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Biomedical subjects

Carlos Simón

Publications and source records attributed to Carlos Simón.

At least 19 recordsLinked to original sources

Heteroparental blastocyst production from microsurgically corrected tripronucleated human embryos.

OBJECTIVE: To prove the efficiency of identification and removal of one of the surplus paternal pronuclei in dispermic IVF zygotes to obtain heteroparental blastocysts. DESIGN: Experimental. SETTING: One hundred fourteen tripronucleated (3PN) embryos from conventional IVF. PATIENT(S): After informed and signed consent, the patients from Instituto Valenciano Infertilidad (IVI), Valencia, donated their abnormally fertilized embryos. INTERVENTION(S): Seventy-two embryos were diploidized by microsurgical removal of the pronucleus located at the farthest position to the second polar body. Forty-two 3PN embryos served as controls. MAIN OUTCOME MEASURE(S): Survival and correction rate; in vitro development up to the blastocyst stage; X, Y, and 18 chromosome determination by triple fluorescent in situ hybridization and, inheritance analysis for 10 polymorphic repeat regions using polymerase chain reaction (PCR) amplification and sequencing. RESULT(S): Seventy-eight percent of 3PN zygotes (56/72) survived manipulation and eventually 51 zygotes had two pronuclei (71%). Forty-one percent of manipulated embryos progressed in vitro to the blastocyst stage (21/51). Fluorescent in situ hybridization analysis performed on eight manipulated embryos confirmed their diploid state; all four controls were triploid. Heteroparental inheritances were also confirmed in four of six manipulated embryos. CONCLUSION(S): Heteroparental blastocysts can be derived from corrected dispermic zygotes.

Adult↗

Effect of sperm glutathione peroxidases 1 and 4 on embryo asymmetry and blastocyst quality in oocyte donation cycles.

OBJECTIVE: To prospectively determine the impact of concrete components of the sperm oxidative glutathione stress system in terms of enzymatic activity and mitochondrial RNA (mRNA) expression on embryo quality and reproductive outcome. Human spermatozoa use the glutathione system to inactivate reactive oxygen metabolites, and there is a close correlation between some components of the glutathione system and male fertility. However, very few data are published regarding this system in sperm cells and its effect on fertilization ability and embryo development in human beings. DESIGN: An oocyte-donation model, used to homogenize the female factor. SETTING: University-affiliated private IVF setting. PATIENT(S): Semen samples from infertile males (n = 43) of couples undergoing oocyte-donation cycles (n = 43). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gene expression and activity of glutathione peroxidases (GPXs) 1 and 4, glutathione reductase, and intracellular glutathione (GSH) by fluorescent quantitative polymerase chain reaction and spectrophotometry, respectively. RESULT(S): Fertilization rate, pronuclear number, asymmetry, and pronuclear body distribution were not correlated with any sperm glutathione parameters that were considered. When day 3 embryo parameters were evaluated, only GPX4 mRNA expression in sperm cells was statistically significantly lower when asymmetric embryos were observed. Also, worst embryo development and morphology on day 5 was statistically significantly correlated with lower sperm GPX1 activity (101.07 vs. 258.8 IU/mg protein). Glutathione system analysis in fresh sperm was not statistically significantly different in patients achieving pregnancy compared with those who not, and we did not find any correlation with implantation rate. CONCLUSION(S): We have been able to correlate embryo morphology on day 3 with the sperm expression of GPX family members. The results indicate that sperm-derived mRNA may condition human embryo quality and persist even to blastocyst stage. The correlation of the sperm GPX family mRNA expression with embryo health appears quite promising for discovery of molecular causes of male infertility.

