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.

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.

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.

Expression of Ha-ras oncogene products in human neuroblastomas and the significant correlation with a patient's prognosis.

Neuroblastomas represent a spectrum of diseases categorized by histological subtypes, age of the patient, and extent of tumor (stage) at diagnosis. In this study we analyzed Ha-ras p21 (protein with molecular weight of 21,000) expression immunohistochemically on 47 primary human neuroblastomas resected at diagnosis. The data demonstrate that the amount of the Ha-ras product correlates with a favorable prognosis (P less than 0.001) and early stages of disease at diagnosis (P less than 0.05). These findings from unmanipulated human neuroblastomas indicate that the Ha-ras gene product (p21) might play a role in the mechanism(s) controlling aggressiveness in this type of tumor in vivo and that the Ha-ras p21 detected by a simple and reproducible immunohistochemical procedure may be of clinical importance in predicting prognosis in patients with this malignancy.

IA antigen-positive epithelioid cells in experimentally induced granulomatous inflammation.

IA antigens on the cell membrane of inflammatory macrophages and epithelioid cells were investigated with immunoelectron microscopic method during development of granulomas induced by subcutaneous inoculation of 10(7) Mycobacterium lepraemurium into mice with and without hypersensitivity. In C57BL/6N (H-2b) immunogenetic high responder mice 6 weeks after infection majority (87%) of infiltrated cells were IA-positive. Two types of the staining reaction, strong and weak reactivity, were recognized among the positive cells. Strongly IA-positive cells showed lower phagocytosis (0.9/cell section) of mycobacteria than the weakly reacted cells (4.9/cell section). The strongly positive cells underwent morphological differentiation into large epithelioid cells during development of the hypersensitivity-type murine lepromas after 10 or more weeks of infection. Types of granulomas and IA-positive cells in C57BL/6N (nu/+) mice were identical to those found in C57BL/6N. In C57BL/6N (nu/nu) athymic nude mice initial infiltrating cells contained 38% of weakly IA-positive macrophages and a small number (7%) of strongly IA-positive macrophages. But the reactivity was lost later and only 4% of IA-positive cells remained in the granulomas without hypersensitivity. CBA/J (H-2k) low responder mice did not show IA-positive cells in either initial or late stage during the development of nonhypersensitivity-type murine lepromas. We suggest that the presence of IA-positive cells, particularly IA-positive epithelioid cells, in the lesions modulates the course of granulomatous tissue reaction in murine lepromas.

Vascular leiomyosarcoma arising from the inferior vena cava diagnosed by intraluminal biopsy.

A 61-year-old woman developed pain in the right thigh, paraplagia of the lower extremities and lumbago in November 1996. A lumbar spine roentgenogram showed lytic change in L2, and magnetic resonance imaging showed a patchy destructive lesion and compression of the dural sac from the right by a tumour. Computed tomography (CT) myelography showed a motheaten destructive lesion in L2 and projection of the tumour into the spinal canal. Abdominal ultrasound, CT and cavography showed dilatation of the inferior vena cava (IVC) and an intraluminal tumour about 2x2.8x4 cm in size in the IVC. The tumour arose from the IVC just beneath the renal vein and extended to just short of the right atrium. Both vertebral and intraluminal biopsy materials showed the same morphology, in which atypical spindle cells admixed with multinucleated giant cells proliferated in a fascicular growth pattern. Neoplastic cells were strongly positive for alpha-smooth muscle actin. We diagnosed vascular leiomyosarcoma arising from the IVC with metastasis to the lumbar vertebrae. Cases of vascular leiomyosarcoma diagnosed by intraluminal biopsy are rare.

Characteristics of monocarboxylates as energy substrates other than glucose in rat brain slices and the effect of selective glial poisoning - a 31P NMR study.

In rat brain slices we examined the differences in the levels of high-energy phosphates in the presence of various energy substrates by using 31P NMR with a time resolution of 4 min at 25 degrees C. In parallel experiments we recorded population excitatory postsynaptic potentials (EPSPs) from granule cells in rat hippocampal slices. During high K(+) stimulation (8 min) phosphocreatine (PCr) decreased to a low level and recovered to the control level in standard artificial cerebrospinal fluid (ACSF) in about 10 min. Population EPSPs disappeared following high-K(+) stimulation and recovered in standard ACSF. In iodoacetic acid (IAA)-pretreated slices, whereas glucose was unable to support energy metabolism, the PCr level, which decreased following high-K(+) stimulation, recovered in ACSF containing lactate or pyruvate. The half-time of recovery of PCr levels in ACSF containing lactate was longer than that containing glucose. Population EPSPs in standard ACSF were maintained for more than 1 h, but those in ACSF containing lactate decreased gradually by about half in 40 min. In IAA-pretreated slices, when further treated with fluorocitrate (100 microM) for 2 h, the recovery of the PCr level in ACSF containing lactate after high-K(+) stimulation was completely abolished, whereas the recovery of the PCr level in ACSF containing pyruvate was unaffected. These results indicate that neurons can utilize pyruvate as well as glucose, but not lactate, as exogenous energy substrates, and that lactate may be metabolized to pyruvate in glial cells and transported to neurons to be utilized as an energy substrate.

Effect of cysteamine on gastric nerve fibers containing gastrin-releasing peptide in the rat.

