Association between health risks and frailty in relation to the degree of housing damage among elderly survivors of the great East Japan earthquake.

BACKGROUND: Many survivors of the Great East Japan Earthquake that occurred in 2011 were at risk of deteriorating health, especially elderly people living in disaster-stricken areas. The objectives of this prospective study were: a) to clarify the different lifestyle and psychosocial factors associated with frailty by sex among the non-disabled elderly survivors, and b) to describe the differences in characteristics stratified by the degree of disaster-related housing damage. METHODS: We followed 2261 Japanese survivors aged ≥65 years (45.3% male; mean age, 71.7 years) without disability or frailty who completed a self-administered questionnaire at baseline. All participants completed a baseline questionnaire in 2011 and at least one identical follow-up questionnaire between 2012 and 2015 regarding lifestyle (smoking status, alcohol intake, physical activity, sedentary lifestyle, and dietary intake) and psychosocial factors (self-rated health, standard of living, psychological distress, and social networks). Frailty was defined as a score of ≥5 on the Kihon Checklist, which is used by the Japanese government to certify the need for long-term care insurance. Adjusted odds ratios and 95% confidence intervals with frailty as the dichotomous dependent variable and health factors as the independent variables were calculated using a multilevel model for repeated measures by sex, followed by stratification analyses by the degree of housing damage. RESULTS: Over the 4-year study period, 510 participants (22.6%) developed frailty. In the post-disaster setting, many of the psychosocial factors remained more prevalent 4 years later among survivors with extensive housing damage. The presence of risk factors regarding the development of frailty differed by the degree of housing damage. Among men, psychological distress, in parallel with a poor social network, was related to frailty among only the participants with extensive housing damage and those living in temporary housing, whereas among women, worsening psychological distress was associated only with no damage and no displaced survivors. Among women with extensive damage and displacement, health outcomes such as overweight and diabetes and poor social networks were strongly related to frailty. CONCLUSIONS: Lifestyle and psychosocial factors associated with the risk of frailty differ by sex and the degree of housing damage.

Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib.

Mutations of calreticulin (CALR) are detected in 25-30% of patients with essential thrombocythemia (ET) or primary myelofibrosis and cause frameshifts that result in proteins with a novel C-terminal. We demonstrate that CALR mutations activated signal transducer and activator of transcription 5 (STAT5) in 293T cells in the presence of thrombopoietin receptor (MPL). Human megakaryocytic CMK11-5 cells and erythroleukemic F-36P-MPL cells with knocked-in CALR mutations showed increased growth and acquisition of cytokine-independent growth, respectively, accompanied by STAT5 phosphorylation. Transgenic mice expressing a human CALR mutation with a 52 bp deletion (CALRdel52-transgenic mice (TG)) developed ET, with an increase in platelet count, but not hemoglobin level or white blood cell count, in association with an increase in bone marrow (BM) mature megakaryocytes. CALRdel52 BM cells did not drive away wild-type (WT) BM cells in in vivo competitive serial transplantation assays, suggesting that the self-renewal capacity of CALRdel52 hematopoietic stem cells (HSCs) was comparable to that of WT HSCs. Therapy with the Janus kinase (JAK) inhibitor ruxolitinib ameliorated the thrombocytosis in TG mice and attenuated the increase in number of BM megakaryocytes and HSCs. Taken together, our study provides a model showing that the C-terminal of mutant CALR activated JAK-STAT signaling specifically downstream of MPL and may have a central role in CALR-induced myeloproliferative neoplasms.

MaquiBright™ standardized maqui berry extract significantly increases tear fluid production and ameliorates dry eye-related symptoms in a clinical pilot trial.

