383 research outputs found
Amygdaloid Kindling and the GABA System
The effect of increased brain GABA levels on fully kindled amygdala seizures was investigated in Long-Evans rats. The newly synthesized GABA-transaminase inhibitor, -Î-acetylenic GABA (GAG) administered on four consecutive days (100 mg/kg, followed by 50 mg/kg, i.p.) was found to either significantly reduce, or eliminate entirely, the behavioral seizures normally produced by amygdala stimulation. The effect is seen after the first injection of GAG although its magnitude was greater on subsequent days. Behavioral seizures reappeared 2 to 3 days after termination of GAG treatment. The duration of electrographic seizures (self-sustained amygdala after-discharge) was either unchanged or greater on the first day of GAG treatment, but was briefer on subsequent days. The duration of afterdischarges returned to normal levels 1 to 2 days earlier than the behavioral seizures after the termination of GAG. Picrotoxin (1.5-2 mg/kg, i.p.) did not antagonize either electrographic or behavioral effects of inhibition produced with GAG. Electrical stimulation of amygdala delivered during the initial sedation stage induced by picrotoxin resulted in further regression of kindled seizures in the majority of animals. Although in doses employed, GAG alleviates amygdaloid-kindled seizures its use requires caution in view of its ability to reduce arousal level. RĂSUMĂ L'effet de l'ĂlĂvation des taux cĂrĂbraux de GABA sur les crises amygdaliennes par effet d'embrasement complet a ĂtĂĂtudiĂ chez des rats Long-Evans. l'injection pendant 4 jours consĂcutifs de 100 mg/kg suivis de 50 mg/kg i.p. d'un inhibiteur de la GABA. Transaminase nouvellement synthĂtisĂ (Î-acetylenic GABA ou GAG) a significativement rĂduit ou mĂme supprimĂ les crises normalement provoquĂes par la stimulation amygdalienne. l'effet est observĂ aprĂs la premiere injection de GAG, mais son importance s'accroit les jours suivants. Les crises rĂapparaissent 2 ou 3 jours aprĂs la fin du traitement au GAG. Du point de vue Ălectrographique, la durĂe de la postdĂcharge amygdalienne autoentretenue est inchingĂe ou accrue le premier jour du traitement, mais elle diminue les jours suivants pour retourner Ă la normale un ou deux jours avant que les crises ne rĂapparaissent aprĂs la fin de ('administration du GAG. l'injection de picrotoxine (1.5-2 mg/kg i.p.) ne s'oppose pas aux effets inhibiteurs du GAG sur les crises ou leur accompagnement EEG. La stimulation Ălectrique de l'amygdala pendant l'Ătape sĂdative initiate induite par la picrotoxine provoque une rĂgression supplĂmentaire des crises d'embrasement chez la majoritĂ des animaux. Bien que, aux doses utilisĂes, le GAG attĂnue les crises amyg-daliennes d'embrasement, son utilisation nĂcessite des prĂcautions compte tenu de sa tendance Ă rĂduire le niveau d'Ăveil. RESUMEN En ratas Long-Evans se ha investigado el efecto del aumento de los niveles cerebrales de GABA, sobre los ataques originados en la amĂgdala totalmente condicionada, (Kindling). El recientemente sintetizado in-hibidor de la GABA transaminasa, Î-acetilĂnico GABA (GAG), redujo significativamente o eliminĂ totalmente las crisis de comportamiento que habitualmente se producen con la estimulaciĂn de la amĂgdala. El efecto se observa despuĂs de la primera in-yecciĂn de GAG pero su magnitud aumentĂ en dias subsiguientes. Las crisis de comportamiento reaparecieron a los 2â3 dĂas de la interrupciĂn del tratamiento con GAG. La duraciĂn de los ataques electrogrĂficos (perservaciĂn de la post-descarga de la amigdala) no se modificĂ, o incluso aumentĂ, en el primer dia de la administraciĂn de GAG pero se redujo en los dias siguientes. La duraciĂn de las post-descargas volviĂ a sus niveles normales 1 o 2 dias antes que la reapariciĂn de las crisis de comportamiento una vez terminado el tratamiento con GAG. La picrotoxina (1.5-2 mg/kg, i.p.) no antagonizĂ los efectos inhibitorios producidos por el GAG sobre el electroencefalograma o las crisis de comportamiento. La estimulaciĂn elĂctrica sobre la amĂgdala, aplicada durante la fase de sedaciĂn inicial inducida por la picrotoxina, condujo a una regresiĂn aĂn mĂs intensa de las crisis condicionadas, en la mayorĂa de los animales. A pesar de que, con las dosis utilizadas, el GAG alivia las crisis de la amĂgdala previamente condicionada, se requiere gran precauciĂn en su utilizaciĂn en vista de su propiedad de reducir el nivel del despertar. ZUSAMMENFASSUNG Die Wirkung erhĂhter GABA-Spiegel des Gehirns auf AmygdalonkrĂmpfe nach Kindling wurden bei Long-Evans-Ratten untersucht. Der neuerdings synthetisierte