Early transition to avacopan from glucocorticoids applied during induction therapy for microscopic polyangiitis with rapidly progressive glomerulonephritis.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic autoimmune disease characterized by necrotizing inflammation of small blood vessels. Glucocorticoids (GC) in combination with rituximab or cyclophosphamide can reduce AAV-related mortality and rescue renal function. However, several side effects associated with these agents, including GC toxicity, are concerning. Avacopan, an inhibitor of the C5a receptor, is now available for AAV treatment and is expected to mitigate GC toxicity. We present a case of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive microscopic polyangiitis (MPA) with rapidly progressive glomerulonephritis treated with an early switch from GC to avacopan in combination with rituximab during induction therapy. Over a 6-month treatment period, clinical remission was achieved and maintained without infection or elevated liver enzyme levels. Efficacy and safety data regarding avacopan for AAV induction therapy remain limited. Therefore, more case reports are required to clarify the role of avacopan in AAV induction and maintenance therapy. Since the MPO-ANCA titer remained elevated despite the clinical remission of AAV in this case, the ANCA titer may not necessarily be a reliable biomarker for predicting AAV relapse when avacopan is applied as an induction therapy for AAV.

Safety of Low-Dose Oral Food Challenges for Hen's Eggs, Cow's Milk, and Wheat: Report from a General Hospital without Allergy Specialists in Japan.

An oral food challenge (OFC) is useful for managing food allergies. However, because OFCs have the risk of severe allergic reactions, including anaphylaxis, conducting OFCs under this situation without allergy specialists is difficult. To investigate the safety of a low-dose OFC for eggs, milk, and wheat in a general hospital without allergy specialists. We retrospectively analyzed the medical records of children who were hospitalized in a general hospital without allergy specialists for a low-dose OFC of egg, milk, or wheat between April 2018 and March 2021. The records of 108 patients were evaluated. The median age was 15.8 months (range: 7.5-69.3 months). Challenged foods were eggs (n = 81), milk (n = 23), and wheat (n = 4). Fifty-three (49.0%) patients showed positive allergic reactions. Thirty-five (66.0%) patients showed grade 1 (mild), 18 (34.0%) showed grade 2 (moderate), and none showed grade 3 (severe) reactions. The interventions comprised antihistamines (n = 18), prednisolone (n = 3), inhaled Β2-agonist (n = 2). No patients required adrenaline and no deaths occurred. Low-dose OFCs may be safe in a general hospital without allergy specialists. Conducting a low-dose OFC may be essential in food allergy practice.

Pup odor and ultrasonic vocalizations synergistically stimulate maternal attention in mice.

Pup ultrasonic vocalizations (USVs), which are emitted by hypothermic pups, and pup odor are thought to be triggers of maternal behavior in mice. We investigated whether pup odor stimulated maternal responses to pup USVs in mother C57BL/6 mice. Two-choice tests were conducted by introducing mothers into a test cage in which a tube was attached on each long wall, and the duration spent in each tube was compared. Pup USVs were reproduced by an ultrasonic speaker at the tube end. In some cases, cotton with pup odor was also presented at the end of the tube. Compared to no stimuli, mothers did not specifically approach the sole presentation of either reproduced pup USVs or pup odor. However, compared to the sole presentation of pup odor, the simultaneous presentation of pup USVs and odor induced a specific approach response. These results suggested that pup USVs and odor synergistically stimulated maternal behavior. In addition, it was confirmed that mothers approached hypothermic pups emitting pup USVs for longer than anesthetized silent pups. To investigate the underlying neural mechanisms, we observed neural responses to various stimuli with the immunohistochemistry of c-fos expression. In the bed nucleus of the stria terminalis, the medial preoptic area, the central nucleus of the amygdala, and the basolateral amygdala, the numbers of c-fos-positive cells were significantly increased following the simultaneous presentation of pup USVs and odor compared to the presentation of each alone, suggesting that these nuclei were involved in multimodal processing related to maternal behavior.

The effects of social experience and gonadal hormones on retrieving behavior of mice and their responses to pup ultrasonic vocalizations.

