Cognitive Frailty is Associated with Fall-Related Fracture among Older People.

OBJECTIVE: Cognitive frailty refers to cognitive impairment and physical frailty. Both cognitive impairment and physical frailty include risks of falling. The purpose of the study is to examine cognitive frailty and falling with/without a fracture. DESIGN: Cross-sectional observation study. SETTING: General communities in Japan. PARTICIPANTS: Data of 10,202 older adults aged ≥ 65 years were collected. MEASUREMENTS: Physical frailty was characterized as slow walking speed and/or muscle weakness. Assessment of cognitive function included word lists memory, attention, executive function, and processing speed. Cognitive impairment refers to one or more cognitive decline indicated by at least 1.5 standard deviations below the threshold after adjusting for age and education. We operationally defined cognitive frailty as having both cognitive impairment and physical frailty. Participants were interviewed about their falling, history of fall-related fractures, and several potentially confounding factors such as demographic characteristics. RESULTS: Multinomial logistic regression analysis revealed that functional decline in all groups, as compared to the robust group, was significantly associated with falling without fractures, after adjusting for the covariates; cognitive impairment group (P = .017), physical frailty group (P = .002), and cognitive frailty group (P < .001). Only the cognitive frailty group had a significant association with fall-related fracture after adjusting for the covariates (OR 1.92, 95% CI: 1.20-3.08, P = .007). CONCLUSION: Cognitive frailty is associated with not only falling but also fall-related fractures. Cognitive frailty may have a greater risk for fall-related fractures than cognitive impairment or physical frailty alone. Future research should examine causal the relationship between fall-related fractures and cognitive frailty.

Long and Short Sleep Duration and Physical Frailty in Community-Dwelling Older Adults.

OBJECTIVE: The objective of this study was to investigate whether older adults who have a particularly long sleep duration are likely to exhibit physical frailty, similar to those with a particularly short sleep duration. DESIGN: Cross-sectional study. SETTING: The National Center for Geriatrics and Gerontology - Study of Geriatric Syndromes. PARTICIPANTS: A total of 9,824 older adults (mean age: 73.6 ± 5.5 years, 4,812 men and 5,012 women) met the entry criteria for this study. MEASUREMENTS: We divided the participants into three groups according to self-reported sleep duration (Short: ≤6 h, Mid: 6.1-8.9 h (control), Long: ≥ 9 h). Physical frailty was characterized based on the criteria from the Cardiovascular Health Study. Multinomial logistic regression analysis was performed to evaluate the effect of sleep duration on physical frailty by sex. RESULTS: Among all participants, the prevalence of physical frailty was higher in the Short (10.5%) and Long (17.9%) groups than in the Mid (7.4%) group (p < 0.001). Multinomial logistic regression analysis showed that both Short and Long groups had a significantly higher odds ratio (OR) for physical frailty than the Mid group [Short: OR 1.53, 95% confidence interval (CI) 1.26-1.87; Long: OR 2.39, 95% CI 1.90-3.00], even after adjusting for age, educational level, number of medications, body mass index, Mini Mental State Examination score, current smoking and alcohol habits, self-perceived health, and medical history. CONCLUSION: Both long and short sleep durations were associated with physical frailty. Further studies are required to confirm the effect of sleep duration on the incidence or worsening of physical frailty in older adults.

Association between Insulin-Like Growth Factor-1 and Frailty among Older Adults.

OBJECTIVES: Frailty is a course experienced in advanced aging. Identification of a biological factor associated with frailty is required. Although serum insulin-like growth factor-1 (IGF-1) is a potential factor related with frailty, consensus has not been reached regarding this relationship. This study aimed to investigate the association between IGF-1 and frailty in older adults. DESIGN: Cross-sectional study. SETTING: Cohort study that was part of the "National Center for Geriatrics and Gerontology - Study of Geriatric Syndromes." PARTICIPANTS: The study participants were 4133 older adults (mean age, 71.8 ± 5.4 years). MEASUREMENTS: We assessed serum IGF-1 levels and frailty status and collected demographic variables, including cognitive function, as covariates. RESULTS: Frailty and pre-frailty were present in 274 subjects (7%) and 1930 subjects (47%), respectively. Subjects were divided into four groups based on quartiles of IGF-1 levels. Multinomial logistic analysis showed that the lowest group had significant odds of pre-frailty (crude model: odds ratio [OR] 1.58, 95% confidence interval [CI] 1.30-1.90, p < .001; adjusted model: OR 1.38, 95% CI 1.13-1.68, p = .002) and frailty (crude model: OR 3.42, 95% CI 2.38-4.92, p < .001; adjusted model: OR 1.54, 95% CI 1.02-2.32, p = .039), compared with the highest group. CONCLUSION: Lower serum IGF-1 levels were independently related with frailty in older adults.