GABA-TYansaminasen-Inhibitor, Gamma-Acetylen-GABA (GAG) wurde an 4 aufeinander-folgenden Tagen in einer Dosis von 100 mg/kg und anschlieliend 50 mg/kg i.p. verabfolgt. Er reduzierte entweder signifikant oder eliminierte vĂllig die anfalls-weisen VerhaltensĂnderungen, die normalerweise durch Stimulation des Amygdalon produziert wurden. Die Wirkung ist nach der Erstinjektion des GAG zu beobachten, obgleich ihr AusmaĂ an folgenden Tagen grĂĂer war. Die VerhaltensanfĂlle kamen 2 bis 3 Tagen nach Beendigung der GAG-Behandlung wieder. Die Dauer der elektrographischen AnfĂlle (sich selbst un-terhaltende Amydalonnachentladungen) blieben entweder gleich oder sie wurden grĂĂer am 1. Tag der GAG-Behandlung, wurden aber kĂrzer an folgenden Tagen. Die Dauer der Nachentladungen nor-malisierte sich 1 bis 2 Tage frĂher als die VerhaltensanfĂlle nach Beendigung des GAG verschwanden. Picrotoxin (1.5 bis 2 mg/kg i.p.) wirken nicht als Antagonist gegenĂber der durch GAG produzierten Hemmung der elektrographischen-oder Verhalten-seffekte. Die elektrische Stimulierung des Amygdalon wĂhrend der initialen Sedierung nach Picrotoxin ver-ursachte bei der Mehrzahl der Tiere einen weiteren RĂckgang der durch Kindling entstandenen AnfĂlle. Obgleich das GAG in den verwandten Dosen, die durch Kindling des Amygdalon erzeugten KrĂmpfe leichter ablaufen lUĂt, erfordert seine Anwendung Vorsicht hinsichtlich seiner FĂhigkeit, das Erreg-barkeitsniveau zu senken.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66112/1/j.1528-1157.1980.tb04058.x.pd
Epidemiology of influenza-associated hospitalization in adults, Toronto, 2007/8
The purpose of this investigation was to identify when diagnostic testing and empirical antiviral therapy should be considered for adult patients requiring hospitalization during influenza seasons. During the 2007/8 influenza season, six acute care hospitals in the Greater Toronto Area participated in active surveillance for laboratory-confirmed influenza requiring hospitalization. Nasopharyngeal (NP) swabs were obtained from patients presenting with acute respiratory or cardiac illness, or with febrile illness without clear non-respiratory etiology. Predictors of influenza were analyzed by multivariable logistic regression analysis and likelihoods of influenza infection in various patient groups were calculated. Two hundred and eighty of 3,917 patients were found to have influenza. Thirty-five percent of patients with influenza presented with a triage temperature â„38.0°C, 80% had respiratory symptoms in the emergency department, and 76% were â„65 years old. Multivariable analysis revealed a triage temperature â„38.0°C (odds ratio [OR] 3.1; 95% confidence interval [CI] 2.3â4.1), the presence of respiratory symptoms (OR 1.7; 95% CI 1.2â2.4), admission diagnosis of respiratory infection (OR 1.8; 95% CI 1.3â2.4), admission diagnosis of exacerbation of chronic obstructive pulmonary disease (COPD)/asthma or respiratory failure (OR 2.3; 95% CI 1.6â3.4), and admission in peak influenza weeks (OR 4.2; 95% CI 3.1â5.7) as independent predictors of influenza. The likelihood of influenza exceeded 15% in patients with respiratory infection or exacerbation of COPD/asthma if the triage temperature was â„38.0°C or if they were admitted in the peak weeks during the influenza season. During influenza season, diagnostic testing and empiric antiviral therapy should be considered in patients requiring hospitalization if respiratory infection or exacerbation of COPD/asthma are suspected and if either the triage temperature is â„38.0°C or admission is during the weeks of peak influenza activity
Complement in the pathogenesis of Alzheimer's disease
The emergence of complement as an important player in normal brain development and pathological remodelling has come as a major surprise to most scientists working in neuroscience and almost all those working in complement. That a system, evolved to protect the host against infection, should have these unanticipated roles has forced a rethink about what complement might be doing in the brain in health and disease, where it is coming from, and whether we can, or indeed should, manipulate complement in the brain to improve function or restore homeostasis. Complement has been implicated in diverse neurological and neuropsychiatric diseases well reviewed elsewhere, from depression through epilepsy to demyelination and dementia, in most complement drives inflammation to exacerbate the disease. Here, I will focus on just one disease, the most common cause of dementia, Alzheimerâs disease. I will briefly review the current understanding of what complement does in the normal brain, noting, in particular, the many gaps in understanding, then describe how complement may influence the genesis and progression of pathology in Alzheimerâs disease. Finally, I will discuss the problems and pitfalls of therapeutic inhibition of complement in the Alzheimer brain
Recent Advances in the Diagnosis and Treatment of Influenza Pneumonia
A potentially fatal complication of influenza infection is the development of pneumonia, caused either directly by the influenza virus, or by secondary bacterial infection. Pneumonia related to the 2009 influenza A pandemic was found to be underestimated by commonly used pneumonia severity scores in many cases, and to be rapidly progressive, leading to respiratory failure. Confirmation of etiology by laboratory testing is warranted in such cases. Rapid antigen and immunofluorescence testing are useful screening tests, but have limited sensitivity. Confirmation of pandemic H1N1 influenza A infection can only be made by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) or viral culture. The most effective preventive measure is annual influenza vaccination in selected individuals. Decisions to administer antiviral medications for influenza treatment or chemoprophylaxis should be based upon clinical and epidemiological factors, and should not be delayed by confirmatory laboratory testing results. Neuraminidase inhibitors (NI) are the agents of choice
Evaluation of the national surveillance system for point-prevalence of healthcare-associated infections in hospitals and in long-term care facilities for elderly in Norway, 2002-2008
<p>Abstract</p> <p>Background</p> <p>Since 2002, the Norwegian Institute of Public Health has invited all hospitals and long-term care facilities for elderly (LTCFs) to participate in two annual point-prevalence surveys covering the most frequent types of healthcare-associated infections (HAIs). In a comprehensive evaluation we assessed how well the system operates to meet its objectives.</p> <p>Methods</p> <p>Surveillance protocols and the national database were reviewed. Data managers at national level, infection control practitioners and ward personnel in hospitals as well as contact persons in LTCFs involved in prevalence data collection were surveyed.</p> <p>Results</p> <p>The evaluation showed that the system was structurally simple, flexible and accepted by the key partners. On average 87% of hospitals and 32% of LTCFs participated in 2004-2008; high level of data completeness was achieved. The data collected described trends in the prevalence of reportable HAIs in Norway and informed policy makers. Local results were used in hospitals to implement targeted infection control measures and to argue for more resources to a greater extent than in LTCFs. Both the use of simplified Centers for Disease Control and Prevention (CDC) definitions and validity of data seemed problematic as compliance with the standard methodology were reportedly low.</p> <p>Conclusions</p> <p>The surveillance system provides important information on selected HAIs in Norway. The system is overall functional and well-established in hospitals, however, requires active promotion in LTCFs. Validity of data needs to be controlled in the participating institutions before reporting to the national level.</p
Predictors of Breast and Cervical Cancer Screening among Chamorro Women in Southern California
This study examined the role of sociodemographic characteristics, health insurance, cancer knowledge, perceived health risk, and having a recent physiciansâ visit on breast and cervical cancer screening utilization among a randomly selected group of Chamorro women (nâ=â250) residing in San Diego, California. Data were collected by a telephone survey and analyzed using multiple logistic regression models. After adjusting for covariates, having a recent full exam was the strongest predictor of having had a Pap exam in the past 2Â years for women 21Â years and older and a clinical breast exam in the past 2Â years for women 40Â years and over
Distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration
Protein misfolding is common across many neurodegenerative diseases, with misfolded proteins acting as seeds for "prion-like" conversion of normally folded protein to abnormal conformations. A central hypothesis is that misfolded protein accumulation, spread and distribution is restricted to specific neuronal populations of the central nervous system and thus predict regions of neurodegeneration. We examined this hypothesis using a highly sensitive assay system for detection of misfolded protein seeds in a murine model of prion disease. Misfolded prion protein seeds were observed widespread throughout the brain accumulating in all brain regions examined irrespective of neurodegeneration. Importantly neither time of exposure nor amount of misfolded protein seeds present determined regions of neurodegeneration. We further demonstrate two distinct microglia responses in prion infected brains, a 11 novel homeostatic response in all regions and an innate immune response restricted to sites of 12 neurodegeneration. Therefore accumulation of misfolded prion protein alone does not define targeting 13 of neurodegeneration which instead results only when misfolded prion protein accompanies a specific 14 innate immune response
Regulation of LRRK2 Expression Points to a Functional Role in Human Monocyte Maturation
Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enhanced risk for Parkinson disease, the second most common human neurodegenerative disorder. Despite major efforts, our understanding of LRRK2 biological function and regulation remains rudimentary. In the present study we analyze LRRK2 mRNA and protein expression in sub-populations of human peripheral blood mononuclear cells (PBMCs). LRRK2 mRNA and protein was found in circulating CD19+ B cells and in CD14+ monocytes, whereas CD4+ and CD8+ T cells were devoid of LRRK2 mRNA. Within CD14+ cells the CD14+CD16+ sub-population of monocytes exhibited high levels of LRRK2 protein, in contrast to CD14+CD16- cells. However both populations expressed LRRK2 mRNA. As CD14+CD16+ cells represent a more mature subset of monocytes, we monitored LRRK2 expression after in vitro treatment with various stress factors known to induce monocyte activation. We found that IFN-Îł in particular robustly increased LRRK2 mRNA and protein levels in monocytes concomitant with a shift of CD14+CD16â cells towards CD14+CD16+cells. Interestingly, the recently described LRRK2 inhibitor IN-1 attenuated this shift towards CD14+CD16+ after IFN-Îł stimulation. Based on these findings we speculate that LRRK2 might have a role in monocyte maturation. Our results provide further evidence for the emerging role of LRRK2 in immune cells and regulation at the transcriptional and translational level. Our data might also reflect an involvement of peripheral and brain immune cells in the disease course of PD, in line with increasing awareness of the role of the immune system in PD
Impaired Inflammatory Responses in Murine Lrrk2-Knockdown Brain Microglia
LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-α, IL-1ÎČ and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-ÎșB-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-ÎșB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-ÎșB homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-ÎșB transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation
Prolonged oral cannabinoid administration prevents neuroinflammation, lowers ÎČ-amyloid levels and improves cognitive performance in Tg APP 2576 mice
Background: Alzheimerâs disease (AD) brain shows an ongoing inflammatory condition and non-steroidal antiinflammatories
diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and antiinflammatory
agents with therapeutic potential.
Methods: We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein
(APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the
drinking water during 4 months) on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose
(18FDG) uptake by positron emission tomography (PET).
Results: Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month
administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice
cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG
uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP
immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density
of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both
cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-a mRNA expression
found in the AD model. Increased cortical b-amyloid (Ab) levels were significantly reduced in the mouse model by
both cannabinoids. Noteworthy both cannabinoids enhanced Ab transport across choroid plexus cells in vitro.
Conclusions: In summary we have shown that chronically administered cannabinoid showed marked beneficial
effects concomitant with inflammation reduction and increased Ab clearanceThis work was supported by the Spanish Ministry of Science and
Technology (SAF 2005-02845 to M.L.C). A.M.M-M. was recipient a fellowship
from the Ministry of Education and Scienc
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