Adult↗

Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a life-threatening condition associated with ovarian stimulation. Its pathophysiology is unknown and its treatment continues to be empirical. Early (E)- and late (L)-OHSS occur in women at risk, though not in all cases. Vascular endothelial growth factor (VEGF) is related to increased vascular permeability in OHSS. We analysed the dynamics of the VEGF system in E- and L-OHSS. METHODS: A prospective cohort of women undergoing IVF-ICSI treatment were divided into groups. E-OHSS: Nonpregnant patients classified as women not at risk (group 1) (n = 11) and patients at risk who did not (group 2) (n = 18) and did (group 3) (n = 8) develop severe OHSS. Blood was drawn on the day of ovum retrieval (day 0) and 3, 6, 10 and 14 days later. L-OHSS: Single pregnancies classified as women who did not (group 4) (n = 8) and did develop (group 5) (n = 4) OHSS. Single pregnancies after oocyte donation (OD) (n = 4) were compared with groups 4 and 5 (IVF-ICSI). Blood was obtained weekly (weeks 4-12). Total VEGF (VEFG-A), free (f)-VEGF and soluble VEGF receptor 1 (sVEGFR-1) in plasma and in serum alpha2-macroglobulin (M) were also measured. RESULTS: Group 3 showed significantly (P < 0.05) higher VEFG-A and f-VEGF than group 1 on day 6 because of lower sVEGFR-1 secretion. Similarly, group 5 had significantly (P < 0.05) more VEFG-A and f-VEGF and less sVEGFR-1 than group 4. Oocyte donation was associated with decreased sVEGFR-1 secretion, and alpha2M was not relevant in OHSS development. CONCLUSION: In E- and L-OHSS, the ability to secrete sVEGFR-1 and bind VEGF seems to be the determinant factor in OHSS. f-VEGF acts locally in the ovary.

Adult↗

Outpatient thoracic surgical programme in 300 patients: clinical results and economic impact.

OBJECTIVE: To evaluate clinical aspects, results and the economic impact of the outpatient thoracic surgery programme (OTSP) developed in our Department. METHODS: Prospective study of 300 patients who entered in the OTSP from April 2001 to March 2005. The procedures performed were video-mediastinoscopy (MC), video-thoracoscopic lung biopsy (LB) and video-thoracoscopic bilateral thoracic sympathectomy (TS). All procedures were performed under general anaesthesia and patients were discharged in 4-6h. We analyse demographic data, the substitution index (SI), the admission rate (AR) and readmission rate (RR) after the procedure. We calculate the economic impact of stay expenses on our hospital and on other Spanish hospitals. RESULTS: The female/male ratio of the 300 patients was 83/217, with a mean age of 58.1 years (range: 15-85 years). There were no deaths. Mediastinoscopy was performed as outpatient procedure in 210 patients (mean age: 65.6 years) out of 244 total MC (SI=86.1%). Two patients were admitted (AR=0.95%) to observe a minimal pneumothorax and because of late night end. There were no readmissions after MC (RR=0%). We included 32 ambulatory patients for lung biopsy (mean age: 61.5 years) out of 64 total LB (SI=50.0%). One patient was admitted because of air leak (AR=3.1%) and there were no readmissions after LB (RR=0%). Fifty-eight patients were included in the OTSP for bilateral sympathectomy (mean age: 27.1 years) out of 83 total TS (SI=69.9%); there were no admissions (AR=0%) and one patient was readmitted after 9 days because of a hemothorax (RR=1.7%). Sixty-four patients out of the 91 not included in the OTSP were included in an 'afternoon surgical programme' and dismissed the morning after surgery, without contraindication for their inclusion in the OTSP. The hospital's total stay saving was 12,668 euros (88,226 euros if performed elsewhere), 42 euros per patient (294 euros per patient if performed elsewhere). CONCLUSION: Video-assisted mediastinoscopy, lung biopsy and bilateral sympathectomy can be included safely in outpatient thoracic surgical programmes. The impact of the economic benefit of OTSP over the conventional hospitalisation depends on the Department's previous policy on hospital stays. Further experience is needed to increase the substitution index and expand the OTSP to other procedures.

Adolescent↗

Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system.

