bluuebunny/crossref_metadata_2025 huggingface dataset:
Neue Therapieansätze bei der Behandlung von Tumoren: Histondeacetylase‐, Methyltransferase‐ und Proteasominhibitoren
Authors: Becker Jürgen C. , Ugurel Selma , Bröcker Eva‐Bettina , Schrama David , Houben Roland
Published: January 2006

Neue Erkenntnisse der Grundlagen und angewandten Forschung zu Fragen der Tumorentstehung und ‐progression bilden die Grundlage für moderne the‐rapeutische Entwicklungen. Gezielte Therapeutika greifen maßgeschneidert in molekulare Veränderungen der Onkogenese ein und ermöglichen so eine effektive und dabei wenig toxische Therapie von Tumoren einschließlich des Melanoms. Tumore basieren sowohl auf (zyto)genetischen als auch auf epige‐netischen Aberrationen. Das Schicksal einer Zelle beruht auf der feinen Balance von Expression und Repression von Genen. Die Beobachtung, dass in der Vielzahl von Tumoren dramatische Veränderungen der DNA‐Methylierung oder der Histonacetylierung vorliegen, führte zur Entwicklung und Charakterisie‐rung von Wirkstoffen, die diesen Umstand adressieren. Histondeacetylaseinhi‐bitoren oder Hemmstoffe der DNA‐Methylierung erlauben die Derepression von Tumorsuppressorgenen, während Proteasomeninhibitoren über eine verminderte Degradierung antitumoraler Proteine wirken. In der vorliegenden Übersicht sollen die theoretischen Grundlagen für diese neuen Therapie‐ansätze dargelegt werden.
Biology of the prolactin family in bovine placenta. I. Bovine placental lactogen: Expression, structure and proposed roles
Authors: TAKAHASHI Toru
Published: January 2006

Bovine placenta produces an array of proteins that are structurally and functionally similar to pituitary prolactin. Bovine placental lactogen (bPL) is a glycoprotein hormone that has lactogenic and somatogenic properties. Purified bPL contains several kinds of isoforms that are created by alternative splicing and/or multiple glycosylation patterns. bPL can activate the prolactin (PRL) receptor‐mediated signaling pathway as well as PRL does. The bPL mRNA is transcribed in trophoblast binucleate cells, and synthesized bPL protein is stored in membrane‐bound secretory granules. The message encoding bPL is first detectable in trophoblast binucleate cells at approximately day 20 of gestation at, or shortly after, the appearance of binucleate cells in the trophoblast. Most binucleate cells are detected as expressed bPL in the placenta. Bovine PL may be the determinant in trophoblast differentiation. Although the biological activities of bPL have long been studied, the precise role of bPL is still largely unclear. This article reviews and discusses the biological roles of bPL, focusing on luteal function, fetal growth and pregnancy‐associated maternal adaptation, mammogenesis and lactogenesis, and placental angiogenesis. The precise biological function of bPL needs to be further evaluated.
Effects of forage‐to‐concentrate ratio in prepartum diet on the dry matter intake and milk yield of periparturient cows during hot weather
Authors: KAMIYA Yuko , KAMIYA Mitsuru , TANAKA Masahito
Published: January 2006

The objective of this experiment was to study the effect of prepartum diets on dry matter intake (DMI) around parturition and on milk production in early lactation during a hot summer. Nine cows due to calve in July or August were assigned to two groups and fed either control (group C; four cows) or high‐concentrate (group H; five cows) diets to meet 110% of their energy requirements from 18 days before the expected calving date to parturition. The proportion of concentrate in the control diet was 35%, and that in the high‐concentrate diet was 45%. For 21 days after parturition, all cows were fed the same diets for lactation ad libitum. The DMI of cows in group H almost met their energy requirements. In group C, the DMI was decreased relative to group H and the concentration of plasma non‐esterified fatty acids was significantly higher (P < 0.05) before parturition. Therefore, the cows in group C were thought to be energy deficient before parturition. After parturition, there were no significant differences in DMI between the two groups. The milk yield of cows in group H tended to be higher than that of cows in group C at 21 days after parturition. Milk protein yield was significantly higher (P < 0.05) in group H 21 days after parturition relative to group C. There were no significant differences in milk composition between the two groups.
Dietary β‐alanine enhances brain, but not muscle, carnosine and anserine concentrations in broilers
Authors: TOMONAGA Shozo , KANEKO Kunio , KAJI Yuji , KIDO Yasuhiro , DENBOW Donald Michael , FURUSE Mitsuhiro
Published: January 2006

Carnosine (β‐alanyl‐L‐histidine) and its derivative anserine (β‐alanyl‐1‐methyl‐L‐histidine) are present in high concentrations in the muscle and brain of chickens. They are known as antioxidants and putative neurotransmitters in the brain. If administration of β‐alanine (β‐Ala), one of the constituents of carnosine, could increase the concentrations of these dipeptides in the brain and muscles, it could improve brain function and increase the commercial value of the meat in chickens. As an early step in investigating this hypothesis, in the present study, the effect of dietary β‐Ala on these dipeptide concentrations in the brain, Musculus pectoralis superficialis, Musculus pectoralis profundus and Musculus biceps femoris was investigated in broilers. Four‐week‐old broilers were given a commercial diet or diet containing 0.5, 1 or 2%β‐Ala for 4 weeks. At the end of the experiment, concentrations of both dipeptides were increased in the brain, while taurine concentration was decreased. In the muscles, concentrations of these dipeptides were unchanged. These results indicate that dietary β‐Ala might influence brain function, but is ineffective in increasing the concentrations of carnosine and anserine in the muscles of broilers.
Performance and welfare of broilers as affected by stocking density and zinc bacitracin supplementation
Authors: RAVINDRAN Velmurugu , THOMAS Donald V. , THOMAS David G. , MOREL Patrick C. H.
Published: January 2006