Impact of Cognitive Frailty on Daily Activities in Older Persons.

OBJECTIVES: To identify the relationships between physical and/or cognitive frailty and instrumental activities of daily living (IADL) functioning in community living older persons. DESIGN: Cross sectional observation study. SETTING: Data extracted from the 2011-2013 of the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes (NCGG-SGS) database. PARTICIPANTS: A total of 8,864 older adults aged ≥ 65 years who were enrolled in the NCGG-SGS. MEASUREMENTS: We characterized physical frailty as limitations in three or more of the following five domains: slow walking speed, muscle weakness, exhaustion, low activity and weight loss. To screen for cognitive impairment, we used the National Center for Geriatrics and Gerontology-Functional Assessment Tool (NCGG-FAT) which included tests of word list memory, attention and executive function (tablet version of the Trail Making Test, part A and B), and processing speed (tablet version of the Digit Symbol Substitution Test). Two or more cognitive impairments indicated by an age-adjusted score of at least 1.5 standard deviations below the reference threshold was characterized as cognitive impairment. Each participant reported on their IADL status (use of public transportation, shopping, management of finances, and housekeeping) and several potential confounders such as demographic characteristics. RESULTS: The overall prevalence of physical frailty, cognitive impairment, and cognitive frailty, i.e. co-occurrence of frailty and cognitive impairment, was 7.2%, 5.2%, and 1.2%, respectively. We found significant relationships between IADL limitations and physical frailty (Odds Ratio (OR) 1.24, 95% confidence interval (95% CI) 1.01 to 1.52), cognitive impairment (OR 1.71, 95% CI 1.39 to 2.11), and cognitive frailty (OR 2.63, 95% CI 1.74 to 3.97). CONCLUSION: Using the NCGG-SGS frailty criteria, we found more participants with physical frailty than with cognitive frailty. The individuals with cognitive frailty had the highest risks of IADL limitations. Future investigation is necessary to determine whether this population is at increased risk for incidence of disability or mortality.

Isogenic enteric neural progenitor cells can replace missing neurons and glia in mice with Hirschsprung disease.

BACKGROUND: Transplanting autologous patient-derived enteric neuronal stem/progenitor cells (ENSCs) is an innovative approach to replacing missing enteric neurons in patients with Hirschsprung disease (HSCR). Using autologous cells eliminates immunologic and ethical concerns raised by other cell sources. However, whether postnatal aganglionic bowel is permissive for transplanted ENSCs and whether ENSCs from HSCR patients can be successfully isolated, cultured, and transplanted in vivo remains unknown. METHODS: ENSCs isolated from the ganglionic intestine of Ednrb(-/-) mice (HSCR-ENSCs) were characterized immunohistochemically and evaluated for their capacity to proliferate and differentiate in vitro. Fluorescently labeled ENSCs were co-cultured ex vivo with aganglionic Ednrb(-/-) colon. For in vivo transplantation, HSCR-ENSCs were labeled with lentivirus expressing green fluorescent protein (GFP) and implanted into aganglionic embryonic chick gut in ovo and postnatal aganglionic Ednrb(-/-) rectum in vivo. KEY RESULTS: HSCR-ENSCs maintain normal capacity self-renewal and neuronal differentiation. Moreover, the Ednrb(-/-) aganglionic environment is permissive to engraftment by wild-type ENSCs ex vivo and supports migratrion and neuroglial differentiation of these cells following transplantation in vivo. Lentiviral GFP-labeled HSCR-ENSCs populated embryonic chick hindgut and postnatal colon of Ednrb(-/-) HSCR, with cells populating the intermuscular layer and forming enteric neurons and glia. CONCLUSIONS & INFERENCES: ENSCs can be isolated and cultured from mice with HSCR, and transplanted into the aganglionic bowel of HSCR littermates to generate enteric neuronal networks. These results in an isogenic model establish the potential of using autologous-derived stem cells to treat HSCR and other intestinal neuropathies.

