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Circulating p53 antibodies (ELISA method), p53 genetic alterations (SSCP), and protein overexpression (immunohistochemistry) were studied in 41 patients with colorectal adenocarcinomas and 10 control patients. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA 19-9) were evaluated in parallel. Ten patients with p53 antibodies and p53 overexpression were selected. Tumor DNA extracts from these 10 patients were analyzed by SSCP. Of all 41 patients, 10 (24%) showed significant levels of p53 antibodies, and p53 accumulation was detected in 20 (48%) patients. In six patients, p53 antibody concentrations decreased rapidly after surgery; in two patients, these levels returned to normal values. Of the 10 selected tumors, eight revealed TP53 gene mutations. Only two patients with high values of both CEA and CA 19-9 developed p53 antibodies. In conclusion, beside classical tumor markers, circulating p53 antibodies may be considered as additional markers for the management of patients with colorectal adenocarcinomas. [ABSTRACT FROM AUTHOR]

There is little information about the relation between mild cardiac troponin I (cTn-I) increase after coronary interventions and late outcome. We therefore focused on the long-term outcome and the clinical, morphologic, and procedural correlates of elevation of cTn-I compared with cardiac troponin T, creatine kinase (CK), CK-MB activity and mass, and myoglobin in 105 patients with successful elective percutaneous transluminal coronary angioplasty (PTCA) for stable or unstable angina. Patients with myocardial infarction and those with unstable angina who had a detectable increase in serum markers before PTCA were excluded. Markers were measured before and after the procedure and for 2 days. Patients were followed up to record recurrent angina, myocardial infarction, cardiac death, repeat PTCA, or elective coronary artery bypass graft surgery. Procedure success was achieved in all cases. Elevation in cTn-I (> or =0.1 microg/L) was observed in 23 of 105 patients (22%) (median peak: 0.25 microg/L); 18% had cardiac troponin T (cTn-T) release (> or = 0.1 microg/L, median peak 0.21); 11.4% CK-MB mass (> or =5 microg/L), and 7.6% myoglobin (> or =90 microg/L) release. Five and 2 patients had elevated CK and CK-MB activity, respectively. Fourteen of 18 patients with cTn-T elevation had a corresponding elevation in cTn-I (kappa 0.68; p = 0.001). Patients positive for cTn-I had more unstable angina (p = 0.042) and heparin before PTCA (p = 0.046), and had longest total time (p = 0.004) and single inflation (p = 0.01). By multivariate logistic regression, predictors of postprocedure cTnI elevation were maximum time of each inflation (odds ratio 9.2; p = 0.0012), type B lesions (odds ratio 6.6; p = 0.013), unstable angina (p = 0.041), and age > or =60 years (p = 0.032). Clinical follow-up was available in 103 patients (98%) (mean 19+/-10 months). Kaplan-Meier survival analysis showed that cTn-I elevation was not an important correlate of cardiac events (p = 0.34, by log-rank analysis). The incidence of recurrent angina, myocardial infarction, cardiac death, and repeat revascularization after 12 months was not different in patients positive or negative for cTn-I. We conclude that cTn-I elevation after successful PTCA is not associated with significantly worse late clinical outcome. Levels of cTn-I allow a much higher diagnostic accuracy in detecting minor myocardial injury after PTCA compared with other markers, but there is no association with periprocedural myocardial cell injury and late outcome when cTn-I and other markers are considered. [ABSTRACT FROM AUTHOR]

