Crosstalk between oxygen signaling and iron metabolism in renal interstitial fibroblasts.

To maintain the oxygen supply, the production of red blood cells (erythrocytes) is promoted under low-oxygen conditions (hypoxia). Oxygen is carried by hemoglobin in erythrocytes, in which the majority of the essential element iron in the body is contained. Because iron metabolism is strictly controlled in a semi-closed recycling system to protect cells from oxidative stress caused by iron, hypoxia-inducible erythropoiesis is closely coordinated by regulatory systems that mobilize stored iron for hemoglobin synthesis. The erythroid growth factor erythropoietin (EPO) is mainly secreted by interstitial fibroblasts in the renal cortex, which are known as renal EPO-producing (REP) cells, and promotes erythropoiesis and iron mobilization. Intriguingly, EPO production is strongly induced by hypoxia through iron-dependent pathways in REP cells. Here, we summarize recent studies on the network mechanisms linking hypoxia-inducible EPO production, erythropoiesis and iron metabolism. Additionally, we introduce disease mechanisms related to disorders in the network mediated by REP cell functions. Furthermore, we propose future studies regarding the application of renal cells derived from the urine of kidney disease patients to investigate the molecular pathology of chronic kidney disease and develop precise and personalized medicine for kidney disease.

PNPO-PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity.

Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.

Nutritional management of heart failure.

Nutrition in the cardiovascular field to date has focused on improving lifestyle-related diseases such as hypertension and diabetes from the viewpoint of secondary prevention. For these conditions, "nutrition for weight loss" is recommended, and nutritional guidance that restricts calories is provided. On the other hand, in symptomatic Stage C and D heart failure, it is known that underweight patients who manifest poor nutrition, sarcopenia, and cardiac cachexia have a poor prognosis. This is referred to as the "Obesity paradox". In order to "avoid weight loss" in patients with heart failure, a paradigm shift to nutritional management to prevent weight loss is needed. Rather than prescribing uniform recommendation for salt reduction of 6 g/day or less, awareness of the behavior change stage model is attracting attention. In this setting, the value of salt restriction will need to be determined to determine the priority level of intervention for undernutrition versus the need to prevent congestive signs and symptoms. In the Intensive Care Unit (ICU)/Cardiac Care Unit (CCU) for acute heart failure, nutritional intervention should be considered within 48 h of admission. Key points are selection of access route, timing of intervention, and monitoring of side effects. In nutritional management at home and in end-of-life care, food is a reflection of an individual's values, as well as a source of joy and encouragement. The importance of digestive tract should also be recognized in heart failure from oral flail to intestinal edema, constipation, and the intestinal bacteria called the heart-gut axis. Finally, we would like to propose a new term "heart nutrition" for nutritional management in patients with heart failure in this review. Compared to the evidence for exercise therapy in heart failure, studies assessing nutritional management remain scarce and there is a need for research in this area in the future.

Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration.

Kidney injury often causes anemia due to a lack of production of the erythroid growth factor erythropoietin (EPO) in the kidneys. Roxadustat is one of the first oral medicines inducing EPO production in patients with renal anemia by activating hypoxia-inducible factors (HIFs), which are activators of EPO gene expression. In this study, to develop prodrugs of roxadustat with improved permeability through cell membrane, we investigated the effects of 8 types of esterification on the pharmacokinetics and bioactivity of roxadustat using Hep3B hepatoma cells that HIF-dependently produce EPO. Mass spectrometry of cells incubated with the esterified roxadustat derivatives revealed that the designed compounds were deesterified after being taken up by cells and showed low cytotoxicity compared to the original compound. Esterification prolonged the effective duration of roxadustat with respect to EPO gene induction and HIF activation in cells transiently exposed to the compounds. In the kidneys and livers of mice, both of which are unique sites of EPO production, a majority of the methyl-esterified roxadustat was deesterified within 6 h after drug administration. The deesterified roxadustat derivative was continuously detectable in plasma and urine for at least 48 h after administration, while the administered compound became undetectable 24 h after administration. Additionally, we confirmed that methyl-esterified roxadustat activated erythropoiesis in mice by inducing Epo mRNA expression exclusively in renal interstitial cells, which have intrinsic EPO-producing potential. These data suggest that esterification could lead to the development of roxadustat prodrugs with improvements in cell membrane permeability, effective duration and cytotoxicity.

