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To: nigel bates who wrote (386)	4/4/2011 6:54:07 PM
From: scaram(o)uche	of 418

Aging Cell. 2011 Jan 18. doi: 10.1111/j.1474-9726.2011.00675.x. [Epub ahead of print] Age-related changes in human hematopoietic stem/progenitor cells. Kuranda K, Vargaftig J, de la Rochere P, Dosquet C, Charron D, Bardin F, Tonnelle C, Bonnet D, Goodhardt M. INSERM UMRS 940, Paris, France Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France Haematopoietic Stem Cell Laboratory, Cancer Research UK London Research Institute, London, UK Département de Biothérapies, Hôpital Saint-Louis, AP-HP; Paris, France Institut Paoli-Calmettes, Centre de Thérapie Cellulaire et Génique, Marseille, France. Abstract Adult stem cells are critical for maintaining cellular homeostasis throughout life, yet the effects of age on their regenerative capacity are poorly understood. All lymphoid and myeloid blood cell lineages are continuously generated from hematopoietic stem cells present in human bone marrow. With age, significant changes in the function and composition of mature blood cells are observed. In this study, we report that age-related changes also occur in the human hematopoietic stem cell compartment. We find that the proportion of multipotent CD34(+) CD38(-) cells increases in the bone marrow of elderly (>70 years) individuals. CD34(+) CD38(+) CD90(-) CD45RA(+/-) CD10(-) and CD34(+) CD33(+) myeloid progenitors persist at the same level in the bone marrow, while the frequency of early CD34(+) CD38(+) CD90(-) CD45RA(+) CD10(+) and committed CD34(+) CD19(+) B-lymphoid progenitors decreases with age. In contrast to mice models of aging, transplantation experiments with immunodeficient NOD/SCID/IL-2R? null (NSG) mice showed that the frequency of NSG repopulating cells does not change significantly with age, and there is a decrease in myeloid lineage reconstitution. An age-related decrease in the capacity of CD34(+) cells to generate myeloid cells was also seen in colony-forming assays in vitro. Thus, with increasing age, human hematopoietic stem/progenitor cells undergo quantitative changes as well as functional modifications. (so maybe we need to include a macrophage agonist in old people's vitamins?.... viewed through the narrow window of a CD33 freak, after about half an hour of thought.... not worth even reading this. :-)

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From: scaram(o)uche	4/27/2011 5:13:54 PM
	of 418

don't read, Tuck.... Neuroscience. 2011 Apr 7. [Epub ahead of print] Topiramate promotes neurological recovery in a new model of traumatic brain injury in rats. Kouzounias K, Kimiskidis VK, Siozos T, Violaris K, Kostomitsopoulos N, Karayannakos PE, Sotirakoglou K, Nanassis K. SourceDepartment of Neurosurgery, Aristotle University of Thessaloniki, Ippokrateio Hospital, Thessaloniki, Greece. Abstract The aim of this study is to investigate the neuroprotective effects of the anticonvulsant topiramate in a new model of traumatic brain injury in rats. A new model of traumatic brain injury, based on the weight-drop technique, was developed for the purpose of this study. Seventy-five male Wistar rats weighing 320-470 g were studied. All rats were anesthetized, subsequently submitted to a round craniectomy in the left parietal region and a weight of 50 g was used for the production of a cortical contusion. In study I, 44 rats were randomized in three groups to receive either topiramate 40 mg/kg (n=13), topiramate 60 mg/kg (n=14), or water for injection (n=17) i.p. 30 min after the injury and every 12 h thereafter for 3 days. The rats were tested clinically 24 h, 72 h, 10 days and 20 days after the injury. On day 21 the animals were sacrificed and the brains were removed and prepared for histopathological analysis. In study II, 19 rats were randomized to receive either topiramate 60 mg/kg (n=10) or water for injection (n=9) i.p. 30 min after the injury and every 12 h (four doses in total). 48 h after the injury the animals were sacrificed and the brains were rapidly removed and analyzed for water content with the dry-wet weight technique. The animals that received topiramate performed significantly better in neurological tests compared to the animals that received vehicle ten (P<0.05) and 20 (P<0.001) days after the injury. There was no difference between the high and the low dose of the drug. Topiramate had no effect on the anatomic volume of the lesion. The animals that received topiramate had a tendency to present with less cerebral edema formation, but the difference was not statistically significant (P>0.05). These findings suggest that topiramate promotes neurological recovery in rats after traumatic brain injury without affecting the final size of the traumatic lesion and that it might play a role in the reduction of post-traumatic cerebral edema.