The influence of stocking density (16, 20 and 24 birds/m2) and zinc bacitracin (0 or 100 mg/kg) on the performance, carcass characteristics and some indirect welfare indicators of broilers were examined in a 35‐day trial. The weight gain, feed intake, liveability and carcass characteristics of broilers grown at densities of 16, 20 and 24 birds per m2 were similar (P > 0.05). Over the whole trial period, however, feed per gain of birds at the highest density (24 birds/m2) was higher (P < 0.05) than those at the other two densities. Litter quality was poorer at high population densities, but there were no welfare implications as indicated by the lack of effect of density on gait scores and the incidence of hock and fat pad burns. Inclusion of zinc bacitracin improved weight gains and feed intake of broilers over the 35‐day trial period at all three stocking densities tested. Zinc bacitracin supplementation had no influence on the feed per gain of birds reared at densities of 16 and 20 birds/m2, but improvements were observed at a density of 24 birds/m2. The relative weights of lymphoid organs (spleen and bursa) were lowered (P < 0.05) with increasing density, suggesting a greater degree of stress on the birds. Zinc bacitracin supplementation had no influence on bursa weights of birds reared at densities of 16 and 20 birds/m2, but increased the bursa weights of birds reared at a density of 24 birds/m2. Overall, these data indicate that, with the removal of in‐feed antibiotics in the future, care should be taken when considering population densities of greater than 20 birds/m2.
Effects of weather on egg characteristics of Isa Brown layers in Ibadan, Nigeria
Authors: DAUDA Taofik Oyedele , ADETAYO Adewale O. , TIAMIYU Adesina K.
Published: January 2006

The effects of weather indices on the performances and egg characteristics of layers was investigated using average egg data from randomly selected layers at the poultry farm of the Federal College of Agriculture, Institute of Agricultural Research and Training, Ibadan, Nigeria, in 2003. The layers used were selected in a randomized complete block design experiment. Data on characteristics of the eggs were obtained from selected eggs, and weather data were obtained from the climatological station of the Institute of Agricultural Research and Training, Ibadan, Nigeria. Canonical correspondence analysis was used to assess the linear relationships between the q and p sets of data obtained (q being the weather indices and p being the egg characteristics). The results of canonical correlation analysis revealed that hen day production and other egg characteristics are associated with some weather indices. Some level of redundancy was detected in the result.
Drug‐Related Visits to a District Hospital Emergency Room
Authors: Juntti‐Patinen Laura , Kuitunen Tapio , Pere Pertti , Neuvonen Pertti J.
Published: January 2006

Abstract: The role of adverse drug reactions (ADRs) as a cause of hospital visits varies depending on the type of hospitals. Our aim was to determine the incidence of drug‐related emergency department visits to a district hospital, and to identify the drugs and patient groups involved. All patient visits to the emergency department of a Finnish district hospital were evaluated prospectively for 6 months. The physician on duty and a clinical pharmacologist selected all possibly drug‐related visits for further scrutinising. The causality assessment (drug‐related or not) was judged according to WHO criteria, based on the patients' files, including laboratory and other data. Of the 7113 evaluated visits, 167 (2.3%) were “certainly” or “probably” drug‐related; 102 (1.4% of all) were related to ADRs and 65 (0.9%) to intentional overdoses. The most common ADRs were gastrointestinal symptoms (n=17) caused by antibiotics, opioids, nonsteroidal antiinflammatory or cytostatic drugs. The International Classification of Disease (ICD‐10) codes on patients' files were insensitive to disclose ADRs. The ADR patients were older (mean age 57 years) than the intentional overdose patients (38 years; P<0.001). Males predominated in the intentional overdose group (38 males, 27 females) but not in the ADR patients. The majority of intentional overdoses was caused by psychotropics. The ADRs lead to hospitalisation in a higher frequency (51%) than did the intentional overdoses (35%). In conclusion, the incidence of “certainly” or “probably” drug‐related visits to the district hospital emergency room was relatively low. The ICH‐10 codes on patients' files were found to be insensitive to disclose the ADRs, even when they lead to hospital admission, casting doubts on the usefulness of ICH codes alone in ADR evaluation.
Effects of Premedication Medicines on the Formation of the CYP3A4‐Dependent Metabolite of Ropivacaine, 2′, 6′‐Pipecoloxylidide, on Human Liver Microsomesin vitro
Authors: Tanaka Einosuke , Nakamura Takako , Inomata Shinichi , Honda Katsuya
Published: January 2006

Abstract:Ropivacaine is a relatively new amide‐type local anaesthetic, mainly used for surgery and postoperative pain relief. In this study we have investigated the interaction between the CYP3A4 metabolite of ropivacaine, 2′,6′‐pipecoloxylidide (PPX), and premedication with, i.e., psychotropic and antianxiety agents (diazepam, midazolam), hypnotics (thiamylal), local anaesthetics (lidocaine), depolarizing muscular relaxants (vecuronium), antihypertensive (clonidine) and H2‐receptor antagonist (cimetidine) using human liver microsomesin vitro.The effects of the interaction between PPX and premedications were examined using a human liver microsomal preparationin vitro.The concentrations of ropivacaine and PPX were determined by HPLC with UV detection. The apparent Michaelis‐Menten constant (Km) and the maximal velocity of total metabolic formation (Vmax) of PPX, the main metabolite of ropivacaine in human liver microsomes, were 17.7 (μM, mean) and 711 (nmol/min./mg protein, mean), respectively. Five premedications (diazepam, lidocaine, cimetidine, vecuronium and clonidine) did not inhibit ropivacaine metabolism in human liver microsomes at concentrations within the therapeutic range. However, midazolam and thiamylal weakly inhibited ropivacaine metabolism in competitive manner (IC507.8 μM and 250 μM, respectively). The results show lack of interaction between ropivacaine and seven premedication medicines within the therapeutic range of ropivacaine using human liver microsomesin vitro.
Pain Perception after Subcutaneous Injections of Media Containing Different Buffers
Authors: Laursen Torben , Hansen Birtha , Fisker Sanne
Published: January 2006

