Salivary Alpha-Amylase Activity and Mild Cognitive Impairment among Japanese Older Adults: The Toon Health Study.

BACKGROUND: There is growing interest in examining objective markers for early identification and behavioral intervention to prevent dementia and mild cognitive impairment in clinical and community settings. OBJECTIVE: To investigate the association between salivary alpha-amylase as an objective measure of psychological stress response and mild cognitive impairment for the implication of psychological stress in the development of mild cognitive impairment. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study involved 865 participants aged ≥ 65 years. A saliva sample was collected in the morning, and the levels of salivary alpha-amylase were assayed. Mild cognitive impairment was evaluated using the Japanese version of the Montreal Cognitive Assessment; a score < 26 was indicative of mild cognitive impairment. A multivariable logistic regression model was used to examine the association of salivary alpha-amylase and mild cognitive impairment after adjusting for age, sex, current drinking status, current smoking status, body mass index, hypertension, diabetes mellitus, physical activity, education, social support, social network, and heart rate variability. RESULTS: Salivary alpha-amylase was associated with mild cognitive impairment (the multivariable-adjusted odds ratio [95% confidence interval] for the 1-standard deviation increment of log-transformed salivary alpha-amylase was 1.24 [1.07-1.44]). This significant association persisted after adjusting for various confounding factors. CONCLUSION: Elevation of salivary alpha-amylase was associated with mild cognitive impairment among Japanese community-dwelling older adults. This suggests that salivary alpha-amylase is a useful objective marker of psychological stress responses associated with mild cognitive impairment.

Variations in the gonadal artery with a single common trunk: embryological hypotheses by observation.

BACKGROUND: A gonadal artery originates as a branch of the abdominal aorta and renal artery inferior to the level of origin of the renal arteries. Variations in multiple right testicular arteries (RTAs) arising from the abdominal aorta are common. We aimed to re-evaluate the unusual courses of gonadal arteries with a single common trunk in relation to the inferior vena cava and left renal vein and explain the developmental anatomy. MATERIALS AND METHODS: The observational cross-sectional study was performed on 54 Japanese adult cadavers (29 men and 25 women). We examined the literature and developed embryological hypotheses on the single common trunk of the gonadal artery. RESULTS: The gonadal artery, testicular artery, and ovarian artery arose from the abdominal aorta in 93.1%, 96.3%, and 89.6% of cases, respectively, and from the renal artery in 4.9%, 3.7%, and 6.3% of cases, respectively. We found two rare variations in the RTAs observed during the routine dissection of two male cadavers; in these two cases, a single common trunk of the RTAs originated from the abdominal aorta. A single common trunk was found in 3.7% of cadavers, 2.0% of sides, and 2.0% of arteries in the gonadal artery and in 6.9% of cadavers, 3.8% of sides, and 3.7% of arteries in the testicular artery. All cases of the single common trunk, including those in past reports, were observed only in men. CONCLUSIONS: Knowledge of the variations in RTAs has important clinical consequences for invasive and non-invasive arterial procedures. In addition, this variation provides a new interpretation of the embryology of the gonadal artery. Variations similar to our findings have not been previously reported. Therefore, different variations concerning the RTA should be considered during surgical and non-surgical evaluations.

Common and separate origins of the left and right inferior phrenic artery with a review of the literature.

In a 94-year-old male cadaver, upon which routine dissection was being conducted, a rare variation was found in the gastrophrenic trunk (GPT), the common trunk of the left gastric artery (LGA), right inferior phrenic artery (RIPA), and left inferior phrenic artery (LIPA); the GPT arises from the abdominal aorta. A hepatosplenic trunk accompanied the variation. In this variation, the RIPA first branched from the GPT and then to the LIPA and LGA. Variations in the common trunk of the LIPA and RIPA in the GPT are common, but to our knowledge, a variation (separate inferior phrenic artery in the GPT) similar to our findings has not been previously reported. We discuss the incidence and developmental and clinical significance of this variation with a detailed review of the literature. Knowledge of such a case has important clinical significance for invasive and non-invasive arterial procedures. Therefore, different variations concerning the LGA and inferior phrenic artery should be considered during surgical and non-surgical evaluations.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

A Comparison of Objective Physical Activity, Muscle Strength, and Depression among Community-dwelling Older Women Living in Sloped Versus Non-sloped Environments.