Background: In the field of male infertility, when sperm is normal/subnormal, a few "add-on" routine tests can complete the basic semen examination., Objectives: The aim of this study was to develop and evaluate a faster, simplified motile sperm organelle morphology examination (MSOME) technique for selected infertile patients with apparently normal/subnormal sperm and, in their background: failure of two or three intrauterine insemination (IUI) cycles, repeatedly fragmented embryos, embryonic development to blastocyst-stage failures, repeated miscarriages, a long period of infertility or 2 or more IVF attempts without pregnancy. Our test results were correlated with IUI, conventional in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and intracytoplasmic morphologically selected sperm injection (IMSI) outcomes., Materials and Methods: We validated an adapted version of the MSOME analysis called the pre-IMSI test (PIT), based on vacuole evaluation alone. 248 infertile patients from our assisted reproductive technology (ART) Center were retrospectively selected and split into three PIT score subgroups (patients with ≤8% (score I), 9 to 15% (score II) and ≥16% normal spermatozoa (score III)) based on the correlation between PIT results and each ART technique outcome. The choice of one or another of these ART techniques had been made according to the usual clinico-biological criteria., Results: Clinical outcomes for each of the three PIT subgroups were compared individually for the different ART techniques. For ICSI, the effect of the PIT score subgroup was significant for clinical pregnancies (p = 0.0054) and presented a trend for live births (p = 0.0614). Miscarriage rates of IVF attempts were statistically different depending on the PIT score (p = 0.0348). Furthermore, the odds ratios of clinical pregnancy rates were significantly different according to PIT score subgroup when comparing ICSI vs. IMSI or IVF vs. ICSI attempts., Discussion: IMSI appears to be recommended when sperm belongs to PIT score I, ICSI when it belongs to PIT score II and IVF or IUI when sperm is of PIT score III quality in selected infertile couples. The lack of statistical power in these PIT subgroups means that we must remain cautious in interpreting results., Conclusion: Our results support the interest of this simplified test for certain couples with normal/subnormal sperm to help choose the most efficient ART technique, even as first-line treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sigala et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The live birth rate following embryo transfer is comparable between spontaneous, stimulated and artificial cycles. However, the pregnancy loss rate appears elevated with hormonal therapy, possibly due to luteal insufficiency. This study aimed to determine whether the serum progesterone level on transfer day differed according to the endometrial preparation method for frozen embryo transfer (FET). Twenty spontaneous cycles (SC), 27 ovarian stimulation cycles (OS) and 65 artificial cycles (AC) were retrospectively studied from May to December 2019 in a single French hospital. The primary endpoint was the level of serum progesterone on the day of FET between the three endometrial preparation methods. The mean serum progesterone level on transfer day was 29.47 ng/ml in the OS group versus 20.03 ng/ml in the SC group and 14.32 ng/ml AC group ( P < 0.0001). Progesterone levels remained significantly different after logistic regression on age and anti-Müllerian hormone (AMH) level. There was no significant difference in demographic and hormone characteristics (age, body mass index, embryo stage of embryo, type of infertility, basal follicle stimulating hormone, luteinizing hormone, estradiol and AMH levels), endometrial thickness, number and type of embryos transferred, duration of infertility, pregnancy rate, live birth rate and pregnancy loss rate. No difference was found in serum progesterone levels between clinical pregnancy with fetal heartbeat and no clinical pregnancy (no pregnancy or pregnancy loss, 17.49 ng/ml vs 20.83 ng/ml, respectively, P = 0.07). The lower serum progesterone level found on FET day in the AC group should be further investigated to see whether this difference has a clinical effect on the live birth rate.

S1P 1 (sphingosine-1-phosphate receptor 1) agonists prevent lymphocyte egress from secondary lymphoid organs and cause a reduction in the number of circulating blood lymphocytes. We hypothesized that S1P 1 receptor modulators with pathway-selective signaling properties could help to further elucidate the molecular mechanisms involved in lymphocyte trapping. A proprietary S1P 1 receptor modulator library was screened for compounds with clear potency differences in β -arrestin recruitment and G protein alpha i subunit (G α i ) protein-mediated signaling. We describe here the structure-activity relationships of highly potent S1P 1 modulators with apparent pathway selectivity for β -arrestin recruitment. The most differentiated compound, D3-2, displayed a 180-fold higher potency in the β -arrestin recruitment assay (EC 50 0.9 nM) compared with the G α i -activation assay (167 nM), whereas ponesimod, a S1P 1 modulator that is currently in advanced clinical development in multiple sclerosis, was equipotent in both assays (EC 50 1.5 and 1.1 nM, respectively). Using these novel compounds as pharmacological tools, we showed that although a high potency in β -arrestin recruitment is required to fully internalize S1P 1 receptors, the potency in inducing G α i signaling determines the rate of receptor internalization in vitro. In contrast to ponesimod, the compound D3-2 did not reduce the number or circulating lymphocytes in rats despite high plasma exposures. Thus, for rapid and maximal S1P 1 receptor internalization a high potency in both G α i signaling and β -arrestin recruitment is mandatory and this translates into efficient reduction of the number of circulating lymphocytes in vivo., (Copyright © 2018 The Author(s).)

The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat-human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-β1-treated primary human lung fibroblasts and transforming growth factor-β1-treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model-human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease.

Cervical agenesis is a rare congenital pathology linked to an anomaly of development of the Mullerian system. We described a case report about a 22-year old woman, consulting for infertility, who had a complete cervical agenesis. The first evaluation suggested a 46 XX karyotype and a normal ovarian reserve. The surgical examination confirmed the absence of cervix with impossibility of catheterization. She became pregnant thanks to an in vitro fertilization (IVF) with transmyometrial embryo transfer. Caesarean was decided at 36 weeks of gestation (WG) due to spontaneous uterine contractions. An injection of medroxyprogesterone was made after the placenta delivery in order to warning the partum hemorrhage. The ultrasound examination, realized 15 days after caesarean, underlined a good uterine involution. The surgery by cervico-vaginal anastomosis can be offered to patients because it offers chances of spontaneous pregnancies. But this surgery exposes women to a risk of failure, and of severe complications such as pain or infection, and might end in a hysterectomy. By choosing the transmyometrial transfer by vaginal way, the patient was exposed to the risk of spontaneous miscarriage. It was raising the problem of the uterine evacuation. This delivery after 34 WG is encouraging for the infertility by cervical agenesis., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The sensitivity of Venturia inaequalis field isolates to inhibitors of the cytochrome bc1 complex at the Qo site (QoIs) was characterised at the molecular, biochemical and physiological level, and compared to other respiration inhibitors. Comparison of a sensitive and a QoI-resistant isolate revealed very high resistance factors both in mycelium growth and spore germination assays. Cross-resistance was observed among QoIs such as trifloxystrobin, azoxystrobin, famoxadone, strobilurin B and myxothiazol. In the mycelium growth assay, antimycin A, an inhibitor of the cytochrome bc1 complex at the Qi site, was less active against the QoI-resistant than against the sensitive isolate. The mixture of QoIs with salicylhydroxamic acid (SHAM), an inhibitor of the alternative oxidase, exerted synergistic effects in the spore germination but not in the mycelium growth assay. Thus, the cytochrome and the alternative respiration pathways are assumed to play different roles, depending on the developmental stage of the fungus. Induction of alternative oxidase (AOX) by trifloxystrobin was observed in mycelium cells at the molecular level for the sensitive but not the resistant isolate. Following QoI treatment, respiration parameters such as oxygen consumption, ATP level, membrane potential and succinate dehydrogenase activity were only slightly reduced in Qo-resistant mycelium cells, and remained at much higher levels than in sensitive cells. In contrast, no difference was observed between sensitive and resistant isolates when NADH consumption was measured. Comparison of the cytochrome b (cyt b) gene of the sensitive and resistant isolates did not reveal any point mutations as is known to occur in resistant isolates of other plant pathogens. It is assumed that QoI resistance in V inaequalis may be based on a compensation of the energy deficiency following QoI application upstream of the NADH dehydrogenase of the respiratory chain.

Background: Few experimental studies report effects of direct contusion on cardiac enzyme release. Cardiac troponins I (cTnI) and T (cTnT) have been shown to be highly sensitive and specific markers of myocardial cell injury. This investigation was designed to determine and compare the acute effects of quantified magnitudes of blunt cardiac trauma upon release of cTnI and cTnT in comparison with creatine kinase (CK) and lactate dehydrogenase (LD)., Methods: In 24 rabbit hearts prepared on a standard Langendorff apparatus, myocardial contusion (MC) was produced by a single blow with a ball falling from a predefined height, delivered directly to the surface of the heart. Hearts were divided into control (n = 6) and various quantified impacts: 75 mJoules (mJ) (n = 6), 100 mJ (n = 6), 200 mJ (n = 6). Coronary effluent samples for cTnI, cTnT, CK, and LD were collected at baseline, immediately after MC and 5, 15, 30, 45, and 60 minutes after MC. At the end of experiment, histologic condition was evaluated., Results: The anti-cTnI and cTnT MAbs used in the cTnI (Access) and cTnT (Elecsys) assays cross-react with cTnI and cTnT of the rabbit. The time-courses of cTnI, cTnT, CK, and LD were monophasic in form. After MC, all parameters rose significantly compared with baseline and with control group. The maximal release occurred immediately after MC. The area under the cTnI curve and the maximal cTnI concentration were linked to the contusion energy when increased at 200 mJ. Maximal concentrations and areas under cTnT, CK, LD time activity curve were not linked to the contusion energy level and showed no between-energy group differences. The correlation found between maximal cTnI and maximal cTnT concentrations was 0.70 (p = 0.0001). Histologic examination showed cellular disruption and after the more severe impact, the extent of pathologic changes was more extensive., Conclusion: After graded experimental MC, maximal cTnI concentration and area under cTnI curve increase with the power of impact kinetic energy. Levels of cTnI allow a much higher accuracy in detecting the extent of myocardial injury postMC in comparison with cTnT, CK, and LD in this experimental study. These results should be consistent with the more extensive cTnI release with more severe impact in patients with blunt chest trauma. Furthermore, because specificity and time-course of release, both cTnI and cTnT should have a role in the diagnosis and evaluation of such patients.

Objective: to compare amino acid concentrations in healthy and malnourished elderly patients., Method: plasma amino acid concentrations were examined in 24 men and women (80-100 years of age) with protein energy malnutrition (PEM) and compared with those of 44 healthy, similarly-aged controls. Plasma samples were determined by using cation exchange columns with ninhydrin detection in an high performance liquid chromatography system., Results: essential amino acid and non-essential amino acid plasma concentrations were significantly decreased in PEM (0.01 < P < 0.0001). Branched-chain amino acids and urea cycle amino acid plasma concentrations fell significantly (P < 0.0001). Plasma concentrations of alanine and glutamic acid + glutamine were also significantly reduced (P < 0.0001)., Conclusions: in underweight elderly patients, the plasma amino acid pattern reflects the severity of the metabolic disturbance.