Abstract: Several hormones are administered by daily subcutaneous injections. Pain caused by subcutaneous injection is an unpleasant condition, which can limit patient compliance. The objective of the present study was to evaluate the perception of pain by subcutaneous injection of two different and commercially available solutions for dispensing recombinant human growth hormone. The solutions are characterised by pH, conservation, and buffer. Isotonic saline was used as reference solution. Fifty‐four healthy volunteers (mean age (±S.E.M.): 35.5±1.1 years) were recruited to the double‐blind, randomised study. All injections were performed pairwise (right and left thigh) in one day by the same experienced nurse. Perception of pain was evaluated by the volunteers immediately after injection and 2 min. after injection into the thigh of three formulations, which differed with respect to pH and buffers (histidine, citrate and saline, respectively). Significantly more participants (38/54) found than the citrate buffer caused more pain than the histidine buffer immediately after injection (P=0.002). Histidine buffer did not cause more pain than saline (P=0.996). After 2 min., there was no difference between the histidine and the citrate buffer (P=1.00), nor between the histidine buffer and saline (P=1.00). In summary, the solution‐containing citrate as buffer caused more pain after subcutaneous injection than the solution with histidine as buffer. Considering patient compliance, it seems advisable to employ histidine‐buffered solution rather than citrate‐buffered solution for dispensing recombinant human growth hormone by daily subcutaneous injections.
Dual Effect of Flurbiprofen on Cell Proliferation and Agonist‐Induced Ca2+ Movement in Human Osteosarcoma Cells
Authors: Tseng Li‐Ling , Cheng He‐Hsiung , Huang Chun‐Jen , Liu Shiuh‐Inn , Kuo Chun‐Chi , Chen Wei‐Chuan , Huang Jong‐Khing , Hsu Shu‐Shong , Chang Hong‐Tai , Kao Cheng‐Hsing , Ho Chin‐Man , Jan Chung‐Ren
Published: January 2006

Abstract: In human MG63 osteosarcoma cells, the effect of flurbiprofen on intracellular Ca2+ concentrations ([Ca2+]i) and proliferation was explored. The proliferation was enhanced by 20–120 μM flurbiprofen, and was decreased by 140–200 μM flurbiprofen. The effect of flurbiprofen on the increases in cytosolic free Ca2+ levels ([Ca2+]i) induced by ATP, bradykinin, histamine and thapsigargin (an inhibitor of the endoplasmic reticulum Ca2+ ATPase), was examined. In cell preincubated with 20 or 80 μM flurbiprofen, the [Ca2+]i increases induced by all agonists were attenuated. In the presence of 20 μM flurbiprofen, the decreased [Ca2+]i responses with the agonists were attributed to a defective Ca2+ influx because this decrease was unobserved in agonists‐induced [Ca2+]i increases in the absence of extracellular Ca2+. In the presence of 80 μM flurbiprofen, both the Ca2+ influx component and the Ca2+ releasing (from organelles) component were defective. These results suggest that flurbiprofen could alter proliferation and inhibit [Ca2+]i increases.
Effect of Chromium Picolinate on Modified Forced Swimming Test in Diabetic Rats: Involvement of Serotonergic Pathways and Potassium Channels
Authors: Khanam Razia , Pillai K. K.
Published: January 2006

Abstract: Depression occurs frequently in patients with diabetes mellitus. Chromium picolinate, an essential trace element is recommended for diabetes and also has been reported to benefit depression, but its mechanism is still debated. To investigate the mechanism, we studied its effects on serum insulin, serum glucose and on modified forced swimming test, a behavioural paradigm for depression in rats. The study involving co‐administration of subactive doses of glimepiride, a K+ channel blocker and chromium picolinate on blood glucose levels and modified forced swimming test was also performed to probe any role of K+ channels in its antidiabetic and antidepressants effects. Streptozotocin (55 mg/kg, intraperitoneally) was injected in rats to induce diabetes (Type 1). After a week, chromium picolinate (8 μg/ml in drinking water) was administered for 4 weeks. Normal rats received similar drug treatment. The subactive doses of chromium picolinate (4 μg/ml in drinking water) and glimeperide (2.5 mg/kg, orally) were co‐administered and their effects on modified forced swimming test and on glucose levels were measured. Chromium picolinate (8 μg/ml in drinking water) produced hypoglycaemia in diabetic and normal rats. It had no effects on the streptozotocin‐induced reduction in insulin levels. Chromium picolinate (8 μg/ml in drinking water) increased swimming with subsequent decrease in immobility. The subactive doses of chromium picolinate and glimeperide showed significant additive effects in modified forced swimming test and reduction in serum glucose concentrations, though statistically insignificant. In conclusion chromium picolinate shows antidepressant action on modified forced swimming test affecting only swimming that suggests serotonergic pathways involvement. The additive effects on swimming in modified forced swimming test and reduction in serum glucose levels shows involvement of K+ channels in antidiabetic and antidepressant actions of chromium picolinate.
Effect of Sodium Bicarbonate in Rats Acutely Poisoned with Dichlorvos
Authors: Stefanovic Danka , Antonijevic Biljana , Bokonjic Dubravko , Stojiljkovic Miloš P. , Milovanovic Zoran A. , Nedeljkovic Mirjana
Published: January 2006