OBJECTIVE: To examine the relationship between the living location and outcomes of physical activity level and physical and psychological functioning in older women. The specific aim was to understand the association between living in a sloped versus non-sloped environment and these outcomes. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: 108 older women aged 65 years or older who resided in Nagasaki prefecture participated. MEASUREMENTS: Physical activity, lung function, muscle strength (hand grip and quadriceps force) and depressive symptoms were assessed objectively. RESULTS: In logistic regression, activity counts per day (OR 0.779, 95%CI 0.715-0.841, p<0.01), activity times per day (OR 0.821, 95%CI 0.801-0.913, p<0.01), hand grip force (OR 0.666, 95%CI 0.558-0.796, p<0.001), and depressed (Center for Epidemiological Studies Depression Scale score ≥16) (OR 1.093, 95%CI 1.019-1.427, p<0.05) showed statistically significant inverse associations with living in a sloped ground. CONCLUSIONS: Since dwelling on sloped ground was associated with negative (lower physical activity levels, lower grip strength, and more depression) outcomes, a comprehensive geriatric assessment, related to all aspects of older women, is recommended. Planning of home exercise programs for the elderly should take such environmental factors into consideration.

N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties.

N-cadherin and HER2/neu were found to be co-expressed in invasive breast carcinomas. To test the contribution of N-cadherin and HER2 in mammary tumor metastasis, we targeted N-cadherin expression in the mammary epithelium of the MMTV-Neu mouse. In the context of ErbB2/Neu, N-cadherin stimulated carcinoma cell invasion, proliferation and metastasis. N-cadherin caused fibroblast growth factor receptor (FGFR) upmodulation, resulting in epithelial-to-mesenchymal transition (EMT) and stem/progenitor like properties, involving Snail and Slug upregulation, mammosphere formation and aldehyde dehydrogenase activity. N-cadherin potentiation of the FGFR stimulated extracellular signal regulated kinase (ERK) and protein kinase B (AKT) phosphorylation resulting in differential effects on metastasis. Although ERK inhibition suppressed cyclin D1 expression, cell proliferation and stem/progenitor cell properties, it did not affect invasion or EMT. Conversely, AKT inhibition suppressed invasion through Akt 2 attenuation, and EMT through Snail inhibition, but had no effect on cyclin D1 expression, cell proliferation or mammosphere formation. These findings suggest N-cadherin/FGFR has a pivotal role in promoting metastasis through differential regulation of ERK and AKT, and underscore the potential for targeting the FGFR in advanced ErbB2-amplified breast tumors.

Endoplasmic reticulum stress response in the rat contusive spinal cord injury model-susceptibility in specific cell types.

STUDY DESIGN: Focus group study. OBJECTIVE: To investigate cell-specific endoplasmic reticulum (ER) stress reactions in contusive spinal cord by evaluating the expression of the glucose-regulated protein 78 (GRP78) and C/EBP homologous transcription factor protein (CHOP) using immunohistochemical staining. SETTING: Data were analysed at Tokai University School of Medicine in Japan. METHODS: The authors generated rat spinal cord injury (SCI) models using an IH-Impactor (100 kdyne(LI), 200 kdyne (HI)). Rats were killed at 1, 3, 5, 7 and 14 days post operation (dpo). Spinal cord sections were prepared and the expression ratio of GRP78 and CHOP was evaluated in oligodendrocyte precursor cells (OPCs) (NG2+), oligodendrocytes (OLs) (APC+), neurons (NeuN+) and astrocytes (GFAP+) using double immunohistochemical staining. We examined an area 8 mm distal from SCI-epicenter. RESULTS: Compared with the sham group, both injured groups had higher GRP78 expression ratio in contused spinal cord at 1 dpo. GRP78 expression ratio was highest in GFAP+ cells of both groups, and lowest in NG2+ cells. Although GRP78 was expressed strongly immediately after SCI in the both groups, increased CHOP expression was observed only in the HI group. The CHOP expression in NG2+ cells was significantly higher than that observed in GFAP+ cells at 5 dpo. CONCLUSION: Although the ER stress response contributes to cell survival in the low-stress SCI conditions, the ER stress response induces an apoptotic cascade in high-stress SCI conditions. The ER response varies according to cell type, with the highest observed in astrocytes, and the lowest observed in oligodendrocyte precursor cells.

Phasic synaptic incorporation of GluR2-lacking AMPA receptors at gonadotropin-releasing hormone neurons is involved in the generation of the luteinizing hormone surge in female rats.

