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Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis 总被引：1，自引：0，他引：1
Mastrogiannaki M Matak P Mathieu JR Delga S Mayeux P Vaulont S Peyssonnaux C 《Haematologica》2012,97(6):827-834
Background
Iron metabolism, regulated by the iron hormone hepcidin, and oxygen homeostasis, dependent on hypoxia-inducible factors, are strongly interconnected. We previously reported that in mice in which both liver hypoxia-inducible factors-1 and -2 are stabilized (the hepatocyte von Hippel-Lindau knockout mouse model), hepcidin expression was strongly repressed and we hypothesized that hypoxia-inducible factor-2 could be the major regulatory component contributing to the hepcidin down-regulation.Design and Methods
We generated and analyzed hepatocyte-specific knockout mice harboring either hypoxia-inducible factor-2α deficiency (Hif2a knockout) or constitutive hypoxia-inducible factor-2α stabilization (Vhlh/Hif1a knockout) and ex vivo systems (primary hepatocyte cultures). Hif2a knockout mice were fed an iron-deficient diet for 2 months and Vhlh/Hif1a knockout mice were treated with neutralizing erythropoietin antibody.Results
We demonstrated that hypoxia-inducible factor-2 is dispensable in hepcidin gene regulation in the context of an adaptive response to iron-deficiency anemia. However, its overexpression in the double Vhlh/Hif1a hepatocyte-specific knockout mice indirectly down-regulates hepcidin expression through increased erythropoiesis and erythropoietin production. Experiments in primary hepatocytes confirmed the non-autonomous role of hypoxia-inducible factor-2 in hepcidin regulation.Conclusions
While our results indicate that hypoxia-inducible factor-2 is not directly involved in hepcidin repression, they highlight the contribution of hepatic hypoxia-inducible factor-2 to the repression of hepcidin through erythropoietin-mediated increased erythropoiesis, a result of potential clinical interest. 相似文献3.
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Takashi Saisu Keishi Yamashita Chiho Suzuki Makoto Kamegaya Kazuhisa Takahashi 《Arthritis \u0026amp; Rheumatology》2010,62(2):609-615
Objective
To clarify whether age at the time of the initial administration of corticosteroids is a risk factor for corticosteroid‐associated osteonecrosis in children with systemic lupus erythematosus (SLE), using magnetic resonance imaging (MRI).Methods
From 1986 to 2007, MRI was used to prospectively study 676 joints, including 72 joints (36 hips and 36 knees) in 18 pediatric patients with SLE (<15 years old), 100 joints (50 hips and 50 knees) in 25 adolescent patients with SLE (15–20 years old), and 504 joints (252 hips and 252 knees) in 126 adult patients with SLE (>20 years old), beginning just after corticosteroid administration, for at least 1 year. The followup rate was 100%.Results
In pediatric patients, osteonecrosis developed in 4 joints (6%; all hips). In adolescent patients, osteonecrosis developed in 49 joints (49%; 18 hips and 31 knees). In adult patients, osteonecrosis developed in 207 joints (41%; 95 hips and 112 knees). The rate of osteonecrosis was significantly lower in pediatric patients than in adolescent or adult patients (P = 0.0001). Logistic regression analysis revealed that adolescent and adult patients had a significantly higher risk for osteonecrosis compared with pediatric patients, with an odds ratio of 10.3 (P < 0.0001). The youngest patients with osteonecrosis in the hip and knee were 14.9 years old and 15.5 years old, respectively. Osteonecrosis did not develop in patients younger than age 14 years.Conclusion
Our results suggest that age at the time of the initial administration of corticosteroids is associated with osteonecrosis in pediatric patients with SLE.5.
