bluuebunny/crossref_metadata_2025 huggingface dataset:
Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock
Authors: Spapen Herbert , Nguyen Duc Nam , Troubleyn Joris , Huyghens Luc , Schiettecatte Johan
Published: April 2010

Introduction

Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction induced by the immuno-inflammatory response to infection. Elevated levels of the brain-specific S100B protein are present in many septic patients and reflect the severity of SAE. Adjunctive treatment with drotrecogin alfa (activated) (DrotAA), the human recombinant form of activated protein C, has been shown to improve mortality in patients with severe sepsis-induced organ failure. We studied the effect of DrotAA on S100B levels in patients with acute septic shock who presented with increased baseline values of this biomarker.

Methods

All patients received standard goal-directed resuscitation treatment. Patients with pre-existing or acute neurological disorders were excluded. Based on the Glasgow coma scale (GCS), patients were classified into two groups: GCS ≥ 13 and GCS <13. DrotAA was given as a continuous infusion of 24 μg/kg/h for 96 h. S100B was measured before sedation and the start of DrotAA (0 h) and at 32 h, 64 h and 96 h and at corresponding time points in patients not treated with DrotAA. The lower limit of normal was < 0.5 μg/L.

Results

Fifty-four patients completed the study. S100B was increased in 29 (54%) patients. Twenty-four patients (9 with GCS ≥ 13 and 15 with GCS <13) received DrotAA. S100B levels in DrotAA-treated patients with a GCS <13, though higher at baseline than in untreated subjects (1.21 ± 0.22 μg/L vs. 0.95 ± 0.12 μg/L; P = 0.07), progressively and significantly decreased during infusion (0.96 ± 0.22 μg/L at 32 h, P = 0.3; 0.73 ± 0.12 μg/L at 64 h, P < 0.05; and 0.70 ± 0.13 μg/L at 96 h, P < 0.05 vs. baseline). This patient group had also significantly lower S100B values at 64 h and at 96 h than their untreated counterparts. In the patients with a GCS ≥ 13, S100B levels were not influenced by DrotAA treatment.

Conclusions

S100B-positivity is present in more than half of the patients with septic shock. When increased S100B levels are used as a surrogate for SAE, adjunctive DrotAA treatment seems to beneficially affect the evolution of severe SAE as discriminated by an admission GCS <13.
Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM®)-guided administration of fibrinogen concentrate and prothrombin complex concentrate
Authors: Schöchl Herbert , Nienaber Ulrike , Hofer Georg , Voelckel Wolfgang , Jambor Csilla , Scharbert Gisela , Kozek-Langenecker Sibylle , Solomon Cristina
Published: April 2010

Introduction

The appropriate strategy for trauma-induced coagulopathy management is under debate. We report the treatment of major trauma using mainly coagulation factor concentrates.

Methods

This retrospective analysis included trauma patients who received ≥ 5 units of red blood cell concentrate within 24 hours. Coagulation management was guided by thromboelastometry (ROTEM®). Fibrinogen concentrate was given as first-line haemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was <10 mm. Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time measured by extrinsic activation test (EXTEM) >1.5 times normal. Lack of improvement in EXTEM MCF after fibrinogen concentrate administration was an indication for platelet concentrate. The observed mortality was compared with the mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC) score.

Results

Of 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received PCC, while 3 patients with recent coumarin intake received only PCC. Twelve patients received FFP and 29 received platelet concentrate. The observed mortality was 24.4%, lower than the TRISS mortality of 33.7% (P = 0.032) and the RISC mortality of 28.7% (P > 0.05). After excluding 17 patients with traumatic brain injury, the difference in mortality was 14% observed versus 27.8% predicted by TRISS (P = 0.0018) and 24.3% predicted by RISC (P = 0.014).

Conclusions

ROTEM®-guided haemostatic therapy, with fibrinogen concentrate as first-line haemostatic therapy and additional PCC, was goal-directed and fast. A favourable survival rate was observed. Prospective, randomized trials to investigate this therapeutic alternative further appear warranted.
Characterization of transglutaminase type II role in dendritic cell differentiation and function
Authors: Matic Ivana , Sacchi Alessandra , Rinaldi Alessandra , Melino Gennaro , Khosla Chaitan , Falasca Laura , Piacentini Mauro
Published: April 2010

TG2 ablation affects DC maturation and functions leading to a decreased pro-inflammatory response upon endotoxic shock stimulation.

DCs play an essential role in the endotoxic shock, and their profound depletion occurs in septic patients and septic mice. TG2−/− mice are more resistant to the endotoxic shock induced by LPS. Here, we studied the cellular and molecular basis of this effect, analyzing the role of the enzyme in DC maturation and function. We show that TG2 is up-regulated drastically during the final, functional maturation of DCs consequent to LPS treatment. In keeping with this finding, the inhibition of the enzyme cross-linking activity determines the impairment of DC function highlighted by wide phenotypic changes associated with a reduced production of cytokines (IL-10, IL-12) after LPS treatment and a lower ability to induce IFN-γ production by naïve T cells. The in vivo analysis of DCs obtained from TG2−/− mice confirmed that the enzyme ablation leads to an impairment of DC maturation and their reduced responsiveness to LPS treatment. In fact, a marked decrease in DC death, TLR4 down-regulation, and impaired up-regulation of MHCII and CD86 were observed in TG2−/− mice. Taken together, these data suggest that TG2 plays an important role in regulating the response of DCs to LPS and could be a candidate target for treating endotoxin-induced sepsis.
CCL5 participates in early protection against Mycobacterium tuberculosis
Authors: Vesosky Bridget , Rottinghaus Erin K , Stromberg Paul , Turner Joanne , Beamer Gillian
Published: April 2010

CCL5-CCR5 interactions localize protective T cells to the lungs and contribute to pulmonary granuloma formation to control early infection with Mycobacterium tuberculosis.

Control of M.tb, the causative agent of TB, requires immune cell recruitment to form lung granulomas. The chemokines and chemokine receptors that promote cell migration for granuloma formation, however, are not defined completely. As immunity to M.tb manifests slowly in the lungs, a better understanding of specific roles for chemokines, in particular those that promote M.tb-protective TH1 responses, may identify targets that could accelerate granuloma formation. The chemokine CCL5 has been detected in patients with TB and implicated in control of M.tb infection. To define a role for CCL5 in vivo during M.tb infection, CCL5 KO mice were infected with a low dose of aerosolized M.tb. During early M.tb infection, CCL5 KO mice localized fewer APCs and chemokine receptor-positive T cells to the lungs and had microscopic evidence of altered cell trafficking to M.tb granulomas. Early acquired immunity and granuloma function were transiently impaired when CCL5 was absent, evident by delayed IFN-γ responses and poor control of M.tb growth. Lung cells from M.tb-infected CCL5 KO mice eventually reached or exceeded the levels of WT mice, likely as a result of partial compensation by the CCL5-related ligand, CCL4, and not because of CCL3. Finally, our results suggest that most T cells use CCR5 but not CCR1 to interact with these ligands. Overall, these results contribute to a model of M.tb granuloma formation dependent on temporal regulation of chemokines rather than on redundant or promiscuous interactions.
Maternal Overweight Programs Insulin and Adiponectin Signaling in the Offspring
Authors: Shankar Kartik , Kang Ping , Harrell Amanda , Zhong Ying , Marecki John C. , Ronis Martin J. J. , Badger Thomas M.
Published: April 2010

Gestational exposure to maternal overweight (OW) influences the risk of obesity in adult life. Male offspring from OW dams gain greater body weight and fat mass and develop insulin resistance when fed high-fat diets (45% fat). In this report, we identify molecular targets of maternal OW-induced programming at postnatal d 21 before challenge with the high-fat diet. We conducted global transcriptome profiling, gene/protein expression analyses, and characterization of downstream signaling of insulin and adiponectin pathways in conjunction with endocrine and biochemical characterization. Offspring born to OW dams displayed increased serum insulin, leptin, and resistin levels (P < 0.05) at postnatal d 21 preceding changes in body composition. A lipogenic transcriptome signature in the liver, before development of obesity, was evident in OW-dam offspring. A coordinated locus of 20 sterol regulatory element-binding protein-1-regulated target genes was induced by maternal OW. Increased nuclear levels of sterol regulatory element-binding protein-1 and recruitment to the fatty acid synthase promoter were confirmed via ELISA and chromatin immunoprecipitation analyses, respectively. Higher fatty acid synthase and acetyl coenzyme A carboxylase protein and pAKT (Thr308) and phospho-insulin receptor-β were confirmed via immunoblotting. Maternal OW also attenuated AMP kinase/peroxisome proliferator-activated receptor-α signaling in the offspring liver, including transcriptional down-regulation of several peroxisome proliferator-activated receptor-α-regulated genes. Hepatic mRNA and circulating fibroblast growth factor-21 levels were significantly lower in OW-dam offspring. Furthermore, serum levels of high-molecular-weight adiponectin (P < 0.05) were decreased in OW-dam offspring. Phosphorylation of hepatic AMP-kinase (Thr172) was significantly decreased in OW-dam offspring, along with lower AdipoR1 mRNA. Our results strongly suggest that gestational exposure to maternal obesity programs multiple aspects of energy-balance regulation in the offspring.
Un Chroniqueur Curieux de Paris Et de La Promenade: Edmond-Jean-François Barbier Et Son Journal (1718–1763)
Authors: Turcot Laurent
Published: April 2010

Dans son journal de 1718 à 1763, Edmond-Jean-François Barbier raconte la ville de Paris et ses événements, ordinaires et extraordinaires. Le présent article se propose d'évaluer la manière dont l'avocat Barbier raconte la promenade et de montrer que son récit témoigne d'une transformation dans la manière de concevoir la promenade. Une pratique associée à la royauté et à la noblesse où prime la fonction de distinction sociale devient, au fil du journal de Barbier, une façon de découvrir et connaître sa ville afin de la raconter. Cette dimension permet de voir comment une source dite littéraire peut aider à comprendre la constitution des pratiques sociales, en l'occurrence la promenade et la transformation d'une ville.

The journal of Edmond-Jean-François Barbier, written from 1718 through 1763, can be considered both as a chronicle of Parisian everyday life and as a diary. This essay analyzes how Barbier narrates the promenade (stroll) and shows that his account illustrates a transformation in the way this pastime was conceived. Originally associated with the monarch and aristocracy, with civility and fashionable social ritual its dominant features, the promenade allowed practitioners to see and, most important, be seen. In his journal Barbier puts the promenade to a new purpose, using it to discover, become acquainted with, and narrate the city. In this light, the promenade creates a newly individualized and subjective relationship between the stroller and the city. This transformation of the stroller's appreciation for and perception of the city was made possible by the establishment of a new social role: the urban stroller. For Barbier, walking becomes an individual pursuit. Barbier's journal thus demonstrates how a literary source can be used to understand the transformation of social practice and of the urban landscape in eighteenth-century Paris.
Medaka as a model for human nonalcoholic steatohepatitis
Authors: Matsumoto Toshihiko , Terai Shuji , Oishi Toshiyuki , Kuwashiro Shinya , Fujisawa Koichi , Yamamoto Naoki , Fujita Yusuke , Hamamoto Yoshihiko , Furutani-Seiki Makoto , Nishina Hiroshi , Sakaida Isao
Published: April 2010

The global incidence of nonalcoholic steatohepatitis (NASH) is increasing and current mammalian models of NASH are imperfect. We have developed a NASH model in the ricefish medaka (Oryzias latipes), which is based on feeding the fish a high-fat diet (HFD). Medaka that are fed a HFD (HFD-medaka) exhibited hyperlipidemia and hyperglycemia, and histological examination of the liver revealed ballooning degeneration. The expression of lipogenic genes (SREBP-1c, FAS and ACC1) was increased, whereas the expression of lipolytic genes (PPARA and CPT1) was decreased. With respect to liver fatty acid composition, the concentrations of n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs had declined and the n-3:n-6 ratio was reduced. Treatment of HFD-medaka with the n-3 PUFA eicosapentaenoic acid (EPA) mitigated disease, as judged by the restoration of normal liver fatty acid composition and normal expression levels of lipogenic and lipolytic genes. Moreover, medaka that were fed a diet deficient in n-3 PUFAs developed NASH features. Thus, NASH can be induced in medaka by a HFD, and the proportion of n-3 PUFAs in the liver influences the progress of NASH pathology in these fish. Our model should prove helpful for the dissection of the causes of human NASH and for the design of new and effective therapies.
Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice
Authors: Bartolomucci Alessandro , Carola Valeria , Pascucci Tiziana , Puglisi-Allegra Stefano , Cabib Simona , Lesch Klaus-Peter , Parmigiani Stefano , Palanza Paola , Gross Cornelius
Published: April 2010

Epidemiological evidence links exposure to stressful life events with increased risk for mental illness. However, there is significant individual variability in vulnerability to environmental risk factors, and genetic variation is thought to play a major role in determining who will become ill. Several studies have shown, for example, that individuals carrying the S (short) allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) have an increased risk for major depression following exposure to stress in adulthood. Identifying the molecular mechanisms underlying this gene-by-environment risk factor could help our understanding of the individual differences in resilience to stress. Here, we present a mouse model of the 5-HTT-by-stress risk factor. Wild-type and heterozygous 5-HTT knockout male mice were subjected to three weeks of chronic psychosocial stress. The 5-HTT genotype did not affect the physiological consequences of stress as measured by changes in body temperature, body weight gain and plasma corticosterone. However, when compared with wild-type littermates, heterozygous 5-HTT knockout mice experiencing high levels of stressful life events showed significantly depressed locomotor activity and increased social avoidance toward an unfamiliar male in a novel environment. Heterozygous 5-HTT knockout mice exposed to high stress also showed significantly lower levels of serotonin turnover than wild-type littermates, selectively in the frontal cortex, which is a structure that is known to control fear and avoidance responses, and that is implicated in susceptibility to depression. These data may serve as a useful animal model for better understanding the increased vulnerability to stress reported in individuals carrying the 5-HTTLPR S allele, and suggest that social avoidance represents a behavioral endophenotype of the interaction between 5-HTT and stress.
Synthesis of a Kinetically Stabilized Homoditopic Nitrile N-Oxide Directed toward Catalyst-free Click Polymerization
Authors: Lee Young-Gi , Yonekawa Morio , Koyama Yasuhito , Takata Toshikazu
Published: April 2010

A kinetically stabilized homoditopic nitrile N-oxide was prepared for a catalyst-free click polymerization that efficiently proceeded via 1,3-dipolar cycloaddition with several bifunctional alkyne, alkene, and nitrile monomers. The polymerization afforded the corresponding polymers with high molecular weights and yields.
Split-Delivery Capacitated Arc-Routing Problem: Lower Bound and Metaheuristic
Authors: Belenguer José-Manuel , Benavent Enrique , Labadi Nacima , Prins Christian , Reghioui Mohamed
Published: April 2010

This paper proposes lower and upper bounds for the split-delivery capacitated arc-routing problem (SDCARP), a variant of the capacitated arc-routing problem in which an edge can be serviced by several vehicles. Recent papers on related problems in node routing have shown that this policy can bring significant savings. It is also more realistic in applications such as urban refuse collection, where a vehicle can become full in the middle of a street segment. This work presents the first lower bound for the SDCARP, computed with a cutting plane algorithm and an evolutionary local search reinforced by a multistart procedure and a variable neighborhood descent. Tests on 126 instances show that the new metaheuristic outperforms on average a published memetic algorithm; achieves small deviations to the lower bound; and finds 44 optima, including 10 new ones.
An Information-Theoretic Sensor Location Model for Traffic Origin-Destination Demand Estimation Applications
Authors: Zhou Xuesong , List George F.
Published: April 2010

To design a transportation sensor network, the decision maker needs to determine what sensor investments should be made, as well as when, how, where, and with what technologies. This paper focuses on locating a limited set of traffic counting stations and automatic vehicle identification (AVI) readers in a network, so as to maximize the expected information gain for the subsequent origin-destination (OD) demand estimation problem. The proposed sensor design model explicitly takes into account several important error sources in traffic OD demand estimation, such as the uncertainty in historical demand information, sensor measurement errors, as well as approximation errors associated with link proportions. Based on a mean square measure, this paper derives analytical formulations to describe estimation variance propagation for a set of linear measurement equations. A scenario-based (SB) stochastic optimization procedure and a beam search algorithm are developed to find suboptimal point and point-to-point sensor locations subject to budget constraints. This paper also provides a number of illustrative examples to demonstrate the effectiveness of the proposed methodology.
"Girls Take Charge": A Community-Based Participatory Research Program for Adolescent Girls
Authors: Mathews Judith R. , Mathews Therese L. , Mwaja Emily
Published: April 2010

Background. Adolescent females are at high risk for health disparities. An approach to minimizing health disparities involves facilitating changes in the environment within the community. Community-based participatory research (CBPR) is an important method of producing community change. Objectives. The objectives were for adolescent females to learn the CBPR process, implement a community health change project, and build capacity by engaging community agencies. Methods. After conducting an assessment of community problems, the adolescents formed a coalition of community partners and implemented a Lead Poisoning Awareness Fair and a "lock-in" to educate about child maltreatment. A pre- and post-test research design was used. Results. The community changes that resulted were policy change for routine lead testing, a DVD about child maltreatment, and care packages for adolescent mothers. Modest increases in knowledge about lead poisoning and child maltreatment occurred. Conclusion. Adolescent females were successful in using CBPR to produce positive community changes.
Settlement Formation and Land Cover and Land Use Change: A Case Study in the Brazilian Amazon
Authors: Caldas Marcellus M. , Simmons Cynthia , Walker Robert , Perz Stephen , Aldrich Stephen , Pereira Ritaumaria , Leite Flavia , Arima Eugenio
Published: April 2010

O presente artigo descreve o processo de criação de um tipo particular de assentamento de reforma agrária, no qual o denominamos "espontâneo". Em adição, o artigo coloca o processo de formação de assentamento dentro de uma conceptualização de mudança de cobertura vegetal e uso da terra, e descreve as causas que levam a formação de assentamento espontâneos em terra devoluta na Amazônia Brasileira. O estudo conclue com recomendações de política agrária.
Experiment or Transition? Revisiting Food Distribution in Cuban Agromercados from the "Special Period"
Authors: Torres Rebecca Maria , Nelson Velvet , Momsen Janet Henshall , Niemeier Debbie A.
Published: April 2010

En 1994 el gobierno cubano permitió la reapertura de los mercados campesinos, en los cuales los granjeros pudieren comercializar la producción agrícola sobrante a precios de mercado. Este "experimento" se inició como una necesidad durante el llamado "Período Especial en Tiempos de Paz". Hoy día, los agromercados son un exitoso punto de distribución alimentaria; esto indica que no son una mera medida temporal. Los propietarios de pequeñas granjas han abastecido la mayoría de los productos ofertados en los agromercados a pesar del limitado acceso a los insumos. En el año 2009 se anunció que más de 45,000 nuevos permisos de uso de la tierra fueron concedidos a productores privados para aumentar la producción doméstica de alimentos, mucha de la cual seguirá vendiéndose en los agromercados. En este documento se revisan los resultados empíricos de encuestas efectuadas en los agromercados un año después de que fueran abiertos con el propósito de examinar el acceso a los insumos y a la infraestructura de la cadena de suministros, tanto por los productores privados como colectivos. Conocer los obstáculos que enfrentan los productores privados, será importante para asegurar que los que reciben las recién distribuidas tierras sean exitosos.
Brain tumor stem cells
Authors: Palm Thomas , Schwamborn Jens C.
Published: April 2010

Since the end of the ‘no-new-neuron’ theory, emerging evidence from multiple studies has supported the existence of stem cells in neurogenic areas of the adult brain. Along with this discovery, neural stem cells became candidate cells being at the origin of brain tumors. In fact, it has been demonstrated that molecular mechanisms controlling self-renewal and differentiation are shared between brain tumor stem cells and neural stem cells and that corruption of genes implicated in these pathways can direct tumor growth. In this regard, future anticancer approaches could be inspired by uncovering such redundancies and setting up treatments leading to exhaustion of the cancer stem cell pool. However, deleterious effects on (normal) neural stem cells should be minimized. Such therapeutic models underline the importance to study the cellular mechanisms implicated in fate decisions of neural stem cells and the oncogenic derivation of adult brain cells. In this review, we discuss the putative origins of brain tumor stem cells and their possible implications on future therapies.
Multiple protective functions of catalase against intercellular apoptosis-inducing ROS signaling of human tumor cells
Authors: Heinzelmann Sonja , Bauer Georg
Published: April 2010