Renal NG2-expressing cells have a macrophage-like phenotype and facilitate renal recovery after ischemic injury.

Pericytes play an important role in the recovery process after ischemic injury of many tissues. Brain pericytes in the peri-infarct area express macrophage markers in response to injury stimuli and are involved in neovascularization. In the kidney, nerve/glial antigen 2 (NG2)+ pericytes have been found to accumulate after renal injury. These accumulated NG2+ cells are not involved in scar formation. However, the role of accumulated NG2+ cells in injured kidneys remains unknown. Here, using a reversible ischemia-reperfusion (I/R) model, we found that renal NG2+ cells were increased in injured kidneys and expressed macrophage markers (CD11b or F4/80) on day 3 after reperfusion. Isolated NG2+ cells from I/R kidneys also had phagocytic activity and expressed anti-inflammatory cytokine genes, including mannose receptor and IL-10. These macrophage-like NG2+ cells did not likely differentiate into myofibroblasts because they did not increase α-smooth muscle actin expression. Intravenous transfusion of renal NG2+ cells isolated from donor mice on day 3 after reperfusion into recipient mice on day 1 after I/R surgery revealed that NG2+ cell-injected mice had lower plasma blood urea nitrogen, reduced kidney injury molecule-1 mRNA expression, ameliorated renal damage, and reduced cellular debris accumulation compared with PBS-injected mice on day 5 after reperfusion. In conclusion, these data suggest that renal NG2+ cells have an M2 macrophage-like ability and play a novel role in facilitating the recovery process after renal I/R injury.NEW & NOTEWORTHY Brain pericytes have macrophage-like activities after injury. However, such properties of pericytes in peripheral tissues have not been investigated. Here, we provide evidence that nerve/glial antigen 2-positive cells increase after renal injury. The population of nerve/glial antigen 2-positive cells, which does not increase expression of myofibroblast-associated gene, express macrophage markers and anti-inflammatory cytokine genes, have phagocytic activity, and play a role in renal recovery after kidney injury.

Clinical practice guidelines for rehabilitation nutrition in cerebrovascular disease, hip fracture, cancer, and acute illness: 2020 update.

BACKGROUND: Individuals undergoing rehabilitation often experience nutritional problems such as malnutrition, but there are no clinical practice guidelines (CPGs) specifically tailored to the combination of rehabilitation and nutritional care for these patients. The Japanese Association for Rehabilitation Nutrition aimed to develop CPGs for rehabilitation nutrition to support clinical decision making in daily practice. METHODS: A CPG committee and development process based on the Grading of Recommendations Assessment, Development and Evaluation system and the Minds Handbook for Clinical Practice Guideline Development 2014 was established. Four clinical questions were defined for patients undergoing rehabilitation for cerebrovascular disease, hip fracture, cancer, and acute illness. Literatures of randomised control trials (RCTs) up to April 2020 were searched for using the MEDLINE, EMBASE, CENTRAL, and Ichushi-web databases. After screening, full-text papers were assessed for eligibility for analysis. Subsequently, studies included in the systematic review were examined regarding their risk of bias, and underwent meta-analyses. A CPG development committee drafted the guidelines based on the systematic review report. Final recommendations were determined by the panel members. RESULTS: Four recommendations were made based on 4 to 9 RCTs for each disease/condition. The certainty of the evidence ranged from very low to low. Overall, the enhanced nutritional care was weakly recommended for rehabilitation patients with cerebrovascular disease, hip fracture, cancer, and acute illnesses. CONCLUSIONS: This CPG provides tentative recommendations for nutritional care of individuals undergoing rehabilitation. Due to low certainty of evidence and small sample sizes of the included studies, more high-quality and larger RCTs are needed to develop more practical CPGs.

Preoperative medications is one of the factor affecting patient-reported outcomes after total hip arthroplasty.