Devika Nair Laura Kidd N. Kevin Krane 《The American journal of the medical sciences》2017,353(4):320-328
Background
Membranoproliferative glomerulonephritis (MPGN) is an uncommon form of glomerulonephritis and it can be particularly difficult to predict outcomes and manage women with this disorder during pregnancy.Materials and Methods
The management of 3 successful pregnancies in women with MPGN from 1 center and previously described cases from the world literature are reviewed. This includes a number of large studies of pregnancy in women with underlying glomerular disease as well as small case series and individual reports. Courses of these pregnancies, maternal and fetal outcomes, and management, when described, were included in this review.Results
Some successful outcomes used antiplatelet therapy and plasmapheresis, but high-dose intravenous, followed by oral, corticosteroid therapy was used most frequently in patients with successful outcomes.Conclusions
The data provided is meant as a guide for clinicians who provide care for women with MPGN who are considering pregnancy or women who present with this disorder while pregnant. 相似文献6.
Trevor D. Faith Leonard Egede Edith M. Williams 《The American journal of the medical sciences》2018,355(2):104-112
Background
Research involving a homogenous cohort of participants belonging to a special population must make considerations to recruit and protect the subjects. This study analyses the ethical considerations made in the peer approaches to lupus self-management project which pilot tested a peer mentoring intervention for African American women with systemic lupus erythematosus.Methods
Considerations made at the outset of the project are described and their justifications and reasoning are given. Through analysis of feedback from a postintervention focus group and mentors' logs, implications on program outcomes and participant satisfaction are discussed.Results
Feedback indicated the importance of recruiting and training capable mentors, consistent contact from study staff to avert adverse events and avert fear or mistrust and careful consideration that must go into the pairing of mentors and mentees. Participant feedback also indicated that sensitive topics must be addressed carefully to prevent distress and dissatisfaction.Conclusions
Applying the lessons learned from this work as well as the considerations that proved successful may improve the contextualization and ethical conduct of behavioral interventions in special populations resulting in improved tailoring and acceptability toward historically underserved individuals. 相似文献7.
Hiromi Nagashima Itaru Fujimura Yutaka Nakamura Yu Utsumi Kohei Yamauchi Yasuhiro Takikawa Yukari Yokoyama Kiyomi Sakata Seiichirou Kobayashi Akira Ogawa 《Respiratory investigation》2018,56(2):184-188
Background
Residents in the district struck by the Great East Japan Earthquake Tsunami (GEJET) suffered from adverse living conditions and various pulmonary diseases.Objectives
To evaluate the influence of GEJET, we performed serial assessment of pulmonary function of approximately 10,000 residents in the district struck by GEJET.Methods
Using a spirometer, we assessed the pulmonary function of approximately 10,000 residents older than 18 years in the Sanriku seacoast, which was struck by the tsunami. Measurements were performed in 2011 and 2012.Results
We compared FVC (forced vital capacity) % pred. and FEV1 (forced expiratory volume in 1 second) % pred. of subjects between 2011 and 2012, by serial spirometry. Of the 7053 subjects studied, including 2611 men and 4442 women, FVC% pred. and FEV1% pred. were significantly higher in 2012 than in 2011. Physical indices including height, body weight and the body mass index (BMI) did not change significantly during this period. Smoking prevalence changed significantly between 2010, 2011, and 2012. Both FVC% pred. and FEV1% pred. of subjects who had quit smoking increased significantly on spirometry carried out in 2012, compared with those in 2011.Conclusions
The pulmonary function expressed as FVC% pred. and FEV1% pred. were significantly higher in 2012 than in 2011 among the subjects studied. The changes in the smoking status may be one of the reasons for the increase in values observed. However, other undetermined factors during recovery from a disaster might have resulted in improved pulmonary function. 相似文献8.
