Prediction of life-space mobility in patients with stroke 2 months after discharge from rehabilitation: a retrospective cohort study.

Purpose: To determine the predictors of life-space mobility among patients with stroke 2 months after discharge from a post-acute rehabilitation unit.Materials and methods: The study population was 1023 patients discharged from a post-acute rehabilitation unit in Japan. We assessed the relationships between life-space mobility 2 months after discharge and age, sex, length of hospital stay, cognition and motor function (Functional Independence Measure), severity of hemiparesis, falls efficacy, physical function (Timed Up and Go (TUG) test), walking distance ability and social support from family and friends.Results: Bivariate and multiple regression analyses showed that life-space mobility was predicted by sex, age, cognitive score at discharge, TUG score <15 s, length of hospital stay and falls efficacy at discharge. Taken together, these factors accounted for 54% of the variability in life-space mobility. A predictive formula was determined for clinical use.Conclusions: The predictive formula provides an objective measure of life-space mobility for stroke patients after discharge. The clinical application of this formula could help health care professionals working in stroke rehabilitation to prepare patients for discharge and to set concrete goals for in-hospital rehabilitation to improve life-space mobility after discharge.Implications for rehabilitationAccurate prediction of the prognosis for life-space mobility 2 months after discharge is useful in establishing clear goals for community-based rehabilitation.Long-term life-space mobility in the community is not only affected by physical function, but also by sex, age, cognitive ability and falls efficacy at discharge.Life-space mobility in female patients is affected by factors reflecting physical function, whereas life-space mobility in male patients is affected by both physical and cognitive function.Prediction of life-space mobility after stroke is important to determine unique mobility goals in rehabilitation and the required use of adaptive equipment after discharge (e.g., returning to work, engaging in a hobby or travelling beyond the immediate neighbourhood).

Disruption of the Obligatory Swallowing Sequence in Patients with Wallenberg Syndrome.

Although the sequence of events involved in swallowing varies among healthy adults, healthy adults demonstrate some consistent patterns, including opening of the upper esophageal sphincter (UES) prior to maximum laryngeal elevation (LE). Previous animal studies suggested that swallowing is regulated by a neuronal network in the medulla, and lateral medullary infarction, or Wallenberg syndrome, frequently causes dysphagia. This retrospective, observational, multicenter study aimed to determine if the sequence of swallowing events was disturbed in patients with Wallenberg syndrome compared with previously published reference data for healthy adults. The study subjects included 35 patients with Wallenberg syndrome admitted to three hospitals in Japan from 1/4/2009 to 31/3/2017. Sixteen timing events, including maximum LE and UES opening, and the intervals between events were measured. If the sequence of events was the same as in healthy adults, the interval value was positive, and if the sequence of events was opposite to that in healthy adults, the value was negative. The median interval from UES opening to maximum LE was - 0.02 s (range - 0.80 to 0.89, 95% CI - 0.14 to 0.10). About half of the Wallenberg cases showed negative values indicating that the sequence was reversed. These results suggest that lateral medullary infarction impairs the sequence of swallowing events.

Sterol regulatory element binding protein 1 trans-activates 25-hydroxy vitamin D3 24-hydroxylase gene expression in renal proximal tubular cells.

The physiological activity of the steroid derived hormone vitamin D is regulated by several enzymatic steps. Both 25-hydroxy vitamin D3 1α-hydroxylase (CYP27B1) and 25-hydroxyvitamin D3 24-hydroxylase (CYP24A1) modulate blood levels of 1,25-dihydroxyvitamin D3, an activated form of vitamin D. We previously demonstrated that CYP27B1 expression was trans-activated by sterol regulatory element binding protein 1 (SREBP1), although whether SREBP1 also regulates CYP24A1 transcription was unclear. Here we investigated the ability of SREBP1 to affect CYP24A1 transcription. In a luciferase reporter assay, mouse and human CYP24A1 promoter activity was strongly activated by SREBP1 in opossum kidney proximal tubular cells (OK-P). Three putative SREs (pSREs) were found in the mouse Cyp24a1 gene promoter and the SREBP1 protein showed specific binding to the pSRE1 element in EMSAs. Site-directed mutagenesis of the pSRE1 element strongly decreased SREBP1-mediated Cyp24a1 gene transcription. Moreover, siRNA-mediated SREBP1 knock-down repressed CYP24A1 expression in human renal proximal tubular epithelial cells (HKC-8). In animal studies, mice given various doses of thyroid hormone (T3) showed dose-dependent reductions in renal Srebp1c and Cyp24a1 mRNA levels. Taken together, our results suggest that SREBP1 trans-activates CYP24A1 expression through SREBP binding elements present in the promoter.

The age-related changes of dietary phosphate responsiveness in plasma 1,25-dihydroxyvitamin D levels and renal Cyp27b1 and Cyp24a1 gene expression is associated with renal α-Klotho gene expression in mice.

