Miracle-dz/UniFAR-FTUs huggingface dataset:
Critical role of histone acetylation by p300 in human placental 11β-HSD2 expression.

CONTEXT Fetal overexposure to glucocorticoids leads to growth restriction. Optimal fetal glucocorticoid level is ensured by the expression of cortisol-inactivating enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in placental syncytiotrophoblasts. The transcription factor selective promoter factor 1 (Sp1) is known to up-regulate 11β-HSD2 expression in the presence of enhanced histone acetylation in syncytiotrophoblasts, but the mechanisms underlying histone acetylation remain unknown. OBJECTIVES The role of p300 in histone acetylation associated with 11β-HSD2 expression in syncytiotrophoblasts was investigated. DESIGN Distribution of p300 in human placenta was studied with immunohistochemistry. The role of p300 in histone-3 (H3) acetylation in association with 11β-HSD2 expression was investigated in cultured primary human placental trophoblasts in the presence of small interfering RNA (siRNA)-mediated knockdown of p300, p300 inhibitor C646, or p300 overexpression. The interaction of Sp1 and p300 was studied with chromatin immunoprecipitation and coimmunoprecipitation. RESULTS Intense staining of p300 was found in the nuclei of trophoblasts. Levels of p300 and acetyl H3K9 and H3K27 associated with 11β-HSD2 promoter were increased in the course of syncytialization and by cAMP pathway activation. Chromatin immunoprecipitation and coimmunoprecipitation revealed p300 and Sp1 on 11β-HSD2 promoter and in the same protein complex in the syncytiotrophoblasts. Overexpression of p300 enhanced 11β-HSD2 expression, which was attenuated by Sp1 knockdown, whereas p300 knockdown and C646 reduced both basal and cAMP-stimulated acetylation of H3K9 and H3K27 associated with 11β-HSD2 expression. CONCLUSIONS Interaction of p300 with Sp1 plays a crucial role in histone acetylation associated with 11β-HSD2 expression in syncytiotrophoblasts, which may have important implications in the establishment of the placental glucocorticoid barrier in gestation.
Chronic fatigue syndrome and increased susceptibility to upper respiratory tract infections and illnesses

Background: Previous research has suggested that chronic fatigue syndrome (CFS) patients report more upper respiratory tract illnesses (URTIs) than controls. Aims: The present study aimed to replicate and extend this research. Method: A prospective study of the incidence of URTIs was conducted. This was similar to previous work involving diary studies but also included objective measures of illness severity (e.g. nasal secretion; sub-lingual temperature) and infection (virus isolation from nasal swabs and antibody changes). Fifty-seven patients with CFS, diagnosed according to the 1994 CDC criteria, were recruited randomly from a volunteer panel compiled of patients who had attended the Cardiff CFS outpatient clinic. A further 57 individuals without CFS were recruited from a general population research panel. Results: The results confirmed that CFS patients report more upper respiratory virus infections and the virological results showed that this was not due to a reporting bias but reflected greater susceptibility to infection. Conclusions: This increased susceptibility to infection in the CFS group can account for the increased reporting of URTIs found in this and previous studies.
Post‐partum haemorrhage and tranexamic acid: a global issue

Post‐partum haemorrhage (PPH) remains the major cause of maternal death worldwide, with the overwhelming majority of bleeding deaths occurring in low income countries. These bleeding deaths occur due to a complex network of biological and socioeconomic factors, including changes to haemostasis and fibrinolysis during pregnancy. Tranexamic acid (TxA) has been shown to reduce death in bleeding trauma patients safely and is effective in reducing bleeding in surgical patients, however its role in PPH has been less well established. We discuss the impact of the recently published World Maternal Antifibrinolytic (WOMAN) trial, which demonstrated a significant reduction in bleeding deaths (Risk ratio 0·81) in women with PPH who received intravenous TxA compared to those receiving placebo. There were no increases in post‐partum thrombotic rates in mothers or breast‐fed babies. This trial has shown that intravenous TxA can be used safely and effectively to treat PPH, and should be implemented widely to reduce death due to PPH. However, for the full benefit of TxA to be fully realised in resource‐constrained settings, the effectiveness of oral or topical administration and/or pre‐emptive dosing need to be investigated.
Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice

Ibrutinib is indicated in Europe for the treatment of several B‐cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib‐treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib.
Sweet and sour after renal transplantation: a qualitative study about the positive and negative consequences of renal transplantation.

OBJECTIVES This qualitative study investigated the renal patients' experience of positive and negative consequences of transplantation, as well as the strategies they use to adapt to the transplantation. DESIGN AND METHODS A qualitative design (30 participants in total), using individual interviews (18 participants) and two focus groups (12 participants in total), was used. RESULTS The results showed that patients experienced a wide range of positive and negative emotions, in particular, guilt, gratefulness, and fear, partly as a result of their normative persuasions. Normative persuasions may transform inherent positive emotions into negative emotions and subsequent maladaptive behaviour. Not only physical limitations but also physical improvements were found to be related to the experience of negative emotions. Finally, the results indicated that patients mainly used adaptive coping strategies to adjust to life after transplantation, such as looking for opportunities, setting different priorities, making own choices, trying to maintain control, taking good care of oneself, and appreciating other things in life. CONCLUSIONS This study offers several new insights regarding the range of experiences of renal patients after transplantation. Health professionals are invited to pay more attention to the full range of positive and negative experiences following transplantation, including the existence of normative persuasions. Health professionals may assist renal patients by helping them to recognize and acknowledge both positive and negative emotions and to encourage the use of more beneficial coping strategies. STATEMENT OF CONTRIBUTION What is already known on this subject? The quality of life (QoL) of renal patients significantly improves after transplantation but the post-transplant QoL is lower compared with the QoL in healthy populations. Patients on dialysis and those who have received a donor kidney tend to use mainly emotion-focused coping strategies. What does this study add? This study offers several new insights regarding experiences of renal patients after transplantation: Patients experience a range of positive and negative emotions like guilt, gratefulness, and fear. Emotions are partly a result of normative persuasions. Persuasions may transform positive emotions into negative emotions and maladaptive behaviour. Physical limitations and improvements can due to the persuasions lead to negative emotions. Patients mainly use adaptive coping strategies.
Interleukin-2 and lanreotide in the treatment of medullary thyroid cancer: in vitro and in vivo studies.

CONTEXT To date no efficacious treatments are available for advanced medullary thyroid carcinoma (MTC). OBJECTIVE We investigated in vitro and in vivo a new strategy for the therapy of MTC, combining human recombinant IL-2 with lanreotide (LAN), a somatostatin analog. METHODS The in vitro effects of LAN on the sensitivity of TT cells, a MTC cell line, to IL-2-stimulated human peripheral blood mononuclear cells were determined by a lactate dehydrogenase release assay. In addition, we evaluated the toxicity, the effects on quality of life, and the antitumor activity of sc low-dose IL-2 in combination with LAN (90 mg every 28 days) in a series of 6 patients with symptomatic and advanced MTC. RESULTS The cytotoxicity of IL-2-activated peripheral blood mononuclear cells was significantly increased in TT cells treated with LAN or LAN plus IL-2 compared with that in TT cells without treatment. The therapy was well tolerated, and a statistically significant improvement of quality of life was observed in patients treated with the combination of LAN and IL-2. After 6 months of therapy, partial response and stable disease have been recorded in 2 and 3 patients, respectively, with a significant decrease in calcitonin levels in 3 patients. CONCLUSIONS Both in vitro and in vivo evidence suggests that the combination of LAN and IL-2 may have a role in the management of advanced and symptomatic MTC. However, these preliminary data require further validation in larger randomized trials.
Spontaneous remission of pulmonary and splenic lesions in sarcoidosis

Abstract A case is described of sarcoidosis involving the lungs and spleen in which the 3-year follow-up under no treatment showed remission of pulmonary infiltration and disappearance of splenic nodules. Computed tomographic findings of splenic sarcoidosis are reviewed, as well as the relationship between splenic and lung changes during follow-up.
Large-scale pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature.

CONTEXT The majority of patients presenting with short stature do not receive a definitive diagnosis. Advances in genetic sequencing allow for large-scale screening of candidate genes, potentially leading to genetic diagnoses. OBJECTIVES The purpose of this study was to discover genetic variants that contribute to short stature in a cohort of children with no known genetic etiology. DESIGN This was a prospective cohort study of subjects with short stature. SETTING The setting was a pediatric endocrinology and genetics clinics at an academic center. PATIENTS A total of 192 children with short stature with no defined genetic etiology and 192 individuals of normal stature from the Framingham Heart Study were studied. INTERVENTION Pooled targeted sequencing using next-generation DNA sequencing technology of the exons of 1077 candidate genes was performed. MAIN OUTCOME MEASURES The numbers of rare nonsynonymous genetic variants found in case patients but not in control subjects, known pathogenic variants in case patients, and potentially pathogenic variants in IGF1R were determined. RESULTS We identified 4928 genetic variants in 1077 genes that were present in case patients but not in control subjects. Of those, 1349 variants were novel (898 nonsynonymous). False-positive rates from pooled sequencing were 4% to 5%, and the false-negative rate was 0.1% in regions covered well by sequencing. We identified 3 individuals with known pathogenic variants in PTPN11 causing undiagnosed Noonan syndrome. There were 9 rare potentially nonsynonymous variants in IGF1R, one of which is a novel, probably pathogenic, frameshift mutation. A previously reported pathogenic variant in IGF1R was present in a control subject. CONCLUSIONS Large-scale sequencing efforts have the potential to rapidly identify genetic etiologies of short stature, but data interpretation is complex. Noonan syndrome may be an underdiagnosed cause of short stature.
Subclinical hypothyroidism and cardiovascular risk: how to end the controversy.

The indications for screening and TSH threshold levels for treatment of subclinical hypothyroidism have remained a clinical controversy for over 20 years. Subclinical thyroid dysfunction is a common finding in the growing population of older adults, occurring in 10–15% among those age 65 and older, and may contribute to multiple common problems of older age, including cardiovascular disease, muscular impairment, mood problems, and cognitive dysfunction (1). In 2004, both the U.S. Preventive Services Task Force (2) and a clinical consensus group of experts (3) concluded that the existing evidence about the association between subclinical hypothyroidism and cardiovascular risks, primarily cross-sectional or case-control studies (4), was insufficient. For example, a frequently cited analysis from the Rotterdam study found a cross-sectional association between subclinical hypothyroidism and atherosclerosis, as measured by abdominal aortic calcification (odds ratio, 1.7; 95% confidence interval [CI], 1.1–2.6) and prevalent myocardial infarction (MI) (odds ratio, 2.3; 95% CI, 1.3–4.0) (5). Conversely, the prospective part of this study included only 16 incident MIs; the hazard ratio (HR) for subclinical hypothyroidism was 2.50, with broad 95% CIs (0.70–9.10). Potential mechanisms for the associations with cardiovascular diseases among adults with subclinical hypothyroidism include elevated cholesterol levels, inflammatory markers, raised homocysteine, increased oxidative stress, insulin resistance, increased systemic vascular resistance, arterial stiffness, altered endothelial function, and activation of thrombosis and hypercoagulability that have all been reported to be associated with subclinical hypothyroidism (1, 6).
Current Techniques in Avian Anesthesia

Abstract Birds often require anesthesia for diagnostic or therapeutic purposes. The provision of anesthesia with a low risk of complications is, in part, associated with a working knowledge of avian cardiopulmonary physiology. Inhalant anesthesia remains the technique of choice for anesthesia of birds. Anesthetic drugs and techniques, including air sac cannulation and intraosseous catheterization, for pet birds (psittacines and passerines) are covered in this review.
PGE2 and PGF2α concentrations in human endometrial fluid as biomarkers for embryonic implantation.

BACKGROUND Prostaglandin (PG) signaling has been implicated in embryonic implantation in several animal species including humans; however, this knowledge has not yet been clinically translated. The objective of this work is to investigate whether PGE2 and PGF2α in endometrial fluid (EF) can be used as biomarkers of human embryonic implantation. PATIENTS AND METHODS Lipidomic profile of human EF (n = 173) obtained through natural cycles, hormonal replacement therapy, controlled ovarian stimulation, and refractory endometrium induced by the insertion of an intrauterine device was analyzed by liquid chromatography and tandem mass spectrometry. Immunohistochemistry, Western blotting, immunolocalization of PG receptors on mouse embryos, embryo adhesion assay, pharmacological interventions, and statistical analysis were conducted. RESULTS PGE2 and PGF2α concentrations increased significantly in the human EF during the window of implantation in natural cycles and assisted reproductive technologies patients undergoing in vitro fertilization and ovum donation. This profile was abrogated in the refractory endometrium. We also demonstrated that PGE2 and PGF2α synthases are located in the endometrial epithelium being hormonally regulated during the window of implantation, and PG receptors are expressed in the trophoectoderm and inner cell mass of mouse blastocysts. Using an in vitro model of embryo adhesion, we demonstrated that inhibition of PGE2 and PGF2α or PG receptors (EP2 and FP) prevents embryo adhesion, which can be overcome by adding these molecules back or using their agonists. Finally, in a pilot study, we demonstrated that PGE2 and PGF2α levels from EF 24 hours prior to embryo transfer could predict pregnancy outcome. CONCLUSIONS Our results suggest that PGE2 and PGF2α concentrations 24 hours prior to embryo transfer are potential noninvasive biomarkers of endometrial receptivity.
The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer.

CONTEXT Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis in need of more effective treatment options. Published evidence indicates many ACCs express the vascular endothelial growth factor receptor (VEGFR), suggesting inhibiting vascular endothelial growth factor signaling could potentially impact tumor growth. OBJECTIVE The objective of the study was to determine the antitumor efficacy of axitinib (AG-013736), a potent, selective inhibitor of VEGFR1, -2, and -3. DESIGN This was a phase II, open-label trial using a two-stage design. PATIENTS Thirteen patients with metastatic ACC previously treated with at least one chemotherapy regimen with or without mitotane participated in the study. INTERVENTION Starting axitinib dose was 5 mg orally twice daily. Dose escalations were permitted if the administered dose was tolerable. RESULTS Thirteen patients were enrolled. Dose escalation was possible in seven patients, but the majority could not tolerate a dose higher than the starting 5 mg, twice-daily dose for prolonged periods of time. All patients experienced known grade 1/2 toxicities, and 10 of 13 patients had at least one grade 3/4 adverse event. No patient tumor could be scored as a Response Evaluation Criteria in Solid Tumors response, although the growth rate on therapy compared with that prior to starting axitinib was reduced in 4 of the 13 patients. The median progression-free survival was 5.48 months, and the median overall survival was longer than 13.7 months. CONCLUSION Axitinib has limited effectiveness in ACC. Together with 48 patients previously reported who received either sorafenib or sunitinib, a total of 61 ACC patients have now been treated with a VEGFR tyrosine kinase inhibitor without an objective Response Evaluation Criteria in Solid Tumors response. Future trials in ACC should look to other targets for possible active agents.
Lifestyle modification programs in polycystic ovary syndrome: systematic review and meta-analysis.

CONTEXT Polycystic ovary syndrome (PCOS) is a prevalent disorder that affects women of childbearing age and may be related to obesity and insulin resistance. OBJECTIVE The purpose of this systematic review was to appraise the evidence of the impact of lifestyle modification (LSM) interventions on outcomes of women with PCOS. DATA SOURCES Sources included Ovid Medline, OVID Embase, OVID Cochrane Library, Web of Science, Scopus, PsycINFO, and CINAHL (up to January 2011). STUDY SELECTION We included randomized controlled trials that enrolled woman of any age with PCOS who received LSM and compared them against women who received no intervention, minimal intervention, or metformin. DATA EXTRACTION Two authors performed the data extraction independently. DATA SYNTHESIS We included 9 trials enrolling 583 women with a high loss to follow-up rate, lack of blinding, and short follow-up. Compared with minimal intervention, LSM significantly reduced fasting blood glucose (weighted mean difference, -2.3 mg/dL; 95% confidence interval, -4.5 to -0.1, I² = 72%, P = .04) and fasting blood insulin (weighted mean difference, -2.1 μU/mL, 95% confidence interval, -3.3 to -1.0, I² = 0%, P < .001). Changes in body mass index were associated with changes in fasting blood glucose (P < .001). Metformin was not significantly better than LSM in improving blood glucose or insulin levels. We found no significant effect of LSM on pregnancy rate, and the effect on hirsutism was unclear. CONCLUSIONS The available evidence suggests that LSM reduces fasting blood glucose and insulin levels in women with PCOS. Metformin has similar effects. Translation of these short-term effects to patient-important outcomes, beyond diabetes prevention, remains uncertain.
Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function.

CONTEXT Uterine leiomyomas are highly prevalent benign tumors of premenopausal women and the most common indication for hysterectomy. However, the exact etiology of this tumor is not fully understood. OBJECTIVE The objective of the study was to evaluate the role of activin-A and myostatin and their signaling pathways in human myometrial and leiomyoma cells. DESIGN This was a laboratory study. SETTING Myometrial and leiomyoma cells (primary and cell lines) were cultured in vitro. PATIENTS The study included premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. INTERVENTIONS Primary myometrial and leiomyoma cells and/or cell lines were treated with activin-A (4 nM) and myostatin (4 nM) for different days of interval (to measure proliferation rate) or 30 minutes (to measure signaling molecules) or 48 hours to measure proliferating markers, extracellular matrix mRNA, and/or protein expression by real-time PCR, Western blot, and/or immunocytochemistry. RESULTS We found that activin-A and myostatin significantly reduce cell proliferation in primary myometrial cells but not in leiomyoma cells as measured by a CyQUANT cell proliferation assay kit. Reduced expression of proliferating cell nuclear antigen and Ki-67 were also observed in myometrial cells in response to activin-A and myostatin treatment. Activin-A also significantly increased mRNA expression of fibronectin, collagen1A1, and versican in primary leiomyoma cells. Finally, we found that activin-A and myostatin activate Smad-2/3 signaling but do not affect ERK or p38 signaling in both myometrial and leiomyoma cells. CONCLUSIONS This study results suggest that activin-A and myostatin can exert antiproliferative and/or fibrotic effects on these cell types via Smad-2/3 signaling.