Pup ultrasonic vocalizations (USVs) are emitted from maternally separated pups and are thought to be a trigger for eliciting maternal behavior in mice. We investigated the effects of social experience and gonadectomy on the retrieving behavior of mice and their responses to pup USVs produced by a nanocrystalline silicon thermo-acoustic emitter. In each experiment, virgin, gonadectomized, sham-operated, sexually experienced, and parenting mice of both sexes were used, and the effects of these manipulations were compared in each sex. The retrieving behavior of both sexes increased with social experience or gonadectomy. In particular, mothers showed the highest retrieving activity among female groups, while castrated male mice showed the highest retrieving activity among male groups. All groups of female mice responded to pup USVs, with the responsiveness of sexually experienced female mice being the most enhanced. Unlike the females, virgin male mice did not respond to pup USVs, although socially experienced or castrated males showed this response; fathers exhibited the highest responsiveness. These results suggest that not only parenting experience, but also mating experience, may enhance retrieving activity and response to pup USVs in mice of both sexes. Nevertheless, the degree to which parenting experience contributed to the enhancement of both activities differed between the sexes. Furthermore, gonadectomy enhanced both activities in both sexes, although its effect was more prominent in males. Overall, our findings suggest that alteration in responsiveness of mice to pup USVs might be one of the changes in parental behavior caused by social experiences or gonadal hormones.

Mitral regurgitation associated with mitral annular dilation in patients with lone atrial fibrillation: an echocardiographic study.

BACKGROUND: Whether and how lone atrial fibrillation (AF) is associated with functional mitral regurgitation (MR) remain unclear. METHOD: We studied 12 lone AF patients without left ventricular (LV) dysfunction and/or dilatation, who underwent mitral valve annuloplasty for functional mitral regurgitation (MR). Ten lone AF patients without MR served as controls. RESULTS: Lone AF Patients with MR had a greater mitral valve annular area and left atrial area than those without MR. There were no differences in LV volumes or LV ejection fraction. CONCLUSIONS: Therefore, we concluded that left atrial dilation and corresponding mitral annular dilation may cause MR in lone AF patients without LV dysfunction and/or dilatation.

Waon therapy improves the prognosis of patients with chronic heart failure.

BACKGROUND: We developed a Waon therapy (soothing warm therapy) and have previously reported that repeated Waon therapy improves hemodynamics, peripheral vascular function, arrhythmias, and clinical symptoms in patients with chronic heart failure (CHF). The aim of this study was to investigate the effect of Waon therapy on the prognosis of CHF patients. PATIENTS AND METHODS: We studied 129 patients with CHF in NYHA functional class III or IV who were admitted to our hospital between January 1999 and March 2001. In the Waon therapy group, 64 patients were treated with a far infrared-ray dry sauna at 60 degrees C for 15 min and then kept on bed rest with a blanket for 30 min. The patients were treated daily for 5 days during admission, and then at least twice a week after discharge. In the control group, 65 patients, matched for age, gender, and NYHA functional class, were treated with traditional CHF therapy. The follow-up time was scheduled for 5 years. RESULTS: Recent, complete follow-up data on each patient were obtained. The overall survival rate was 84.5% (Kaplan-Meier estimate). Twelve patients died in the control group and 8 patients died in the Waon therapy group at 60 months of follow-up. Cardiac events due to heart failure or cardiac death occurred in 68.7% of the control group but only 31.3% of the Waon therapy group (P<0.01) at 60 months of follow-up. CONCLUSION: Waon therapy reduced cardiac events in patients with CHF. This therapy is a promising non-pharmacological treatment for CHF.

Beneficial effects of Waon therapy on patients with chronic heart failure: results of a prospective multicenter study.

BACKGROUND: We conducted a prospective multicenter case-control study to confirm the clinical efficacy and safety of Waon therapy on chronic heart failure (CHF). METHODS: Patients (n=188) with CHF were treated with standard therapy for at least 1 week, and then were randomized to Waon therapy (n=112) or a control group (n=76). All patients continued conventional treatment for an additional 2 weeks. The Waon therapy group was treated daily with a far infrared-ray dry sauna at 60 degrees C for 15 min and then kept on bed rest with a blanket for 30 min for 2 weeks. Chest radiography, echocardiography, and plasma levels of brain natriuretic peptide (BNP) were measured before and 2 weeks after treatment. RESULTS: NYHA functional class significantly decreased after 2 weeks of treatment in both groups. Chest radiography also showed a significant decrease of the cardiothoracic ratio in both groups (Waon therapy: 57.2+/-8.0% to 55.2+/-8.0%, p<0.0001; control: 57.0+/-7.7% to 56.0+/-7.1%, p<0.05). Echocardiography demonstrated that left ventricular diastolic dimension (LVDd), left atrial dimension (LAD), and ejection fraction (EF) significantly improved in the Waon therapy group (LVDd: 60.6+/-7.6 to 59.1+/-8.4 mm, p<0.0001; LAD: 45.4+/-9.3 mm to 44.1+/-9.4 mm, p<0.05; EF: 31.6+/-10.4% to 34.6+/-10.6%, p<0.0001), but not in the control group (LVDd: 58.4+/-10.3 mm to 57.9+/-10.4 mm; LAD: 46.3+/-9.7 mm to 46.2+/-10.1 mm; EF: 36.6+/-14.1% to 37.3+/-14.0%). The plasma concentration of BNP significantly decreased with Waon therapy, but not in the control group (Waon: 542+/-508 pg/ml to 394+/-410 pg/ml, p<0.001; control: 440+/-377 pg/ml to 358+/-382 pg/ml). CONCLUSION: Waon therapy is safe, improves clinical symptoms and cardiac function, and decreases cardiac size in CHF patients. Waon therapy is an innovative and promising therapy for patients with CHF.

