CCR2-dependent placental migration of inflammatory monocytes suppresses abnormal pregnancies caused by Toxoplasma gondii infection.

Toxoplasma gondii (T. gongii) is a zoonotic protozoan parasite that causes congenital toxoplasmosis, including fetal death, abortion, stillbirth, morphological abnormalities, and premature birth. Primary T. gondii infection in pregnant women results in congenital toxoplasmosis. C-C chemokine receptor (CCR) 2 is reportedly a critical host defense factor against T. gondii infection. However, details of the role of CCR2 in the host immune response to T. gondii in congenital toxoplasmosis remain unclear. Here, we infected pregnant CCR2-deficient mice with T. gondii, resulting in stillbirth, embryonic resorption, fetal morphological abnormalities, and preterm delivery at significantly higher rates than those in pregnant wild-type mice. Consistent with the severity of abnormal pregnancy, a large area of placental hemorrhage and a large number of T. gondii infections around the hemorrhagic area were observed in the placentas of CCR2-deficient mice. In addition, the accumulation of inflammatory monocytes in the placenta was reduced in CCR2-deficient mice during infection. We further confirmed that the adoptive transfer of inflammatory monocytes collected from wild-type mice into T. gondii-infected pregnant CCR2-deficient mice effectively suppressed placental damage and abnormal pregnancy. Collectively, CCR2 contributes to pregnancy maintenance by regulating the migration of inflammatory monocytes into the placenta of T. gondii-infected pregnant mice.

Oral roxadustat three times weekly in ESA-naïve and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: Results from two phase 3 studies.

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for anemia of dialysis-dependent chronic kidney disease (CKD). Japanese hemodialysis patients with anemia of CKD previously naïve to, or converted from, erythropoiesis-stimulating agents (ESAs) were enrolled in two open-label, noncomparative studies of titrated oral roxadustat administered three times weekly. ESA-naïve patients (n = 75) were randomized to roxadustat (initial dose, 50 or 70 mg) for 24 weeks; ESA-converted patients (n = 164) were assigned to roxadustat (initial dose, 70 or 100 mg based on prior ESA dose) for 52 weeks. Efficacy outcomes included average hemoglobin (Hb, weeks 18-24 or 46-52), change of Hb from baseline to weeks 18 to 24 (ΔHb18-24 ) or weeks 46 to 52 (ΔHb46-52 ), and maintenance rate (proportion of patients who achieved average Hb of 10.0-12.0 g/dL for weeks 18-24 or weeks 46-52). Treatment-emergent adverse events (TEAEs) were monitored. Mean (SD) Hb was 10.93 (0.79) g/dL (weeks 18-24) (ESA-Naïve Study), and 10.93 (0.69; weeks 18-24) g/dL and 11.11 (0.67; weeks 46-52) g/dL (ESA-Converted Study). Mean (SD) ΔHb18-24 was 2.26 (1.02) g/dL (ESA-Naïve Study) and -0.03 (0.90) g/dL (ESA-Converted Study); mean (SD) ΔHb46-52 was 0.12 (0.83) g/dL (ESA-Converted Study). The overall maintenance rate was 73.0% (54/74) (ESA-Naïve Study) (weeks 18-24), and 79.1% (129/163; weeks 18-24) and 71.2% (116/163; weeks 46-52) (ESA-Converted Study). Nasopharyngitis was the most common TEAE. Two deaths, considered unrelated to roxadustat, occurred in the ESA-Converted Study. Roxadustat effectively corrected and maintained Hb, regardless of previous ESA treatment, in Japanese anemic CKD patients on hemodialysis.

Multiple imputation for longitudinal data in the presence of heteroscedasticity between treatment groups.

Multiple imputation is a promising approach for handling of missing data. One uncertainty in applications of the multiple imputation to randomized controlled trials with longitudinal data is whether the imputation should be carried out across all subjects simultaneously or by treatment group separately, which leads to two different strategies for building imputation procedures and/or models. Indeed, it has not been sufficiently addressed and well-documented how the two imputation strategies work in the analysis of the longitudinal data. We consider situations in the presence of heteroscedasticity between treatment groups and conducted extensive simulation studies to examine how the choice of imputation strategy had impacts on the estimation of treatment effects under an assumption of missing at random mechanism. The choice of analysis model was also assessed. The simulation studies suggested that in the presence of heteroscedasticity, the separate imputation by treatment group was robust enough to provide unbiased and precise estimation of the treatment effects; in contrast, the simultaneous imputation, which is frequently used in applications, led to serious biases and poor coverage probabilities of 95% confidence interval for the treatment effects. The heteroscedasticity should be dealt with in more careful manners for the longitudinal data analysis, and if it could be the case in hand, we recommend using the separate imputation by treatment group, as well as applying unequal variance analysis methods for complete data with imputed values. The methods were illustrated with data from two real examples of pediatric research and mental health research.