AIM: Dry eye symptoms, resulting from insufficient tear fluid generation, represent a considerable burden for a largely underestimated number of people. We concluded from earlier pre-clinical investigations that the etiology of dry eyes encompasses oxidative stress burden to lachrymal glands and that antioxidant MaquiBright™ Aristotelia chilensis berry extract helps restore glandular activity. METHODS: In this pilot trial we investigated 13 healthy volunteers with moderately dry eyes using Schirmer test, as well as a questionnaire which allows for estimating the impact of dry eyes on daily routines. Study participants were assigned to one of two groups, receiving MaquiBright™ at daily dosage of either 30 mg (N.=7) or 60 mg (N.=6) over a period of 60 days. Both groups presented with significantly (P<0.05) improved tear fluid volume already after 30 days treatment. Schirmer test showed an increase from baseline 16.3±2.6 mm to 24.4±4.8 mm (P<0.05) with 30 mg MaquiBright™ and from 18.7±1.9 mm to 27.6±3.4 mm with 60 mg (P<0.05), respectively. Following treatment with 30 mg MaquiBright™ for further 30 days, tear fluid volume dropped slightly to 20.5±2.8 mm, whereas the improvement persisted with 60 mg treatment at 27.1±2.7 mm after 60 days treatment (P<0.05 vs. baseline). RESULTS: The burden of eye dryness on daily routines was evaluated employing the "Dry Eye-related Quality of life Score" (DEQS), with values spanning from zero (impact) to a maximum score of 60. Participants had comparable baseline values of 41.0±7.7 (30 mg) and 40.2±6.3 (60 mg). With 30 mg treatment the score significantly decreased to 21.8±3.9 and 18.9±3.9, after 30 and 60 days, respectively. With 60 mg treatment the DEQS significantly decreased to 26.9±5.3 and 11.1±2.7, after 30 and 60 days, respectively. Blood was drawn for safety analyses (complete blood rheology and -chemistry) at all three investigative time points without negative findings. CONCLUSION: In conclusion, while daily supplementation with 30 mg MaquiBright™ is effective, the dosage of 60 significantly increased tear fluid volume at all investigative time points and decreased dry eye symptoms to almost a quarter from initial values after two months treatment.

TET2 is essential for survival and hematopoietic stem cell homeostasis.

Ten-Eleven-Translocation 2 (TET2) is an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) and thereby alters the epigenetic state of DNA; somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies. To study the function of TET2 in vivo, we analyzed Ayu17-449 (TET2(trap)) mice, in which a gene trap insertion in intron 2 of TET2 reduces TET2 mRNA levels to about 20% of that found in wild-type (WT) mice. TET2(trap/trap) mice were born at Mendelian frequency but died at a high rate by postnatal day 3, indicating the essential role of TET2 for survival. Loss of TET2 results in an increase in the number of hematopoietic stem cells (HSCs)/progenitors in the fetal liver, and TET2(trap/trap) HSCs exhibit an increased self-renewal ability in vivo. In competitive transplantation assays, TET2(trap/trap) HSCs possess a competitive growth advantage over WT HSCs. These data indicate that TET2 has a critical role in survival and HSC homeostasis.

What are the reliable radiological indicators of lumbar segmental instability?

We examined the reliability of radiological findings in predicting segmental instability in 112 patients (56 men, 56 women) with a mean age of 66.5 years (27 to 84) who had degenerative disease of the lumbar spine. They underwent intra-operative biomechanical evaluation using a new measurement system. Biomechanical instability was defined as a segment with a neutral zone > 2 mm/N. Risk factor analysis to predict instability was performed on radiographs (range of segmental movement, disc height), MRI (Thompson grade, Modic type), and on the axial CT appearance of the facet (type, opening, vacuum and the presence of osteophytes, subchondral erosion, cysts and sclerosis) using multivariate logistic regression analysis with a forward stepwise procedure. The facet type was classified as sagittally orientated, coronally orientated, anisotropic or wrapped. Stepwise multivariate regression analysis revealed that facet opening was the strongest predictor for instability (odds ratio 5.022, p = 0.009) followed by spondylolisthesis, MRI grade and subchondral sclerosis. Forward stepwise multivariate logistic regression indicated that spondylolisthesis, MRI grade, facet opening and subchondral sclerosis of the facet were risk factors. Symptoms evaluated by the Short-Form 36 and visual analogue scale showed that patients with an unstable segment were in significantly more pain than those without. Furthermore, the surgical procedures determined using the intra-operative measurement system were effective, suggesting that segmental instability influences the symptoms of lumbar degenerative disease.

Absence of gain-of-function JAK1 and JAK3 mutations in adult T cell leukemia/lymphoma.

