Association of Activities of Daily Living with Body Weight Change 3 Months After Stroke Onset.

OBJECTIVES: To investigate the relationship between body weight loss and activities of daily living (ADL) 3 months after stroke onset. MATERIALS AND METHODS: This retrospective cohort study included 81 patients at a rehabilitation hospital after receiving acute treatment at our hospital (mean age 70.7 years). Patients were divided into two groups, namely independent and non-independent, based on their ADL 3 months after stroke. Receiver operating characteristic (ROC) curves were constructed with the ADL independence possibility as the objective variable and body weight change rate (%) at 3 months as the explanatory variable. Patients were classified using the weight change rate calculated from the ROC curve and the NIHSS cut-off values, and the ADL independence percentage was compared. RESULTS: The ADL-independent group had significantly lesser body weight loss than the non-independent group (median rate of body weight change: -2.7% vs. -7.2%; p<0.001). The area under the ROC curve was 0.76. The cut-off value was -5.6% for the body weight change rate. When participants with NIHSS ≤ 8 points were selected, the ADL-independent participants' proportion was significantly higher in the body weight loss ≤ -5.6% group than in the > -5.6% group (56.0% vs. 15.4%, p=0.016). However, there was no significant difference in the ADL-independent participants' proportion when those with NIHSS >8 points were selected (p=0.19). CONCLUSIONS: Our findings indicate that weight loss after stroke onset is associated with non-independent ADL at 3 months. Weight maintenance from the onset is important for ADL independence, especially in patients with mild to moderate stroke.

Involvement of neutrophil recruitment and protease-activated receptor 2 activation in the induction of IL-18 in mice.

Activated neutrophils produce serine proteases, which activate cells through protease-activated receptor 2 (PAR2). As proteinase 3 (PR3) induces the secretion of interleukin (IL)-18 from epithelial cells in combination with lipopolysaccharide (LPS) in vitro, we examined whether neutrophils, serine proteases, and PAR2 are involved in the induction of serum IL-18 and IL-18-dependent liver injury in mice treated with heat-killed Propionibacterium acnes and LPS. LPS-induced serum IL-18 levels in P. acnes-primed mice were reduced significantly by anti-Gr-1 injection (depletion of neutrophils and macrophages) but not by a macrophage "suicide" technique, using liposomes encapsulating clodronate. The IL-18 induction was decreased significantly by coadministration of a serine protease inhibitor [Nafamostat mesilate (FUT-175)] with LPS. Serum levels of tumor necrosis factor alpha and liver enzymes induced by P. acnes and LPS were abolished by anti-Gr-1 treatment, and concomitantly, liver injury (necrotic change and granuloma formation) and Gr-1(+) cell infiltration into the liver were prevented by the treatment. A deficiency of PAR2 in mice significantly impaired IL-18 induction by treatment with P. acnes and LPS, and only slight pathological changes in hepatic tissues occurred in the PAR2-deficient mice treated with P. acnes and LPS. Furthermore, coadministration of exogenous murine PR3 or a synthetic PAR2 agonist (ASKH95) with LPS in the anti-Gr-1-treated mice restored the serum IL-18 levels to those in control mice treated with P. acnes and LPS. These results indicate that neutrophil recruitment and PAR2 activation by neutrophil serine proteases are critically involved in the induction of IL-18 and IL-18-dependent liver injury in vivo.

Abrogation of bronchial eosinophilic inflammation and attenuated eotaxin content in protease-activated receptor 2-deficient mice.

Protease-activated receptor 2 (PAR2) belongs to the PAR family (PAR1 to PAR4), which is activated by serine proteases (trypsin, tryptase, etc.). In this study, we evaluated the role of PAR2 in allergic inflammation of airways using PAR2-deficient (PAR2(-/-)) mice. In wild- type mice, infiltration of eosinophils and high eotaxin content were found in bronchoalveolar lavage fluid (BALF) after ovalbumin (OA) sensitization and following challenge. In contrast, both OA-induced infiltration of eosinophils and increase of eotaxin content were abrogated in BALF from PAR2(-/-) mice. The activation of PAR2 might be essential in the production of eotaxin and consequential allergic inflammation in airways.

Deficiency of PAR-2 gene increases acute focal ischemic brain injury.

The expression profile of the protease-activated receptor-2 (PAR-2) and effects of PAR-2 gene knockout (PAR-2 KO) on the infarct size were investigated after 60 minutes of transient middle cerebral artery occlusion (tMCAO) in mice in relation to phosphorylated extracellular signal-regulated kinase (p-ERK) and astrocyte activation. PAR-2 was normally distributed mainly in neurons of the central nervous system (CNS), and strongly upregulated at 8-24 hours after tMCAO. Deficiency of PAR-2 gene significantly increased the infarct volume and the number of TUNEL-positive cells at 24 hours of reperfusion. The strong neuronal expression of p-ERK was induced at 5 minutes as a peak after reperfusion in wild-type mice, but the signal change was significantly reduced in PAR-2 KO mice. Astroglial activation was also greatly inhibited at 24 hours after tMCAO in PAR-2 KO mice. These results show that the deficiency of PAR-2 gene increases the acute ischemic cerebral injury associating with suppression of neuronal ERK activation and reactive astroglial activation.

Lack of effect of proteinase-activated receptor-2 (PAR-2) deletion on the pathophysiological changes produced by lipopolysaccharide in the mouse: comparison with dexamethasone.

This study tested the hypothesis that activation of proteinase-activated receptor-2 (PAR-2) contributes towards the pathophysiology of lipopolysaccharide (LPS)-induced shock in the mouse. The effects of LPS on plasma glucose, biochemical markers of hepatic, renal and pancreatic exocrine function and lung content of myeloperoxidase (MPO) were examined in homozygous PAR-2 knockout mice (PAR-2 -/-) and genetically equivalent, homozygous PAR-2 +/+ mice. The effect of LPS was also examined in normal mice receiving dexamethasone (10 mg kg(-1), i. p.) or saline as a positive control. At six hours after intraperitoneal injection, LPS (40 mg kg(-1)) produced an increase in rectal temperature, hypoglycaemia and elevations in serum concentrations of alanine aminotransferase (ALT), creatinine and lipase, as well as an increase in lung MPO content. Dexamethasone treatment reduced LPS-induced hypoglycaemia and elevation of serum ALT concentrations but did not modify elevations in serum creatinine and lipase concentrations or the increase in lung MPO content. The changes in serum concentrations of glucose, ALT, creatinine and lipase produced by LPS in PAR-2 -/- mice were not different from those seen in wild-type or PAR-2 +/+ mice. These data suggest that activation of PAR-2 may not play a pivotal role in LPS-induced multi-organ dysfunction.

Essential role for proteinase-activated receptor-2 in arthritis.

Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis.

Effect of protease-activated receptor-2 deficiency on allergic dermatitis in the mouse ear.

To investigate the involvement of protease-activated receptor-2 (PAR-2) in allergic dermatitis, we generated PAR-2-deficient (PAR-2(-/-)) mice. Ear thickness, contact hypersensitivity (CH) induced by topical application of picryl chloride (PC) or oxazolone (Ox) after sensitization, and vascular permeability after ear passive cutaneous anaphylaxis (PCA) were compared between wild-type (WT) and PAR-2(-/-) mice. Ear thickness was almost the same in untreated WT and PAR-2(-/-) mice. Topical application of PC or Ox thickened the ears at 6, 24 and 48 h after challenge with a peak at 24 h in WT mice. In PAR-2(-/-) mice, the ear swelling induced by both PC and Ox was suppressed at every time point, and significant inhibition was found at 24 h in PC-induced CH and at 24 and 48 h in Ox-induced CH. Histopathological observation of the ears at 24 h after challenge revealed that PC- or Ox-induced ear edema and infiltration of inflammatory cells in WT mice were greatly attenuated in PAR-2(-/-) mice. The vascular permeability in the ears after PCA was not different between WT and PAR-2(-/-) mice. These results strongly suggest that PAR-2 plays a crucial role in type IV allergic dermatitis but not in type I allergic dermatitis.