Abstract: The development of effective antidotes against organophosphates such as dichlorvos has been a persistent challenge over the past decades. Therapy of organophosphate poisoning is based on the administration of atropine and oxime as standard antidotes. The present study was undertaken to evaluate the ability of sodium bicarbonate to improve protective effects of standard antidotes in rats poisoned with dichlorvos. The aim of this experiment was to establish the correlation between protective effects and biochemical parameters relevant for acid‐base status. In order to examine the protective effect of both standard antidotes and their combinations, groups of experimental animals were poisoned subcutaneously with increasing doses of dichlorvos. Immediately thereafter, rats were treated with atropine 10 mg/kg intramuscularly, oximes 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally. These antidotes were administered either as single doses or in combinations. In the biochemical part of the experiments, rats were poisoned with dichlorvos 1.3 LD50 (10.64 mg/kg) subcutaneously and immediately thereafter treated with atropine 10 mg/kg intramuscularly, oximes (trimedoxime or obidoxime) 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally either as single doses or in combinations. Parameters relevant for acid‐base status were measured 10 minutes after the administration of antidotes. The results of our study indicate that addition of sodium bicarbonate to standard antidotes significantly improves protective effects of atropine, obidoxime and trimedoxime. Correlation between protection and biochemical outcome is clearly evident when sodium bicarbonate is being added to atropine.
Effects of cyhalothrin on the transient outward potassium current in central neurons ofHelicoverpa armigera
Authors: WANG YONG , HE BING‐JUN , ZHAO QIANG , LIANG ZHI , LIU AN‐XI
Published: January 2006

AbstractThe effects of cyhalothrin on the transient outward potassium current in central neurons ofHelicoverpa armigerawere studied by using the patch clamp techniques. The results showed that before using cyhalothrin (10−5mmol/L), activation potential was approximately ‐40 mV, after application of the drug, the activation potential shifted roughly 10 mV to the negative potential direction, so channels can be activated more easily. Before and after cyhalothrin application, the change of current amplitude was insignificant. The value of V1/2and k of activation curves did not change significantly, however, the V1/2of the inactivation curves changed significantly. Inactivation curves significantly shifted to a negative direction, so that inactivation of the channels was hastened. It is indicated that there may exit a primary way in which cyhalothrin provides neurotoxicity to the nervous system through the regulation of activation potentials and inactivation state of IAchannels.
Differences in nutrient uptake between the fat body and embryonic primary cultures of silkworm (Bombyx mori)
Authors: MATINDOOST LEILA , SENDI JALAL J. , JAHI HOORIEH SOLEIMAN , ETEBARI KAYVAN
Published: January 2006

Abstract
Nutrition utilization and by‐product formation in cultured insect cells has been investigated in several insect cells and has been of great interest to cell culturists and physiologists. In this research the biochemical changes in embryonic and fat body primary cultures of silkworm, Bombyx mori, have been compared. TC‐100 medium supplemented with 10% and 20% FBS was used in embryonic and fat body primary cultures, respectively. Medium was renewed every week and the amount of glucose, uric acid, urea, total protein and alkaline phosphatase were measured in the samples from medium of primary cultures using spectrophotometeric methods. All biochemical macromolecules except uric acid showed significant changes. Glucose decreased in embryonic tissues, while in fat body culture its amount increased. Urea accumulation in embryonic culture was higher than in the fat body cultures. Since urea is a by‐product, this accumulation could be due to higher utilization of amino acids. Total protein showed considerable changes and was consumed by embryonic culture more than the fat body's. Alkaline phosphatase showed stronger activity in embryonic cells.
Functional response of the ladybird, Cydonia vicina nilotica to cowpea aphid, Aphis craccivora in the laboratory
Authors: MANDOUR NASSER SAID , EL‐BASHA NESREN ABDEL‐SALLAM , LIU TONG‐XIAN
Published: January 2006

Abstract
The functional response of Cydonia vicina nilotica Muls. (Coleoptera: Coccinellidae) to six densities of Aphis craccivora Koch (Homoptera: Aphididae) nymphs on broad bean (Vicia faba Linn.) was investigated in the laboratory. A linear relationship between the rate of consumption and prey density was observed with r2 values between 0.58 and 0.97. Plotting prey density against prey killed by four larval instars, and adult males and females of C. vicina nilotica fit well with the type II model of Holling's disc equation. Adult females consumed the highest number of prey, followed by fourth instars and adult males. Based on the functional response data, the model predicts a maximum of 144.9, 116.3, 86.2, 80.0, 72.5 and 20.0 nymphs to be consumed per day by an individual adult female, fourth instar, adult male, third, second and first instars, respectively. The differences in the responses of the predator to aphid densities are discussed.
A Very Incomplete Comprehensive Theory of Alzheimer's Disease
Authors: DAVIES PETER
Published: January 2006

Abstract: For this meeting, I was asked to put down some ideas toward the development of theories of the etiology and pathogenesis of Alzheimer's disease. This charge has led to a first attempt to consider the “big picture,” at least as seen from my viewpoint. Many details of the schemes I propose could be discussed in much greater depth, but I have tried to avoid getting bogged down in this way. It is sometimes valuable to step back from our own little domains of research and to attempt to integrate what we have collectively discovered into a more comprehensive framework.
Role of Blood Vessels in Producing Pathological Changes in the Brain with Alzheimer's Disease
Authors: MIYAKAWA TAIHEI , KIMURA TAKEMI , HIRATA SHINICHI , FUJISE NOBORU , ONO TSUNEHIKO , ISHIZUKA KOKO , NAKABAYASHI JUN
Published: January 2006

Abstract: Vascular factors have been shown to be highly involved in the deposition of the amyloid β‐protein (Aβ) in the brain of Alzheimer's disease (AD). However, the detailed mechanism remains unknown. Here, we showed that more numerous deposits of Aβ40 and Aβ42 in the brain were found in AD patients than in controls. Together with evidence of no difference in the level of Aβ40 and Aβ42 in sera between sporadic AD and conrols, a certain dysfunction of the blood‐brain barrier could induce an abnormal transport of Aβ from sera to the parenchyma in AD. In addition, vascular Aβ deposits and mature Aβ plaques stained by Congo red in AD brains contained more Aβ40 than Aβ42, whereas Congo red‐negative immature plaques mainly consisted of Aβ42. Our confocal laser scanning microscopy demonstrated an intimate relationship between Aβ40 and the vascular network. The amount of mature plaques but not that of immature plaques was reportedly correlated with the severity of dementia in AD patients. These results suggest that serum‐derived Aβ40 and/or Aβ42 cause Aβ40 deposition in and around blood vessels through unknown but possible mechanisms such as (1) endocytosis of Aβ40, (2) selective transport Aβ40 and Aβ42 into blood vessels and the parenchyma, respectively, and (3) proteolysis of Aβ42 into Aβ40 induced by a putative carboxyl dipeptidase in blood vessels including vascular feet, which is involved in Aβ fibrillation and cognitive deterioration in the patients. Therefore, the accumulation of Aβ40 associated with blood vessels may play a critical role in the development of AD.
Role of Aberrant Nitric Oxide Synthase‐3 Expression in Cerebrovascular Degeneration and Vascular‐mediated Injury in Alzheimer's Disease
Authors: DE LA MONTE SUZANNE M. , SOHN YOON K. , ETIENNE DANNIE , KRAFT JOANNY , WANDS JACK R.
Published: January 2006

Abstract:Nitric oxide (NO) is an important signaling molecule that is generated through the catalytic activity of nitric oxide synthase (NOS). In the brain, NO mediates neuronal survival, synaptic plasticity, vascular smooth muscle relaxation, and endothelial cell permeability. Previous studies demonstrated aberrant expression of the NOS‐III gene in neurons and glial cells in brains with Alzheimer's disease (AD). Since NOS‐III is also expressed in vascular cells, and cerebrovascular disease (CVD) frequently complicates the pathology of AD, we investigated the role of NOS‐III in relation to CVD in AD. Vasculopathy in AD+CVD was characterized by thickening and hyalinization of the media of small and medium‐size vessels, variable degrees of β‐amyloid (Aβ) deposition, and increased apoptosis of vascular smooth muscle and endothelial cells, particularly involving white matter vessels. These abnormalities were correlated with reduced levels of NOS‐III expression in cerebral vessels. Double‐labeling studies demonstrated that the low levels of cerebrovascular NOS‐III were associated with increased levels of the pro‐apoptosis gene product, p53 in smooth muscle and endothelial cells, suggesting a role for altered NOS‐III expression in AD‐associated vascular degeneration. Constitutively reduced cerebrovascular NOS‐III expression and NO production could also lead to cerebral hypoperfusion due to impaired vasodilation responses, and diminished capacity to remove respiratory waste products and toxins from the extracellular space due to reduced capillary permeability. The role for phosphodiesterases as modulators of NOS activity is discussed, as these molecules represent potential therapeutic targets given their cell type and cyclic nucleotide specificities of action.
Traumatic Brain Injury Elevates the Alzheimer's Amyloid Peptide Aβ42 in Human CSF: A Possible Role for Nerve Cell Injury
Authors: EMMERLING M. R. , MORGANTI‐KOSSMANN M. C. , KOSSMANN T. , STAHEL P. F. , WATSON M. D. , EVANS L. M. , MEHTA P. D. , SPIEGEL K. , KUO Y.‐M. , ROHER A. E. , RABY C. A.
Published: January 2006

Abstract: The increased risk for Alzheimer's Disease (AD) associated with traumatic brain injury (TBI) suggests that environmental insults may influence the development of this age‐related dementia. Recently, we have shown that the levels of the β‐amyloid peptide (Aβ1–42) increase in the cerebrospinal fluid (CSF) of patients after severe brain injury and remain elevated for some time after the initial event. The relationships of elevated Aβ with markers of blood‐brain barrier (BBB) disruption, inflammation, and nerve cell or axonal injury were evaluated in CSF samples taken daily from TBI patients. This analysis reveals that the rise in Aβ1–42 is best correlated with possible markers of neuronal or axonal injury, the cytoskeletal protein tau, neuron‐specific enolase (NSE), and apolipoprotein E (ApoE). Similar or better correlations were observed between Aβ1–40 and the three aforementioned markers. These results imply that the degree of brain injury may play a decisive role in determining the levels of Aβ1–42 and Aβ1–40 in the CSF of TBI patients. Inflammation and alterations in BBB may play lesser, but nonetheless significant, roles in determining the Aβ level in CSF after brain injury.
A Newly Formed Amyloidogenic Fragment due to a Stop Codon Mutation Causes Familial British Dementia
Authors: GHISO J. , VIDAL R. , ROSTAGNO A. , MEAD S. , RÉVÉSZ T. , PLANT G. , FRANGIONE B.
Published: January 2006

Abstract: Familial British dementia (FBD) is an early‐onset autosomal dominant disorder characterized by progressive cognitive impairment, spasticity, and cerebellar ataxia. Hippocampal neurofibrillar degeneration and widespread parenchymal and vascular amyloid deposits are the main neuropathological lesions. Amyloid fibrils are composed of a novel 34 amino acid subunit (ABri) with no sequence identity to any known amyloid molecule. The peptide derives from a larger precursor protein codified by a single gene BRI on chromosome 13. Affected family members have a single base substitution at the stop codon of the BRI gene that generates a longer open‐reading frame resulting in a larger precursor protein. The release of the 34 C‐terminal amino acids from the mutated precursor originates the ABri amyloid subunit. Our discovery of a new amyloid associated with the development of dementia supports the concept that amyloid peptides may be of primary importance in the initiation of neurodegeneration.
Relationship between Severe Amyloid Angiopathy, Apolipoprotein E Genotype, and Vascular Lesions in Alzheimer's Disease
Authors: OLICHNEY J. M. , HANSEN L. A. , LEE J. H. , HOFSTETTER C. R. , KATZMAN R. , THAL L. J.
Published: January 2006

Abstract: In this brief review, we aim to describe the complex relationship between cerebral amyloid angiopathy (CAA), apolipoprotein E (ApoE), and cerebrovascular lesions in Alzheimer's disease (AD). First, we review the evidence that CAA is associated with, and may cause, specific types of vascular lesions (VLs). In addition to being a leading cause of lobar hemorrhages in the elderly, CAA has been implicated as a likely cause of small infarcts, microinfarcts, and incomplete infarctions in the deep white matter. We also review the role that ApoE4 (the major genetic risk factor for AD) has in predisposing toward CAA, coronary artery disease, and possibly toward cerebrovascular disease. Last, we provide evidence that the association between CAA and VLs is not a spurious one due to an increase in the ApoE4 genotype. Even within patient groups with the same ApoE genotype (specifically, E4/4 homozygotes and E3/3 homozygotes), our recent analyses have found significant increases in VLs in association with severe CAA. We discuss the implications of this finding as advancing a pathogenic role for severe CAA in producing many of the VLs commonly found in AD cases.
Aβ Vasoactivity in Vivo
Authors: SUO ZHIMING , SU GEORGE , PLACZEK ANDON , KUNDTZ AMY , HUMPHREY JAMES , CRAWFORD FIONA , MULLAN MIKE
Published: January 2006

Abstract: Bilateral temporoparietal hypoperfusion has been frequently observed early in the Alzheimer's disease (AD) process. The β‐amyloid (Aβ) peptide is believed to play a central role in the pathogenesis of AD. In vitro experiments have shown that freshly solubilized Aβ enhances constriction of cerebral and peripheral vessels. We proposed that in vivo, Aβ would also have vasoactive properties. To test this hypothesis, we intraarterially infused freshly solubilized Aβ1–40 in rats and observed changes in peripheral blood pressure, cerebral blood flow, and cerebrovascular resistance. We found that infusion of Aβin vivo significantly increased the blood pressure in hypotensive rats but not in normotensive and hypertensive rats. Moreover, Aβ infusion also resulted in a decreased blood flow and increased vascular resistance specifically in cerebral cortex but not in heart or kidneys. These data suggest that Aβ has a direct and specific constrictive effect on cerebral vessels in vivo, which may contribute to the cerebral hypoperfusion observed early in the AD process.
Lipoproteins in the Central Nervous System
Authors: LADU MARY JO , REARDON CATHERINE , VAN ELDIK LINDA , FAGAN ANNE M. , BU GUOJUN , HOLTZMAN DAVID , GETZ GODFREY S.
Published: January 2006

Abstract: Although the synthesis and metabolism of plasma lipoproteins are well characterized, little is known about lipid delivery and clearance within the central nervous system (CNS). Our work has focused on characterizing the lipoprotein particles present in the cerebrospinal fluid (CSF) and the nascent particles secreted by astrocytes. In addition to carrying lipids, we have found that β‐amyloid (Ab) associates with lipoproteins, including the discoidal particles secreted by cultured astrocytes and the spherical lipoproteins found in CSF. We believe that association with lipoproteins provides a means of transport and clearance for Aβ. This process may be further influenced by an interaction between Ab and apoprotein E (apoE), the primary protein component of CNS lipoproteins. Specifically, we have investigated the formation and physiologic relevance of a SDS‐stable complex between apoE and Aβ. In biochemical assays, native apoE2 and E3 (associated with lipid particles) form an SDS‐stable complex with Ab that is 20‐fold more abundant than the apoE4:Aβ complex. In cell culture, native apoE3 but not E4 prevents Aβ‐induced neurotoxicity by a mechanism dependent on cell surface apoE receptors. In addition, apoE and the inhibition of apoE receptors prevent Aβ‐induced astrocyte activation. Therefore, we hypothesize that the protection from Aβ‐induced neurotoxicity afforded by apoE3 may result from clearance of the peptide by SDS‐stable apoE3:Aβ complex formation and uptake by apoE receptors.
Amyloid‐β‐induced Degeneration of Human Brain Pericytes Is Dependent on the Apolipoprotein E Genotype
Authors: VERBEEK MARCEL M. , VAN NOSTRAND WILLIAM E. , OTTE‐HÖLLER IRENE , WESSELING PIETER , DE WAAL ROBERT M. W.
Published: January 2006

Abstract: Amyloid‐β (Aβ) deposition in cerebral vessels (cerebral amyloid angiopathy, CAA) is accompanied by degeneration of vascular cells, including pericytes and smooth muscle cells. Previous studies indicated that specific Aβ protein isoforms are toxic for cultured human brain pericytes and smooth muscle cells. In particular, Aβ1–40 carrying the E22Q mutation, as in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA‐D), is toxic. We investigated the effects of the Aβ‐binding protein apolipoprotein E (ApoE) on the toxicity of Aβ for cultured human brain pericytes. We compared the toxicity of HCHWA‐D Aβ1–40 for pericyte cultures with different ApoE genotypes, studied the accumulation of Aβ and ApoE in these different cell cultures, and investigated the effects of exogenous ApoE. Pericyte cultures with an ApoE ɛ2/ɛ3 genotype were more resistant to HCHWA‐D Aβ1–40 treatment than cultures with a ɛ3/ɛ3 or ɛ3/ɛ4 genotype. Cell death was highest in cultures homozygous for ApoE ɛ4. The extent to which both Aβ and ApoE accumulated at the cell surface was parallel to the degree of toxicity. The addition of purified ApoE resulted in a decrease in cell death. These data suggest that ApoE4 may direct Aβ more efficiently than other ApoE isoforms into a pathological interaction with the HBP cell surface. The results of this study are in line with the observations that inheritance of the ApoE ɛ4 allele increases the risk of developing Alzheimer's disease, and that the ApoE ɛ2 allele has a relatively protective effect.
Inherent Abnormalities in Energy Metabolism in Alzheimer Disease: Interaction with Cerebrovascular Compromise
Authors: BLASS JOHN P. , SHEU REX KWAN‐FU , GIBSON GARY E.
Published: January 2006

Abstract:Alzheimer disease (AD) is a form of the dementia syndrome. AD appears to have a variety of fundamental etiologies that lead to the neuropathological manifestations which define the disease. Patients who are at high risk to develop AD typically show impairments of cerebral metabolic ratein vivoeven before they show any evidence of the clinical disease on neuropsychological, electrophysiological, and neuroimaging examinations. Therefore, impairment in energy metabolism in AD can not be attributed to loss of brain substance or to electrophysiological abnormalities. Among the characteristic abnormalities in the AD brain are deficiencies in several enzyme complexes which participate in the mitochondrial oxidation of substrates to yield energy. These include the pyruvate dehydrogenase complex (PDHC), the α‐ketoglutarate dehydrogenase complex (KGDHC), and Complex IV of the electron transport chain (COX). The deficiency of KGDHC may be due to a mixture of causes including damage by free radicals and perhaps to genetic variation in theDLSTgene encoding the core protein of this complex. Inherent impairment of glucose oxidationbythe AD brain may reasonably be expected to interact synergistically with an impaired supply of oxygen and glucosetothe AD brain, in causing brain damage. These considerations lead to the hypothesis that cerebrovascular compromise and inherent abnormalities in the brain's ability to oxidize substrates can interact to favor the development of AD, in individuals who are genetically pre‐disposed to develop neuritic plaques.
Insulin Effects on Glucose Metabolism, Memory, and Plasma Amyloid Precursor Protein in Alzheimer's Disease Differ According to Apolipoprotein‐E Genotype
Authors: CRAFT SUZANNE , ASTHANA SANJAY , SCHELLENBERG GERARD , BAKER LAURA , CHERRIER MONIQUE , BOYT ADAM A. , MARTINS RALPH N. , RASKIND MURRAY , PESKIND ELAINE , PLYMATE STEPHEN
Published: January 2006

Abstract: Higher fasting plasma insulin levels and reduced CSF‐to‐plasma insulin‐ratios, suggestive of insulin resistance, have been observed in patients with Alzheimer's disease (AD) who do not possess an apolipoprotein E (ApoE)‐ɛ4 allele. Insulin has also been implicated in processing of β‐amyloid and amyloid precursor protein (APP). We examined the effects of intravenous insulin administration while maintaining euglycemia on insulin‐mediated glucose disposal, memory, and plasma APP in patients with AD and normal adults of varying ApoE genotypes. AD subjects without an ɛ4 allele had significantly lower insulin‐mediated glucose disposal rates than did AD patients with an ɛ4 allele (p < 0.03) or than did normal adults without an ɛ4 allele (p < 0.02). AD subjects without an ɛ4 allele also showed significant memory facilitation with insulin administration (p < 0.04), whereas the AD‐ɛ4 group did not. Insulin reduced APP levels for AD patients without an ApoE ɛ4 allele, but raised APP for AD patients with an ApoE ɛH4 allele These results document ApoE‐related differences in insulin metabolism in AD that may relate to disease pathogenesis.
Can PET Data Differentiate Alzheimer's Disease from Vascular Dementia?
Authors: NAGATA KEN , MARUYA HIROSHI , YUYA HIROMICHI , TERASHI HIROO , MITO YASUNORI , KATO HARUHISA , SATO MIKA , SATOH YUICHI , WATAHIKI YASUHITO , HIRATA YUTAKA , YOKOYAMA ERIKO , HATAZAWA JUN
Published: January 2006

