Freezing of gait and white matter changes: a tract-based spatial statistics study.

BACKGROUND: We hypothesized that the integrity of white matter might be related to the severity of freezing of gait in age-related white matter changes. METHODS: Twenty subjects exhibiting excessive hyperintensities in the periventricular and deep white matter were recruited. The subjects underwent the Freezing of Gait Questionnaire, computerized gait analyses, and diffusion tensor magnetic resonance imaging. Images of axial, radial and mean diffusivity, and fractional anisotropy were calculated as indices of white matter integrity and analyzed with tract-based spatial statistics. RESULTS: The fractional anisotropy, mean, axial and radial diffusivity averaged across the whole white matter structure were all significantly correlated with Freezing of Gait Questionnaire scores. Regionally, a negative correlation between Freezing of Gait Questionnaire scores and fractional anisotropy was found in the left superior longitudinal fasciculus beneath the left premotor cortex, right corpus callosum, and left cerebral peduncle. The scores of the Freezing of Gait Questionnaire were positively correlated with mean diffusivity in the left corona radiata and right corpus callosum, and with both axial and radial diffusivity in the left corona radiata. The white matter integrity in these tracts (except the corpus callosum) showed no correlation with cognitive or other gait measures, supporting the specificity of those abnormalities to freezing of gait. CONCLUSION: Divergent pathological lesions involved neural circuits composed of the cerebral cortex, basal ganglia and brainstem, suggesting that freezing of gait has a multifactorial nature

Angle-resolved photoemission study of untwinned PrBa2_2Cu3_3O7_7: undoped CuO2_2 plane and doped CuO3_3 chain

We have performed an angle-resolved photoemission study on untwinned PrBa$_2$Cu$_3$O$_7$, which has low resistivity but does not show superconductivity. We have observed a dispersive feature with a band maximum around ($\pi$/2,$\pi$/2), indicating that this band is derived from the undoped CuO$_2$ plane. We have observed another dispersive band exhibiting one-dimensional character, which we attribute to signals from the doped CuO$_3$ chain. The overall band dispersion of the one-dimensional band agrees with the prediction of $t-J$ model calculation with parameters relevant to cuprates except that the intensity near the Fermi level is considerably suppressed in the experiment.Comment: 6 pages, 10 figure

Angle-resolved photoemission study of insulating and metallic Cu-O chains in PrBa2_2Cu3_3O7_7 and PrBa2_2Cu4_4O8_8

We compare the angle-resolved photoemission spectra of the hole-doped Cu-O chains in PrBa$_2$Cu$_3$O$_7$ (Pr123) and in PrBa$_2$Cu$_4$O$_8$ (Pr124). While, in Pr123, a dispersive feature from the chain takes a band maximum at $k_b$ (momentum along the chain) $\sim$ $\pi/4$ and loses its spectral weight around the Fermi level, it reaches the Fermi level at $k_b$ $\sim$ $\pi/4$ in Pr124. Although the chains in Pr123 and Pr124 are approximately 1/4-filled, they show contrasting behaviors: While the chains in Pr123 have an instability to charge ordering, those in Pr124 avoid it and show an interesting spectral feature of a metallic coupled-chain system.Comment: 4 pages, 5 figures, to be published in PR

Human Microglia Transplanted in Rat Focal Ischemia Brain Induce Neuroprotection and Behavioral Improvement