Endoscopic delivery of enteric neural stem cells to treat Hirschsprung disease.

BACKGROUND: Transplantation of enteric neural stem cells (ENSC) holds promise as a potential therapy for enteric neuropathies, including Hirschsprung disease. Delivery of transplantable cells via laparotomy has been described, but we propose a novel, minimally invasive endoscopic method of cell delivery. METHODS: Enteric neural stem cells for transplantation were cultured from dissociated gut of postnatal donor mice. Twelve recipient mice, including Ednrb(-/-) mice with distal colonic aganglionosis, underwent colonoscopic injection of ENSC under direct vision using a 30-gauge Hamilton needle passed through a rigid cystoureteroscope. Cell engraftment, survival, and neuroglial differentiation were studied 1-4 weeks after the procedure. KEY RESULTS: All recipient mice tolerated the procedure without complications and survived to sacrifice. Transplanted cells were found within the colonic wall in 9 of 12 recipient mice with differentiation into enteric neurons and glia. CONCLUSIONS & INFERENCES: Endoscopic injection of ENSC is a safe and reliable method for cell delivery, and can be used to deliver a large number of cells to a specific area of disease. This minimally invasive endoscopic approach may prove beneficial to future human applications of cell therapy for neurointestinal disease.

Renal vein extension using an autologous renal vein in a living donor with double inferior vena cava: a case report.

BACKGROUND: When the kidney from a living donor with a double inferior vena cava (IVC) is harvested for renal transplantation, the short length of the renal vein may eventually create a technical problem for graft implantation. Herein, we have reported a rare case of renal vein extension using an autologous renal vein in a living donor with a double IVC. CASE REPORT: A 70-year-old man with end-stage renal disease owing to autosomal-dominant polycystic kidney disease underwent a living donor kidney graft from his wife who had a double IVC. Because of the enlarged kidneys, the patient underwent a bilateral native nephrectomy with concomitant renal transplantation to create space in the pelvis. At nephrectomy, the recipient's renal vein was used to extend the donor renal vein. On the back table, the vein graft was sutured to the donor renal vein, permitting a 3.0-cm extension. RESULTS: The transplantation was performed safely without any complications; the recipient's renal function and blood flow were excellent after the operation. CONCLUSION: This case illustrated that an autologous renal vein graft is a preferable option to extend of short donor renal vein for recipients who require a simultaneous native nephrectomy.

Effects of tissue age, presence of neurones and endothelin-3 on the ability of enteric neurone precursors to colonize recipient gut: implications for cell-based therapies.

BACKGROUND Most enteric neurones arise from neural crest cells that originate in the post-otic hindbrain, and migrate into and along the developing gastrointestinal tract. There is currently great interest in the possibility of cell therapy to replace diseased or absent enteric neurones in patients with enteric neuropathies, such as Hirschsprung's disease. However, it is unclear whether neural crest stem/progenitor cells will be able to colonize colon (i) in which the mesenchyme has differentiated into distinct layers, (ii) that already contains enteric neurones or (iii) that lacks a gene expressed by the gut mesenchyme, such as endothelin-3 (Et-3). METHODS Co-cultures were used to examine the ability of enteric neural crest-derived cells (ENCCs) from E11.5 mouse gut to colonize a variety of recipient hindguts. KEY RESULTS Enteric neural crest-derived cells migrated and gave rise to neurones in E14.5 and E16.5 aneural colon in which the external muscle layers had differentiated, but they did not migrate as far as in younger colon. There was no evidence of altered ENCC proliferation, cell death or neuronal differentiation in older recipient explants. Enteric neural crest-derived cells failed to enter most recipient E14.5 and E16.5 colon explants already containing enteric neurones, and the few that did showed very limited migration. Finally, ENCCs migrated a shorter distance and a higher proportion expressed the pan-neuronal marker, Hu, in recipient E11.5 Et-3(-/-) colon compared to wild-type recipient colon. CONCLUSIONS & INFERENCES Age and an absence of Et-3 from the recipient gut both significantly reduced but did not prevent ENCC migration, but the presence of neurones almost totally prevented ENCC migration.

