Incidence and Prevalence of Infectious Diseases and Their Risk Factors among Patients Who Use Visiting Nursing Services in Japan.

This study aimed to clarify the incidence of infectious diseases and the associated risk factors among patients who use visiting nursing services in Japan. We conducted a one-year follow up cohort study with 419 participants. The incidence and period prevalence rate of infectious diseases were 0.63 and 15.0%, respectively. In the multiple logistic regression analysis, the presence of chronic respiratory failure, Parkinson's disease, dermatosis other than pressure ulcers, and the inability to perform oral self-care were significantly related to the contraction of an infectious disease.

Leg symptoms associated with sacroiliac joint disorder and related pain.

OBJECTIVE: The symptoms of sacroiliac joint (SIJ) disorders are usually detected in the buttock and groin, and occasionally referred to the thigh and leg. However, lumbar disorders also cause symptoms in these same body regions. The presence of a characteristic, symptomatic pattern in the legs would be useful for diagnosing SIJ disorders. This study aimed to identify specific leg symptoms in patients with SIJ pain originating from the posterior sacroiliac ligament and determine the rate of occurrence of these symptoms. PATIENTS AND METHODS: The source population consisted of 365 consecutive patients from February 2005 to December 2007. One hundred patients were diagnosed with SIJ pain by a periarticular SIJ injection (42 males and 58 females, average age 46 years, age range, 18-75 years). A leg symptom map was made by subtracting the symptoms after a periarticular SIJ injection from the initial symptoms, and evaluating the rate of each individual symptom by area. RESULTS: Ninety-four patients reported pain at or around the posterior-superior iliac spine (PSIS). Leg symptoms comprised pain and a numbness/tingling sensation; ≥60% of the patients had these symptoms. Pain was mainly detected in the back, buttock, groin, and thigh areas, while numbness/tingling was mainly detected in the lateral to posterior thigh and back of the calf. CONCLUSIONS: Leg symptoms associated with SIJ pain originating from the posterior sacroiliac ligament include both pain and numbness, which do not usually correspond to the dermatome. These leg symptoms in addition to pain around the PSIS may indicate SIJ disorders.

Individual and environmental factors related to stage of change in exercise behavior: a cross-sectional study of female Japanese undergraduate students.

BACKGROUND: The purpose of the current study was to examine the association between the level of exercise behavior and individual and environmental factors related to exercise behavior among female Japanese undergraduate students. METHODS: The participants were 2482 female Japanese undergraduate students. Participants' level of exercise behavior was measured by the stage of change to exercise in the transtheoretical model. Individual and environmental factors related to exercise behavior were assessed using body mass index, self-efficacy, social support, perceived positive and negative aspects of exercise, perceived neighborhood environment, attitude toward physical education lessons in childhood and puberty, and depression. RESULTS: Scores for self-efficacy, social support, positive aspects of exercise, and perceived neighborhood environment were significantly higher among women who were more active compared with those who were inactive. On the other hand, scores for negative aspects of exercise and depression were greater among inactive women compared with those who were insufficiently active and/or active. In addition, past attitude toward exercise in primary school, junior high school, and high school was associated with current level of exercise behavior. CONCLUSIONS: This cross-sectional study confirmed that psychosocial and environmental factors were closely associated with level of exercise behavior among female Japanese undergraduate students.

Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling.

Fetal hypoxia is a common risk factor that has been associated with a range of CNS disorders including epilepsy, schizophrenia, and autism. Cellular and molecular mechanisms through which hypoxia may damage the developing brain are incompletely understood but are likely to involve disruption of the laminar organization of the cerebral cortex. Lysophosphatidic acid (LPA) is a bioactive lipid capable of cortical influences via one or more of six cognate G protein-coupled receptors, LPA(1-6), several of which are enriched in fetal neural progenitor cells (NPCs). Here we report that fetal hypoxia induces cortical disruption via increased LPA(1) signaling involving stereotyped effects on NPCs: N-cadherin disruption, displacement of mitotic NPCs, and impaired neuronal migration, as assessed both ex vivo and in vivo. Importantly, genetic removal or pharmacological inhibition of LPA(1) prevented the occurrence of these hypoxia-induced phenomena. Hypoxia resulted in overactivation of LPA(1) through selective inhibition of G protein-coupled receptor kinase 2 expression and activation of downstream pathways including G(αi) and Ras-related C3 botulinum toxin substrate 1. These data identify stereotyped and selective hypoxia-induced cerebral cortical disruption requiring LPA(1) signaling, inhibition of which can reduce or prevent disease-associated sequelae, and may take us closer to therapeutic treatment of fetal hypoxia-induced CNS disorders and possibly other forms of hypoxic injury.

Lysophosphatidic acid signaling may initiate fetal hydrocephalus.

Fetal hydrocephalus (FH), characterized by the accumulation of cerebrospinal fluid, an enlarged head, and neurological dysfunction, is one of the most common neurological disorders of newborns. Although the etiology of FH remains unclear, it is associated with intracranial hemorrhage. Here, we report that lysophosphatidic acid (LPA), a blood-borne lipid that activates signaling through heterotrimeric guanosine 5'-triphosphate-binding protein (G protein)-coupled receptors, provides a molecular explanation for FH associated with hemorrhage. A mouse model of intracranial hemorrhage in which the brains of mouse embryos were exposed to blood or LPA resulted in development of FH. FH development was dependent on the expression of the LPA(1) receptor by neural progenitor cells. Administration of an LPA(1) receptor antagonist blocked development of FH. These findings implicate the LPA signaling pathway in the etiology of FH and suggest new potential targets for developing new treatments for FH.

Health promotion behaviors of residents with hypertension in Iwate, Japan and North Carolina, USA.

AIM: The aim of this study was to compare the health promotion practises of rural residents in northern Japan (n = 212) to those in south-eastern North Carolina, USA (n = 105), using the Health Promotion Lifestyle II (HPLP) scale. METHODS: A comparative and descriptive design examined the relationships between health-related behaviors and demographic and physiological variables, and compared cross-cultural patterns. RESULTS: The Japanese participants scored significantly higher on the total HPLP II score, as well as on the subscales of health responsibility, nutrition, interpersonal support, and stress management. No significant differences were found in the HPLP II subscales for spiritual growth or physical activity between the groups. The subscale scores for both the participants from Japan and the participants from North Carolina were lowest for physical activity. For the participants from North Carolina, the HPLP II subscale scores were highest for spirituality and interpersonal relationships. The predictive factors of variation in the scores of the HPLP II for the participants from North Carolina included being married and not working. No significant demographic predictor was found for the HPLP II scores of the Japanese participants. CONCLUSIONS: The study's findings add to an increased understanding of the cultural variations in the health-promoting behaviors of persons with hypertension. Providing health promotion strategies for hypertension remains an urgent issue for nurses and other health-care providers in both Japan and North Carolina, USA.

Roles for lysophospholipid S1P receptors in multiple sclerosis.

Sphingosine 1-phosphate (S1P) signaling in the treatment of multiple sclerosis (MS) has been highlighted by the efficacy of FTY720 (fingolimod), which upon phosphorylation can modulate S1P receptor activities. FTY720 has become the first oral treatment for relapsing MS that was approved by the FDA in September 2010. Phosphorylated FTY720 modulates four of the five known S1P receptors (S1P(1), S1P(3), S1P(4), and S1P(5)) at high affinity. Studies in human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have revealed that FTY720 exposure alters lymphocyte trafficking via sequestration of auto-aggressive lymphocytes within lymphoid organs, representing the current understanding of its mechanism of action. These effects primarily involve S1P(1), which is thought to attenuate inflammatory insults in the central nervous system (CNS). In addition, FTY720's actions may involve direct effects on S1P receptor-mediated signaling in CNS cells, based upon the known expression of S1P receptors in CNS cell types relevant to MS, access to the CNS through the blood-brain barrier (BBB), and in vitro studies. These data implicate lysophospholipid signaling--via S1P(1) and perhaps other lysophospholipid receptors--in therapeutic approaches to MS and potentially other diseases with immunological and/or neurological components.

FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation.

Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720 (fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte trafficking through receptor subtype S1P(1). However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720 might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional assessment, based on clinical score, of conditional null mouse mutants lacking S1P(1) in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P(1) on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P(1) was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P(1) on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies.

LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis.

Lysophosphatidic acid (LPA) is a potent lipid mediator with a wide variety of biological actions mediated through G protein-coupled receptors (LPA(1-6)). LPA(4) has been identified as a G(13) protein-coupled receptor, but its physiological role is unknown. Here we show that a subset of LPA(4)-deficient embryos did not survive gestation and displayed hemorrhages and/or edema in many organs at multiple embryonic stages. The blood vessels of bleeding LPA(4)-deficient embryos were often dilated. The recruitment of mural cells, namely smooth muscle cells and pericytes, was impaired. Consistently, Matrigel plug assays showed decreased mural cell coverage of endothelial cells in the neovessels of LPA(4)-deficient adult mice. In situ hybridization detected Lpa4 mRNA in the endothelium of some vasculatures. Similarly, the lymphatic vessels of edematous embryos were dilated. These results suggest that LPA(4) regulates establishment of the structure and function of blood and lymphatic vessels during mouse embryogenesis. Considering the critical role of autotaxin (an enzyme involved in LPA production) and Gα(13) in vascular development, we suggest that LPA(4) provides a link between these 2 molecules.