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From: scaram(o)uche	6/23/2011 1:07:00 PM
	of 418

Proc Natl Acad Sci U S A. 2011 Jun 20. [Epub ahead of print] Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. Albayram O, Alferink J, Pitsch J, Piyanova A, Neitzert K, Poppensieker K, Mauer D, Michel K, Legler A, Becker A, Monory K, Lutz B, Zimmer A, Bilkei-Gorzo A. Institute of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, and Institute of Neuropathology, University of Bonn, 53127 Bonn, Germany. Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.

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To: scaram(o)uche who wrote (389)	6/24/2011 6:52:53 AM
From: nigel bates	of 418

A side effect of many commonly used drugs appears to increase the risks of both cognitive impairment and death in older people, according to new research led by the University of East Anglia. As part of the Medical Research Council’s Cognitive Function and Ageing Studies (CFAS) project, the study is the first systematic investigation into the long term health impacts of ‘anticholinergic activity’ – a known potential side effect of many prescription and over the counter drugs which affects the brain by blocking a key neurotransmitter called acetylcholine. The findings are published today by the Journal of the American Geriatrics Society... uea.ac.uk List of drugs in the study, sorted by anticholinergic burden: uea.ac.uk

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To: DewDiligence_on_SI who wrote (391)	6/27/2011 11:29:47 AM
From: nigel bates	of 418

Filter or espresso ? GHENT, Belgium, 27 June 2011 - Ablynx [Euronext Brussels: ABLX] today announced that it has earned a €5 million milestone payment following Boehringer Ingelheim’s decision to initiate development with the lead Nanobody candidate that was selected in May 2010. In January 2007, Boehringer Ingelheim and Ablynx announced a worldwide research and licensing agreement to discover and develop new therapies for Alzheimer’s disease using Ablynx’s Nanobodies against a single disease target. The collaboration has a potential value of $265 million in upfront and milestone payments plus undisclosed royalties on product sales. Boehringer Ingelheim is solely responsible for the development, manufacturing and commercialisation of any products resulting from the collaboration. “We are delighted that Boehringer Ingelheim is making further progress with the Nanobody lead candidate which has the potential to be a first-in-class therapy for Alzheimer’s disease and we look forward to this product advancing into the clinic in 2012. This is the second milestone payment that we have received as part of our Alzheimer’s research collaboration with Boehringer Ingelheim,” said Dr. Edwin Moses, Chairman and CEO of Ablynx. He added: “This programme illustrates the wide applicability and advantages of our Nanobody platform in addressing diseases as complex as Alzheimer’s.

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From: scaram(o)uche	8/22/2011 9:59:01 AM
	of 418

J Neuroinflammation. 2011 Aug 18;8(1):102. [Epub ahead of print] Anandamide inhibits Theiler's virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB1 receptors. Mestre L, Inigo PM, Mecha M, Correa FG, Hernangomez-Herrero M, Loria F, Docagne F, Borrell J, Guaza C. BACKGROUND: VCAM-1 represents one of the most important adhesion molecule involved in the transmigration of blood leukocytes across the blood-brain barrier (BBB) that is an essential step in the pathogenesis of MS. Several evidences have suggested the potential therapeutic value of cannabinoids (CBs) in the treatment of MS and their experimental models. However, the effects of endocannabinoids on VCAM-1 regulation are poorly understood. In the present study we investigated the effects of anandamide (AEA) in the regulation of VCAM-1 expression induced by Theiler's virus (TMEV) infection of brain endothelial cells using in vitro and in vivo approaches. METHODS: i) in vitro: VCAM-1 was measured by ELISA in supernatants of brain endothelial cells infected with TMEV and subjected to AEA and/or cannabinoid receptors antagonist treatment. To evaluate the functional effect of VCAM-1 modulation we developed a blood brain barrier model based on a system of astrocytes and brain endothelial cells co-culture. ii) in vivo: CB1 receptor deficient mice (Cnr1-/-) infected with TMEV were treated with the AEA uptake inhibitor UCM707 for three days. VCAM-1 expression and microglial reactivity were evaluated by immunohistochemistry. RESULTS: Anandamide-induced inhibition of VCAM-1 expression in brain endothelial cell cultures was mediated by activation of CB1 receptors. The study of leukocyte transmigration confirmed the functional relevance of VCAM-1 inhibition by AEA. In vivo approaches also showed that the inhibition of AEA uptake reduced the expression of brain VCAM-1 in response to TMEV infection. Although a decreased expression of VCAM by UCM-707 was observed in both, wild type and CB1 receptor deficient mice (Cnr1-/-), the magnitude of VCAM-1 inhibition was significantly higher in the wild type mice. Interestingly, Cnr1-/- mice showed enhanced microglial reactivity and VCAM-1 expression following TMEV infection, indicating that the lack of CB1 receptor exacerbated neuroinflammation. CONCLUSIONS: Our results suggest that CB1 receptor dependent VCAM-1 inhibition is a novel mechanism for AEA-reduced leukocyte transmigration and contribute to a better understanding of the mechanisms underlying the beneficial role of endocannabinoid system in the Theiler's virus model of MS. free full text (haven't looked at it)...... jneuroinflammation.com