Maternal approaches to pup ultrasonic vocalizations produced by a nanocrystalline silicon thermo-acoustic emitter.

When infant rodents are isolated from their mother and littermates, they cool rapidly and emit ultrasonic vocalizations (USVs). The effect of pup USVs on the mother has been investigated using models of pup USVs from ultrasonic speakers. We used a nanocrystalline silicon thermo-acoustic emitter (nc-Si emitter) to investigate mothers' responses to digitally reproduced pup USVs in mice. The nc-Si emitter could reproduce ultrasonic sounds more accurately than conventional emitters. We compared the sound properties of pup USVs and reproduced USVs. We then investigated maternal responses to hypothermic pups, which emit USVs, and anesthetized pups, which are silent, as well as maternal responses to pup USVs reproduced by the nc-Si emitter and a silent mode. The nc-Si emitter can reproduce pup USVs very accurately in terms of duration, frequency, and sound pressure level. Mothers approached reproduced digitally recorded pup USVs from the nc-Si emitter and their behavior was similar to their behavior toward hypothermic pups. In contrast, mothers did not approach other synthesized ultrasounds, such as double-duration USVs, double-silence domain ultrasounds nor double-ultrasonic domain ultrasounds, indicating that they approach the specific profiles of pup USVs. These results indicate that the nc-Si emitter can be useful to elucidate the role of ultrasonic acoustic communication in rodents.

Thermal therapy improves left ventricular diastolic function in patients with congestive heart failure: a tissue doppler echocardiographic study.

OBJECTIVES: We previously reported that systemic thermal therapy using 60 degrees C dry sauna improves left ventricular systolic function and clinical symptoms in patients with chronic heart failure. The aim of this study was to investigate the effects of thermal therapy on left ventricular diastolic function. METHODS: We examined transmitral inflow and mitral annular velocity before and after sauna in 10 patients with congestive heart failure using pulsed and tissue Doppler echocardiography. RESULTS: Left ventricular and left atrial dimensions and left ventricular percentage fractional shortening did not change after sauna. Early diastolic mitral inflow velocity (E) increased and the deceleration time of the E wave decreased significantly after sauna compared to before sauna. Early diastolic mitral annular velocity (E') significantly increased after sauna. The deceleration time of E' significantly decreased after sauna compared to before sauna. The E/E' significantly decreased 30 min after sauna. CONCLUSIONS: Thermal therapy improves acute left ventricular diastolic function in patients with congestive heart failure.

Value of mitral valve tenting volume determined by real-time three-dimensional echocardiography in patients with functional mitral regurgitation.

This study sought to evaluate mitral valve tenting volume (TnV) as a clinical parameter using real-time 3-dimensional echocardiography in patients with functional mitral regurgitation (MR). In 27 patients with functional MR and 4 controls without mitral disease, real-time 3-dimensional echocardiographic images were obtained to measure TnV frame by frame from presystole to end-systole. The maximal and minimal TnVs during systole were identified in each patient, and mitral annular areas and tenting heights were also measured. Using 2-dimensional echocardiography, tenting area (TnA) was measured from the apical long-axis, apical 4-chamber, and apical 2-chamber views. The regurgitant orifice area was measured by the proximal isovelocity surface area method. Maximal and minimal TnVs occurred at the time of 2 +/- 6% and 78 +/- 6% of whole systolic duration, respectively, and the systolic percentage change of TnV was related to that of tenting height but not to that of mitral annular area. TnA on the long-axis images was significantly larger than that on the 4- and 2-chamber images (2.5 +/- 1.4 vs 1.7 +/- 1.3 and 1.9 +/- 1.4 cm(2), respectively, p <0.001). Regurgitant orifice area was significantly correlated with maximal TnV (r = 0.90), minimal TnV (r = 0.86), and TnA on the long-axis (r = 0.79), 4-chamber (r = 0.75), and 2-chamber (r = 0.73) images. Among minimal TnV and 3 TnAs, minimal TnV was the only independent determinant of regurgitant orifice area (p <0.001). Minimal TnV >or=3.90 ml identified significant functional MR with a sensitivity of 86% and a specificity of 100%. In conclusion, TnV derived from real-time 3-dimensional echocardiography is a preferable novel single index for assessing mitral valve tethering in functional MR to TnA that is dependent on the location of 2-dimensional planes.

Determinants of recurrent or residual functional tricuspid regurgitation after tricuspid annuloplasty.

BACKGROUND: The durability of tricuspid valve (TV) repair by annuloplasty is limited. Identification of mechanisms of recurrent or residual tricuspid regurgitation (TR) after annuloplasty is necessary to improve results of TV repair. The purpose of this study was to investigate echocardiographic determinants of mid-term outcome after TV annuloplasty. METHODS AND RESULTS: This study consisted of 39 patients with functional TR who had echocardiography preoperatively, early postoperatively (5+/-2 days), and >1 year (20+/-6 months) after TV annuloplasty. Detailed echocardiographic measurements were performed, including TR severity, TV annular dimension, TV leaflet displacement, left ventricular (LV) function, and right ventricular (RV) function and pressures. Preoperative leaflet tethering height and area predicted early and mid-term outcome of annuloplasty. Early postoperative LV ejection fraction and TR severity influenced degree of TR >1 year after surgery. In addition, increased RV pressure was related to worse TR during late follow-up. CONCLUSIONS: Although TV tethering is an important determinant of recurrent or residual TR, LV and RV function and pressures impact repair durability. These factors identify patients at risk for repair failure; such individuals require development of additional surgical strategies to improve results of tricuspid valve repair and close surveillance after surgery.

Elevated serum interleukin-18 levels might reflect the high risk of hospitalization in patients on peritoneal dialysis.

BACKGROUND: Interleukin (IL)-18 is a potent pro-inflammatory cytokine and plays a central role in atherosclerotic plaque rupture and accelerates atherosclerosis. AIM: The aim of this study was to determine serum IL-18 levels in patients on peritoneal dialysis (PD) and to assess their relationship with hospitalization. METHODS: Forty-three PD patients and 20 healthy individuals were enrolled in this study. We investigated the relationship of the serum concentrations of IL-18 and other well-established atherosclerotic markers, such as asymmetric dimethylarginine (ADMA). Hospitalization data from over a 18-month period were prospectively obtained on all 43 PD patients. Classic factors were entered into a Cox regression model to predict first hospitalization. RESULTS: The serum levels of IL-18 in patients on PD were significantly higher than those of healthy individuals (228.5 +/- 140.3 pg/mL vs 154.8 +/- 44.7 pg/mL, P < 0.05, respectively). Furthermore, serum IL-18 levels showed a positive correlation with duration of PD, serum beta2 microglobulin and serum ADMA levels. Mean serum levels of IL-18 were significantly higher among patients who had experienced at least one hospitalization than those who had not (279.9 +/- 164.3 vs 158.5 +/- 43.9 pg/mL, P = 0.0426). Furthermore, the relative risk for first hospitalization for each increase in IL-18 (pg/mL) levels was associated with a 1.182 (95% confidence interval, 1.012-1.364; P = 0.0071) increase in the risk for future hospitalization events. CONCLUSION: The present study suggests the elevated serum IL-18 levels might increase the risk for future hospitalization in patients on PD.

Electrical conduction disturbance effects on dynamic changes of functional mitral regurgitation.

OBJECTIVES: The aim of this study was to investigate the relationship between dynamics of functional mitral regurgitation (MR) and the degree of electrical conduction disturbance, and to evaluate the impact of cardiac resynchronization therapy (CRT) on MR severity and its phasic pattern. BACKGROUND: Mechanisms of phasic changes of functional MR, which may be determined by annulus dilation and tethering of the leaflet, remain unclear. METHODS: Transthoracic two-dimensional echocardiography was performed in 60 patients with functional MR. A biventricular pacemaker was implanted in 19 patients. The mitral annulus area (MAA) and the tenting area (TA) were measured from apical views. The MR volume and fraction were assessed by the quantitative pulsed Doppler method. Instantaneous regurgitation flow rate was measured by proximal flow convergence method. A dynamic change in MR flow rate was evaluated by frame-by-frame analysis throughout systole. RESULTS: A phasic pattern with two peaks at early- and late-systole and decrease in mid-systole was noticed in 57 patients. The early-systolic peak of MR was larger than the late-systolic peak (128.4 +/- 64.3 ml/s vs. 73.9 +/- 55.1 ml/s, p < 0.001). The ratio of flow rate at these two peaks correlated with QRS duration (r = 0.55, p < 0.001). Early-systolic flow rate reduced after CRT (143.9 +/- 60.8 ml/s to 90.7 +/- 54.1 ml/s, p < 0.05), but late-systolic flow rate did not (61.5 +/- 55.0 ml/s to 51.2 +/- 40.9 ml/s, p = NS). A similar pattern was observed for TA, whereas MAA did not change after CRT. CONCLUSIONS: Biphasic pattern was found in functional MR, and the ratio of flow rate at two peaks correlated with QRS duration. The CRT decreased regurgitation flow volume by reducing early-systolic MR but not late-systolic MR, resulting in the change in phasic pattern of functional MR.

Long-term use of vitamin E-coated polysulfone membrane reduces oxidative stress markers in haemodialysis patients.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and an independent predictor of overall mortality and cardiovascular outcome in haemodialysis (HD) patients. In the present study, we compared the effects of a vitamin E-coated polysulfone membrane (PSE) and a non-vitamin E-coated polysulfone membrane (PS) on oxidative stress markers such as ADMA. METHODS: Thirty-one HD patients were enrolled to this investigation. They were allocated into two groups: in the PSE group (n = 16), PSE was used for 6 months, followed by PS for an additional 12 months; in the PS group (n = 15), PS was used for the entire observation period. Plasma ADMA, oxidized low density lipoprotein (Ox-LDL) and malondialdehyde LDL (MDA-LDL) levels were measured at baseline, 3, 6, 12 and 18 months. Plasma ADMA in peritoneal dialysis (PD) patients and in healthy individuals was also measured. RESULTS: Predialysis concentrations of ADMA (0.72+/- 0.13 nmol/ml) were significantly higher in the HD group than in both PD patients (0.63+/-0.10 nmol/ml, P<0.01) and healthy individuals (0.44+/-0.01 nmol/ml, P<0.0001). Treatment with PSE for 6 months significantly reduced predialysis levels of ADMA (0.54+/-0.09 nmol/ml) compared with baseline (0.74+/-0.12 nmol/ml; P<0.01). Predialysis levels of Ox-LDL and MDA-LDL after 6 months therapy with PSE were also significantly lower than baseline values. Treatment with PS subsequent to treatment with PSE again increased ADMA, Ox-LDL and MDA-LDL back to baseline levels. In the PS group, ADMA, Ox-LDL and MDA-LDL levels remained unchanged during the entire treatment period of 18 months. CONCLUSIONS: We confirmed that use of PSE reduced ADMA that had accumulated in HD patients. This finding indicates that PSE exerts anti-oxidant activity. A randomized controlled study will be required to determine whether PSE prevents cardiovascular diseases and other dialysis-related complications by reducing oxidative stress.

Repeated thermal therapy diminishes appetite loss and subjective complaints in mildly depressed patients.

OBJECTIVE: We observed that repeated thermal therapy improved appetite loss and general well-being in patients with chronic heart failure. The purpose of this study is to clarify the effects of repeated thermal therapy in mildly depressed patients with appetite loss and subjective complaints. METHODS: Twenty-eight mildly depressed inpatients with general fatigue, appetite loss, and somatic and mental complaints were randomly assigned to thermal therapy group (n = 14) or nonthermal therapy group (n = 14). Patients in the thermal therapy group were treated with 60 degrees C far-infrared ray dry sauna for 15 minutes and were then kept at bed rest with a blanket for 30 minutes once a day, 5 days a week for a total of 20 sessions in 4 weeks. RESULTS: Four weeks after admission, somatic complaints, hunger, and relaxation scores significantly improved (p < .001, p < .0001, p < .0001, respectively) and mental complaints slightly improved (p = .054) in the thermal therapy group compared with the nonthermal therapy group. Furthermore, the plasma ghrelin concentrations and daily caloric intake in the thermal therapy group significantly increased compared with the nonthermal therapy group (p < .05). CONCLUSIONS: These findings suggest that repeated thermal therapy may be useful for mildly depressed patients with appetite loss and subjective complaints.

The effects of repeated thermal therapy for two patients with chronic fatigue syndrome.

OBJECTIVE: This paper describes the successful treatment of two patients with chronic fatigue syndrome (CFS) using repeated thermal therapy. METHODS: Two patients with CFS underwent treatment with prednisolone (PSL), with no satisfactory effect. They were subjected to thermal therapy that consisted of a far-infrared ray dry sauna at 60 degrees C and postsauna warming. The therapy was performed once a day, for a total of 35 sessions. After discharge, these subjects continued the therapy once or twice a week on an outpatient basis for 1 year. RESULTS: Symptoms such as fatigue, pain, sleep disturbance, and low-grade fever were dramatically improved after 15 to 25 sessions of thermal therapy. Although PSL administration was discontinued, the subjects showed no relapse or exacerbation of symptoms during the first year after discharge. The patients became socially rehabilitated 6 months after discharge. CONCLUSIONS: These results suggest that repeated thermal therapy might be a promising method for the treatment of CFS.

Repeated sauna therapy increases arterial endothelial nitric oxide synthase expression and nitric oxide production in cardiomyopathic hamsters.

BACKGROUND: Vascular endothelial dysfunction is involved in the pathophysiology of chronic heart failure (CHF). It has been reported that sauna therapy, which allows thermal vasodilation, improves vascular endothelial dysfunction in patients with CHF. The present study investigates the mechanisms through which sauna therapy improves endothelial dysfunction induced by CHF. METHODS AND RESULTS: Normal control and male TO-2 cardiomyopathic hamsters were used. Thirty-week-old TO-2 hamsters were treated daily with an experimental far infrared-ray dry sauna system for 15 min at 39 degrees C followed by 20 min at 30 degrees C. This procedure raised the rectal temperatures by about 1 degrees C. Arterial endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein expressions were examined, and serum concentrations of nitrate were measured. The expression of eNOS mRNA in the aortas of normal controls did not change, whereas those of the TO-2 hamsters decreased with age. Four weeks of sauna therapy significantly increased eNOS mRNA expression in the aortas of TO-2 hamsters compared with those that did not undergo sauna therapy. Sauna therapy also upregulated aortic eNOS protein expression. Serum nitrate concentrations of the TO-2 hamsters were increased by 4 weeks of sauna therapy compared with those that did not undergo sauna. CONCLUSION: Repeated sauna therapy increases eNOS expression and NO production in cardiomyopathic hamsters with heart failure.

The critical role of SRC homology domain 2-containing tyrosine phosphatase-1 in recombinant human erythropoietin hyporesponsive anemia in chronic hemodialysis patients.

The molecular mechanism of anemia that is hyporesponsive to recombinant human erythropoietin (rHuEPO) in hemodialysis patients without underlying causative factors has not been investigated fully in hematopoietic stem cell system. Circulating CD34+ cells (1 x 10(4)) were isolated from rHuEPO hyporesponsive hemodialysis patients (EPO-H; n = 9), patients who were responsive to rHuEPO (EPO-R; n = 9), and healthy control subjects (n = 9). The patients with known causes of EPO hyporesponsiveness were eliminated from the current study. The cells were cultured in STEM PRO 34 liquid medium, supplemented with rHuEPO, IL-3, stem cell factor, and granulocyte-macrophage colony stimulating factor for 7 d and then transferred to a semisolid methylcellulose culture medium for performing burst forming unit-erythroid (BFU-E) colony assay. Expression of src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1), phosphorylated Janus kinase 2 (p-JAK2), and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) was assessed with Western blot analysis. In EPO-H patients, SHP-1 antisense or scrambled S-oligos were included in the culture medium, and its effects were evaluated. The number of circulating CD34+ cells was not statistically different among the three groups, and their proliferation rates were similar for 7 d in culture. However, BFU-E colonies were significantly decreased in EPO-H patients compared with EPO-R and control groups. The mRNA and protein expression of SHP-1 and p-SHP-1 was significantly increased, whereas that of p-STAT5 was reduced in EPO-H patients. The inclusion of SHP-1 antisense S-oligo in culture suppressed SHP-1 protein expression associated with p-STAT5 upregulation, increase in p-STAT5-regulated genes, and partial recovery of BFU-E colonies. In EPO-H hemodialysis patients, the EPO signaling pathway is attenuated as a result of dephosphorylation of STAT5 via upregulation of SHP-1 phosphatase activity, and SHP-1 may be a novel target molecule to sensitize EPO action in these patients.