Janus kinase 1 (JAK1) and JAK3 plays a critical role in lymphocyte proliferation and differentiation. Somatic JAK1 mutations are found in 18% of adult precursor T acute lymphoblastic leukemias and somatic JAK3 mutations are found in 3.3% of cutaneous T cell lymphomas. Some of the mutations are confirmed as a gain-of-function mutation and are assumed to be involved in leukemogenesis. Adult T cell leukemia/lymphoma (ATLL) is a type of T cell neoplasm, and activation of JAK/STAT pathways is sometimes observed in them. We investigated JAK1 and JAK3 mutations in 20 ATLL patients. No JAK1 mutations were found, and five types of single nucleotide polymorphisms were observed in 12 cases, whose frequencies almost match those in Asian populations. As for JAK3, a synonymous mutation was found in one case. JAK1 and JAK3 mutations are unlikely involved in the leukemogenesis of ATLL.

Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F.

An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.

Evidence of lymphangiogenesis in Warthin's tumor of the parotid gland.

The details of the pathogenesis of cystadenolymphoma (Warthin's tumor) of the parotid gland are still unclear. Neovascularization is considered to be a pivotal factor for solid tumor progression and biological behavior of the tumor. Using double-labeling immunohistochemistry for LYVE-1 and CD34 (specific markers for lymphatic and vascular endothelial cells, respectively) this study analyzes lymphatic vessel density (LVD) and blood vessel density (BVD) in 10 Warthin's tumors and 10 pleomorphic adenomas of the parotid gland as well as in 5 normal parotid glands and 5 normal parotid lymph nodes. There was no significant difference in the intratumoral LVD and BVD among pleomorphic adenoma and normal parotid gland tissue. In contrast, the intratumoral LVD and BVD were significantly higher in Warthin's tumor than pleomorphic adenoma, normal parotid gland and parotid lymph node (P<0.0001 versus P<0.004). The increase in lymphatic vessels in Warthin's tumor suggests that epithelial tumor cells might promote lymphangiogenesis in this kind of lesions.

Lithium intercalation into opened single-wall carbon nanotubes: storage capacity and electronic properties.

The effects of structure and morphology on lithium storage in single-wall carbon nanotube (SWNT) bundles were studied by electrochemistry and nuclear magnetic resonance techniques. SWNTs were chemically etched to variable lengths and were intercalated with Li. The reversible Li storage capacity increased from LiC(6) in close-end SWNTs to LiC(3) after etching, which is twice the value observed in intercalated graphite. All the nanotubes became metallic upon intercalation of Li, with the density of states at the Fermi level increasing with increasing Li concentration. The enhanced capacity is attributed to Li diffusion into the interior of the SWNTs through the opened ends and sidewall defects.

Gastrointestinal stromal tumor of the duodenal ampulla: report of a case.

We report herein the case of a 77-year-old woman with a gastrointestinal stromal tumor (GIST) of the duodenal ampulla. The tumor, which was removed by pancreatoduodenectomy due to its malignant potential, showed expansive growth in the muscular coat of the duodenal ampulla. Histologically, the tumor cells were spindle-shaped or round, and exhibited fascicular or storiform growth pattern with frequent mitotic figures. The immunohistochemical and ultrastructural results suggested that the tumor may have originated from the interstitial cells of Cajal in the muscular coat of the duodenal ampulla. To our knowledge, this is the first case of malignant GIST of the duodenal ampulla to be reported in Japan.

[Antigenicity and phototoxicity of water-soluble extract from Salacia reticulata (Celastraceae)].

The antigenicity and phototoxicity of water-soluble extract from Salacia reticulata (SRE) were examined in guinea pigs. In a study of active systemic anaphylaxis reaction, neither the oral administration group (64 or 320 mg/kg, 5 times/week, 3 weeks) nor the subcutaneous administration group (64 mg/kg, 1 time/week, 3 weeks) exhibited any anaphylactic reaction. Moreover, sensitization with serum obtained from these animals did not induce passive cutaneous anaphylaxis reaction in normal animals. In a phototoxicity study, oral administration of SRE (320 mg/kg) induced neither erythema nor edema. These results suggest that SRE is not antigenic or phototoxic.

Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): structure-requirement of hydroxyanthraquinones for estrogenic activity.

