Browsing by Subject "PROGESTERONE"

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  • Skrifvars, Markus B.; French, Craig; Bailey, Michael; Presneill, Jeffrey; Nichol, Alistair; Little, Lorraine; Durantea, Jacques; Huet, Olivier; Haddad, Samir; Arabi, Yaseen; McArthur, Colin; Cooper, D. James; Bellomo, Rinaldo; EPO-TBI Investigators & ANZICS (2018)
    The EPO-TBI study randomized 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal, or death during maximal care) and non-cerebral (death following withdrawal or during maximal care, which had a non-cerebral cause). The study included 305 patients treated with EPO and 297 treated with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (interquartile range [IQR] 5-16) compared with 29 days (IQR 7-56) (p = 0.01) for non-cerebral COD. When assessing subgroups by admission CT scan injury findings, we found no significant differential effects of EPO compared with placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to intensive care unit (ICU) admission (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.61, p = 0.001, p for interaction = 0.003) and in this subgroup, fewer patients died of cerebral causes in the EPO than in the placebo group (5% compared with 14%, p = 0.03). In conclusion, most TBI deaths were from cerebral causes that occurred during the first 2 weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomization.
  • Montserrat Rivera del Alamo, Maria; Reilas, Tiina; Galvao, Antonio; Yeste, Marc; Katila, Terttu (2018)
    Treatment with intrauterine devices (IUD) prolongs luteal phases in mares, but the mechanism for this has not been fully elucidated. The aims of the present study were to examine how IUDs affect the uterus to induce longer luteal phases, particularly the role of cyclooxygenase-2 (COX-2) in the maintenance of the corpus luteum (CL). Twenty-seven reproductively normal mares were included: 12 were inseminated (AI), and 15 were fitted with IUDs. Blood samples for progesterone were obtained on Days 0, 3, 5, 7, 9, 11, 13, 14, and 15 (relative to day of ovulation). The groups were further divided into non-pregnant (AI-N, n = 4), pregnant (AI-P, n = 8), normal (IUD-N, n = 8) and prolonged luteal phase (IUD-P, n = 7) based on ultrasonic examinations and serum progesterone concentrations on Days 14 and 15. Blood sampling to quantify the PGF(2 alpha) metabolite (PGFM) was performed through a catheter hourly from 15:00 to 20:00 h on Day 14, and from 6:00 until 13:00 h on Day 15. On Day 15, a low-volume uterine lavage followed by an endometrial biopsy was performed. Estradiol concentration in the Day 15 serum and lavage fluid was determined, while the abundance of COX-2 was evaluated in the biopsy specimens using western blotting (WB) and irnmunohistochemistry (IHC). All pregnant mares were negative for COX-2 in IHC samples and 5 of 8 were negative in WB samples while all mares of the IUD-N group were positive for COX-2. Of the seven mares in the IUD-P group, five and four were negative for COX-2 with the IHC and WB samples, respectively. The results from this study indicate that IUDs, when effective, suppress COX-2, leading to the inhibition of PGF2 alpha release and maintenance of CL.
  • Englund, Johanna; Ritchie, Alexandra; Blaas, Leander; Cojoc, Hanne; Pentinmikko, Nalle; Dohla, Julia; Iqbal, Sharif; Patarroyo, Manuel; Katajisto, Pekka (2021)
    Epithelial attachment to the basement membrane (BM) is essential for mammary gland development, yet the exact roles of specific BM components remain unclear. Here, we show that Laminin alpha 5 (Lama5) expression specifically in the luminal epithelial cells is necessary for normal mammary gland growth during puberty, and for alveologenesis during pregnancy. Lama5 loss in the keratin 8-expressing cells results in reduced frequency and differentiation of hormone receptor expressing (HR+) luminal cells. Consequently, Wnt4-mediated crosstalk between HR+ luminal cells and basal epithelial cells is compromised during gland remodeling, and results in defective epithelial growth. The effects of Lama5 deletion on gland growth and branching can be rescued by Wnt4 supplementation in the in vitro model of branching morphogenesis. Our results reveal a surprising role for BM-protein expression in the luminal mammary epithelial cells, and highlight the function of Lama5 in mammary gland remodeling and luminal differentiation.