Qiushi Sun Yuan Liu Bo Liu Yingying Liu 《The American journal of the medical sciences》2018,355(3):220-227
Background
Patients with colorectal cancer (CRC) who are sensitive to epidermal growth factor antibodies inevitably acquire drug resistance. This study aimed to determine the usefulness of liquid biopsies for prognosis and clinical correlation.Materials and Methods
For liquid biopsy tests, we extracted blood from 140 CRC patients with matched tumor samples. Circulating tumor cells (CTCs) and tumor DNA (ctDNA) were extracted before surgery and treatment. Samples were quantified and tested for mutations in KRAS, NRAS and BRAF. Kaplan-Meier analyses were performed for different groups of patients for association to overall survival.Results
Among the 140 CRC cases, we observed good agreement collectively in the molecular signatures of CTCs and ctDNA with matched tumor specimens (97% concordance). Patients who were subsequently refractory to either cetuximab or panitumumab showed changes in the molecular profiles and were positive for KRAS, NRAS or BRAF. Interestingly, we observed that most of these changes were detected in CTCs analyses first. Stratified analyses conducted by the change in molecular profiles showed this group of patients to have worse survival outcome compared with the wild type group.Conclusions
Monitoring CRC patients’ molecular changes in response to treatment via CTCs and ctDNA can provide real-time information to disease changes. The study demonstrated that the emergence of secondary mutations were strongly associated to poorer survival after treatment. 相似文献9.
Corey J. Ketchem Cory Kucera Aditya Barve Levi J. Beverly 《The American journal of the medical sciences》2018,355(5):488-496
Background
Successful treatment of leukemia requires new medications to combat drug resistance, but the development of novel therapies is an arduous and risky endeavor. Repurposing currently approved drugs or those already in clinical development to treat other indications is a more practical approach. Moreover, combinatorial therapeutics are often more efficacious than single agent therapeutics because the former can simultaneously target multiple pathways that mitigate tumor aggressiveness and induce cancer cell death.Material and Methods
In this study, we combined the class III antiarrhythmic agent amiodarone and the BH3 mimetic ABT-263 based on data from a prior drug screen to assess the degree of apoptotic induction in 2 human leukemia cell lines.Results
The combination yielded statistically significant increases in apoptosis in both cell lines by downregulating AKT activity and increasing cleaved caspase-3.Conclusions
Overall, our findings suggest that combining K+ channel blockers with prosurvival Bcl-2 family inhibitors is a promising therapeutic approach in treating leukemia. 相似文献10.
Ping Li Shuo Lin Jinhui Cui Ling Li Shuisheng Zhou Jianhui Fan 《The American journal of the medical sciences》2018,355(2):149-152
Backgrounds
This study aimed to evaluate the relationship between neck circumference (NC) and gestational diabetes mellitus (GDM), and the efficacy of NC in predicting GDM by comparing with pregestational body mass index (preBMI) in southern Chinese woman.Marerials and Methods
A total of 371 pregnant women (97 GDM and 274 normal pregnant women) were recruited from the third affiliated hospital of Sun Yat-Sen University, Guangzhou, China. NC was measured at 11-13+6 gestational weeks. GDM was diagnosed through a 75-g oral glucose tolerance test at 24-28 gestational weeks. Using the receiver-operator characteristic (ROC) curve analysis, we evaluated the association between NC and GDM.Results
The area under the receiver operator characteristic curves were 0.65 (95% CI: 0.60-0.70) for NC and 0.64 (95% CI: 0.59-0.69) for preBMI in diagnosing GDM and no difference was found between them (P = 0.66). NC ≥ 33.8 cm was determined to be the best cut-off level for identifying subjects with GDM (sensitivity 68.04% and specificity 59.12%). Multivariate logistic regression analysis showed that a large NC in the first trimester was an independent risk factor for the development of GDM (odds ratio [OR] = 1.29, 95% CI: 1.72-7.45).Conclusions
NC, as well as preBMI, might be a novel anthropometric index for GDM screening. The increase of NC could be an independent risk factor for GDM in first trimester pregnancy. 相似文献11.
Oktay Bilgir Belma Gökçen Ferda Bilgir Aslı Guler Mehmet Calan Arif Yuksel Behnaz Aslanıpour Murat Akşit Giray Bozkaya 《The American journal of the medical sciences》2018,355(1):37-43
Background
Growing evidence suggest that macrophage migration inhibitory factor (MIF) plays a vital role in glucose metabolism. We aimed to ascertain whether MIF levels are altered in subjects with prediabetes and also to determine the relationship between MIF and metabolic parameters as well as visceral fat mass.Material and Methods
This cross-sectional study included 40 subjects with prediabetes and 40 age-, body mass index (BMI)- and sex-matched subjects with normal glucose tolerance. Circulating MIF levels were measured using enzyme-linked immunosorbent assay. Metabolic parameters of recruited subjects were evaluated. Visceral fat mass was measured using bioelectrical impedance method.Results
Circulating MIF levels were found to be elevated in subjects with prediabetes compared to controls (26.46 ± 16.98 versus 17.44 ± 11.80 ng/mL, P = 0.007). MIF positively correlated with BMI, visceral fat mass and indirect indices of homeostasis model assessment of insulin resistance. In linear regression model, an independent association was found between MIF levels and metabolic parameters, including BMI, visceral fat mass and homeostasis model assessment of insulin resistance. Multivariate logistic regression analyses revealed that the odds ratio for prediabetes was higher in subjects in the highest quartile of MIF compared to those in the lowest quartile, after adjusting for potential confounders.Conclusions
Increased MIF levels are associated with the elevation of prediabetic risk. 相似文献12.
Celensia Tolson Lauren E. Richey Yujing Zhao Jeffrey E. Korte Kathleen Brady Louise Haynes Eric G. Meissner 《The American journal of the medical sciences》2018,355(6):553-558
Background
Persons with HIV infection who do not achieve virologic suppression contribute significantly to the ongoing HIV epidemic and have an increased risk of clinical sequelae related to immunosuppression. The extent to which substance use and mental health diagnoses affect HIV outcomes and the care continuum has not been previously assessed at the Medical University of South Carolina (MUSC), a large academic HIV clinic.Methods
To address this knowledge gap and identify targets for intervention, we performed a retrospective chart review to examine associations of substance use and mental health diagnoses with hospitalization and virologic suppression.Results
Patients with substance use or mental health diagnoses had increased rates of hospitalization and lower rates of sustained longitudinal HIV suppression. Prevalence of distinct substance-related disorders differed by race and sex. Although cocaine, alcohol and cannabis use were common, documented opiate use disorder was surprisingly infrequent given the ongoing opioid epidemic in South Carolina.Conclusions
These data suggest effective assessment and treatment of substance use disorders will help improve the HIV care continuum in South Carolina. 相似文献13.
Atsuhito Ushiki Shuhei Nozawa Masanori Yasuo Kazuhisa Urushihata Hiroshi Yamamoto Masayuki Hanaoka Keisaku Fujimoto 《Respiratory investigation》2017,55(1):33-38
Background
Field walk tests such as the incremental shuttle walk test (ISWT) are simple tests for assessing the degree of disability in individuals with chronic obstructive pulmonary disease (COPD). In the present study, the correlations between exercise performance in the ISWT, lung function, and health status were examined in patients with COPD of varying severities.Methods
A retrospective examination of 277 COPD patients was performed using the ISWT and lung function tests along with assessment of health status using St. George?s Respiratory Questionnaire (SGRQ). In addition, we assessed the correlations between the walking distance, lung function parameters, and SGRQ scores.Results
ISWT distances were poorly correlated with lung function parameters and SGRQ scores in mild COPD patients. In contrast, ISWT distances were significantly correlated with pulmonary function parameters, such as vital capacity (%predicted) and forced expiratory volume in one second, and SGRQ scores in moderate and severe COPD patients.Conclusions
The ISWT is more independent of health status and pulmonary function in patients with mild COPD compared to moderate or severe cases. Therefore, the exercise capacity of patients with mild COPD should be estimated by the ISWT. 相似文献14.
Ami L. DeWaters Matthieu Chansard Antonio Anzueto Mary Jo Pugh Eric M. Mortensen 《The American journal of the medical sciences》2018,355(1):21-26
Background
Major depressive disorder (“depression”) has been identified as an independent risk factor for mortality for many comorbid conditions, including heart failure, cancer and stroke. Major depressive disorder has also been linked to immune suppression by generating a chronic inflammatory state. However, the association between major depression and pneumonia has not been examined. The aim of this study was to examine the association between depression and outcomes, including mortality and intensive care unit admission, in Veterans hospitalized with pneumonia.Materials and Methods
We conducted a retrospective national study using administrative data of patients hospitalized at any Veterans Administration acute care hospital. We included patients ≥65 years old hospitalized with pneumonia from 2002-2012. Depressed patients were further analyzed based on whether they were receiving medications to treat depression. We used generalized linear mixed effect models to examine the association of depression with the outcomes of interest after controlling for potential confounders.Results
Patients with depression had a significantly higher 90-day mortality (odds ratio 1.12, 95% confidence interval 1.07-1.17) compared to patients without depression. Patients with untreated depression had a significantly higher 30-day (1.11, 1.04-1.20) and 90-day (1.20, 1.13-1.28) mortality, as well as significantly higher intensive care unit admission rates (1.12, 1.03-1.21), compared to patients with treated depression.Conclusion
For older veterans hospitalized with pneumonia, a concurrent diagnosis of major depressive disorder, and especially untreated depression, was associated with higher mortality. This highlights that untreated major depressive disorder is an independent risk factor for mortality for patients with pneumonia. 相似文献15.
Wen Jiun Liu Ramli Musa Thian Fook Chew Christopher Thiam Seong Lim Zaki Morad Mohamad Adam bin Bujang 《The American journal of the medical sciences》2018,355(4):322-330
Background
The effect of dialysis treatment is complex, with both clinical and socio-psychological effects. In this study, we aimed to assess the psychological status of this growing population of end-stage renal disease.Methods
Using the Short Form of Depression, Anxiety and Stress Scale (DASS21) questionnaire, we aimed (1) to measure the psychological states of hemodialysis (HD) or peritoneal dialysis (PD) subjects from 15 sites, (2) to compare DASS21 scores between HD and PD, and (3) to identify the associated demographic and medical factors of better psychological states.Results
A total of 1,332 were eligible for analysis. Stress (48%) recorded the highest negative emotional states, followed by depression (37%) and anxiety (20%). By multivariate analysis, normal body mass index weight status, religion and absence of coronary artery disease were associated with lower score for depression, anxiety and stress, respectively. Tertiary education was associated with the lowest score in depression and anxiety, whereas HD had a lower score in stress than PD. A younger age was associated with worse DASS21 score of anxiety and stress.Conclusions
Obesity, religion and coronary artery disease were significantly associated with all 3 symptoms of depression, anxiety and stress. Older age has a protective effect on anxiety and stress. Further study is needed to evaluate the relationship between these significant factors and each psychological state. 相似文献16.
Inma Castilla-Cortazar Julieta Rodriguez de Ita Gabriel Amador Aguirre Fabiola Castorena-Torres Jesús Ortiz-Urbina Mariano García-Magariño Rocío García de la Garza Carlos Diaz Olachea Martha Irma Elizondo Leal 《The American journal of the medical sciences》2017,353(5):425-432
Background
Fanconi anemia (FA) is a condition characterized by genetic instability and short stature, which is due to growth hormone (GH) deficiency in most cases. However, no apparent relationships have been identified between FA complementation group genes and GH. In this study, we thereby considered an association between FA and Laron syndrome (LS) (insulin-like growth factor 1 [IGF-1] deficiency).Methods
A 21-year-old female Mexican patient with a genetic diagnosis of FA was referred to our research department for an evaluation of her short stature. Upon admission to our facility, her phenotype led to a suspicion of LS; accordingly, serum levels of IGF-1 and IGF binding protein 3 were analyzed and a GH stimulation test was performed. In addition, we used a next-generation sequencing approach for a molecular evaluation of FA disease-causing mutations and genes involved in the GH-IGF signaling pathway.Results
Tests revealed low levels of IGF-1 and IGF binding protein 3 that remained within normal ranges, as well as a lack of response to GH stimulation. Sequencing confirmed a defect in the GH receptor signaling pathway.Conclusions
To the best of our knowledge, this study is the first to suggest an association between FA and LS. We propose that IGF-1 administration might improve some FA complications and functions based upon IGF-1 beneficial actions observed in animal, cell and indirect clinical models: erythropoiesis modulation, immune function improvement and metabolic regulation. 相似文献17.
