bleeding. Finally, the author discusses four RCTS separately comparing an oral direct factor Xa inhibitor (edoxaban, rivaroxaban, or apixaban) with LMWH for CAT treatment. DOACS showed non-inferior efficacy, although rivaroxaban and edoxaban showed higher bleeding rates, especially in gastrointestinal cancers. Expert opinion: DOACS have a convenient route of administration and do not require laboratory monitoring, although choice of anticoagulants for CAT depends on factors such as tumor type, bleeding risk, concomitant drugs, and comorbidities
Laparoscopic myomectomy following GnRH therapy
No full textAdministration of GnRH analogues before laparoscopic myomectomy is effective for volume reduction of myoma
A FEM comparison of wear in two metal-on-metal total hip prostheses
No full textThe contact mechanics of two metal-on-metal (MOM) total hip prostheses was studied
by means of the finite element method (FEM). The purpose of the work was to compare two
total hip replacements (DuromTM and MetasulTM) with regard to the amount of wear debris
released. Wear on the bearing surfaces was evaluated following Reye hypotheses from the pressure
distribution, computed by means of three-dimensional FEM models; an approximate analytical
model based on Hertz contact theory has also been developed and discussed. The results
show that in the dry friction condition the DuromTM joint releases almost twice as much wear
volume as produced by the MetasulTM joint. Therefore, while DuromTM implants can improve
hip stability by increasing the prosthetic impingement-free range of motion (PIF-ROM),
MetasulTM prostheses can be a valuable solution whenever wear represents a critical choice factor
Heparin-induced thrombocy-topenia and COVID-19
No full textHeparin-induced thrombocytopenia (HIT) has not been included as a possible cause of thrombocytopenia in Coronavirus Disease 2019 (COVID-19) patients. We report a case of HIT in a patient with COVID-19 treated with heparin. A 78-year-old man was admitted to our hospital for acute respiratory failure and acute renal failure due to SARS-CoV-2 infection; in intensive care unit, one 5000IU heparin dose (day 0, platelet count 305000/μL). On day 2, haemoglobin started to decrease and heparin was stopped. On day 10, platelet count was 153000/μL and 5000IU calcium heparin subcutaneously twice daily was started. The platelet further decreased, reaching 49000/μL on day 17, and the patient was investigated for suspected HIT: an IgG specific chemiluminescence test for heparin-PF4 antibodies was positive and a femoral DVT was found at ultrasound. Argatroban was started, platelet count increased without any bleeding and thrombosis complication. Our experience shows that HIT may develop in heparin treated COVID-19 patients and should be included among the possible cause of thrombocytopenia in such patients. © the Author(s), 2021
Cytomegalovirus-associated recurrent abortion and infertility successfully treated with hyperimmunoglobulins
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