  • Khatun, Masuma; Sorjamaa, Anna; Kangasniemi, Marika; Sutinen, Meeri; Saio, Tuuia; Liakka, Annikki; Lehenkari, Petri; Tapanainen, Juha S.; Vuolteenaho, Olli; Chen, Joseph C.; Lehtonen, Siri; Piltonen, Terhi T. (2017)
    Objective Intrinsic inflammatory characteristics play a pivotal role in stem cell recruitment and homing through migration where the subsequent change in niche has been shown to alter these characteristics. The bone marrow mesenchymal stem cells (bmMSCs) have been demonstrated to migrate to the endometrium contributing to the stem cell reservoir and regeneration of endometrial tissue. Thus, the aim of the present study was to compare the inflammation-driven migration and cytokine secretion profile of human bmMSCs to endometrial mesenchymal stem cells (eMSCs) and endometrial fibroblasts (eSFs). Materials and methods The bmMSCs were isolated from bone marrow aspirates through culturing, whereas eMSCs and eSFs were FACS-isolated. All cell types were tested for their surface marker, proliferation profiles and migration properties towards serum and inflammatory attractants. The cytokine/chemokine secretion profile of 35 targets was analysed in each cell type at basal level along with lipopolysaccharide (LPS)-induced state. Results Both stem cell types, bmMSCs and eMSCs, presented with similar stem cell surface marker profiles as well as possessed high proliferation and migration potential compared to eSFs. In multiplex assays, the secretion of 16 cytokine targets was detected and LPS stimulation expanded the cytokine secretion pattern by triggering the secretion of several targets. The bmMSCs exhibited higher cytokine secretion of vascular endothelial growth factor (VEGF)A, stromal cell-derived factor-1 alpha (SDF)-1 alpha, interleukin-1 receptor antagonist (IL-1RA), IL-6, interferon-gamma inducible protein (IP)-10, monocyte chemoattractant protein (MCP)1, macrophage inflammatory protein (MIP) 1 alpha and RANTES compared to eMSCs and/or eSFs after stimulation with LPS. The basal IL-8 secretion was higher in both endometrial cell types compared to bmMSCs. Conclusion Our results highlight that similar to bmMSCs, the eMSCs possess high migration activity while the differentiation process towards stromal fibroblasts seemed to result in loss of stem cell surface markers, minimal migration activity and a subtler cytokine profile likely contributing to normal endometrial function
  • Stoer, N. C.; Botteri, E.; Ghiasvand, R.; Busund, M.; Vangen, S.; Lund, E.; Veierod, M. B.; Weiderpass, E. (2019)
    Background The association between reproductive factors and risk of cutaneous melanoma (CM) is unclear. We investigated this issue in the Norwegian Women and Cancer cohort study. Objectives To examine the association between the reproductive factors age at menarche, menstrual cycle length, parity, age at first and last birth, menopausal status, breastfeeding duration and length of ovulatory life, and CM risk, overall and by histological subtypes and anatomical site. Methods We followed 165 712 women aged 30-75 years at inclusion from 1991-2007 to the end of 2015. Multivariable Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results The mean age at cohort enrolment was 49 years. During a median follow-up of 18 years, 1347 cases of CM were identified. No reproductive factors were clearly associated with CM risk. When stratifying by histological subtype we observed significant heterogeneity (P = 0 center dot 01) in the effect of length of ovulatory life on the risk of superficial spreading melanoma (HR 1 center dot 02, 95% CI 1 center dot 01-1 center dot 04 per year increase) and nodular melanoma (HR 0 center dot 97, 95% CI 0 center dot 94-1 center dot 01 per year increase). When stratifying by anatomical site, menopausal status (HR 0 center dot 54, 95% CI 0 center dot 31-0 center dot 92, postmenopausal vs. premenopausal) and menstrual cycle length (HR 1 center dot 07, 95% CI 1 center dot 01-1 center dot 13, per day increase) were associated with CM of the trunk, and significant heterogeneity between anatomical sites was observed for menopausal status (P = 0 center dot 04). Conclusions In this large population-based Norwegian cohort study, we did not find convincing evidence of an association between reproductive factors and risk of CM.
  • Raj, Rahul; Kaprio, Jaakko; Korja, Miikka; Mikkonen, Era D.; Jousilahti, Pekka; Siironen, Jari (2017)
    Background Previous epidemiological studies suggest that working-aged persons with a history of moderate-to-severe traumatic brain injury (TBI) may have an increased risk for developing neurodegenerative disease (NDD) while persons with a history of mild TBI do not. In this comprehensive nationwide study in Finland, we assessed the risk of NDD and history of moderate-to-severe TBI in the working-age population. Methods and findings We performed a population-based follow-up study using the Finnish Care Register for Health Care to identify all persons between the ages of 18 and 65 years hospitalized during 1987-2014 due to TBI who did not have a baseline NDD diagnosis. We compared the risk of hospitalization with NDD between persons hospitalized due to moderate-to-severe TBI (intracranial lesions) and persons hospitalized due to mild TBI (no intracranial lesions). Follow-up NDD diagnoses were recorded from 1 year following the TBI to the end of 2014. NDD diagnoses included dementia, Parkinson disease, and amyotrophic lateral sclerosis. We used a Cox proportional hazards model, adjusting for age, sex, education, and socioeconomic group, to assess the association between TBI and NDD. In total, 19,936 and 20,703 persons with a history of moderate-to-severe TBI and mild TBI, respectively, were included. The overall time at risk was 453,079 person-years (median 10 years per person). In total, 3.5% (N = 696) persons in the moderate-to-severe TBI group developed NDD compared to 1.6% (N = 326) in the mild TBI group. After adjusting for covariates, moderate-to-severe TBI was associated with an increased risk for NDD, with a hazard ratio (HR) of 1.8 (95% CI 1.6-2.1) compared to mild TBI. Of the NDD subtypes, only moderate-to-severe TBI was associated with an increased risk for dementia (HR 1.9, 95% CI 1.6-2.2). Yet, this large-scale epidemiological study does not prove that there is a causal relationship between moderate-to-severe TBI and NDD. Further, the Care Register for Health Care includes only hospitalized persons; thus, patients diagnosed with NDD in the outpatient setting may have been missed. Additional limitations include the potential for miscoding and unmeasured confounds. Conclusions In working-aged persons, a history of moderate-to-severe TBI is associated with an increased risk for future dementia but not for Parkinson disease or amyotrophic lateral sclerosis.
  • Heinosalo, T.; Gabriel, M.; Kallio, L.; Adhikari, P.; Huhtinen, K.; Laajala, T. D.; Kaikkonen, E.; Mehmood, A.; Suvitie, P.; Kujari, H.; Aittokallio, T.; Perheentupa, A.; Poutanen, M. (2018)
    STUDY QUESTION: What is the role of SFRP2 in endometriosis? SUMMARY ANSWER: SFRP2 acts as a canonical WNT/CTNNBI signaling agonist in endometriosis, regulating endometriosis lesion growth and indicating endometriosis lesion borders together with CTNNBI (also known as beta catenin). WHAT IS KNOWN ALREADY: Endometriosis is a common, chronic disease that affects women of reproductive age, causing pain and infertility, and has significant economic impact on national health systems. Despite extensive research, the pathogenesis of endometriosis is poorly understood, and targeted medical treatments are lacking. WNT signaling is dysregulated in various human diseases, but its role in extraovarian endometriosis has not been fully elucidated. STUDY DESIGN, SIZE, DURATION: We evaluated the significance of WNT signaling, and especially secreted frizzled-related protein 2 (SFRP2), in extraovarian endometriosis, including peritoneal and deep lesions. The study design was based on a cohort of clinical samples collected by laparoscopy or curettage and questionnaire data from healthy controls and endometriosis patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Global gene expression analysis in human endometrium ( n = 104) and endometriosis (n = 177) specimens from 47 healthy controls and 103 endometriosis patients was followed by bioinformatics and supportive qPCR analyses. Immunohistochemistry, Western blotting, primary cell culture and siRNA knockdown approaches were used to validate the findings. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 220 WNT signaling and CTNNBI target genes analysed, 184 genes showed differential expression in extraovarian endometriosis (P <0.05) compared with endometrium tissue, including SFRP2 and CTNNI. Menstrual cycle-dependent regulation of WNT genes observed in the endometrium was lost in endometriosis lesions, as shown by hierarchical clustering. Immunohistochemical analysis indicated that SFRP2 and CTNNBI are novel endometriosis lesion border markers, complementing immunostaining for the known marker CD10 (also known as MME). SFRP2 and CTNNBI localized similarly in both the epithelium and stroma of extraovarian endometriosis tissue, and interestingly, both also indicated an additional distant lesion border, suggesting that WNT signaling is altered in the endometriosis stroma beyond the primary border indicated by the known marker CD10. SFRP2 expression was positively associated with pain symptoms experienced by patients (P <0.05), and functional loss of SFRP2 in extraovarian endometriosis primary cell cultures resulted in decreased cell proliferation (P <0.05) associated with reduced CTNNBI protein expression (P = 0.05). LIMITATIONS REASONS FOR CAUTION: SFRP2 and CTNNBI improved extraovarian endometriosis lesion border detection in a relatively small cohort (n = 20), although larger studies with different endometriosis subtypes in variable cycle phases and under hormonal medication are required. WIDER IMPLICATIONS OF THE FINDINGS: The highly expressed SFRP2 and CTNNBI improve endometriosis lesion border detection, which can have clinical implications for better visualization of endometriosis lesions over CD10. Furthermore, SFRP2 acts as a canonical WNT/CTNNBI signaling agonist in endometriosis and positively regulates endometriosis lesion growth, suggesting that the WNT pathway may be an important therapeutic target for endometriosis.
  • Kim, Jinsil; Stirling, Kara J.; Cooper, Margaret E.; Ascoli, Mario; Momany, Allison M.; McDonald, Erin L.; Ryckman, Kelli K.; Rhea, Lindsey; Schaa, Kendra L.; Cosentino, Viviana; Gadow, Enrique; Saleme, Cesar; Shi, Min; Hallman, Mikko; Plunkett, Jevon; Teramo, Kari A.; Muglia, Louis J.; Feenstra, Bjarke; Geller, Frank; Boyd, Heather A.; Melbye, Mads; Marazita, Mary L.; Dagle, John M.; Murray, Jeffrey C. (2013)