Intermittent Oral Dosing of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with Anemia: A Randomized, Phase 3, Multicenter, Open-Label Study.

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed to treat anemia in chronic kidney disease (CKD) patients. This Phase 3, randomized, open-label, 24-week study investigated the efficacy and safety of roxadustat in Japanese CKD patients with anemia on peritoneal dialysis (PD) who were previously treated or not treated with erythropoiesis stimulating agents (ESAs). Patients not previously receiving ESA (ESA-Naïve group) were randomized to roxadustat at a starting dose of 50 or 70 mg three times weekly; patients previously receiving ESA (ESA-Converted group) switched from ESA to roxadustat 70 or 100 mg three times weekly depending on the prior ESA dose. Outcomes included maintenance rate of average hemoglobin (Hb) level within 10-12 g/dL at weeks 18-24, cumulative response rate at end of treatment (Hb thresholds, 10.0 g/dL or 10.5 g/dL; Hb increase, ≥1.0 g/dL), and average Hb levels at weeks 18-24. Safety was assessed by occurrence of treatment-emergent adverse events (TEAEs). Fifty-six patients were enrolled (ESA-Naïve, n = 13; ESA-Converted, n = 43). Maintenance rates (weeks 18-24) were 92.3% (95% CI: 64.0-99.8; ESA-Naïve) and 74.4% (95% CI: 58.8-86.5; ESA-Converted). Cumulative response rate was 100.0% in the ESA-Naïve group. Average Hb levels (weeks 18-24) were 11.05 g/dL (95% CI: 10.67-11.42; ESA-Naïve) and 10.93 g/dL (95% CI: 10.73-11.13; ESA-Converted). Common TEAEs included nasopharyngitis and back pain. Roxadustat was well tolerated and effective in maintaining target Hb levels in CKD patients on PD who were previously treated or not treated with ESA.

Evaluation of Food and Spherical Carbon Adsorbent Effects on the Pharmacokinetics of Roxadustat in Healthy Nonelderly Adult Male Japanese Subjects.

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open-label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat. Subjects in the food effect study received a single dose of 100-mg roxadustat under fed and fasted conditions. Subjects in the SCA/roxadustat drug-drug interaction study received a single dose of 100-mg roxadustat alone, concomitantly with SCA, and 1 and 2 hours before and after SCA to consider the real-world clinical situation and assess any potential impact of a lag time on the pharmacokinetics of roxadustat. Primary outcomes for both studies were area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of drug in blood plasma. In the food effect study (N = 16), the geometric mean ratio (fed/fasted) and 90% confidence interval for area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of roxadustat were 94.44 (89.93-99.18) and 79.88 (72.09-88.52), respectively. In the SCA/roxadustat drug-drug interaction study, all geometric mean ratios and 90% confidence intervals (roxadustat + SCA/roxadustat) were within the no-effect boundaries of 80% and 125%. Roxadustat was generally well tolerated. The effect of food on the pharmacokinetics of roxadustat and the drug-drug interaction between roxadustat and SCA do not appear to be clinically relevant and support the safe use of roxadustat under these conditions.

Immediate effects of rhythmic auditory stimulation on gait in stroke patients in relation to the lesion site.

[Purpose] Rhythmic auditory stimulation has been used in gait training for stroke patients. However, few studies have investigated its effects in relation to lesion sites. Therefore, this study examined the immediate effects of rhythmic auditory stimulation on gait in stroke patients with lesions in different regions. [Subjects and Methods] One hundred and five patients were recruited and divided into five groups according to the lesion site: cerebellum, pons and medulla, thalamus, putamen, and corona radiata. During training, participants walked to an auditory, continuous rhythmic beat, which was set to each individual's cadence. [Results] Pre- versus post-test measures revealed significant increases in velocity and stride length in the cerebellum, pons and medulla, and thalamus groups. Although the putamen and corona radiata groups demonstrated increases in velocity and stride length, the increases were not significant. [Conclusion] Rhythmic auditory stimulation was effective in facilitating the prediction of motor timing and gait rhythm in stroke patients with lesions in the cerebellum, pons and medulla, and thalamus, which are associated with impairment of the timing mechanism.