Reproductive success depends on a robust and appropriately timed preovulatory luteinizing hormone (LH) surge, which is induced by the activation of gonadotropin-releasing hormone (GnRH) neurons in response to positive feedback from increasing estrogen levels. Here we document an increase in postsynaptic GluR2-lacking Ca2+ -permeable AMPA-type glutamate receptors (CP-AMPARs) at synapses on GnRH neurons on the day of proestrus in rats, coincident with the increase in estrogen levels. Functional blockade of CP-AMPARs depressed the synaptic responses only on the day of proestrus and concomitantly attenuated the LH surge. Thus, the phasic synaptic incorporation of postsynaptic CP-AMPARs on GnRH neurons is involved in the generation of the LH surge.

N-cadherin regulates mammary tumor cell migration through Akt3 suppression.

N-cadherin is a cell-cell adhesion molecule that plays a role in breast cancer metastasis. Here, we show that in vivo expression of N-cadherin in the PyMT mouse model, which enhances mammary tumor metastasis, results in selective inhibition of Akt3 expression and phosphorylation. Similarly, exogenous expression of N-cadherin in PyMT or MCF-7 mammary tumor cells enhanced cell motility and caused a dramatic reduction in Akt3 expression and phosphorylation. Moreover, knockdown of Akt3 in PyMT tumor cells increased cell motility and disrupted mammary morphogenesis, but had no effect on cell proliferation. Conversely, overexpression of wild-type Akt3 in PyMT-N-cadherin cells inhibited cell motility promoted by N-cadherin. Taken altogether, these findings demonstrate that N-cadherin suppresses Akt3 to promote cell motility and highlight the intricate regulation of Akt isoforms by N-cadherin during metastasis.

p21CIP1 mediates reciprocal switching between proliferation and invasion during metastasis.

Cell proliferation and invasion are critical for malignant progression, yet how these processes relate to each other and whether they regulate one another during metastasis is unknown. We show that invasiveness of breast cancer cells is associated with growth arrest due to p21CIP1 upregulation. Knockdown of p21CIP1 increases cell proliferation and suppresses invasion. Since p21CIP1 acts to inhibit cyclin E during cell-cycle progression, we demonstrated that a constitutively active form of cyclin E had similar effects to p21CIP1 inhibition resulting in enhanced cell growth and suppressed invasiveness. We tested these findings in vivo in the Polyoma middle T mammary tumor model in which p21CIP1 was deleted. p21CIP1 knockout mice exhibited dramatic suppression of metastasis, independent of tumor growth, which was rescued by p21CIP1. Metastasis suppression by p21CIP1 ablation was associated with striking cytoskeletal reorganization leading to a non-invasive and highly proliferative state. Thus, p21CIP1 regulates metastasis by mediating reciprocal switching between invasion and proliferation.

Endovascular treatment of intractable bleeding from a traumatic pseudoaneurysm of the internal maxillary artery.

Traumatic pseudoaneurysms of the internal maxillary artery (IMA) are rare and difficult to treat. A 58-year-old man with a traumatic pseudoaneurysm of the IMA presented with intractable nasal and oral hemorrhage during dual antiplatelet therapy. Transcatheter artery embolization with N-butyl cyanoacrylate (NBCA) completely occluded the pseudoaneurysm. Transcatheter artery embolization with NBCA is a feasible and effective treatment because of its shorter treatment time and lower incidence of recurrence.

Identification of lactose ureide, a urea derivative of lactose, in milk and milk products.

With the widespread consumption of milk, the complete characterization of the constituents of milk and milk products is important in terms of functionality and safety. In this study, a novel nonreducing carbohydrate was separated from powdered skim milk and was identified using electron spray ionization-mass spectrometry (m/z 385.1[M + H(+)]), ¹H, ¹³C, ¹H¹H-correlation spectroscopy, and heteronuclear single quantum-nuclear magnetic resonance spectra. The carbohydrate was identified as a lactose derivative of urea, N-carbamoyl-o-ß-D-galactopyranosyl-(1-4)-D-glucopyranosylamine (lactose ureide, LU). For the HPLC analysis of LU in milk and milk products, benzoylated LU, hepta-o-benzoyl lactose ureide (melting point 137-139°C; m/z 1,113 [M + H⁺]; wavelength of maximum absorption, λ(max), 229 nm; molar extinction coefficient, ε, 8.1037 × 107), was used as a standard. The crude nonreducing carbohydrate fraction from raw milk, thermally processed milk, and milk products such as powdered milks were directly benzoylated and subjected to HPLC analysis using an octadecylsilyl column to determine the quantity of LU. The content of LU in 10% solutions of powdered skim milk and powdered infant formula (5.0±1.1 and 4.9±1.5 mg/L, respectively) were almost 3-fold higher than that of UHT milk (1.6±0.5 mg/L) and higher than that of low-temperature, long-time-processed (pasteurized at 65°C for 30 min) milk (1.2±0.3 mg/L) and the fresh raw milk sample (0.3±0.1 mg/L). A time-course of the LU content in raw milk during heating at 110°C revealed that LU increased with time. From these results, it is likely that LU is formed by the Maillard-type reaction between the lactose and urea in milk and milk products. Because the concentration of LU in milk increased with the degree of processing heat treatment, it could serve as an indicator of the thermal deterioration of milk. Although it is known that the human intestine is unable to digest LU, the gastrointestinal bacteria in human subjects are able to digest and utilize urea nitrogen in formation of essential amino acids that are available to the host human. These findings suggest that LU in milk might have a functional role in human health.

"Brush Sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease.

BACKGROUND AND PURPOSE: SWI is a high spatial resolution MR imaging technique showing magnetic inhomogeneity that could demonstrate increased oxygen extraction in focal cerebral ischemia. The aim of this study was to investigate the characteristics in the signal intensity of DMVs by using SWI and to determine whether this method could indicate the severity of the hemodynamics in MMD by evaluating the correlation between SWI stage and hemodynamics on SPECT. MATERIALS AND METHODS: Consecutive MMD patients were prospectively analyzed before treatment. Routine MR imaging including SWI was performed, and the number of the conspicuous DMVs draining into the subependymal veins was classified: stage 1, mild (< 5); stage 2, moderate (5-10); and stage 3, severe (> 10). The SWI stage was evaluated in correlation with clinical presentations, and CBF and CVR were quantified by using a SPECT iodine 123 N-isopropyl-p-iodoamphetamine split-dose method. RESULTS: Patients were 12 males and 21 females (range, 8-66 years), consisting of 4 asymptomatic patients, 13 patients with TIA, 9 patients with infarct, and 7 patients with hemorrhage. There was a significant difference in CVR among clinical presentations, though there was no difference in age, Suzuki stage, or CBF. Conversely, SWI stage was significantly higher in patients with TIA and infarct than asymptomatic patients (P < .01). Higher SWI stage significantly had lower CBF and CVR in the middle cerebral artery area (P < .05). CONCLUSIONS: SWI stage strongly correlates with ischemic presentations in MMD and also correlates with hemodynamics on SPECT, especially CVR. Increased conspicuity of DMVs, known as "brush sign", could predict the severity of MMD.

Characterization of microbial consortia that reductively dechlorinate 4-chlorophenol and transform phenol to benzoate enriched from estuarine sediment of Lake Shinji.

Monochlorophenols were degraded to benzoate via phenol by the initial dechlorination and the subsequent conversion of phenol to benzoate in anaerobic sediment samples of estuarine Lake Shinji under methanogenic conditions. To characterize bacteria that dechlorinate 4-chlorophenol and transform phenol to benzoate, we analyzed the microbial community structure of the enrichment culture with each 4-chlorophenol and phenol by the limiting dilution method with polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) of 16S rRNA gene. After serial dilution of the culture, the 4-chlorophenol-dechlorinating culture consisted of two dominant bacteria, one of which was most homologous with Dehalobacter sp. In the enriched culture with phenol, minor band homologous with Cryptanaerobacter phenolicass corresponded to the transformation activity.

An 8-month-old boy with congenital fibromuscular dysplasia presenting with shock caused by sudden renal hemorrhage.

Fibromuscular dysplasia (FMD) is a non-atheromatous, non-inflammatory, multifocal segmental angiopathy. FMD is the most common cause of pediatric renovascular hypertension. Aneurysmal formation of the main renal artery and distal branches is a rare complication of FMD in infancy. We report an 8-month-old boy with FMD presenting with shock caused by sudden renal hemorrhage that necessitated removal of one kidney. A diagnosis of renovascular hypertension resulting from intimal type FMD with aneurysmal formation was made on the basis of the presence of hypertension, elevation of PRA and aldosterone activity, pathological findings and the results of renal angiography. Our findings suggest that it is therefore necessary to consider FMD with aneurysmal formation as a possible cause of hypertension and renal hemorrhage in infants.

Two patients with focal segmental glomerulosclerosis complicated by cyclosporine-induced reversible posterior leukoencephalopathy syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a distinctive clinicoradiological entity observed in a variety of clinical settings. Cyclosporine (CyA)-RPLS has been reported in a few patients with focal segmental glomerulosclerosis (FSGS); however, there had been no reports on developed RPLS after the re-administration of CyA treatment. We report two patients with FSGS who developed CyA-induced RPLS and summarize the results of a literature review for similar patients. The two patients with FSGS presented here were a 4-year-old boy and a 9-year-old boy, who presented with steroid-resistant nephrotic syndrome (NS) and were treated with CyA. The first patient developed CyA-induced RPLS at the 7th day after the start of CyA treatment, and the second patient at the 16th day after the re-start of CyA treatment. The two patients complained of a visual disorder and exhibited signs of a disturbance in consciousness and hypertension. Electroencephalography (EEG) examinations revealed a generalized slow wave pattern, and magnetic resonance imaging (MRI) disclosed an area of high signal intensity in the white matter. Subsequently, CyA was discontinued and neurological symptoms improved and recrudescence of RPLS did not occur. Our findings suggest that patients with FSGS and NS who are treated with CyA should be closely monitored for the possible onset of RPLS, presenting as a disturbance in consciousness, visual disturbances and/or convulsions.

Effects of herbicides on Lemna gibba and recovery from damage after prolonged exposure.

To determine the potential impact of contaminants on the aquatic vascular plants Lemna sp., toxicity tests are usually conducted for a 4- to 14-day exposure, and the toxicity is usually expressed as EC50. However, the effects of longer exposure and the recovery potential after exposure to chemicals are other important factors which should be considered. We present the relative risks of a variety of exposure scenarios and recovery potentials from damage, using herbicides with different modes of action. Toxicity was assessed on the basis of both EC50 and relative growth rate (RGR) compared with untreated controls in exposure and recovery. The EC50 of atrazine was found to be 89 ppb, and its phytostatic concentrations were 1600 and 800 ppb for exposure periods of 14 and 28 days, respectively, and no phytocidal effects were observed up to 3200 ppb for a 28-day exposure. The RGR in recovery was not affected by the RGR in exposure, and regrowth was possible even after complete inhibition of growth for 28 days at the highest concentration tested. Alachlor, with an EC50 of 31 ppb, was phytostatic at 400 ppb for a 14-day exposure and phytocidal at 200 ppb for 21- and 28-day exposures. Paraquat, with an EC50 of 31 ppb, showed phytocidal rather than phytostatic effects. All phytostatic fronds could not grow in the recovery period, and the phytocidal concentration decreased with exposure period, from 80 ppb for a 7-day exposure to 20 ppb for 21- and 28-day exposures. The RGR of alachlor and paraquat in recovery was dependent on the RGR in exposure. In the case of cyclosulfamuron, phytostatic concentrations were 100 and 50 ppb for 7- and 14-day exposures, respectively. In the case of exposures longer than 21 days, however, it exhibited phytocidal activity at 10 ppb. The results of this study suggest that it is important to examine the effects of chemicals over a longer exposure period as well as the recovery potential from damage for reliable ecological risk assessment.

Efficacy of DynaCT digital angiography in the detection of the fistulous point of dural arteriovenous fistulas.

BACKGROUND AND PURPOSE: Identifying the precise hemodynamic features, including the fistulous point, is essential for treatments of dural arteriovenous fistulas (DAVFs). This study illustrates the efficacy of DynaCT digital angiograms obtained from a 3D C-arm CT to directly visualize the location of the fistulous points in DAVFs. MATERIALS AND METHODS: This retrospective study observed 14 consecutive patients with DAVFs, which included 7 cavernous sinuses, 4 transverse-sigmoid sinuses, 2 convexity-superior sagittal sinuses, and 1 tentorial sinus. In the assessment of the practical applicability for the diagnosis of DAVFs, images obtained from 2D digital subtraction angiography (DSA) and DynaCT were comparatively evaluated. RESULTS: In all patients, DynaCT digital angiography could clearly demonstrate the feeding arteries, the fistulous points, and the draining veins. Significant anatomic landmarks for the fistulous points with relationships to osseous structures were also provided. Compared with 2D DSA, DynaCT digital angiograms demonstrated 12 additional findings in 8 patients (57%), including the detection of the fistulous points (n = 7), the feeders (n = 1), the retrograde leptomeningeal drainage (n = 1), the draining veins (n = 1), and the venous anomaly (n = 2). CONCLUSIONS: In comparison with 2D DSA, DynaCT may provide more detailed information to evaluate DAVFs. DynaCT digital angiograms have a high contrast and isotropic spatial resolution, allowing a reliable visualization of small vessels and fine osseous structures. Such detailed information, especially for the location of the fistulous points, could be very useful for either the endovascular or the surgical treatments of DAVFs.