BACKGROUND AND PURPOSE: Microglia are resident immunocompetent and phagocytic cells of central nervous system (CNS), which produce various cytokines and growth factors in response to injury and thereby regulate disease pathology. The purpose of this study is to investigate the effects of microglial transplantation on focal cerebral ischemia model in rat. METHODS: Transient middle cerebral artery occlusion (MCAO) in rats was induced by the intraluminal filament technique. HMO6 cells, human microglial cell line, were transplanted intravenously at 48 hours after MCAO. Functional tests were performed and the infarct volume was measured at 7 and 14 days after MCAO. Migration and cell survival of transplanted microglial cells and host glial reaction in the brain were studied by immunohistochemistry. Gene expression of neurotrophic factors, cytokines and chemokines in transplanted cells and host rat glial cells was determined by laser capture microdissection (LCM) and quantitative real time-PCR. RESULTS: HMO6 human microglial cells transplantation group demonstrated significant functional recovery compared with control group. At 7 and 14 days after MCAO, infarct volume was significantly reduced in the HMO group. In the HMO6 group, number of apoptotic cells was time-dependently reduced in the infarct core and penumbra. In addition, number of host rat microglia/macrophages and reactive astrocytes was significantly decreased at 7 and 14 days after MCAO in the penumbra. Gene expression of various neurotrophic factors (GDNF, BDNF, VEGF and BMP7) and anti-inflammatory cytokines (IL4 and IL5) was up-regulated in transplanted HMO6 cells of brain tissue compared with those in culture. The expression of GDNF and VEGF in astrocytes in penumbra was significantly up-regulated in the HMO6 group. CONCLUSIONS: Our results indicate that transplantation of HMO6 human microglial cells reduces ischemic deficits and apoptotic events in stroke animals. The results were mediated by modulation of gliosis and neuroinflammation, and neuroprotection provided by neurotrophic factors of endogenous and transplanted cells-origin

Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients.</p> <p>Methods/Design</p> <p>This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation.</p> <p>Discussion</p> <p>This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps.</p> <p>Trial registration</p> <p>This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as <a href="http://www.clinicaltrials.gov/ct2/show/UMIN000006254">UMIN000006254</a></p

Understanding the benefit of metformin use in cancer treatment

Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR) signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed

Colocalization of 14-3-3 Proteins with SOD1 in Lewy Body-Like Hyaline Inclusions in Familial Amyotrophic Lateral Sclerosis Cases and the Animal Model

Background and Purpose: Cu/Zn superoxide dismutase (SOD1) is a major component of Lewy body-like hyaline inclusion (LBHI) found in the postmortem tissue of SOD1-linked familial amyotrophic lateral sclerosis (FALS) patients. In our recent studies, 14-3-3 proteins have been found in the ubiquitinated inclusions inside the anterior horn cells of spinal cords with sporadic amyotrophic lateral sclerosis (ALS). To further investigate the role of 14-3-3 proteins in ALS, we performed immunohistochemical analysis of 14-3-3 proteins and compared their distributions with those of SOD1 in FALS patients and SOD1-overexpressing mice. Methods: We examined the postmortem brains and the spinal cords of three FALS cases (A4V SOD1 mutant). Transgenic mice expressing the G93A mutant human SOD1 (mutant SOD1-Tg mice), transgenic mice expressing the wild-type human SOD1 (wild-type SOD1-Tg mice), and non-Tg wild-type mice were also subjected to the immunohistochemical analysis. Results: In all the FALS patients, LBHIs were observed in the cytoplasm of the anterior horn cells, and these inclusions were immunopositive intensely for pan 14-3-3, 14-3-3$\beta$, and 14-3-3$\gamma$. In the mutant SOD1-Tg mice, a high degree of immunoreactivity for misfolded SOD1 (C4F6) was observed in the cytoplasm, with an even greater degree of immunoreactivity present in the cytoplasmic aggregates of the anterior horn cells in the lumbar spinal cord. Furthermore, we have found increased 14-3-3$\beta$ and 14-3-3$\gamma$ immunoreactivities in the mutant SOD1-Tg mice. Double immunofluorescent staining showed that C4F6 and 14-3-3 proteins were partially co-localized in the spinal cord with FALS and the mutant SOD1-Tg mice. In comparison, the wild-type SOD1-Tg and non-Tg wild-type mice showed no or faint immunoreactivity for C4F6 and 14-3-3 proteins (pan 14-3-3, 14-3-3$\beta$, and 14-3-3$\gamma$) in any neuronal compartments. Discussion: These results suggest that 14-3-3 proteins may be associated with the formation of SOD1-containing inclusions, in FALS patients and the mutant SOD1-Tg mice.Mathematic

Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use

Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug–drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress