Low anti-Müllerian hormone level is not a risk factor for early pregnancy loss in IVF/ICSI treatment

STUDY QUESTION: Is a low ( SUMMARY ANSWER: A low or moderately low serum AMH level does not associate with miscarriage, non-visualized pregnancy loss or overall early pregnancy loss rate in the IVF/ICSI treatment. WHAT IS KNOWN ALREADY: Low AMH predicts poor ovarian response and small oocyte yield in IVF/ICSI treatment, but its value in the evaluation of live birth rate (LBR) is modest Little is known about the risk of early pregnancy loss in ART among women with low AMH. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study on 1383 women undergoing their first oocyte retrieval for IVF/ICSI in Helsinki University Hospital in Helsinki, Finland, between 2012 and 2016, with all associated fresh (n = 1315) and frozen-thawed (n = 1418) ET cycles finished by August 2018. AMH was measured within 12 months before the IVF/ICSI stimulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of all the women, 235 (17.0%) had low (= 2.0 mu g/L) AMH. The primary outcomes were miscarriage, non-visualized pregnancy loss and early pregnancy loss (miscarriage and non-visualized pregnancy loss combined) after fresh or frozen-thawed ET. The impact of AMH on these outcomes was calculated in three populations: among all women who became pregnant, among women with AMH MAIN RESULTS AND THE ROLE OF CHANCE: Of 1123 pregnancies, 285 (25.4%) ended in non-visualized pregnancy loss and 143 (12.7%) in miscarriage. The LBR was 24.6% per ET (673/2733). Low or moderately low AMH, compared with normal AMH, did not associate with miscarriage or non-visualized pregnancy loss in analyses among all women who became pregnant (adjusted relative risk (RR) for miscarriage vs live birth, 0.70 and 95% CI 0.42-1.17 in low AMH and adjusted RR, 1.00 and 95% CI, 0.68-1.49 in moderately low AMH; adjusted RR for non-visualized pregnancy loss vs live birth, 0.90 and 95% CI, 0.65-1.23 in low AMH and adjusted RR, 1.09 and 95% CI 0.85-1.41 in moderately low AMH), nor did low or moderately low AMH associate with the overall early pregnancy loss rate (adjusted RR for early pregnancy loss vs live birth, 0.86 and 95% CI, 0.68-1.10 in low AMH and adjusted RR, 1.01 and 95% CI, 0.86-1.27 in moderately low AMH). Results remained similar after restricting the analysis to women with AMH LIMITATIONS, REASONS FOR CAUTION: The number of miscarriages in women with low AMH was moderately small, limiting the power of the study. The real-world clinical setting of the study restricted the ability to control for all factors causing selection bias. WIDER IMPLICATIONS OF THE FINDINGS: The cLBR was higher among women with normal AMH than among women with low or moderately low AMH in their first IVF/ICSI treatment because these women had more oocytes and embryos. Women with low or moderately low AMH did not have an increased risk for early pregnancy loss. This information is reassuring for couples and useful in counseling. These results are also valuable when assessing the overall effectiveness of IVF/ICSI treatment.Peer reviewe

I4U Submission to NIST SRE 2018: Leveraging from a Decade of Shared Experiences

The I4U consortium was established to facilitate a joint entry to NIST speaker recognition evaluations (SRE). The latest edition of such joint submission was in SRE 2018, in which the I4U submission was among the best-performing systems. SRE'18 also marks the 10-year anniversary of I4U consortium into NIST SRE series of evaluation. The primary objective of the current paper is to summarize the results and lessons learned based on the twelve sub-systems and their fusion submitted to SRE'18. It is also our intention to present a shared view on the advancements, progresses, and major paradigm shifts that we have witnessed as an SRE participant in the past decade from SRE'08 to SRE'18. In this regard, we have seen, among others, a paradigm shift from supervector representation to deep speaker embedding, and a switch of research challenge from channel compensation to domain adaptation.Comment: 5 page

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

Marked alveolar apoptosis/proliferation imbalance in end-stage emphysema

BACKGROUND: Apoptosis has recently been proposed to contribute to the pathogenesis of emphysema. METHODS: In order to establish if cell fate plays a role even in end-stage disease we studied 16 lungs (9 smoking-associated and 7 α1antitrypsin (AAT)-deficiency emphysema) from patients who had undergone lung transplantations. Six unused donor lungs served as controls. Apoptosis was evaluated by TUNEL analysis, single-stranded DNA laddering, electron microscopy and cell proliferation by an immunohistochemical method (MIB1). The role of the transforming growth factor (TGF)-β1 pathway was also investigated and correlated with epithelial cell turnover and with the severity of inflammatory cell infiltrate. RESULTS: The apoptotic index (AI) was significantly higher in emphysematous lungs compared to the control group (p ≤ 0.01), particularly if only lungs with AAT-deficiency emphysema were considered (p ≤ 0.01 vs p = 0.09). The proliferation index was similar in patients and controls (1.9 ± 2.2 vs 1.7 ± 1.1). An increased number of T lymphocytes was observed in AAT-deficiency lungs than smoking-related cases (p ≤ 0.05). TGF-β1 expression in the alveolar wall was higher in patients with smoking-associated emphysema than in cases with AAT-deficiency emphysema (p ≤ 0.05). A positive correlation between TGF-βRII and AI was observed only in the control group (p ≤ 0.005, r(2 )= 0.8). A negative correlation was found between the TGF-β pathway (particularly TGF-βRII) and T lymphocytes infiltrate in smoking-related cases (p ≤ 0.05, r(2 )= 0.99) CONCLUSION: Our findings suggest that apoptosis of alveolar epithelial cells plays an important role even in end-stage emphysema particularly in AAT-deficiency disease. The TGFβ-1 pathway does not seem to directly influence epithelial turnover in end-stage disease. Inflammatory cytokine different from TGF-β1 may differently orchestrate cell fate in AAT and smoking-related emphysema types

Induction and regulation of matrix metalloproteinase-12in human airway smooth muscle cells

BACKGROUND: The elastolytic enzyme matrix metalloproteinase (MMP)-12 has been implicated in the development of airway inflammation and remodeling. We investigated whether human airway smooth muscle cells could express and secrete MMP-12, thereby participating in the pathogenesis of airway inflammatory diseases. METHODS: Laser capture microdissection was used to collect smooth muscle cells from human bronchial biopsy sections. MMP-12 mRNA expression was analysed by quantitative real-time RT-PCR. MMP-12 protein expression and secretion from cultured primary airway smooth muscle cells was further analysed by Western blot. MMP-12 protein localization in bronchial tissue sections was detected by immunohistochemistry. MMP-12 activity was determined by zymography. The TransAM AP-1 family kit was used to measure c-Jun activation and nuclear binding. Analysis of variance was used to determine statistical significance. RESULTS: We provide evidence that MMP-12 mRNA and protein are expressed by in-situ human airway smooth muscle cells obtained from bronchial biopsies of normal volunteers, and of patients with asthma, COPD and chronic cough. The pro-inflammatory cytokine, interleukin (IL)-1β, induced a >100-fold increase in MMP-12 gene expression and a >10-fold enhancement in MMP-12 activity of primary airway smooth muscle cell cultures. Selective inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase and phosphatidylinositol 3-kinase reduced the activity of IL-1β on MMP-12, indicating a role for these kinases in IL-1β-induced induction and release of MMP-12. IL-1β-induced MMP-12 activity and gene expression was down-regulated by the corticosteroid dexamethasone but up-regulated by the inflammatory cytokine tumour necrosis factor (TNF)-α through enhancing activator protein-1 activation by IL-1β. Transforming growth factor-β had no significant effect on MMP-12 induction. CONCLUSION: Our findings indicate that human airway smooth muscle cells express and secrete MMP-12 that is up-regulated by IL-1β and TNF-α. Bronchial smooth muscle cells may be an important source of elastolytic activity, thereby participating in remodeling in airway diseases such as COPD and chronic asthma

IL-17RA Is Required for CCL2 Expression, Macrophage Recruitment, and Emphysema in Response to Cigarette Smoke

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA−/− mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA−/− mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema

Induction of the interleukin 6/ signal transducer and activator of transcription pathway in the lungs of mice sub-chronically exposed to mainstream tobacco smoke

<p>Abstract</p> <p>Background</p> <p>Tobacco smoking is associated with lung cancer and other respiratory diseases. However, little is known about the global molecular changes that precede the appearance of clinically detectable symptoms. In this study, the effects of mainstream tobacco smoke (MTS) on global transcription in the mouse lung were investigated.</p> <p>Methods</p> <p>Male C57B1/CBA mice were exposed to MTS from two cigarettes daily, 5 days/week for 6 or 12 weeks. Mice were sacrificed immediately, or 6 weeks following the last cigarette. High density DNA microarrays were used to characterize global gene expression changes in whole lung. Microarray results were validated by Quantitative real-time RT-PCR. Further analysis of protein synthesis and function was carried out for a select set of genes by ELISA and Western blotting.</p> <p>Results</p> <p>Globally, seventy nine genes were significantly differentially expressed following the exposure to MTS. These genes were associated with a number of biological processes including xenobiotic metabolism, redox balance, oxidative stress and inflammation. There was no differential gene expression in mice exposed to smoke and sampled 6 weeks following the last cigarette. Moreover, cluster analysis demonstrated that these samples clustered alongside their respective controls. We observed simultaneous up-regulation of <it>interleukin 6 </it>(<it>IL-6</it>) and its antagonist, <it>suppressor of cytokine signalling </it>(<it>SOCS3</it>) mRNA following 12 weeks of MTS exposure. Analysis by ELISA and Western blotting revealed a concomitant increase in total IL-6 antigen levels and its downstream targets, including phosphorylated signal transducer and activator of transcription 3 (Stat3), basal cell-lymphoma extra large (BCL-XL) and myeloid cell leukemia 1 (MCL-1) protein, in total lung tissue extracts. However, in contrast to gene expression, a subtle decrease in total SOCS3 protein was observed after 12 weeks of MTS exposure.</p> <p>Conclusion</p> <p>Global transcriptional analysis identified a set of genes responding to MTS exposure in mouse lung. These genes returned to basal levels following smoking cessation, providing evidence to support the benefits of smoking cessation. Detailed analyses were undertaken for IL-6 and its associated pathways. Our results provide further insight into the role of these pathways in lung injury and inflammation induced by MTS.</p

Association of MMP - 12 polymorphisms with severe and very severe COPD: A case control study of MMPs - 1, 9 and 12 in a European population

BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity