Role of non-face-to-face social contacts in moderating the association between living alone and mental health among community-dwelling older adults: a cross-sectional study.

OBJECTIVE: We examined the association between living alone and mental health and the moderating effects of face-to-face and non-face-to-face social contacts, among community-dwelling older adults. STUDY DESIGN: Cross-sectional study. METHODS: This cross-sectional study recruited Japanese adults older than 60 years, who attended health check-ups held in a suburban town hall in July and August of 2018 and 2019. As mental health outcomes, depression was assessed using the Geriatric Depression Scale 15-items, loneliness was assessed using the University of California, Los Angeles Loneliness Scale 3-items, and happiness was self-rated on a 10-point scale. Face-to-face social contacts were evaluated by participants' frequency of meetings with relatives or friends, whereas non-face-to-face contacts were measured by the frequency of interactions via letter, telephone or e-mail. Multivariable linear regression analysis was conducted to examine the association between living alone with each mental health outcome and the effect modifications of having face-to-face and non-face-to-face social contacts. RESULTS: Data from 300 older adults were analysed. The participants' mean age was 73.0 years, 51.3% were female, and 16.0% lived alone. Living alone was significantly associated with poorer mental health. Regarding loneliness and low happiness, having face-to-face and non-face-to-face contacts more than once a week alleviated the adverse association of living alone (loneliness: face-to-face contacts, P = 0.020; non-face-to-face contacts, P = 0.028; happiness: face-to-face contacts, P = 0.020; non-face-to-face contacts, P = 0.001). CONCLUSIONS: Our findings suggest that non-face-to-face, as well as face-to-face social contacts have a moderating effect on the adverse association of living alone with loneliness and happiness.

Sphingosylphosphorylcholine induces α-smooth muscle actin expression in human lung fibroblasts and fibroblast-mediated gel contraction via S1P2 receptor and Rho/Rho-kinase pathway.

Chronic airway diseases like COPD and asthma are usually accompanied with airway fibrosis. Myofibroblasts, which are characterized by expression of smooth muscle actin (α-SMA), play an important role in a variety of developmental and pathological processes, including fibrosis and wound healing. Sphingosylphosphorylcholine (SPC), a sphingolipid metabolite, has been implicated in many physiological and pathological conditions. The current study tested the hypothesis that SPC may modulate tissue remodeling by affecting the expression of α-SMA in human fetal lung fibroblast (HFL-1) and fibroblast mediated gel contraction. The results show that SPC stimulates α-SMA expression in HFL-1 and augments HFL-1 mediated collagen gel contraction in a time- and concentration-dependent manner. The α-SMA protein expression and fibroblast gel contraction induced by SPC was not blocked by TGF-ß1 neutralizing antibody. However, it was significantly blocked by S1P2 receptor antagonist JTE-013, the Rho-specific inhibitor C3 exoenzyme, and a Rho-kinase inhibitor Y-27632. These findings suggest that SPC stimulates α-SMA protein expression and HFL-1 mediated collagen gel contraction via S1P2 receptor and Rho/Rho kinase pathway, and by which mechanism, SPC may be involved in lung tissue remodeling.

Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics.

BACKGROUND: The fraction of exhaled nitric oxide (FENO) is reduced by anti-inflammatory treatment in asthma. However, the FENO level is also regulated by individual demographics and there is considerable variation among clinically stable patients. OBJECTIVE: We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma. METHODS: This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expiratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12-weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were examined (Study 2). RESULTS: A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identifying the patients with poorly controlled asthma. The persistent high FENO group (≥ 40 p.p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma.

Estrogen receptor-positive breast cancer in Japanese women: trends in incidence, characteristics, and prognosis.

BACKGROUND: The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. PATIENTS AND METHODS: We examined the characteristics of the tumors treated in three time periods between 1982 and 2010. Estrogen receptor (ER), progesterone receptor (PgR) and HER2 status were assessed by immunohistochemistry. Correlation of hormone receptor levels with clinicopathological factors and prognosis was analyzed in ER-positive, HER2-negative breast cancer in two age groups (≤50 years versus >50 years). RESULTS: The frequency of ER-positive breast cancer in women aged 50 years or younger increased greatly over the interval studied (1982-1991: 52.5%, 1992-2001: 72.6%, 2002-2010: 87.1%, P < 0.0001). The frequency of ER-positive tumors also significantly increased in women over 50 years of age (1982-1991: 69.4%, 1992-2001: 73.3%, 2002-2010: 78.6%, P = 0.029). In ER-positive, HER2-negative breast cancer, tumor grade was negatively correlated with expression levels of ER and PgR. Prognosis for patients with ER-positive, HER2-negative disease significantly improved over time, due to advances in adjuvant therapies. CONCLUSION: It is necessary to establish risk factors, both genetic and environmental, capable of predicting the risk of ER-positive breast cancer and thus enable the efficient selection of candidates for hormone receptor-targeted chemoprevention.

Lung diseases directly associated with rheumatoid arthritis and their relationship to outcome.

The outcome and cause of death of each lung disease directly associated with rheumatoid arthritis (RA-LD) have been poorly investigated. A retrospective study was conducted of 144 patients with RA-LD, in whom the median follow-up period after the initial visit for a respiratory examination was 4.5 yrs. A total of 57 patients were identified with usual interstitial pneumonia (UIP), 31 with bronchiectasis, 16 with nonspecific interstitial pneumonia (NSIP), 11 with bronchiolitis, five with organising pneumonia (OP), five with diffuse alveolar damage (DAD) and 19 with combined disease. The 5-yr survival rates were 36.6% in the UIP group, 87.1% in the bronchiectasis group, 93.8% in the NSIP group, 88.9% in the bronchiolitis group, 60.0% in the OP group and 20.0% in the DAD group. Survival of patients with DAD was worse than that of patients with UIP. Overall, survival of patients with UIP was worse than that of patients with bronchiectasis, NSIP or bronchiolitis. Of the 144 patients, 71 (49.3%) died, of whom 58 (81.7%) died due to respiratory lesions. Of patients with RA-LD, patients with DAD experienced the highest mortality, and the survival of patients with UIP was worse than that of patients with NSIP.

Statins inhibit matrix metalloproteinase release from human lung fibroblasts.

Pleiotropic effects of statins have been reported to include inhibition of matrix metalloproteinase (MMP) release from macrophages and endothelial cells. We evaluated whether statins would inhibit MMP release from human lung fibroblasts, which play a major role in remodelling processes. Monolayer and three-dimensional (3D) collagen gel cultures of fibroblasts were used. Cytokines (tumour necrosis factor-alpha and interleukin-1alpha) were used to induce MMP release and mRNA expression. Collagen degradation induced by cytokines and neutrophil elastase (NE) was evaluated by quantifying hydroxyproline. Atorvastatin inhibited MMP-1 and -3 release and mRNA expression in both culture systems. Similar results were obtained with simvastatin and fluvastatin. In 3D cultures where cytokines also stimulated MMP-9 release, atorvastatin also inhibited MMP-9 release. In 3D cultures, cytokines together with NE induced collagen degradation, which was also inhibited by atorvastatin. The effect of atorvastatin was reversed by mevalonate and geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate. The current data suggest that statins may modulate remodelling processes mediated by fibroblasts by inhibiting MMP release.

Immunosuppressive effect of prolactin-induced protein: a new insight into its local and systemic role in chronic allergic contact dermatitis.

BACKGROUND: Prolactin-induced protein (PIP) has been shown to bind to CD4 and is speculated to block CD4-HLA-DR interaction. However, the immunomodulatory effect of PIP on chronic allergic contact dermatitis (ACD) remains to be elucidated. OBJECTIVES: To define the role of PIP during the immunoresponse. METHODS: Using a low-dose oxazolone-induced mouse chronic ACD model, expression of PIP was examined immunohistologically. Furthermore, effects of continued exposure to a peptide mimicking the major binding site of PIP (amino acids 106-132) for CD4 was examined in a mouse chronic ACD model. RESULTS: We clarified that keratinocytes, dermal infiltrating cells and spleen infiltrating mononuclear cells are positively stained with anti-PIP antibody. The PIP peptide significantly downregulated oxazolone-induced mouse ACD compared with controls. We also found that inflammation of the control ear, to which the PIP peptide had not been applied, was also suppressed in a synchronized manner in the late phase of ACD. CONCLUSIONS: These findings suggest that PIP might have a local and systemic immunosuppressive effect in mouse chronic ACD.

Construction of syndromic surveillance using a web-based daily questionnaire for health and its application at the G8 Hokkaido Toyako Summit meeting.

We constructed a syndromic surveillance system to collect directly information on daily health conditions directly from local residents via the internet [web-based daily questionnaire for health surveillance system (WDQH SS)]. This paper considers the feasibility of the WDQH SS and its ability to detect epidemics. A verification study revealed that our system was an effective surveillance system. We then applied an improved WDQH SS as a measure against public health concerns at the G8 Hokkaido Toyako Summit meeting in 2008. While in operation at the Summit, our system reported a fever alert that was consistent with a herpangina epidemic. The highly mobile WDQH SS described in this study has three main advantages: the earlier detection of epidemics, compared to other surveillance systems; the ability to collect data even on weekends and holidays; and a rapid system set-up that can be completed within 3 days.

3-Nitrotyrosine inhibits fibroblast-mediated collagen gel contraction and chemotaxis.

Reactive nitrogen species induce tissue inflammation and nitrate tyrosine residues of various kinds of proteins. Recent studies have established that the free amino acid form of 3-nitrotyrosine induces cytotoxity and growth inhibition and alters the cellular function in cultured cells. The aim of this study was to evaluate whether 3-nitrotyrosine could affect tissue remodelling in fibroblasts. To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess the fibroblast-mediated contraction of floating gels and chemotaxis towards fibronectin. In addition, the ability of fibroblasts to release fibronectin, transforming growth factor (TGF)-beta1, fibronectin and vascular endothelial growth factor (VEGF) was assessed. 3-Nitrotyrosine significantly inhibited gel contraction (p<0.01) compared with control and this inhibition was abolished by nitric oxide synthase (NOS) inhibitor. 3-Nitrotyrosine did not affect TGF-beta1 and VEGF but significantly decreased fibronectin release (p<0.01) into the media. 3-Nitrotyrosine significantly inhibited chemotaxis towards fibronectin through suppression of alpha(5)beta(1) integrin expression (p<0.01). NOS inhibitor also reversed 3-nitrotyrosine-inhibited chemotaxis (p<0.01). Finally, 3-nitrotyrosine enhanced the expression of the inducible type of NOS (p<0.01) and nitric oxide release (p<0.01) through nuclear factor-kappaB activation. These results suggest that the free amino acid form of 3-nitrotyrosine can affect the tissue repair process by modulating nitric oxide production.

Structural features of Ca2+/calmodulin-dependent protein kinase II revealed by electron microscopy.

The molecular conformation of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) from the rat forebrain and cerebellum was studied by means of EM using a quick-freezing technique. Each molecule appeared to be composed of two kinds of particles, with one larger central particle and smaller peripheral particles and had shapes resembling that of a flower with 8 or 10 "petals". A favorable shadowing revealed that each peripheral particle had a thin link to the central particle. We predicted that the 8-petal molecules and 10-petal molecules were octamers and decamers of CaM kinase II subunits, respectively, each assembled with the association domains of subunits gathered in the center, and the catalytic domains in the peripheral particles. Binding of antibodies to the enzyme molecules suggested that molecules with 8 and 10 peripheral particles were homopolymers composed only of beta subunit and of alpha subunit, respectively, specifying that CaM kinase II consists of homopolymer of either alpha or beta subunits.

Differential targeting of protein kinase C and CaM kinase II signalings to vimentin.

Hydrolysis of inositol phospholipids by receptor stimulation activates two separate signaling pathways, one leading to the activation of protein kinase C (C kinase) via formation of diacylglycerol. The other is the inositol trisphosphate (IP3)/Ca2+ pathway and a major downstream kinase which is activated is Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). To examine signaling pathways of C kinase and CaM kinase II to the cytoskeletal protein vimentin, we prepared monoclonal antibodies YT33 and MO82 which recognize the phosphorylation state of vimentin by C kinase and by CaM kinase II, respectively. Ectopic expression of constitutively active C kinase or CaM kinase II in primary cultured astrocytes by microinjection of the corresponding expression vectors induced phosphorylation of vimentin at each specific phosphorylation site, followed by reorganization of vimentin filament networks. In contrast, simultaneous activation of C kinase and CaM kinase II by inositol phospholipid hydrolysis with receptor stimulation led to an exclusive phosphorylation of vimentin at the CaM kinase II site, not at the site of C kinase. These results indicate that the intracellular targeting of C kinase and CaM kinase II signalings to vimentin is regulated separately, under physiological conditions.

Successful therapeutic use of a single-dose of rituximab on relapse in adults with minimal change nephrotic syndrome.

Minimal change nephrotic syndrome (MCNS) usually is considered to have a good renal prognosis, but the frequency of relapses is a therapeutic challenge to physicians. The treatment of patients with multiple relapses remains a matter of controversy, because few controlled studies are available. We report the case of a 25-year-old man who experienced relapses of MCNS. Single-dose rituximab therapy (total dose 500 mg) was given during the fourth relapse. Complete remission occurred 10 days later, when no CD19/20-positive B cells were detected in the blood. This the first report of efficacy of single-dose rituximab therapy to treat multi-relapsing MCNS in an adult patient.

High-dose chemotherapy and autologous peripheral blood stem cell transfusion for adult and adolescent patients with small round cell sarcomas.

The treatment of small-round-cell tumors (SRCT) in adult patients remains a challenge to clinicians. In the present study, we analyzed the feasibility and efficacy of high-dose chemotherapy (HDCT) followed by autologous peripheral blood stem-cell rescue as a consolidation therapy exclusively for patients with good disease control through a single regimen of induction chemotherapy and local therapy. Twenty-one patients (12 females, median age 22.0 years) were analyzed, including seven cases with rhabdomyosarcoma (RMS) and 14 cases with Ewing's family tumors (EFT). Overall, survival was 46% and failure-free survival (FFS) was 33% at 3 years. Patients with EFT had better FFS than those with RMS, with an estimated 3-year FFS of 50% (P<0.01). There was a single case of possible treatment-related death and two cases of secondary malignancies. This study cannot conclusively determine the beneficial effects of HDCT for improving treatment outcomes in adult SRCTs due to the small number of subjects. However, study findings suggest that a subgroup of patients with EFT may obtain prolonged survival benefits from this therapy.

An elderly female who survived more than 30 years following a diagnosis of Takayasu's arteritis, complicated by fatal intestinal amyloidosis.

Compared to young patients with Takayasu's arteritis (TA), little information about elderly patients with TA has been reported. Additionally, no reports were found regarding TA cases with complications of intestinal amyloidosis. This is a case report of an elderly female, who developed intestinal amyloidosis, during late-stage TA. After years of outpatient management, she developed sudden severe dyspnea with pulmonary effusion, requiring hospitalization. After this event, betamethasone was replaced by methotrexate (MTX) for the next 34 months, but it seemed ineffective. After 1.5 years, she developed intractable diarrhea, followed by increases in BUN and serum creatinine (Cr), requiring several courses of hemodialysis. Colonoscopy revealed the presence of amyloid in her intestine, although she died of complicated sepsis caused by MRSA infection. This may be the first paper describing intestinal amyloidosis in a TA patient. Additionally, her case is rare in that she lived more than 30 years after the onset and diagnosis of TA.

Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever.

Fever is triggered by an elevation of prostaglandin E(2) (PGE(2)) in the brain. However, the mechanism of its elevation remains unanswered. We herein cloned the rat glutathione-dependent microsomal prostaglandin E synthase (mPGES), the terminal enzyme for PGE(2) biosynthesis, and examined its induction in the rat brain after intraperitoneal injection of pyrogen lipopolysaccharide (LPS). In Northern blot analysis, mPGES mRNA was weakly expressed in the brain under the normal conditions but was markedly induced between 2 and 4 hr after the LPS injection. In situ hybridization study revealed that LPS-induced mPGES mRNA signals were mainly associated with brain blood vessels, especially vein or venular-type ones, in the whole brain area. Immunohistochemical study demonstrated that mPGES-like immunoreactivity was expressed in the perinuclear region of brain endothelial cells, which were identified as von Willebrand factor-positive cells. Furthermore, in the perinuclear region of the endothelial cells, mPGES was colocalized with cyclooxygenase-2 (COX-2), which is the enzyme essential for the production of the mPGES substrate PGH(2). Inhibition of cyclooxygenase-2 activity resulted in suppression of both PGE(2) level in the CSF and fever (Cao et al., 1997), suggesting that the two enzymes were functionally linked and that this link is essential for fever. These results demonstrate that brain endothelial cells play an essential role in the PGE(2) production during fever by expressing COX-2 and mPGES.