OBJECTIVE: To summarize the effects of novel hormones (leptin, ghrelin, adiponectin, resistin, and PYY3-36) secreted from adipose tissue and the gastrointestinal tract that have been discovered to exert different effects on several reproductive functions, such as the hypothalamic-pituitary-gonadal axis, embryo development, implantation physiology, and clinically relevant conditions. DESIGN: A MEDLINE computer search was performed to identify relevant articles. RESULT(S): Leptin and ghrelin exert important roles on body weight regulation, eating behavior, and reproduction, acting on the central nervous system and target reproductive organs. As a marker of adequate nutritional stores, these hormones may act on the central nervous system to initiate the complex process of puberty and maintain normal reproductive function. In addition, leptin and ghrelin and their receptors are involved in reproductive events such as gonadal function, embryo development, and embryo-endometrial interaction. CONCLUSION(S): Leptin and ghrelin and other adipose tissue-secreted hormones have significant effects on reproduction. Acting through the brain, these hormones may serve as links between adipose tissue and the reproductive system to supply and regulate energy needs for normal reproduction and pregnancy. Future studies are needed to further clarify the role of these hormones in reproductive events and other related gynecological conditions.

Adiponectin↗

Human embryo culture.

Human embryonic stem cells (hESCs) are derived from preimplantation embryos. Approximately 60% of human embryos are blocked during in vitro development. Although statistics are inconclusive, experience demonstrates that hESCs are more effectively derived from high-quality embryos. In this way, optimal human embryo culture conditions are a crucial aspect in any derivation laboratory. Embryos can be cultured solely with sequential media or cocultured on a monolayer of a given cell type. This chapter explores general aspects of human embryonic development, the concept of sequential culture and coculture, and specific protocols and procedures in which the authors are experienced, including the results obtained.

Coculture Techniques↗

Derivation of clinical-grade human embryonic stem cells.

Embryonic stem cells proliferate in vitro while maintaining an undifferentiated state, and are capable of differentiating into most cell types under appropriate conditions. These properties imply great potential in the treatment of various diseases and disabilities. In fact, the first clinical trials with hESC for treating spinal cord injuries will begin next year. However, therapeutic application of human embryonic stem cell derivatives is compromised by the exposure of existing lines to animal and human components, with the subsequent risk of contamination with retroviruses and other pathogens, which can be transmitted to patients. The scientific community is striving to avoid the use of xenogeneic or allogeneic components in the process of derivation new hESC lines. This review summarizes attempts that have been made to avoid these contaminants and the breakthroughs achieved in the derivation of clinical-grade hESC that could be used for therapeutic purposes.

Animals↗

Derivation and characterization of three new Spanish human embryonic stem cell lines (VAL -3 -4 -5) on human feeder and in serum-free conditions.

A total of 184 human embryos, frozen for >5 years, were donated; informed consent was obtained according to Spanish law 45/2003. Survival rate was 40% and three out of 24 blastocysts (12.5%) developed into putative hESC lines, named VAL-3, VAL-4, and VAL-5. The derivation process was performed on microbiologically tested and irradiated human foreskin fibroblasts and designed to minimize contact with xeno-components in knockout DMEM supplemented with knockout serum replacement, and basic fibroblast growth factor. Fingerprinting and HLA typing of the cell lines allowed their identification and traceability. Karyotype was normal for VAL-3 (46XY), VAL-4 (46XX) and VAL-5 (46XX). All three hESC lines expressed specific markers for non-differentiation (Nanog, stage-specific embryonic antigen-4 [SSEA-4], tumour-related antigen [TRA]-1-60, and TRA-1-81) and were negative for SSEA-1. RT-PCR further demonstrated the expression of Oct-4, Sox2, Rex-1, Nanog, Cripto, Thy-1, and Lefty-A. Furthermore, they were found to be negative for classical differentiation markers such as neurofilament heavy chain (ectoderm), renin (mesoderm), and amylase (endoderm). All three cell lines displayed high levels of telomerase activity, and were shown to successfully overcome cryopreservation and thawing. Finally, these three new hESC lines have demonstrated the potential to differentiate in vitro and in vivo (teratoma formation) into cell types originating from all three germ layers.

Animals↗

Obesity and assisted reproductive technology outcomes.

Obesity is a rising health problem in Western societies. It has been related to increased morbidity and mortality rates due to several pathologies. In the field of gynaecology and reproduction, obesity is associated with menstrual disorders, hirsutism, infertility, miscarriage and obstetric complications. It is known to impair human reproduction through different mechanisms such as insulin resistance, hyperandrogenism and elevated leptin levels. Weight management and dietary intervention can reverse this situation and improve reproductive function. Obesity can also impair the outcome of assisted reproductive technologies. The lower probability of a healthy live birth described in obese women seems to be the result of a combination of lower implantation and pregnancy rates, higher preclinical and clinical miscarriage rates and increased complications during pregnancy for both mother and fetus. Studies performed in infertile women undergoing assisted reproduction technologies indicate that the ovary plays a leading, but not exclusive, role in the fertility prognosis of these patients. The endocrine and metabolic environment may affect oocyte quality and, therefore, embryo development, implantation and pregnancy outcome. The endometrium seems to play a subtle role in the more negative reproductive outcome of obese women, according to recent studies based on the ovum donation model.

Endometrium↗

The role of the leptin in reproduction.

PURPOSE OF REVIEW: Since its discovery in 1994, leptin has appeared to be a pleiotrophic hormone, governing energy homeostasis and affecting many tissues in the body. Numerous pieces of evidence have accumulated showing that leptin potentially plays an important role in the control of the reproductive function. RECENT FINDINGS: This review presents the major concepts for the role of leptin in the modulation of reproductive function. As a marker of the nutritional status, leptin affects the hypothalamo-pituitary-gonadal axis, regulating gonadotrophin-releasing hormone and luteinising hormone secretion, and appears to be a permissive factor in the onset of the puberty. This protein and its receptor have been found in the reproductive tissues, indicating that this system could be also implicated in several processes such as embryo development, implantation and pregnancy. Moreover, disorders of the leptin system have been related to some reproductive pathologies such as pre-eclampsia and polycystic ovary syndrome. However, controversy surrounds several aspects of the action of leptin in reproduction that require a deeper investigation of this system. SUMMARY: Results to date suggest that this system could be implicated in important reproductive processes such as embryonic development and implantation. Moreover, understanding the role of leptin might be useful for new treatments in reproductive pathologies.

Embryo Implantation↗

The implantation of every embryo facilitates the chances of the remaining embryos to implant in an IVF programme: a mathematical model to predict pregnancy and multiple pregnancy rates.

BACKGROUND: We aimed to assess the validity of a theoretical mathematical model to predict the pregnancy rate and the multiple pregnancy rate in IVF/oocyte donation programmes on the basis of the implantation rate and the number of transferred embryos. METHODS: A total of 1835 embryo transfers corresponding to three different programmes in two centres with different implantation rates were analysed. Pregnancy and multiple pregnancy rates observed in the aforementioned programmes were compared with those obtained following different mathematical models. Four models were tested: binomial model, ground model, maternal variability model and collaborative model. The goodness of fit was performed by means of the maximum likelihood fit method. RESULTS: The binomial model could not predict the pregnancy rate, and especially the multiple pregnancy rate. The multiple pregnancy rate predicted following the binomial model was much lower than observed, up to 40-fold reduced. Ground model and maternal variability model adjusted to the data with more precision, but were still not accurate. Finally, the collaborative model reproduced with very great accuracy both pregnancy rate and the multiple pregnancy rate. A collaborative parameter of 22% was found, implying that the implantation probability of each embryo is increased by 22% for every embryo previously implanted. CONCLUSIONS: Embryonic implantation does not follow a binomial law, showing that the implantation is not independent from the number of embryos implanted. The best fit to the data is obtained following a collaborative model by which the implantation of one embryo is facilitated by the implantation of other embryo(s). The mathematical formula of the collaborative model predicts very accurately the pregnancy rate and the multiple pregnancy rate in IVF/oocyte donation programmes, based on the implantation rate of this specific programme and the number of embryos transferred up to five embryos. We recommend using the aforementioned formula to quantify the pregnancy rate and the risk of multiple pregnancy in the counselling of the infertile couple at embryo transfer. Such a formula is freely available at www.ifca.unican.es/matorras/mathpreg/.

Embryo Implantation↗

Age and uterine receptiveness: predicting the outcome of oocyte donation cycles.

CONTEXT: The impact of advancing age on uterine receptiveness has always been a concern of the medical establishment. Oocyte donation (OD) is the perfect model for ascertaining the extent of this relationship, but the literature is somewhat unreliable, mainly due to the limited samples on which the studies are based and insufficient control of important variables such as embryo quality. SETTING: The present work was developed in a private infertility clinic. PATIENTS OR OTHER PARTICIPANTS: We retrospectively evaluate the results of 3089 OD cycles that ended up in a d 3 embryo transfer. Severe male factor infertility was an exclusion criterion. MAIN OUTCOME MEASURES: The impact of patients' age on pregnancy, implantation, and miscarriage rates and obstetric outcome is analyzed, as is the relevance of endometrial thickness, serum estradiol levels, and duration of exogenous estrogen therapy to said rates. RESULTS: Pregnancy and implantation rates are significantly reduced and miscarriage rate is significantly increased from 45 yr of age onward. Concerning obstetric outcome, incidences of hypertension, proteinuria, premature rupture of membranes, second- and third-trimester hemorrhage, and preterm delivery are higher and mean birth weight is lower in this age group. With regard to endometrial preparation, estrogen therapy lasting more than 7 wk is associated with reduced PR and IR (P = 0.01 and P = 0.02, respectively). CONCLUSIONS: The results of OD cycles and obstetric outcome are significantly worse when recipients are 45 yr of age or older. Concerning endometrial preparation, results are significantly worse when estrogen therapy lasts more than 7 wk.

Abortion, Spontaneous↗

Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles.

Controlled ovarian hyperstimulation (COH) used in IVF produces lower implantation rates per embryo transferred compared to natural cycles utilized in ovum donation, suggesting a suboptimal endometrial development. Endometrial receptivity has recently been investigated in natural menstrual cycles with the aid of microarray technology. The aim of this study is to investigate the impact of COH using urinary gonadotrophins with a long protocol with GnRH agonists without progesterone supplementation (similar to the natural cycle) on endometrial gene expression profiles during the window of implantation by comparing the profiles at day hCG + 7 of COH versus LH + 7 of a previous natural cycle in the same women. For this purpose we have used microarray technology by Affymetrix (GeneChip HG_U133A), which allows more than 22,000 genes to be tested simultaneously. Results were validated by semi-quantitative PCR and quantitative PCR experiments. We found that more than 200 genes showed a differential expression of more than 3-fold when COH and normal cycles were compared at hCG + 7 versus LH + 7. We simultaneously re-analysed the LH + 2 versus LH + 7 endometrial gene expression profiles in previous natural cycles in the same subject using this specific GeneChip, the results obtained were consistent with our own published results. This is the first time that gene expression profiles of the endometrium during COH are reported. The large degree of gene expression disturbance is surprising and highlights the need for further efforts to optimize COH protocols.

Embryo Implantation↗

First derivation in Spain of human embryonic stem cell lines: use of long-term cryopreserved embryos and animal-free conditions.

The first two human embryonic stem cell lines (VAL-1 and VAL-2) have been derived in Spain with long-term cryopreserved embryos under animal-free conditions. In the first series, 40 human embryos that had been cryopreserved at day 2 of development were thawed after >5 years. A derivation efficiency of 5% per frozen embryo or 12.5% per blastocyst was obtained.

Cryopreservation↗

Serum luteinizing hormone in patients undergoing ovarian stimulation with gonadotropin-releasing hormone antagonists and recombinant follicle-stimulating hormone and its relationship with cycle outcome.

The serum LH was determined on days 3, 6, and 8 of stimulation and on the day of hCG in 110 normogonadotropic patients undergoing controlled ovarian hyperstimulation (COH) for IVF induced with GnRH antagonists and recombinant FSH, creating three groups of patients according to Tukey's hinges (percentiles 25 and 75) for each determination. No differences were observed between the number of oocytes recovered or the fertilization, implantation, and pregnancy rates (PR) of the groups, although patients with high serum LH levels during stimulation showed significantly higher serum E2 levels on the day of hCG.

Adolescent↗

FISH screening of aneuploidies in preimplantation embryos to improve IVF outcome.

Preimplantation genetic diagnosis (PGD) has transformed the approach to the infertility patient in the IVF setting. Although the principal applications of PGD have been to prevent the transmission of sex-linked diseases, in time and with growing knowledge of the chromosomal abnormalities observed in preimplantation embryos, its applications have widened. Nowadays, apart from its implications in the prevention of transmission of chromosomal and genetic abnormalities, PGD is being used with increased frequency to improve the IVF outcome in patients with advanced maternal age (> or =38 years of age), recurrent miscarriage (> or =2 miscarriages), recurrent IVF failure (> or =3 failed IVF attempts) and severe male infertility. A high incidence of chromosomal abnormalities has been observed in these patient groups.

Abortion, Habitual↗

Embryo aneuploidy screening for unexplained recurrent miscarriage: a minireview.

PROBLEM: The aim of this study was to investigate the incidence of chromosomal abnormalities in unexplained recurrent miscarriage (RM) patients and assess the role of pre-implantation genetic diagnosis (PGD) in preventing subsequent pregnancy loss and improving pregnancy outcome. METHOD OF STUDY: Pre-implantation genetic diagnosis was performed in 241 RM cycles and in 35 cycles in patients undergoing PGD for sex-linked diseases (control group). Chromosomes 13, 16, 18, 21, 22, X and Y were analysed by fluorescence in situ hybridization. RESULTS: The implantation and pregnancy rates in RM patients were 26.4 and 36.5% versus 20.6 and 29.0% in the control group, respectively. The percentage of abnormal embryos was significantly increased in RM patients compared with controls. CONCLUSIONS: Recurrent miscarriage is associated with a higher incidence of chromosomally abnormal embryos. In vitro fertilization (IVF) plus PGD is an important step in the management of these couples.

Abortion, Habitual↗

Semen characteristics in human immunodeficiency virus (HIV)- and hepatitis C (HCV)-seropositive males: predictors of the success of viral removal after sperm washing.

BACKGROUND: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-seropositive males can now father children safely, avoiding transmission risks to the mother and the children using sperm washing and nested PCR (nPCR) techniques. Nevertheless, we still lack enough data to determine the reasons why approximately 10% of the performed sperm washes remain positive, thus forcing the repetition of the treatment. Semen quality in infected males is also essential to these procedures. We aimed to determine the predictive value of the semen parameters, sperm washing procedure and the infection status for the post-wash viral positivity, as well as the correlation between the semen and the disease features. METHODS: Semen characteristics were evaluated in 136 samples provided from 125 males. We also included a control group of 125 males matched by age and length of sexual abstinence. At the time of semen retrieval, 70 of them were infected with HIV (45 also with HCV, 64.3%), and 55 of them with HCV alone. nPCR for viral detection was performed in each sample. RESULTS: Thirteen out of 136 (9.5%) of the samples were positive for one or more viral detections (HIV RNA, HIV DNA and HCV RNA, when needed). From a total of 240 nPCR viral analyses, 16 were positive (6.6%). None of the seminal parameters were adequate to predict post-wash results, nor was a positive result dependent on the volumes used in the semen wash. A positive correlation was found between post-wash progressive motility and CD4 blood levels, as well as a negative correlation between progressive motility and time of evolution of the disease in HIV-infected males. CONCLUSIONS: Semen analysis, according to the World Health Organization criteria, of HIV- and HCV-affected patients showed no differences from that of non-infected males. Moreover, low CD4 blood levels, and a long evolution of the disease do not negatively affect sperm motility.

Anti-Retroviral Agents↗