LPA receptors: subtypes and biological actions.

Lysophosphatidic acid (LPA) is a small, ubiquitous phospholipid that acts as an extracellular signaling molecule by binding to and activating at least five known G protein-coupled receptors (GPCRs): LPA(1)-LPA(5). They are encoded by distinct genes named LPAR1-LPAR5 in humans and Lpar1-Lpar5 in mice. The biological roles of LPA are diverse and include developmental, physiological, and pathophysiological effects. This diversity is mediated by broad and overlapping expression patterns and multiple downstream signaling pathways activated by cognate LPA receptors. Studies using cloned receptors and genetic knockout mice have been instrumental in uncovering the significance of this signaling system, notably involving basic cellular processes as well as multiple organ systems such as the nervous system. This has further provided valuable proof-of-concept data to support LPA receptors and LPA metabolic enzymes as targets for the treatment of medically important diseases that include neuropsychiatric disorders, neuropathic pain, infertility, cardiovascular disease, inflammation, fibrosis, and cancer.

Non-Edg family lysophosphatidic acid (LPA) receptors.

Lysophosphatidic acid (LPA; 1- or 2-acyl-sn-glycero-3-phosphate) is a bioactive phospholipid with mitogenic and/or morphological effects on many cell types. In addition, LPA has been reported to play important roles in various biological processes. It was originally thought that the cellular effects of LPA are mediated by three subtypes of G-protein-coupled receptors: LPA(1)/Edg2, LPA(2)/Edg4, and LPA(3)/Edg7. They share 50-57% amino acid identities and, together with five sphingosine-1-phosphate receptors (S1P(1)/Edg1, S1P(2)/Edg5, S1P(3)/Edg3, S1P(4)/Edg6, and S1P(5)/Edg8), comprise the endothelial cell differentiation gene (Edg) family. However, even after finding of the Edg family LPA receptors, the existence of an additional LPA receptor(s) has been implied by several reports. In 2003, we identified p2y9/GPR23 as a fourth LPA receptor, LPA(4), which is structurally distant from the Edg family LPA receptors. LPA(4)/p2y9/GPR23 has stimulated identification of two additional LPA receptors, LPA(5)/GPR92/GPR93 and LPA(6)/p2y5. These findings made us aware of the existence of a novel "non-Edg" LPA receptor family. This review article focuses on the identification, properties and possible functions of the non-Edg family LPA receptors: LPA(4)/p2y9/GPR23, LPA(5)/GPR92/GPR93 and LPA(6)/p2y5.

Lysophosphatidic acid (LPA) and its receptors.

Lysophosphatidic acid (LPA), a bioactive phospholipid, and its family of cognate G protein-coupled receptors have demonstrated roles in many biological functions in the nervous system. To date, five LPA receptors have been identified, and additional receptors may exist. Most of these receptors have been genetically deleted in mice toward identifying biological and medically relevant roles. In addition, small molecule agonists and antagonists have been reported. Here we review recent data on the nervous system functions of LPA signaling, and summarize data on reported agonists and antagonists of LPA receptors.

Diagram specific to sacroiliac joint pain site indicated by one-finger test.

BACKGROUND: The sacroiliac joint (SIJ) can be a source of low back and lower limb pain. The SIJ pain can originate not only from the joint space but also from the ligaments supporting the joint. Its diagnosis has been difficult because the physical and radiological examinations have proved less than satisfactory. Thus, to know the specific sites of SIJ pain, if these exist, could be very useful for making the diagnosis. The purpose of the present study was to identify the main site of SIJ pain according to the patient's pointing with one finger and to confirm the site by a pain-provocation test and periarticular lidocaine injection. METHODS: Forty-six of 247 consecutive patients with low back pain at our outpatient clinic, who could indicate with one finger the main site of the pain, which presented at only one site and was reproducible, were the subjects of this study. The main site of pain was anatomically confirmed by fluoroscopy. Then, a periarticular SIJ injection was performed. The patients were blindly assessed and a diagram of the main site of the SIJ pain was made. RESULTS: There were 19 males and 27 females and the age averaged 50 years. Eight patients showed a positive placebo response and were excluded from this study. Twenty-five of the remaining 38 patients indicated the main site of pain at the posterior-superior iliac spine (PSIS) or within 2 cm of the PSIS, and 18 of these patients showed a positive effect with periarticular SIJ block. The other 13 patients, including 2 patients with a positive response to the periarticular block, did not show the PSIS as the main site of pain. CONCLUSIONS: Our study clearly indicated that when patients point to the PSIS or within 2 cm of it as the main site of low back pain, using one finger, the SIJ should be considered as the origin of their low back pain.

Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport.

Cysteinyl leukotrienes (CysLTs) are potent mediators of inflammation synthesized by the concerted actions of 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), leukotriene C(4) synthase, and additional downstream enzymes, starting with arachidonic acid substrate. CysLTs produced by macrophages, eosinophils, mast cells, and other inflammatory cells activate 3 different high-affinity CysLT receptors: CysLT(1)R, CysLT(2)R, and GPR 17. We sought to investigate vascular sites of CysLT(2)R expression and the role and mechanism of this receptor in mediating vascular permeability events. Vascular expression of CysLT(2)R was investigated by reporter gene expression in a novel CysLT(2)R deficient-LacZ mouse model. CysLT(2)R was expressed in small, but not large, vessels in mouse brain, bladder, skin, and cremaster muscle. Intravital, in addition to confocal and electron, microscopy investigations using FITC-labeled albumin in cremaster postcapillary venule preparations indicated rapid CysLT-mediated permeability, which was blocked by application of BAY-u9773, a dual CysLT(1)R/CysLT(2)R antagonist or by CysLT(2)R deficiency. Endothelial human CysLT(2)R overexpression in mice exacerbated vascular leakage even in the absence of exogenous ligand. The enhanced vascular permeability mediated by CysLT(2)R takes place via a transendothelial vesicle transport mechanism as opposed to a paracellular route and is controlled via Ca(2+) signaling. Our results reveal that CysLT(2)R can mediate inflammatory reactions in a vascular bed-specific manner by altering transendothelial vesicle transport-based vascular permeability.

LPA4/p2y9/GPR23 mediates rho-dependent morphological changes in a rat neuronal cell line.

Lysophosphatidic acid (LPA) is a potent lipid mediator that evokes a variety of biological responses in many cell types via its specific G protein-coupled receptors. In particular, LPA affects cell morphology, cell survival, and cell cycle progression in neuronal cells. Recently, we identified p2y(9)/GPR23 as a novel fourth LPA receptor, LPA(4) (Noguchi, K., Ishii, S., and Shimizu, T. (2003) J. Biol. Chem. 278, 25600-25606). To assess the functions of LPA(4) in neuronal cells, we used rat neuroblastoma B103 cells that lack endogenous responses to LPA. In B103 cells stably expressing LPA(4), we observed G(q/11)-dependent calcium mobilization, but LPA did not affect adenylyl cyclase activity. In LPA(4) transfectants, LPA induced dramatic morphological changes, i.e. neurite retraction, cell aggregation, and cadherin-dependent cell adhesion, which involved Rho-mediated signaling pathways. Thus, our results demonstrated that LPA(4) as well as LPA(1) couple to G(q/11) and G(12/13), whereas LPA(4) differs from LPA(1) in that it does not couple to G(i/o). Through neurite retraction and cell aggregation, LPA(4) may play a role in neuronal development such as neurogenesis and neuronal migration.

Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family.

Lysophosphatidic acid (LPA) is a bioactive lipid mediator with diverse physiological and pathological actions on many types of cells. LPA has been widely considered to elicit its biological functions through three types of G protein-coupled receptors, Edg-2 (endothelial cell differentiation gene-2)/LPA1/vzg-1 (ventricular zone gene-1), Edg-4/LPA2, and Edg-7/LPA3. We identified an orphan G protein-coupled receptor, p2y9/GPR23, as the fourth LPA receptor (LPA4). Membrane fractions of RH7777 cells transiently expressing p2y9/GPR23 displayed a specific binding for 1-oleoyl-LPA with a Kd value of around 45 nm. Competition binding and reporter gene assays showed that p2y9/GPR23 preferred structural analogs of LPA with a rank order of 1-oleoyl- > 1-stearoyl- > 1-palmitoyl- > 1-myristoyl- > 1-alkyl- > 1-alkenyl-LPA. In Chinese hamster ovary cells expressing p2y9/GPR23, 1-oleoyl-LPA induced an increase in intracellular Ca2+ concentration and stimulated adenylyl cyclase activity. Quantitative real-time PCR demonstrated that mRNA of p2y9/GPR23 was significantly abundant in ovary compared with other tissues. Interestingly, p2y9/GPR23 shares only 20-24% amino acid identities with Edg-2/LPA1, Edg-4/LPA2, and Edg-7/LPA3, and phylogenetic analysis also shows that p2y9/GPR23 is far distant from the Edg family. These facts suggest that p2y9/GPR23 has evolved from different ancestor sequences from the Edg family.