The methanolic extract from the roots of Polygonum (P.) cuspidatum was found to enhance cell proliferation at 30 or 100 microg/mL in MCF-7, an estrogen-sensitive cell line. By bioassay-guided separation from P. cuspidatum with the most potent activity, emodin and emodin 8-O-beta-D-glucopyranoside were isolated as active principles. The methanolic extracts from Polygonum, Cassia, Aloe, and Rheum species, which were known to contain anthraquinones, also showed the MCF-7 proliferation. As a result of the evaluation of various anthraquinones from plant sources and synthetic anthraquinones, aloe-emodin, chrysophanol, chrysophanol 8-O-beta-D-glucopyranoside, and 1,8-dihydroxyanthraquinone showed weak activity. On the other hand, alizalin and 2,6-dihydroxyanthraquinone as well as emodin having the 2- and/or 6-hydroxyl groups showed potent activity. These results show that the unchelated hydroxyl group is essential for strong activity. Emodin and 2,6-dihydroxyanthraquinone also inhibited 17beta-estradiol binding to human estrogen receptors (ERs) with K(i) values of 0.77 and 0.31microM for ERalpha and 1.5 and 0.69 microM for ERbeta. These findings indicate that hydroxyanthraquinones such as emodin are phytoestrogens with an affinity to human estrogen receptors.

Dimeric sesquiterpene thioalkaloids with potent immunosuppressive activity from the rhizome of Nuphar pumilum: structural requirements of nuphar alkaloids for immunosuppressive activity.

Potent immunosuppressive dimeric sesquiterpene thioalkaloids, 6-hydroxythiobinupharidine, 6,6'-dihydroxythiobinupharidine, 6-hydroxythionuphlutine B and 6'-hydroxythionuphlutine B, were isolated from the rhizome of Nuphar pumilum together with five inactive quinolizidine alkaloids, neothiobinupharidine, nupharidine, deoxynupharidine, 7-epideoxynupharidine and nupharolutine. These dimeric sesquiterpene thioalkaloids were found to significantly inhibit anti-sheep erythrocyte plaque forming cell formation in mouse splenocytes at 1 microM. At this concentration. 6-hydroxythiobinupharidine, 6-hydroxythionuphlutine B and 6'-hydroxythionuphlutine B did not show cytotoxic effects to mouse splenocytes, and 6,6'-dihydroxythiobinupharidine also showed only minor or minimal cytotoxicity. By comparison of the inhibitory activity of several Nuphar alkaloids on anti-sheep erythrocyte plaque forming cell formation, some structural requirements of Nuphar alkaloids for immunosuppressive activity were obtained. Namely, the 6- or 6'-hydroxyl group at the quinolizidine ring of dimeric sesquiterpene thioalkaloids is essential for the immunosuppressive effect. The number of hydroxyl groups appears to be related to the cytotoxicity, and the influence on splenocytes is greater with increasing numbers of hydroxyl groups.

[Polyphenol constituents from Salacia species: quantitative analysis of mangiferin with alpha-glucosidase and aldose reductase inhibitory activities].

Mangiferin, three catechins, and two catechin dimers were isolated from the roots of Salacia reticulata (SRE), and examined their inhibitory activities against several carbohydrate metabolize enzymes (sucrase, maltase, isomaltase, alpha-amylase, and aldose reductase). Among them, mangiferin was found to inhibit sucrase, isomaltase, and aldose reductase from rat with IC50 values of 87, 216 and 1.4 micrograms/ml, respectively. The inhibitory activities of mangiferin are competitive for sucrase and isomaltase with inhibitor constant (Ki) 55 micrograms/ml and 70 micrograms/ml, respectively. In order to determine the mangiferin contents in the water extracts from the roots of S. reticulata, a quantitative analytical method by means of HPLC was developed and the mangiferin contents in SRE were determined to be in the range of 0.9-2.3% by the application of this method. A high linear correlation (r = 0.934) was observed between the mangiferin contents and the sucrase inhibitory activity. In addition, this analytical procedure of mangiferin was found to be applicable for other Salacia species (S. oblonga, S. chinensis, and S. prinoides). Thus, the quantitative HPLC analysis of mangiferin was supposed to be suitable for the quality control of Salacia species and its products.

Development of the lymphatic network in the muscle coat of the rat jejunum as revealed by enzyme-histochemistry.