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From: tuck	10/6/2011 1:29:52 PM
	1 Recommendation of 418

[Alzheimer's as an infectious disease?] >>Molecular Psychiatry , (4 October 2011) \| doi:10.1038/mp.2011.120 De novo induction of amyloid-ß deposition in vivo R Morales, C Duran-Aniotz, J Castilla, L D Estrada and C Soto Abstract Alzheimer's disease (AD), the most common type of senile dementia, is associated to the build-up of misfolded amyloid-ß (Aß) in the brain. Although compelling evidences indicate that the misfolding and oligomerization of Aß is the triggering event in AD, the mechanisms responsible for the initiation of Aß accumulation are unknown. In this study, we show that Aß deposition can be induced by injection of AD brain extracts into animals, which, without exposure to this material, will never develop these alterations. The accumulation of Aß deposits increased progressively with the time after inoculation, and the Aß lesions were observed in brain areas far from the injection site. Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention.<< and some color from Derek Lowe: pipeline.corante.com Cheers, Tuck

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From: scaram(o)uche	12/1/2011 2:24:46 PM
	of 418

Endocrinology. 2011 Nov 22. [Epub ahead of print] Topiramate Treatment Protects Blood-Brain Barrier Pericytes from Hyperglycemia-Induced Oxidative Damage in Diabetic Mice. Price TO, Eranki V, Banks WA, Ercal N, Shah GN. Division of Endocrinology (T.O.P., V.E., G.N.S.), Department of Internal Medicine, Saint Louis University, Edward A. Doisy Research Center, St. Louis, Missouri 63104; Veterans Affairs Puget Sound Health Care Center/Geriatric Research Education and Clinical Centers, S-182 (W.A.B.), Seattle, Washington 98108; and Department of Chemistry (N.E.), Missouri University of Science and Technology, Rolla, Missouri 65409. Diabetes mellitus causes cerebral microvasculature deterioration and cognitive decline. The specialized endothelial cells of cerebral microvasculature comprise the blood-brain barrier, and the pericytes (PC) that are in immediate contact with these endothelial cells are vital for blood-brain barrier integrity. In diabetes, increased mitochondrial oxidative stress is implicated as a mechanism for hyperglycemia-induced PC loss as a prerequisite leading to blood-brain barrier disruption. Mitochondrial carbonic anhydrases (CA) regulate the oxidative metabolism of glucose and thus play an important role in the generation of reactive oxygen species and oxidative stress. We hypothesize that the inhibition of mitochondrial CA would reduce mitochondrial oxidative stress, rescue cerebral PC loss caused by diabetes-induced oxidative stress, and preserve blood-brain barrier integrity. We studied the effects of pharmacological inhibition of mitochondrial CA activity on streptozotocin-diabetes-induced oxidative stress and PC loss in the mouse brain. At 3 wk of diabetes, there was significant oxidative stress; the levels of reduced glutathione were lower and those of 3-nitrotyrosine, 4-hydroxy-2-trans-nonenal, and superoxide dismutase were higher. Treatment of diabetic mice with topiramate, a potent mitochondrial CA inhibitor, prevented the oxidative stress caused by 3 wk of diabetes. A significant decline in cerebral PC numbers, at 12 wk of diabetes, was also rescued by topiramate treatment. These results provide the first evidence that inhibition of mitochondrial CA activity reduces diabetes-induced oxidative stress in the mouse brain and rescues cerebral PC dropout. Thus, mitochondrial CA may provide a new therapeutic target for oxidative stress related illnesses of the central nervous system.

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