Masahiro Shimada Atsuhisa Tamura Kyoko Yokosuka Kei Kusaka Hirotoshi Matsui Hideaki Nagai Ken Ohta 《Respiratory investigation》2018,56(4):365-368
Background
In current guidelines, the role of immune checkpoint inhibitors is not yet determined in the treatment strategy for NSCLC harboring ALK translocations.Case
A 51-year-old woman with lung adenocarcinoma harboring ALK translocation was treated with alectinib until PD. After the second (CDDP/PEM) and third (crizotinib) line treatment, a second biopsy was performed, revealing PD-L1 tumor proportion score of 70–80% and G1202R mutation of ALK. Pembrolizumab was selected for the fourth line, leading to PR for more than 6 months.Conclusions
While alectinib might induce resistance to ALK-TKI, it could increase PD-L1 positive cells to become sensitive to PD-1/PD-L1 inhibitors. 相似文献18.
Hiroyoshi Machida Yoko Shibata Sumito Inoue Akira Igarashi Yoshikane Tokairin Keiko Yamauchi Tomomi Kimura Kento Sato Hiroshi Nakano Michiko Nishiwaki Maki Kobayashi Sujeong Yang Yukihiro Minegishi Kodai Furuyama Tomoka Yamamoto Tetsu Watanabe Tsuneo Konta Yoshiyuki Ueno Isao Kubota 《Respiratory investigation》2018,56(1):34-39
Background
Diabetes has been reported as a comorbidity of chronic obstructive pulmonary disease (COPD) in Western countries, but it has not been demonstrated in epidemiological reports in Japan. The purpose of this study was to clarify whether the relationship between airflow obstruction and diabetes can be confirmed in a Japanese general population.Methods
From 2004 to 2006, blood sampling and pulmonary function tests were performed on 3045 people over the age of 40 years in annual health check-ups held in Takahata, Yamagata Prefecture, Japan. Pulmonary function was re-evaluated in 2009 and 2011.Results
The prevalence of diabetes did not differ between subjects with and without airflow obstruction. Furthermore, although body mass index decreased, no increase in the prevalence of diabetes was observed with the progression of airflow obstruction. The annual changes in forced expiration volume in 1 s (FEV1) did not differ depending on the presence or absence of diabetes in the study population.Conclusion
There was no difference in the prevalence of diabetes between subjects with airflow obstruction and those without. As patients with COPD in Japan are thinner than in the West, diabetes may not be a common comorbidity in Japanese patients with COPD. 相似文献19.
Shinobu Osanai Toshiyuki Ogasa Kazuhiro Sumitomo Naoyuki Hasebe 《Respiratory investigation》2018,56(1):21-27
Background
There is limited information about the respiratory function of ever-smokers without lung disorders. We sought to assess the effects of smoking habits on respiratory function in subjects without lung disorders.Methods
Subjects were recruited from among patients without any evidence of respiratory disorders who visited rural primary care clinics. Each participant was asked to answer a questionnaire that included questions smoking history. Their forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were measured.Results
We analyzed 802 subjects (364 men and 438 women). The means of the lambda-mu-sigma method derived z-score of FEV1 (zFEV1) both in current-smokers and ex-smokers were lower than that in never-smokers. The mean zFEV1 in the ever-smokers with more than 30 pack-years of smoking history were lower than that in the ever-smokers with less smoking history. Univariate analysis showed that there were significant negative correlations between pack-years and zFEV1 both in the ex-smokers and current-smokers. There was no significant correlation between the duration of smoking cessation and zFEV1 in the ex-smokers.Conclusions
Our data suggests that respiratory function in healthy ever-smokers is decreased based on smoking habits in a dose-dependent manner. Even after a long period of smoking cessation, the decreased respiratory function seems to be maintained in ex-smokers. 相似文献20.
Parasuram Krishnamoorthy Aditi Kalla Vincent M. Figueredo 《The American journal of the medical sciences》2018,355(5):425-427