Effect of ATP on binding of Ca2+/calmodulin-dependent protein kinase II with calmodulin.

Binding of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) with calmodulin was directly determined by the poly(ethylene glycol) precipitation method. Calmodulin bound to CaM kinase II alpha and beta polypeptides in a molar ratio of about 1:1 in the presence of ATP, but the binding was reduced in the absence of ATP. Affinity of CaM kinase II for calmodulin increased in the presence of ATP and the autophosphorylation was observed under the conditions. ADP and adenosine beta, gamma-imidoadenosine 5'-triphosphate, hydrolysis resistant analogues, also increased the binding of CaM kinase II with calmodulin. CaM kinase II substrate syntide 2 did not increase the binding of the kinase with calmodulin. These findings indicate that the affinity of CaM kinase II for calmodulin and the amount of calmodulin bound to the kinase increase by the binding of ATP.

omega-Hydroxylation of docosahexaenoic acid or arachidonic acid in human colonic well differentiated adenocarcinoma homogenate.

Human colonic well differentiated adenocarcinoma homogenate was incubated with NADPH and docosahexaenoic acid (22:6(n-3)) or arachidonic acid (20:4(n-6)) as a substrate. On a selected ion monitoring chromatogram obtained with reversed phase-high-performance liquid chromatography thermospray mass spectrometry, omega-hydroxydocosahexaenoic acid (omega-HDHE) or omega-hydroxyeicosatetraenoic acid (omega-HETE) from an incubation mixture of the homogenate was detected in significant amount, compared to that from a colonic region remote from the carcinoma. In contrast, epoxydocosapentaenoic acids and the dihydroxy derivatives from 22:6(n-3) or epoxyeicosatrienoic acids and the dihydroxy derivatives from 20:4(n-6) were detected in low amounts, compared to that from a colonic region remote from the carcinoma. The results suggest that highly active NADPH-dependent omega-oxidations of polyunsaturated fatty acids occur in colonic adenocarcinoma homogenate.

Ultrastructural study of the extra-articular Leeds-Keio ligament prosthesis.

BACKGROUND: There have been several histological studies of the Leeds-Keio ligament in anterior cruciate ligament reconstruction, but there have been few of the Leeds-Keio ligament in the extra-articular portion. AIMS/METHODS: To report the histological and ultrastructural findings of two cases of medial patellofemoral ligament reconstruction using the Leeds-Keio ligament, removed 6.1 years and 8.7 years after implantation. RESULTS: In both cases, the tissue over the Leeds-Keio ligament was a ligament-like tissue. Electron microscopy showed that the diameter of the collagen fibrils in the tissue over the Leeds-Keio ligament was unimodal in the case investigated 6.1 years after implantation but bimodal in the case investigated after 8.7 years. CONCLUSIONS: The tissue over the Leeds-Keio ligament may continue to grow with prolonged periods of mechanical stress.

Prognostic factors and a scoring system for patients with skeletal metastasis.

Between 1992 and 1999, we treated 350 patients with skeletal metastases. A multivariable analysis of the patients was conducted using the Cox proportional hazards model. We identified five significant prognostic factors for survival, namely, the site of the primary lesion, the performance status (Eastern Cooperative Oncology Group status 3 or 4), the presence of visceral or cerebral metastases, any previous chemotherapy, and multiple skeletal metastases. The score for each significant factor was derived from the corresponding estimated regression coefficients (natural logarithm of the hazard ratio). The prognostic score was calculated by adding all the scores for individual factors. The rate of survival was 31% at six months and 11% at one year for the patients with a prognostic score of 6 or more. By contrast, patients with a prognostic score of 2 or less had a rate of survival of 98% at six months and 89% at one year. This scoring system can be used to determine the optimal treatment for patients with pathological fractures or epidural compression.

Metabolic reprogramming during TGFß1-induced epithelial-to-mesenchymal transition.

Metastatic progression, including extravasation and micrometastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFß1)-induced epithelial-to-mesenchymal transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Overexpressed Snail1, a transcription factor mediating TGFß1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knockdown was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFß1-induced EMT and metastasis.