In this study, we investigated the relationship between age-related changes in renal α-Klotho gene expression, vitamin D metabolism and the responsiveness of dietary phosphate in 1, 2 and 13 month-old mice fed a high phosphate (phosphate 1.2%) diet or low phosphate (phosphate 0.02%) diet for 5 days. We found that 1,25-dihydroxyvitamin D levels in plasma were significantly lower in the high phosphate group than the low phosphate group for 1 and 2 month-old mice, but not 13 month-old mice. In addition, in the high phosphate group plasma 1,25-dihydroxyvitamin D levels were decreased in 2 month-old mice relative to 1 month-old mice, but 13 month-old mice had higher levels than 2 month-old mice. In fact, plasma 1,25-dihydroxyvitamin D levels showed a significant correlation with vitamin D metabolism gene Cyp27b1 and Cyp24a1 mRNA expression in the high phosphate group. Interestingly, renal α-Klotho mRNA and protein levels were significant change with age. Furthermore, α-Klotho mRNA expression showed a significant negative correlation with plasma 1,25-dihydroxyvitamin D levels in the high phosphate group. Our results suggest that age-related alterations in renal α-Klotho expression could affect the responsiveness of dietary phosphate to vitamin D metabolism.

Dietary phosphate exacerbates intestinal inflammation in experimental colitis.

The recent widespread consumption of Western diets and food additives worldwide is associated with excessive inorganic phosphate intake. However, researchers have known little about the impact of dietary phosphate intake on the development of inflammatory bowel disease to date. In this study, we investigated the effects of dietary phosphate on intestinal inflammation in experimental colitis. Sprague-Dawley rats were fed different phosphate diets (0.5%, 1.0% and 1.5% phosphate) with or without dextran sulfate sodium. For in vitro study, the effects of phosphate on proinflammatory cytokine induction and reactive oxygen species production in RAW264.7 macrophage were examined. Dietary phosphate exacerbated intestinal inflammation in experimental colitis in a dose-dependent manner, as assessed by the clinical disease activity score, colon length, and histology. Furthermore, the high phosphate diet increased myeloperoxidase activity and proinflammatory cytokine mRNA expression through the activation of nuclear factor κB in the inflamed colon. In addition, high phosphate loading in RAW264.7 cells directly enhanced reactive oxygen species production and proinflammatory cytokine gene expression. Our results demonstrated that the high phosphate diet exacerbated intestinal inflammation in experimental colitis. These findings have important therapeutic implications for inflammatory bowel disease patients.

Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice.

Enhancement of regulatory T cell (Treg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of Treg cell homeostasis and function. We investigated how IL-2 pathway defects impact Treg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD Treg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, Treg cell frequency was preserved through expansion of CD25(low), effector phenotype Treg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD Treg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD Treg cells in the spleen and blood, but had reduced efficacy on lymph node Treg cells. In contrast, NOD CD8(+) and CD4(+) effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD Treg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2.

Dietary phosphate supplementation delays the onset of iron deficiency anemia and affects iron status in rats.

Inorganic phosphate (Pi) plays critical roles in bone metabolism and is an essential component of 2,3-diphosphoglycerate (2,3-DPG). It has been reported that animals fed a low-iron diet modulate Pi metabolism, whereas the effect of dietary Pi on iron metabolism, particularly in iron deficiency anemia (IDA), is not fully understood. In this study, we hypothesized the presence of a link between Pi and iron metabolism and tested the hypothesis by investigating the effects of dietary Pi on iron status and IDA. Wistar rats aged 4 weeks were randomly assigned to 1 of 4 experimental dietary groups: normal iron content (Con Fe)+0.5% Pi, low-iron (Low Fe)+0.5% Pi, Con Fe+1.5% Pi, and Low Fe+1.5% Pi. Rats fed the 1.5% Pi diet for 14 days, but not for 28 days, maintained their anemia state and plasma erythropoietin concentrations within the reference range, even under conditions of low iron. In addition, plasma concentrations of 2,3-DPG were significantly increased by the 1.5% Pi diets and were positively correlated with plasma Pi concentration (r=0.779; P<.001). Dietary Pi regulated the messenger RNA expression of iron-regulated genes, including divalent metal transporter 1, duodenal cytochrome B, and hepcidin. Furthermore, iron concentration in liver tissues was increased by the 1.5% Pi in Con Fe diet. These results suggest that dietary Pi supplementation delays the onset of IDA and increases plasma 2,3-DPG concentration, followed by modulation of the expression of iron-regulated genes.

Downregulation of renal type IIa sodium-dependent phosphate cotransporter during lipopolysaccharide-induced acute inflammation.

The type IIa sodium-dependent phosphate cotransporter (Npt2a) plays a critical role in reabsorption of inorganic phosphate (Pi) by renal proximal tubular cells. Pi abnormalities during early stages of sepsis have been reported, but the mechanisms regulating Pi homeostasis during acute inflammation are poorly understood. We examined the regulation of Pi metabolism and renal Npt2a expression during lipopolysaccharide (LPS)-induced inflammation in mice. Dose-response and time-course studies with LPS showed significant increases of plasma Pi and intact parathyroid hormone (iPTH) levels and renal Pi excretion, while renal calcium excretion was significantly decreased. There was no difference in plasma 1,25-dihydroxyvitamin D levels, but the induction of plasma intact fibroblast growth factor 23 levels peaked 3 h after LPS treatment. Western blotting, immunostaining, and quantitative real-time PCR showed that LPS administration significantly decreased Npt2a protein expression in the brush border membrane (BBM) 3 h after injection, but there was no change in renal Npt2a mRNA levels. Moreover, tumor necrosis factor-α injection also increased plasma iPTH and decreased renal BBM Npt2a expression. Importantly, we revealed that parathyroidectomized rats had impaired renal Pi excretion and BBM Npt2a expression in response to LPS. These results suggest that the downregulation of Npt2a expression in renal BBM through induction of plasma iPTH levels alter Pi homeostasis during LPS-induced acute inflammation.