Erythropoietin (EPO) is a principal regulator that promotes proliferation and terminal differentiation of erythroid progenitor cells. EPO receptors are expressed not only in hematopoietic lineage cells but also in the cardiovascular system. We performed animal experiments using transgene-rescued EPO receptor null mutant mice (EpoR−/−rescued) that express the EPO receptor exclusively in the hematopoietic cells. The results of these experiments suggest that endogenous EPO/EPO receptor system in the heart exerts cardioprotective effects against myocardial injury induced by ischemia followed by reperfusion and pressure-overload induced left ventricular dysfunction. Many animal experiments have shown that the administration of recombinant human EPO also elicits cardioprotective effects against myocardial injury induced by ischemia and reperfusion. In contrast to the promising results of these animal experiments, recent clinical trials failed to demonstrate the reduction in infarct size or improvement of cardiac function by the administration of recombinant human EPO in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. It should be tested in future clinical studies whether a relatively low dose of recombinant human EPO or its derivatives that have no erythropoietic action reduces infarct size and ameliorates cardiac dysfunction in patients with acute myocardial infarction. In this article, we review implications of anemia associated with chronic heart failure, roles of the endogenous EPO/EPO receptor system, and the effects of the administration of erythropoiesis-stimulating agents in pathologic conditions of the heart by focusing on the EPO receptor as a potential candidate of novel therapeutic targets in cardiovascular diseases.
The concept of “patient enablement” involves patients' perceptions of ability to understand and cope with illness. Improving enablement is an important goal of medical consultations for patients with chronic illness. To measure “enablement,” a post-medical-consultation patient-reported questionnaire was developed and named “Patient Enablement Instrument (PEI)” in the United Kingdom. Unfortunately, there has been no tool to evaluate patient enablement in Japan. Therefore, this study aimed to develop PEI Japanese version, to examine its validity and reliability, and to clarify the constitution of concept about patient enablement among Japanese patients. The translation process included forward translation, expert panel back-translation, following the standard WHO process. Participants were 256 individuals (157 men and 99 women; mean age 62.9 ± 11.8 years) receiving a regular outpatient treatment due to chronic illness at the Department of Cardiology, Respiratory, or Endocrinology and Metabolism in a regional hospital. To assess validity, we compared PEI with Medical Interview Satisfaction Scale (MISS) by correlation coefficient, which was 0.55 (P < 0.01). Furthermore, factor analysis indicated that PEI had two principal factors labeled “coping with illness and health maintenance” and “confidence in oneself and independence”. For an evaluation of reliability, internal consistency was calculated (Cronbach's alpha = 0.875). In conclusion, two principal factors comprise patient enablement measured by PEI with satisfactory validity and reliability. PEI Japanese version will be a useful tool to evaluate and improve medical consultations in Japan.
The fallopian tube has numerous functions, including ovum pick-up, the place of fertilization of the ovum and cleavage of the embryo, and transfer of the embryo to the uterus. Tubal pathology impairs functions of the fallopian tube and reduces fertility. The degree of tubal pathology determines the possibility for fertility. The evaluation of the fallopian tube is necessary to determine the management plan of infertility. Hysterosalpingography (HSG) is often performed as a first line approach to assess tubal patency and the presence of adhesions; however, HSG has limitations in detecting tubal pathology. In the current study, we evaluated the significance of laparoscopy in determining the optimal management plan for infertile patients with suspected tubal pathology revealed by HSG. Between 1997 and 2009, 127 patients with suspected tubal pathology as demonstrated by HSG underwent laparoscopy at Kinki University Hospital, and a retrospective analysis was performed. Of 87 patients with unilateral tubal pathology revealed by HSG, 20 patients (23.0%) were given an indication for assisted reproductive technology (ART), based on the laparoscopic findings. Of 40 patients with bilateral tubal pathology revealed by HSG, 33 patients (82.5%) with bilateral tubal pathology detected by laparoscopy were given a high indication for ART. Laparoscopy enables exact evaluation of the fallopian tube and selection of the optimal management plan in infertile patients with suspected tubal pathology revealed by HSG. Therefore, laparoscopy should be performed in infertile patients with suspected tubal pathology revealed by HSG, as it is of diagnostic importance.
The cytokine interleukin-6 (IL-6) is released from working skeletal muscles and reportedly plays key roles in their glucose homeostasis. However, it is unclear whether IL-6 plays such roles in the masseter muscle (MM), which is important in normal and pathological chewing behaviors, such as bruxism and/or prolonged clenching. When restrained (R+) in a narrow cylinder blocked at the front end with a thin plastic strip, a mouse gnaws away (G+) the strip to escape. The absolute weight of plastic gnawed away serves as an index of MM activity. Using this model, we examined the roles of IL-6 in MM with the following results. R+G+ increased the expression levels of IL-6 and glucose transporter 4 (Glut4) mRNAs in MM and the serum level of IL-6 protein. IL-6-deficient mice exhibited about 60% less gnawing activity than wild-type mice at 3-4 h after the start of R+G+, slower recovery of glycogen levels (indicating poorer glucose supply) in MM after R+G+, and no significant change in Glut4 mRNA in MM upon R+G+. During an R+G+ test conducted after “training” (repeated R+G+ sessions), wild-type mice exhibited greater gnawing activity than untrained controls, but no increase in IL-6 mRNA in MM. IL-6 mRNA increased in MM when hard food was eaten by mice raised on soft food for 3 weeks from weaning, but not in those raised on (accustomed to) hard food. Thus, IL-6 may maintain glucose homeostasis in MM in support of unusually strenuous activity, but not of accustomed activity levels.