Although the reported clinical outcomes of total hip arthroplasty (THA) for hip osteoarthritis are satisfactory, not all patients are completely satisfied. Thus, there is interest in predicting postoperative satisfaction before surgery. The influence of comorbidities and preoperative medications on the incidence of complications and duration of hospitalization following THA has become apparent. However, studies about the associations of preoperative medication with clinical outcomes of THA are limited. Therefore, this study aimed to clarify the relationship between preoperative medications and postoperative patient-reported outcomes. This retrospective cross-sectional multicenter study enrolled post-THA patients (79 patients, 90 hips) who were examined from February to March 2019 in eight general hospitals. Outcome measures included patient-reported outcome as Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ) score. Preoperative medications were investigated from medical records. Medications were categorized, and analgesics were categorized into non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, pregabalin, duloxetine, neurotropin (an extract from inflammatory rabbit skin inoculated by vaccinia virus), and opioid. To identify the factors associated with JHEQ score, the patients were divided into lower (<55 score) and higher (≥55) JHEQ score groups. Spearman rank correlation coefficient (r) showed significant difference between the total number of preoperative medications and postoperative JHEQ movement subscale (r = -0.37, p < 0.01), mental subscale (r = -0.29, p < 0.01), and JHEQ (r = -0.30, p < 0.01) scores. In the multiple logistic regression analysis, only the total number of preoperative medications was identified as a risk factor for lower JHEQ score (p < 0.01). This study clarified an inverse correlation between the total preoperative medication count and postoperative outcomes and found that larger total count of preoperative medications is a risk factor of poor postoperative patient-reported outcomes of THA.

Steroids Inhibit Eosinophil Accumulation and Downregulate Hematopoietic Chemotaxic Prostaglandin D2 Receptor in Aspirin-Exacerbated Respiratory Disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by eosinophilic rhinosinusitis, nasal polyposis, aspirin sensitivity, and asthma. Aims/Objectives: This study aims to identify a mechanism to target for the future treatment of AERD via the elucidation of the effect of systemic steroids on the expression of hematopoietic prostaglandin D2 synthase (HPGDS) and chemotaxic prostaglandin D2 (DP2) receptor relative to eosinophil activation in the nasal polyps of patients with AERD. MATERIALS AND METHODS: Among 37 patients undergoing endoscopic sinus surgery, 28 received systemic steroids preoperatively. Nasal polyps were harvested from all 37 patients. After routine processing of paraffin sections, immunohistochemistry was performed using specific antibodies for HPGDS, eosinophil peroxidase (EPX), and DP2. RESULTS: Expression of HPGDS, DP2, and EPX by eosinophils was higher and more frequent in patients with non-preoperative steroid therapy. Likewise, HPGDS and DP2 were highly expressed in activated eosinophils in the nasal polyps, but not in normal eosinophils. CONCLUSION AND SIGNIFICANCE: This study provides clear evidence that systemic steroid therapy inhibits eosinophil activation and decreases HPGDS and DP2 expression in patients with AERD, indicating a reduction in prostaglandin D2 production and hence control hyperplasia of nasal polyps.

Initial Rotational Instability of the Tapered Wedge-Shaped Type Cementless Stem.

BACKGROUND: Because the tapered wedge-shaped type cementless stem has a small anteroposterior width and a low occupation rate in the medullary space, postoperative rotational instability and stem subsidence due to inadequate proximal fixation are concerns. The purpose of this study was to clarify the relationship between the rotational instability of the tapered wedge-shaped type cementless stem and femoral canal shape. METHODS: A total of 61 primary total hip arthroplasties with the tapered wedge-shaped type cementless stem Accolade® TMZF (11 males, 50 females; mean age 60 years) from January 2012 to June 2015 who underwent computed tomography before surgery and within 4 weeks and 1 year after surgery were evaluated. The preoperative femoral neck anteversion angle, preoperative femoral canal flair index, the degree of postoperative stem subsidence within 1 year after operation, and the degree of rotational change in the stem setting angle within 1 year after operation were investigated. RESULTS: The mean preoperative femoral neck anteversion angle was 32.2° ± 17.8° (0°-69°), and the mean preoperative canal flair index was 3.68 ± 0.58 (2.44-5.55). There were no stem subsidence cases within 1 year after operation. The mean degree of rotational change in the stem from immediately to 1 year after surgery was -0.4° ± 1.7° (-3°-3°). There was no significant correlation between the canal flair index and the rotational change in the stem. In addition, the mean difference between the preoperative femoral neck anteversion angle and the stem rotational angle immediately after surgery was only 1.3° ± 5.3° (-29°-15°). CONCLUSIONS: In all cases, including stove-pipe cases, the degree of rotational change in the Accolade® TMZF stem from immediately to 1 year after surgery was within 3°. In other words, regardless of femoral canal shape, the tapered wedge-shaped type cementless stem has little initial rotational instability.