In rats, changes in gastric nerve fibers containing gastrin-releasing peptide (GRP) in cysteamine-induced duodenal ulcer were investigated in relation to the dynamics of gastrin-producing cells (G-cells). Marked increases in gastric acid secretion and serum gastrin level were observed from 2 h after the administration of cysteamine. The number of G-cells was significantly decreased from 2 h after the injection of cysteamine. Two and 4 h after the administration of cysteamine, the G-cells showed ultrastructural changes characterized by a markedly decreased number of secretory granules. Circulating GRP levels were significantly elevated from 2 h after the administration of cysteamine. In the control group given vehicle only, nerve fibers showing immunoreaction for GRP formed a fine network in the gastric wall and were densely distributed in the oxyntic mucosa, located close to capillaries and demonstrated varicosities that contained either small clear vesicles or GRP-immunopositive vesicles with large cores. Eight h after the administration of cysteamine, there was depleted GRP immunoreactivity, evidenced by a markedly decreased number of vesicles, with large electron-dense cores, in the oxyntic mucosa. These findings suggest that, in cysteamine-induced duodenal ulcer, alterations in gastric nerve fibers containing GRP may be related to hypergastrinemia.

Clinicopathological and immunohistochemical study of cancer arising from Barrett's esophagus.

In Japan, Barrett's esophageal cancer is a very rare disease. We examined clinicopathologically and immunohistologically 4 patients with Barrett's esophageal cancer who underwent surgical resection in our department. Barrett's esophageal mucosa was classified into 3 types for detailed observation. Specialized columnar epithelium (SCE) remained on the orifice side of carcinoma, and progression to adenocarcinoma was observed in some dysplastic glands. positive findings were detected on p53 immunohistochemical staining, and the ki-67 labeling index was higher than other types. SCE-type Barrett's esophagus may be a precancerous lesion arising prior to the development of adenocarcinoma.

Primary melanocytoma arising from the thoracic leptomeninges case.

Primary melanocytoma arising from the leptomeninges of the spinal cord is very rare. A surgical specimen of a thoracic meningeal tumor was resected from a 75-year-old woman complaining of gait disturbance was investigated. Magnetic resonance imaging and myelography showed a dumb-bell-type tumor in the subdural space at the 1st to 2nd thoracic vertebrae. The tumor was subtotally resected because of adhesion to the lamina and thoracic medulla. The localized, gelatinous black tumor showed a well-defined margin without dissemination or infiltration. The tumor had a thin capsule and was composed of solid proliferation of neoplastic melanocytes. Neither whorl formation nor foci of palisaded nuclei were observed. The neoplastic cells were of two major types: an epithelioid- or polygonal-shaped type and a spindle-shaped type, and had a large nucleus, a prominent nucleolus, coarse chromatin, and melanin-pigments in their cytoplasm. Only a few mitotic figures were observed. They were positive for HMB-45 and S-100 protein. This case was considered to be primary melanocytoma arising from the thoracic leptomeninges.

Transient isolated thyrotropin deficiency associated with cavernous sinus syndrome.

The cause and course of isolated thyrotropin (TSH) deficiency are not well understood. We report a 65-year-old man with a transient, probable isolated TSH deficiency associated with cavernous sinus syndrome secondary to tympanitis. On his admission, serum TSH and triiodothyronine levels were very low. No TSH response to thyrotropin releasing hormone (TRH) was observed. However, 6 years later, TSH response to TRH was restored. The present case showed that inflammation in the cavernous sinus could be one of the causes of TSH deficiency. Further, it demonstrated that TSH deficiency is not always permanent and the reevaluation of pituitary function is necessary.

[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 bioactive functions in hydrangeae dulcis folium. II. Antiulcer, antiallergy, and cholagoic effects of the extract from hydrangeae dulcis folium].

In order to develop new bioactive functions of Hydrangeae Dulcis Folium, the fermented and dried leaves of Hydrangea macrophylla Seringe var. thunbergii Makino, effects of the methanolic extract from the crude drug on antiucler, antiallergic, cholagoic, and various pharmacological actions were investigated. Consequently, the methanolic extract was found to exhibit potent antiulcer, antiallergic, and cholagoic activities. By monitoring with these activities, it was found that the active constituents were contained in the lipophilic portion of the methanolic extract. Furthermore, the known lipophilic constituents such as phyllodulcin and hydrangenol were found to show little antiulcer and cholagoic activities, while it was also found that they showed antiallergic activity on Schultz-Dale reactions.

[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.

[Upper and lower airway diseases in children with persistent cough].

Persistent cough is a frequent and frustrating problem in the pediatric field. One hundred and seventy two children presenting with persistent cough for longer than 2 weeks were evaluated by both otolaryngologists and pediatricians. One hundred and twenty nine cases (75%) were found to have lower airway diseases, of which bronchial asthma, bronchitis and pneumonia, in that order, were the most common. One hundred and forty two cases (82%) had sinusitis, in 34 cases of which no causative diseases except sinusitis were found to be responsible for the persistent cough. Sinusitis was found in 90% of patients with pneumonia, 81% of those with bronchitis and 65% of those with poorly controlled asthma cases. These results revealed that sinusitis is an important causative factor for persistent cough in children. All the patients with pneumonia and bronchitis were cured by antibiotic administration for 2 weeks, whereas conservative treatment of sinusitis for as long as 6 months was less satisfactory resulting in only 60% cure, 18% improvement and 22% without improvement. In cases with sinusitis and lower airway diseases, continuous treatment for sinusitis is necessary even after treatment of the lower airway diseases has been completed.

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.