The process of lymphangiogenesis was studied in the muscle coat of the rat small intestine by light and scanning and transmission electron microscopy; identification of lymphatic vessels was made by 5'-nucleotidase staining. Light and scanning electron microscopy demonstrated that the intramuscular lymphatic network formation, which started only postnatally, was attributable to the vascular sprouting of slender lymphatic endothelial projections and to a splitting of the vessels, causing intervascular meshes of various sizes. The growing lymphatics were consistently closed by the endothelial cells, which were characterized by an abundance of cell organelles and prominent cytoplasmic processes. The cells often revealed close contacts with the processes of developing smooth muscle cells in the jejunal muscle coat, suggesting a possible role for the latter cells in the guidance of the lymphatic extension. The present study is the first to suggest the closed nature of lymphatics persisting throughout their development, even at the initial stage of lymphangiogenesis.

Injury to the gastric mucosa and cellular dynamics in a rat model of duodenogastric reflux: the possible significance of gastrin induction and a heat shock protein.

Injury to the gastric mucosa caused by duodenogastric reflux (DGR) is often encountered after gastrectomy or truncal vagotomy (V) with pyloroplasty. This study was designed to investigate the histological features of the gastric mucosa under such conditions. A rat model of DGR and DGR+V was established and the thickness of the oxyntic mucosa was measured. Cellular dynamics in the presence of injury to the gastric mucosa caused by DGR were investigated by the immunohistochemical staining of bromodeoxyuridine (BrdU) and heat shock protein 70 (HSP70). The relationship between persistent hypergastrinemia and mucosal injury was also studied. Duodenogastric reflux activated the intracellular induction of HSP70 in our rat model of DGR. Hypergastrinemia was noted in the V group. Compared with values from the DGR group, the numbers of BrdU-labeled cells increased, the glandular proliferation zone expanded, and the thickness of the oxyntic mucosa was significantly higher in the DGR+V group. Compared with the DGR group, there was greater induction of HSP in the DGR+V group during the acute stage. This finding suggests that denervation of the gastric mucosa and hypergastrinemia after vagotomy may be associated with the expression of HSP.

Ultrastructural and histochemical characterization of special muscle cells in the monkey small intestine.

The ultrastructure, three-dimensional arrangement, and histochemical features of special muscle cells in the monkey small intestine were investigated. The cells formed a special layer separated from the main part by a connective tissue space along the submucosal surface of the circular muscle coat. Scanning electron microscopy using alkali maceration demonstrated this inner sublayer to be a continuous thin sheet consisting of irregularly-shaped muscle cells equipped with many cytoplasmic projections and caveolae. Other ultrastructural features included direct contact with interstitial cells, due to their close association with nerve fibers of the deep muscular plexus. Histochemical examination revealed significant alkaline phosphatase activity and immunoreactivity for vascular smooth muscle alpha actin in these muscle cells, whereas the ordinary circular muscle cells were immunopositive for enteric smooth muscle gamma actin. These findings suggest that the special muscle cells play an important role in regulating the radial stretch of the monkey small intestinal wall.

Alcohol absorption inhibitors from bay leaf (Laurus nobilis): structure-requirements of sesquiterpenes for the activity.

Through a bioassay-guided separation using inhibitory activity on blood ethanol elevation in oral ethanol-loaded rat, various sesquiterpenes having an alpha-methylene-gamma-butyrolactone moiety, costunolide (1), dehydrocostus lactone (2), zaluzanin D (3), reynosin (4), santamarine (5), 3alpha-acetoxyeudesma-1,4(15),11(13)-trien-12,6alpha-+ ++olide (6) and 3-oxoeudesma-1,4,11(13)-trien-12,6alpha-olide (7), were isolated as the active principle from the leaves of Laurus nobilis (bay leaf, laurel). In order to characterize the structure requirement for the activity, several reduction products (2a-2d) and amino acid adducts (2e, 2f) of the alpha-methylene-gamma-butyrolactone moiety were synthesized from 2 and the inhibitory activities of these sesquiterpenes, together with alpha-methylene-gamma-butyrolactone (12) and its related compounds (13-16), were examined. These results indicated that the gamma-butyrolactone or gamma-butyrolactol moiety having alpha-methylene or alpha-methyl group was essential for the inhibitory activity on ethanol absorption. Since 1, 2 and 12 showed no significant effect on glucose absorption, these sesquiterpenes appeared to selectively inhibit ethanol absorption. In addition, the acute toxicities of 1 and 2 in a single oral administration were found to be lower than that of 12.