The Differences in Imaging Findings Between Painless and Painful Osteoarthritis of the Hip.

PURPOSE: In osteoarthritis of the hip, the pain may be strong even if the deformity is mild, but the pain may be mild even if the deformity is severe. If the factors related to the pain can be identified on imaging, reducing such factors can alleviate the pain, and effective measures can be taken for cases where surgery cannot be performed. In addition, imaging findings related to the pain are also important information for determining the procedures and the timing of surgery. Thus, the purpose of this study was to identify the differences in features of osteoarthritis seen on imaging between painless and painful osteoarthritis of the hip. METHODS: The subjects were the patients with hip osteoarthritis who visited our department in 2015 and who underwent x-ray, computed tomography (CT), and magnetic resonance imaging (MRI), a total of 29 patients (54 hip joints; mean age 63 years; 8 males and 21 females). The degree of osteoarthritis was determined using the Tönnis grade from the x-ray image. The cartilage morphology, intensity changes of bone marrow on MRI (subchondral bone marrow lesions [BMLs]), osteophytes, joint effusions, and paralabral cysts were scored based on the Hip Osteoarthritis MRI Scoring System (HOAMS). The cross-sectional area of the psoas major muscle at the level of the iliac crest was measured on CT, and the psoas index (PI; the cross-sectional area ratio of the psoas major muscle to the lumbar 4/5 intervertebral disc) was calculated to correct for the difference in physique. Then, the relationships between these and visual analog scale (VAS) scores of pains were evaluated. RESULTS: The average VAS was 55.4 ± 39 mm. The PI and all items of HOAMS correlated with the VAS. The average VAS of Tönnis grade 3 osteoarthritis was 75.8 ± 26 mm. When investigating only Tönnis grade 3 osteoarthritis, the differences between cases with less than average pain and those with above average pain were the BML score in the central-inferior femoral head (P = .0213), the osteophyte score of the inferomedial femoral head (P = .0325), and the PI (P = .0292). CONCLUSION: Investigation of the differences between painless and painful osteoarthritis of the hip showed that the cases with more pain have BMLs of the femoral head on MRI that extend not only to the loading area, but also to the central-inferior area. Even with the same x-ray findings, the pain was stronger in patients with severe psoas atrophy. Thus, the instability due to muscle atrophy may also play a role in the pain of hip osteoarthritis.

The location of the fracture determines the better solution, osteosynthesis or revision, in periprosthetic femoral fractures.

PURPOSE: Periprosthetic femoral fractures are difficult to treat, but few reports have included many periprosthetic femoral fractures. The purpose of this study was to investigate the trends and characteristics of a large number of periprosthetic femoral fractures and to determine the best treatment strategy for such fractures. METHODS: The fracture type according to the Vancouver classification, the stem fixation style of previous surgery, the elapsed time from previous surgery, and the treatment method for periprosthetic fractures of 51 patients with periprosthetic femoral fractures who were seen between 2006 and 2018 were investigated. RESULTS: The types of fractures according to the Vancouver classification were: type A 5.9%, type B1 47%, type B2 20%, type B3 2.0%, and type C 25%. Of the previous surgeries, 76% were cementless fixation, and 24% were cemented fixation. The mean duration from previous surgery to periprosthetic femoral fracture was 8 years and 7 months (1-358 months), and injury within 1 year from previous surgery was most commonly observed (24%). As treatment for periprosthetic femoral fractures, conservative treatment was performed in 8%, and surgery was performed in 92%. Of the surgery cases, 53% underwent osteosynthesis, and 39% underwent revision surgery. Of type B1 surgery cases, 58% were treated with osteosynthesis, and 33% underwent revision surgery, although type B1 had no stem loosening. CONCLUSION: Many periprosthetic femoral fractures occurred within 1 year after the previous surgery. Therefore, preventive measures for periprosthetic femoral fractures should be started immediately after total hip replacement. In addition, revision surgery was performed even if the stem was not loosened in cases where it was judged that sufficient osteosynthesis could not be performed.

Palliative Care in Patients with Advanced Heart Failure.

The heart failure (HF) guidelines recommend palliative care; however, it can often be difficult to determine the timing of palliative care referral. Because HF with fluid retention and low-cardiac output may trigger several unpleasant symptoms, continuous HF treatment is required to alleviate these symptoms in advanced HF. The patients with HF often suffer from total pain; therefore, the support from a multidisciplinary team plays a crucial role to improve quality of life of the patients and their families not only in the terminal phase but also from the early stage.

The Neural Crest as the First Production Site of the Erythroid Growth Factor Erythropoietin.

While the neural crest is considered the fourth germ layer that originates a variety of tissues during mammalian development, we recently discovered that some neural crest cells and neuroepithelial cells play a unique role in secreting a vital hematopoietic hormone, erythropoietin (EPO), in mouse embryos. EPO production by the neural crest is transient in mid-stage embryos but essential for the first erythropoiesis in the yolk sac and for sufficient oxygen supply in the whole embryo growing in utero. The site of EPO production shifts from the neural crest to the liver in late embryonic stages, followed by interstitial fibroblasts of the kidneys in adults. Interestingly, the transition of EPO production sites synchronizes with the transition of erythropoietic sites during mouse development from the yolk sac and the fetal liver to the bone marrow. EPO produced by the neural crest and the neuroepithelium is first stored around the production sites and delivered to the yolk sac as an endocrine hormone for erythropoiesis after heartbeat activation. The fact that EPO is produced by some human cell lines derived from neuroblastoma, which mainly originates from the neural crest, provides evidence that the neural crest secretes EPO for primitive erythropoiesis not only in mouse but also in human embryos. Here, we introduce and discuss recent progress in studies on the mechanism of EPO production by the neural crest and its roles in erythropoietic development and in the fate of EPO-producing neural crest cells.

Iron attenuates erythropoietin production by decreasing hypoxia-inducible transcription factor 2α concentrations in renal interstitial fibroblasts.

Iron is an essential mineral for oxygen delivery and for a variety of enzymatic activities, but excessive iron results in oxidative cytotoxicity. Because iron is primarily used in red blood cells, defective erythropoiesis caused by loss of the erythroid growth factor erythropoietin (Epo) elevates iron storage levels in serum and tissues. Here, we investigated the effects of iron in a mouse model of Epo-deficiency anemia, in which serum iron concentration was significantly elevated. We found that intraperitoneal injection of iron-dextran caused severe iron deposition in renal interstitial fibroblasts, the site of Epo production. Iron overload induced by either intraperitoneal injection or feeding decreased activity of endogenous Epo gene expression by reducing levels of hypoxia-inducible transcription factor 2α (HIF2α), the major transcriptional activator of the Epo gene. Administration of an iron-deficient diet to the anemic mice reduced serum iron to normal concentration and enhanced the ability of renal Epo production. These results demonstrate that iron overload due to Epo deficiency attenuates endogenous Epo gene expression in the kidneys. Thus, iron suppresses Epo production by reducing HIF2α concentration in renal interstitial fibroblasts.

O-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1.

Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the proteasome bounce-back response mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored, using immunoprecipitation and mass spectrometry, the possible existence of nuclear proteins that cooperate with NRF1 and identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1) as two proteins capable of forming a complex with NRF1. O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes. Meta-analysis of breast and colorectal cancers revealed positive correlations in the relative protein abundance of OGT and proteasome subunits. OGT inhibition was effective at sensitizing cancer cells to a proteasome inhibitor both in culture cells and a xenograft mouse model. Since active O-GlcNAcylation is a feature of cancer metabolism, our study has clarified a novel linkage between cancer metabolism and UPS function and added a new regulatory axis to the regulation of the proteasome activity.

Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response.

Lipotoxicity plays an important role in the progression of chronic kidney damage via various mechanisms, such as endoplasmic reticulum stress. Several studies proposed renal lipotoxicity in glomerular and tubular cells but the effect of lipid on renal erythropoietin (EPO)-producing (REP) cells in the interstitium has not been elucidated. Since renal anemia is caused by derangement of EPO production in REP cells, we evaluated the effect of palmitate, a representative long-chain saturated fatty acid, on EPO production and the endoplasmic reticulum stress pathway. EPO production was suppressed by palmitate (palmitate-conjugated bovine serum albumin [BSA]) or a high palmitate diet, but not oleic acid-conjugated BSA or a high oleic acid diet, especially under cobalt-induced pseudo-hypoxia both in vitro and in vivo. Importantly, suppression of EPO production was not induced by a decrease in transcription factor HIF activity, while it was significantly associated with endoplasmic reticulum stress, particularly transcription factor ATF4 activation, which suppresses 3'-enhancer activity of the EPO gene. ATF4 knockdown by siRNA significantly attenuated the suppressive effect of palmitate on EPO production. Studies utilizing inherited super-anemic mice (ISAM) mated with EPO-Cre mice (ISAM-REC mice) for lineage-labeling of REP cells showed that ATF4 activation by palmitate suppressed EPO production in REP cells. Laser capture microdissection confirmed ATF4 activation in the interstitial area of ISAM-REC mice treated with palmitate-conjugated BSA. Thus, endoplasmic reticulum stress induced by palmitate suppressed EPO expression by REP cells in a manner independent of HIF activation. The link between endoplasmic reticulum stress, dyslipidemia, and hypoxia may contribute to development and progression of anemia in CKD.

HIF-dependent and reversible nucleosome disassembly in hypoxia-inducible gene promoters.

Hypoxia causes dramatic changes in gene expression profiles, and the mechanism of hypoxia-inducible transcription has been analyzed for use as a model system of stress-inducible gene regulation. In this study, changes in chromatin organization in promoters of hypoxia-inducible genes were investigated during hypoxia-reoxygenation conditions. Most of the hypoxia-inducible gene promoters were hypersensitive to DNase I under both normal and hypoxic conditions, and our data indicate an immediate recruitment of transcription factors under hypoxic conditions. In some of the hypoxia-inducible promoters, nucleosome-free DNA regions (NFRs) were established in parallel with hypoxia-induced transcription. We also show that the hypoxia-inducible formation of NFRs requires that hypoxia-inducible transcription factors (HIFs) bind to the promoters together with the transcriptional coactivator CBP. Within 1 h after the hypoxia exposure was ended (reoxygenation), HIF complexes were dissociated from the promoter regions. Within 24 h of reoxygenation, the hypoxia-induced transcription returned to basal levels and the nucleosome structure was reassembled in the hypoxia-inducible NFRs. Nucleosome reassembly required the function of the transcriptional coregulator SIN3A. Thus, reversible changes in nucleosome organization mediated by transcription factors are notable features of stress-inducible gene regulation.

18F-FPYBF-2, a new F-18 labelled amyloid imaging PET tracer: biodistribution and radiation dosimetry assessment of first-in-man 18F-FPYBF-2 PET imaging.

OBJECTIVE: Recently, a benzofuran derivative for the imaging of ß-amyloid plaques, 5-(5-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)- N-methylpyridin-2-amine (18F-FPYBF-2) has been validated as a tracer for amyloid imaging and it was found that 18F-FPYBF-2 PET/CT is a useful and reliable diagnostic tool for the evaluation of AD (Higashi et al. Ann Nucl Med, https://doi.org/10.1007/s12149-018-1236-1 , 2018). The aim of this study was to assess the biodistribution and radiation dosimetry of diagnostic dosages of 18F-FPYBF-2 in normal healthy volunteers as a first-in-man study. METHODS: Four normal healthy volunteers (male: 3, female: 1; mean age: 40 ± 17; age range 25-56) were included and underwent 18F-FPYBF-2 PET/CT study for the evaluation of radiation exposure and pharmacokinetics. A 10-min dynamic PET/CT scan of the body (chest and abdomen) was performed at 0-10 min and a 15-min whole-body static scan was performed six times after the injection of 18F-FPYBF-2. After reconstructing PET and CT image data, individual organ time-activity curves were estimated by fitting volume of interest data from the dynamic scan and whole-body scans. The OLINDA/EXM version 2.0 software was used to determine the whole-body effective doses. RESULTS: Dynamic PET imaging demonstrated that the hepatobiliary and renal systems were the principal pathways of clearance of 18F-FPYBF-2. High uptake in the liver and the gall bladder, the stomach, and the kidneys were demonstrated, followed by the intestines and the urinary bladder. The ED for the adult dosimetric model was estimated to be 8.48 ± 1.25 µSv/MBq. The higher absorbed doses were estimated for the liver (28.98 ± 12.49 and 36.21 ± 15.64 µGy/MBq), the brain (20.93 ± 4.56 and 23.05 ± 5.03µ Gy/MBq), the osteogenic cells (9.67 ± 1.67 and 10.29 ± 1.70 µGy/MBq), the small intestines (9.12 ± 2.61 and 11.12 ± 3.15 µGy/MBq), and the kidneys (7.81 ± 2.62 and 8.71 ± 2.90 µGy/MBq) for male and female, respectively. CONCLUSIONS: The ED for the adult dosimetric model was similar to those of other agents used for amyloid PET imaging. The diagnostic dosage of 185-370 MBq of 18F-FPYBF-2 was considered to be acceptable for administration in patients as a diagnostic tool for the evaluation of AD.

Relationship between clinical results of total hip replacement and postoperative activities including weeding and snow shovelling.

INTRODUCTION: Weeding or snow shovelling is indispensable for life in farm villages of northern countries. Clarifying the relationships between the degrees of these activities after total hip replacement (THR) and the clinical results of THR may enable us to predict the results of THR for high-level activity patients. The relationships between work activities after THR and the results were investigated. METHODS: The subjects were 95 post-THR patients, who consulted 6 hospitals in August 2012. First, the Japanese Orthopaedic Association Hip-Disease Evaluation Questionnaire (JHEQ) and a questionnaire on postoperative activity were administered. Then, the Japanese Orthopaedic Association hip score (JOA score) was evaluated. RESULTS: The subjects' average age was 68 years. The average period after surgery was 4 years and 5 months. Weeding and snow shovelling were performed after THR in 44.2% and 40.0% of cases, respectively. The rate of farming after surgery (25.6%) was greater than that of swimming (21.1%). Both the JOA score and JHEQ were higher in those who played sports after THR than in those who did not (p = 0.003, p = 0.0046). The JOA score of those who performed work activities after THR was higher than that of those who did not (p = 0.0295). CONCLUSIONS: Nearly half of patients performed weeding or snow shovelling after THR, and about 1/4 of the patients engaged in farming after THR. The clinical results in cases doing sports and work activities after THR were better than those of cases not doing such activities. Therefore, these activities may be positively recommended.

Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes.

Placental activation of the renin-angiotensin system (RAS) plays a key role in the pathogenesis of preeclampsia. Reactive oxygen species (ROS) are thought to affect placental angiogenesis, which is critical for preventing preeclampsia pathology. We examined the role of ROS in preeclampsia by genetically modifying the Keap1-Nrf2 pathway, a cellular antioxidant defense system, in a mouse model of RAS-induced preeclampsia. Nrf2 deficiency would be expected to impair cellular antioxidant responses; however, Nrf2 deficiency in preeclamptic mice improved maternal and fetal survival, ameliorated intra-uterine growth retardation, and augmented oxidative DNA damage. Furthermore, the placentas of Nrf2-deficient mice had increased endothelial cell proliferation with dense vascular networks. In contrast, the placentas of preeclamptic mice with overactive Nrf2 showed repressed angiogenesis, which was associated with decreased expression of genes encoding angiogenic chemokines and cytokines. Our findings support the notion that ROS-mediated signaling is essential for maintaining placental angiogenesis in preeclampsia and may provide mechanistic insight into the negative results of clinical trials for antioxidants in preeclampsia.