Sodium alginate oligosaccharides attenuate hypertension in spontaneously hypertensive rats fed a low-salt diet.

We investigated the effects of sodium alginate oligosaccharides (alginate) on the development of spontaneous hypertension in rats. Spontaneous hypertensive rats were treated with alginate for 7 weeks. Systolic blood pressure (SBP) and cardiovascular and kidney damage were assessed. Systolic blood pressure increased in SHRs and this elevation was attenuated with alginate treatment. The heart weight tended to decline. Alginate did not change plasma cholesterol levels or urinary sodium excretions. The slightly higher urinary protein excretion in SHRs was not changed with the treatment; however, morphologic glomerular damage was significantly attenuated. Sodium alginate oligosaccharide attenuates spontaneous hypertension in SHRs, and may help prevent early-stage kidney injury.

Japanese traditional miso soup attenuates salt-induced hypertension and its organ damage in Dahl salt-sensitive rats.

OBJECTIVE: We investigated the effects of long-term miso soup drinking on salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats. METHODS: Dahl S rats were divided into four groups that consumed 1) water, 2) a 0.9% NaCl solution, 3) a 1.3% sodium NaCl solution, or 4) miso soup containing 1.3% NaCl. They were followed for 8 wk. Systolic blood pressure and hypertensive organ damage were determined. RESULTS: Systolic blood pressure increased in an age- and dose-dependent manner in Dahl S rats drinking salt solutions. The systolic blood pressure increase was significantly less in the Dahl S rats that drank miso soup, although the ultimate cumulative salt loading was greater than that in the Dahl S rats given the 1.3% NaCl solution. This blood pressure decrease was associated with a morphologic attenuation of glomerular sclerosis in the kidney and collagen infiltration in the heart. Urinary protein excretions were less in the miso group than in the rats given the 1.3% NaCl solution. The fractional excretion of sodium was increased and that of potassium was decreased in Dahl S rats given the 1.3% NaCl solution, and these effects were reversed in rats given miso soup toward the values of the control. CONCLUSION: We found that long-term miso soup drinking attenuates the blood pressure increase in salt-induced hypertension with organ damage. This may be caused by a possible retardation of sodium absorption in the gastrointestinal tract or by the direct effects of nutrients in the miso soup from soybeans. The decrease was associated with decreases in cardiovascular and renal damage.

Sodium alginate oligosaccharides attenuate hypertension and associated kidney damage in Dahl salt-sensitive rats fed a high-salt diet.

OBJECTIVES: In this article, the antihypertensive effects of sodium alginate oligosaccharides, enzymatic products of high molecular natural alginate from sea weeds, in Dahl salt-sensitive (Dahl S) rats were investigated. MATERIAL AND METHODS: Dahl S rats fed a high-salt (4% NaCl) diet were treated with sodium alginate oligosaccharides (4% or 8% w/w) for 7 weeks. Systolic blood pressure (SBP) was measured by the tail-cuff method, and hypertensive cardiovascular benefits and kidney damage were assessed. Glomerular function and morphological sclerosis were determined. RESULTS: SBP increased in an age-dependent manner in the untreated Dahl S rats. Sodium alginate oligosaccharide treatment attenuated the increase in SBP in a dose-dependent manner. The heart and aortic walls weighed less in the rats treated with sodium alginate oligosaccharides than in the untreated rats. The SBP reduction was associated with a decrease in urinary protein excretion and an increase in the creatinine clearance rate. Sodium alginate oligosaccharides significantly attenuated hypertensive glomerular sclerosis and arterial injury in the kidney. Fractional excretion of sodium (FENa) decreased in low-salt Dahl S rats and increased with a salt challenge. The alginate oligosaccharides decreased FENa in high-salt Dahl S rats. CONCLUSIONS: The results of this study suggest that sodium alginate oligosaccharides attenuate salt-induced hypertension in Dahl S rats. This reduction is associated with decreases in cardiovascular and renal damage.