Myelodysplastic syndrome (MDS), characterized by the decreased production of blood cells, often progresses to acute myeloid leukemia (AML), a sign of poor prognosis of MDS. In AML, the Wnt/β-catenin pathway is aberrantly activated, suggesting that the increased pathway activity may be correlated with the development and prognosis of MDS. SOX7 protein, encoded by the sex-determining region Y-box 7 (SOX7) gene, inhibits the activity of the Wnt/β-catenin pathway. Because the DNA methylation can regulate the transcription of SOX7 gene, we used the methylation-specific PCR to investigate the methylation status of the CpG island in MDS patients to determine the potential correlation of the SOX7 methylation with the development and prognosis of MDS. We found that the CpG island of the SOX7 gene was methylated in 58.1% (97/167) of MDS patients, but not in any healthy control. Furthermore, the percentage of patients with the methylated CpG island of the SOX7 gene was significantly higher in patients at advanced stages of MDS than in the patients at early stages. The increased percentages of this SOX7 methylation were also correlated with age, marrow blast levels, and International Prognostic Scoring System (IPSS) risk. After prognostic analysis, we found that patients with the methylated CpG island of the SOX7 gene had shorter overall survival and cumulative survival than patients with unmethylated CpG island. Our findings suggest that the methylation of the CpG island of the SOX7 gene can be used as a predictive factor for the development and prognosis of MDS patients.
Therapies with prolonged exposure to high-concentration oxygen are common in the treatment of critical pulmonary and cardiac conditions in newborns. However, prolonged exposure to hyperoxia could result in lung damages and developmental disorders manifested as acute lung injury and bronchopulmonary dysplasia, respectively. Calcitonin gene-related peptide (CGRP) has been shown to have a broad regulatory effect on the respiratory system. In this study, we explored the protective effects of CGRP on the hyperoxia-induced lung damage. Newborn Sprague-Dawley rats were randomly divided into three groups: normoxia, hyperoxia, and hyperoxia with CGRP. Hyperoxia groups were exposed to 95% oxygen for 14 days and treated once every other day with saline or CGRP. Hyperoxia exposure reduced the survival rate to 73%, when compared with the 93% survival rate observed in the normoxia group. The survival rate was improved to 84% with CGRP treatment. Treatment with CGRP under hyperoxia significantly alleviated the hyperoxia-induced lung histomorphological changes and the increases in leukocyte counts and total protein levels in bronchoalveolar lavage fluid that reflect the pulmonary microvasular damages. CGRP treatment also restored the decreased activity of superoxide dismutase, while it decreased the increased level of malondialdehyde in the lung tissues. Importantly, CGRP treatment significantly decreased the magnitude of the hyperoxia-mediated increase in the expression levels of tumor necrosis factor-α mRNA and transforming growth factor-β 1 protein. In conclusion, the hyperoxia-induced acute lung injury is associated with both oxidative stress and inflammatory responses, and CGRP may ameliorate the hyperoxia-induced lung injury by down-regulating these processes.
Tumor hypoxia is a hallmark of malignant tumors, and is a major factor in the resistance to anti-cancer therapies, particularly radiotherapy. Indeed, tumor blood flow often fluctuates, and thus the oxygen supply is often reduced, thereby inducing tumor hypoxia. We decided to explore whether post-occlusive reactive hyperemia, a physiological reaction known to occur in normal tissues, could be induced through a malignant tumor, basal cell carcinoma (BCC), in which angiogenesis occurs, as in all malignant tumors. Skin blood flow was measured in twelve patients with BCC, using Laser Speckle Contrast Imaging to determine BCC perfusion after three minutes of vascular occlusion, induced by limb tourniquet for limb tumors (4 BCC), and/or by clamping the pedicle of a skin flap with the BCC at its center, for other tumor locations (12 BCC). We demonstrated for the first time that post-occlusive reactive hyperemia occurs in malignant tumors in humans. BCC perfusion curves were similar to those of healthy skin, characterized by a peak of hyperemia after reperfusion followed by a progressive return to the pre-occlusion perfusion level. Induction of post-occlusive reactive hyperemia in malignant tumors is therefore a novel investigational approach that could lead to a new adjuvant tool to increase the efficacy of chemotherapy and radiotherapy, respectively through the synchronized temporary increase of tumor perfusion and oxygenation.
Patients with advanced chronic kidney disease (CKD) show decreased hemoglobin levels. We aimed to verify the changes of red blood cell (RBC) number according to glomerular filtration rate (GFR) levels and its influence on the clinical outcome. With the data from routine health checkups of 114,496 adults, we grouped the subjects according to quartile levels of RBC number in each gender. Mortality data were from the National Statistical Office. RBC number was increased with decreasing GFR and/or the presence of a component of metabolic syndrome (MS) in subjects with GFR ≥ 50 ml/min/1.73 m2. The estimated mean RBC number of subjects with GFR 89-50 ml/min/1.73 m2 was higher compared to those with GFR ≥ 100 ml/min/1.73 m2 by ANCOVA. In men, the death rate was the highest in the 1st quartile group (1Q) of RBC number (1.22%), followed by the 2nd quartile group (2Q, 0.42%), the 3rd quartile group (3Q, 0.39%), and the 4th quartile group (4Q, 0.29%) (p < 0.001). The hazard ratio (HR) of death in 2Q, 3Q and 4Q was 0.446, 0.580, and 0.440, respectively, compared to 1Q (p < 0.001). Among men in 1Q group, subjects with hemoglobin < 14.0 g/dL showed higher mortality rate than those with hemoglobin 14.0-14.9 g/dL or ≥ 15.0 g/dL (2.3% : 0.8% : 1.1%, respectively, p < 0.001). In conclusion, the RBC number was increased according to declines of GFR in the range of GFR ≥ 50 ml/min/1.73 m2 and was an important risk factor for mortality.