Abstract: The present study endeavored to differentiate Alzheimer's disease (AD) from vascular dementia (VaD) by comparing the metabolic and hemodynamic parameters. Positron emission tomographic (PET) studies were carried out in 13 patients with probable AD and 20 patients with VaD. PET findings were not included in the diagnostic criteria of AD or VaD. Using oxygen‐15 labeled compounds, cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), cerebral blood volume, and vascular transit time (VTT) were measured quantitatively during the resting state. To evaluate vascular reactivity (VR), CBF was also measured during 7% CO2 inhalation. Regional CBF from the parietal cortex positively correlated with the neuropsychological scores in both AD and VaD groups. The typical parietotemporal pattern of hypoperfusion and hypometabolism was observed in the AD group, whereas the frontal lobe including the cingulate and superior frontal gyri were predominantly affected in the VaD group. The occipital cortex was preserved in both groups. A significant increase of the OEF was found in the parietotemporal areas in the AD group. No significant prolongation was seen with VTT. There was a marked difference in VR between the two groups: VR was depleted in the VaD group, whereas VR was normal in the AD group. The increased OEF with preserved vascular reserve seen in AD may implicate participation of a vascular factor in the pathogenesis of AD, possibly at the capillary level. Thus, PET provides important functional information in discriminating AD from VaD by comparing the patterns of hypoperfusion and/or hypometabolism, and in the understanding of the underlying hemodynamic pathophysiology.
Skin Biopsy Value and Leukoaraiosis
Authors: RUCHOUX M. M. , BRULIN P. , LETEURTRE E. , MAURAGE C. A.
Published: January 2006

Abstract: In the field of leukoaraiosis, the identification of CADASIL and its link to Notch 3 mutation has shed light on the pathogenesis of white matter (WM) abnormalities related to small‐vessel disease. Since 1993, its systemic vascular involvement allows skin biopsy diagnosis and research on tissues before postmortem examination. We received 160 skin biopsies from patients presenting subcortical dementia, recurrent strokes, behavioral disturbances or migraines, and suspected CADASIL. Almost all the patients lacked the well‐known vascular risk factors. The ultrastructural study was systematically carried out looking at the vessel walls and the other components found in skin. In a third, we found endothelial changes, destruction of vascular smooth muscle cells (VSMCs), and characteristic granular osmiophilic material (GOM). In these cases, the genetic analysis confirmed the Notch 3 mutation. Curiously, the skin biopsies from the other two thirds presented marked alterations within the vessel walls. Such changes included destruction of VSMCs, lack of GOM, and replacement of these cells by an extracellular matrix. Frequently, we noticed endothelial pathological changes as well as other tissue impairments. By now, we are able to describe eight different groups of lesions according to either the prevalence of a lesion or the asssociation of different lesions.

The skin biopsy ultrastructural study seems to be highly informative given that we can observe vessel lesions and association of impairments in various tissues that might, in part, explain the brain vessel involvement and then the leukoaraiosis and probably some clinical symptoms. Moreover, these vessel lesions often belonged to young people (30–50 years old), and many of them seemed to run in families. These new data associated with early onset of clinical symptoms and leukoaraiosis would be extremely valuable in clarifying the wide field of leucoencephalopathy and might provide genetic research with new issues.
Hereditary Vascular Dementia Linked to Notch 3 Mutations: CADASIL in British Families
Authors: THOMAS N. J. , MORRIS C. M. , SCARAVILLI F. , JOHANSSON J. , ROSSOR M. , DE LANGE R. , ST CLAIR D. , NICOLL J. , BLANK C. , COULTHARD A. , BUSHBY K. , INCE P. G. , BURN D. , KALARIA R. N.
Published: January 2006

Abstract: The most common form of familial vascular dementia is considered to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is now also increasingly manifest in the United Kingdom. CADASIL has been previously dubbed as a familial form of Binswanger disease. However, unlike in Binswanger disease CADASIL does not involve hypertension or other risk factors associated with cardiovascular disease. CADASIL appears to be essentially a disorder of the arteries that is linked to single missense mutations in the NOTCH 3 gene locus on chromosome 19. The pathogenesis of the disorder or the genetic mechanism leading to brain infarcts and dementia is not known. The elucidation of the microvascular pathology evident in CADASIL may be an interesting way to delineate effects of defective genes on brain cells from systemic vascular influences.
Alterations of Alzheimer's Disease in the Cholesterol‐fed Rabbit, Including Vascular Inflammation: Preliminary Observations
Authors: SPARKS D. LARRY , KUO YU‐MIN , ROHER ALEX , MARTIN TIM , LUKAS RONALD J.
Published: January 2006

Abstract: We determined the levels of endothelial inflammation using MECA‐32 antibody and a4 nicotinic receptor subunit densities employing [3H]epibatidine binding in the brains of Alzheimer's disease (AD) patients, cholesterol‐fed rabbits, and appropriate controls. We also assessed rabbit brain for β‐amyloid levels and immunohistochemical localization, and for evidence of blood‐brain barrier breach using normally‐excluded Evans Blue dye. Dietary cholesterol induced a twofold increase in β‐amyloid concentration in rabbit hippocampal cortex, which may be related to the appearance of β‐amyloid immunoreactivity in the neuropil. Epibatidine binding was significantly decreased in AD superior frontal cortex, but unchanged in the superior frontal cortex of cholesterol‐fed rabbits. Increased vascular MECA‐32 immunoreactivity occurred in AD and cholesterol‐fed rabbit brain. Evans Blue dye could be found in the parenchyma of cholesterol‐fed rabbits only, and appeared as pockets of dye surrounding small blood vessels. The data suggest that vascular inflammation can lead to breach of the blood‐brain barrier, which may produce biochemical derangements in surrounding brain tissue that are conducive to production of β‐amyloid.