[Right lung cancer with right aortic arch].

An abnormal shadow was detected on chest X-ray mass screening in an asymptomatic 63-year-old man. The further examinations revealed the shadow to be primary lung cancer (Rt. S6. adenocarcinoma, cT2N0M0, c-stage IB) with right aortic arch. We used 3 dimentional-computed tomography (3D-CT) to assess an anatomical feature of vessels in detail. The right lower lobectomy and the dissection of medi astinal lymph nodes was performed. We confirmed no abnormal anatomy of pulmonary artery and vein at surgery, and it was possible to perform right lower lobectomy with the common procedure. Since lymph node was found by intraopetrative pathological examination, since no metastasis from interlobar to subcarinal lymph node was found, we did not perform dissection of upper mediastinal dissection, which was equivalent to ND2a lymph nodes dissection of the left lung cancer in General Rule for Clinical and Pathological Record of Lung Cancer. The patient with right aortic arch is known to have variant anatomy of other intrathoracic vessels occasionally. 3D-CT was quite useful in assessing anatomical feature, and enabled us to perform safe operation.

Usefulness of bone metabolic markers in the diagnosis and follow-up of bone metastasis from lung cancer.

Ninety-one lung cancer patients were evaluated to determine the usefulness of bone metabolic markers in the diagnosis and follow-up of bone metastases and also to investigate their clinical usefulness as an adjunct to bone scintigraphy. Both bone resorption markers, ICTP and fDPD, and bone formation markers, Al-p, BAL, PICP and BGP, were evaluated in 47 patients with and 44 without bone metastasis. The patients with bone metastasis were classified according to the bone metastatic burden, and they were also separately classified into groups according to the course of the bone metastasis. ICTP, fDPD, Al-p and BAL were significantly elevated (P < 0.001) in patients with bone metastasis, but PICP and BGP were not. Receiver-operating characteristic (ROC) curves of these markers revealed that ICTP was most highly correlated with the diagnosis of bone metastasis. The sensitivity of ICTP (71.4%) and fDPD (61.0%) were good with high specificity. T scores of ICTP, fDPD and BAL tended to be higher at higher grades of bone metastasis. T-scores of ICTP, fDPD and BAL were elevated in the newly diagnosed cases and progressed cases, but the T-scores of ICTP and fDPD in those cases were higher than that of BAL. In the follow-up study, ICTP was well correlated with uncontrolled or controlled bone metastasis. Thus, bone resorption markers, especially ICTP, could be a good indicator of the progression and multiplicity of disease, and it could help in the follow-up and in the monitoring of therapy for bone metastasis from lung cancer.

[Perioperative management of patients with Meigs syndrome].

We report our perioperative management of three cases of Meigs syndrome. The major pre-operative problems in Meigs syndrome are physical trouble caused by giant mass in peritoneal space, respiratory distress, and poor nutrition. These problems must be settled before the operation. The important points in the pre-operative management are 1) respiratory care employing the intermittent positive pressure breathing (IPPB) and the pleural effusion drainage, and 2) the correction of intravascular volume and the concentration of albumin and hemoglobin by transfusion of massive lactated Ringer solution and albumin solution and/or whole blood when they are necessary. During the operation, the epidural anesthesia under spontaneous breathing is the best method of anesthesia. According to circumstances, we adopt the intra-tracheal intubation with continuous positive airway pressure breathing (CPAP). We can generally deal with excessive bleeding by transfusion of lactated Ringer solution and plasma expander, during the first half of operation. By the end of the operation, however, the correction of the concentration of albumin and hemoglobin must be made by the fresh frozen plasma and blood transfusion. After the operation, we use epidural analgesia to control the postoperative pain. We have succeeded in the treatment of three cases of Meigs syndrome owing to our perioperative management as described above.

Effects of progesterone and estradiol on aminopeptidase A (AAP) and leucine aminopeptidase (LAP) activities in the pregnancy serum and placenta of the rat.

We investigated the effects of estradiol and progesterone on placental aminopeptidase A and leucine aminopeptidase activities in pregnant rats. Estradiol (0.5, 1.0 and 2 mg/day) plus progesterone (5, 10 and 20 mg/day) was given for five days starting from the 16th day. Changes in both enzyme activities in the serum, placental cytosol and microsome caused by the steroids were analyzed. Aminopeptidase A activities in all three compartments and leucine aminopeptidase activities in the serum and cytosol were stimulated by estradiol (1.0 mg/day) plus progesterone (10 mg/day). Since we previously found that the placental aminopeptidases degrade peptide hormones, our present study suggests that steroids effect the metabolism of peptide hormones of fetal and/or maternal origin.

Loss of suppressor T cell function and circulating immune complexes in chronic active liver diseases.

Suppressor T cell function is decreased in patients with chronic active liver diseases (CALD). To account for the alterations, we examined the effect of sera of patients with various liver diseases on concanavalin A (Con A) induced suppressor T cell activity of normal individuals. The suppressor T cell activity was inhibited by heat-inactivated serum pretreatment in 13 of 27 cases of patients with CALD and in five of 11 cases of patients with acute viral hepatitis, whereas only two sera of 18 patients with other liver diseases affected suppressor cell activity. Using a 125I-C1q-binding test, a significant correlation (P less than 0.01) was detected between the degree of inhibition in the development of suppressor T cells and the level of circulating immune complexes in the sera of CALD patients. The blocking effect of patients' sera disappeared when the immune complexes were removed with polyethylene glycol. These data suggest that circulating immune complexes modulate cellular immunity in patients with CALD by influencing the suppressor T cell function.

Lymphocyte suppressor cell activity in acute and chronic liver disease.

We investigated lymphocyte suppressor cell activity in 53 patients with acute and chronic liver diseases. Suppressor cells were generated by preincubation of peripheral blood mononuclear cells (PBM) with concanavalin A (Con A) for 48 hr. Suppressor cell activity was evaluated by inhibition of Con A-stimulated blast transformation and by inhibition of pokeweed mitogen-induced immunoglobulin (Ig) synthesis of fresh allogeneic normal PBM in the second-set cultures. Of 29 patients with chronic active liver diseases (CALD), defective suppressor cell activities were observed in eight cases (28%) for Ig synthesis and 16 cases (55%) for blast transformation study. The suppressor cell activities were decreased in two (22%) of nine cases with chronic persistent hepatitis and one (17%) of six cases with inactive cirrhosis for both Ig synthesis and blast transformation. In contrast, suppressor activities were inducible in all nine patients with acute viral hepatitis. The histocompatibility antigen DR4 was significantly increased in CALD patients, but there was no correlation between this antigen and suppressor cell activity. These findings suggest that altered lymphocyte suppressor cells in patients with CALD may contribute to the continuing liver cell injury in this disease.

Antibody dependent cellular cytotoxicity in chronic active liver diseases.

Antibody-dependent cellular cytotoxicity (ADCC) of peripheral blood lymphocytes for Chang cells coated with antibody to liver specific membrane lipoprotein was studied in patients with chronic active liver diseases (CALD) to investigate the pathogenesis of liver cell injury. Of 20 CALD patients, a reduced ADCC was found in 5 cases, whereas an increased ADCC was noted in 8 cases. The remaining 7 cases showed a normal ADCC. There was a significant correlation (p less than 0.01) between a decreased ADCC and an increased level of immune complexes in the sera of CALD patients when a 125I-Clq binding test was used. When sera from ADCC patients, which had a high level of circulating immune complexes, or aggregated human IgG was added, ADCC of normal lymphocytes was significantly inhibited (p less than 0.01) compared with that of lymphocytes alone. These results suggest that circulating immune complexes play a role on the pathogenesis of liver damage in CALD.