Tumor cells are protected against intercellular reactive oxygen species (ROS)-mediated apoptosis signaling mediated by the HOCl and/or the nitric oxide (NO)/peroxynitrite signaling pathway. We have recently shown that tumor cell resistance against HOCl signaling can be abrogated through inhibition of catalase. The protection of tumor cells against the NO/peroxynitrite signaling pathway has remained enigmatic so far. Here, we show that suboptimal inhibition of catalase by 3-aminotriazole or a monoclonal antibody against catalase, as well as partial knockdown of catalase by specific siRNA allows selective reactivation of the NO/peroxynitrite pathway in MKN 45 gastric carcinoma cells, followed by the HOCl pathway at higher inhibitor or siRNA concentrations. In SKN-MC Ewing sarcoma cells, catalase inhibition causes apoptosis induction solely based on the NO/peroxynitrite pathway. Protection against NO/peroxynitrite signaling is shown to be due to the potential of catalase to decompose peroxynitrite. The direct interaction of catalase with peroxynitrite is verified through the detection of compound I (CAT FeIV=O+·) after the interaction of peroxynitrite with catalase. In a complementary experiment, addition of catalase protects sensitive transformed cells against ROS-mediated apoptosis induction. Thus, the expression of membrane-associated catalase is sufficient to protect tumor cells against multiple intercellular ROS-mediated signaling pathways.
The mitochondria permeability transition pore complex in the brain with interacting proteins – promising targets for protection in neurodegenerative diseases
Authors: Azarashvili Tamara , Stricker Rolf , Reiser Georg
Published: April 2010

Mitochondria increasingly attract attention as control points within the mechanisms of neuronal death. Mitochondria play a central role in swinging the balance in favor of either survival or death of brain tissue. Cell death in vertebrates proceeds mostly via the mitochondrial pathway of apoptosis. Permeability transition pore (PTP) development in mitochondria is a decisive stage of apoptosis. Therefore, regulation of the permeability of both outer and inner mitochondrial membranes helps to induce neuroprotection. Through PTP control, mitochondria can to a large degree manage the intracellular calcium homeostasis, and thus control the potent death cascade initiated by excess calcium. Here we summarize the evidence for the role of mitochondria in brain cell death. We describe the involvement of the 18-kDa translocator protein (TSPO; previously called peripheral benzodiazepine receptor), and of two new mitochondrial proteins, that is, 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) and p42IP4(also designated centaurin α1; ADAP 1), in the control of the PTP. Furthermore, ligands of TSPO, as well as substrates of CNP, are possible modulators of PTP function. This scenario of control and regulation of PTP function might provide multiple important targets, which are suitable for developing protective strategies for neurons and non-neuronal brain cells in therapies of neurodegenerative diseases.
Chronic Morphine Treatment Impaired Hippocampal Long-Term Potentiation and Spatial Memory via Accumulation of Extracellular Adenosine Acting on Adenosine A1Receptors
Authors: Lu Gang , Zhou Qi-Xin , Kang Shuo , Li Qing-Lin , Zhao Liang-Cai , Chen Jia-Dong , Sun Jian-Feng , Cao Jun , Wang Yu-Jun , Chen Jie , Chen Xiao-Yan , Zhong Da-Fang , Chi Zhi-Qiang , Xu Lin , Liu Jing-Gen
Published: April 2010

Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20–100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A1receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-α/β activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.
Multiple Timescale Encoding of Slowly Varying Whisker Stimulus Envelope in Cortical and Thalamic NeuronsIn Vivo
Authors: Lundstrom Brian Nils , Fairhall Adrienne L. , Maravall Miguel
Published: April 2010

Adaptive processes over many timescales endow neurons with sensitivity to stimulus changes over a similarly wide range of scales. Although spike timing of single neurons can precisely signal rapid fluctuations in their inputs, the mean firing rate can convey information about slower-varying properties of the stimulus. Here, we investigate the firing rate response to a slowly varying envelope of whisker motion in two processing stages of the rat vibrissa pathway. The whiskers of anesthetized rats were moved through a noise trajectory with an amplitude that was sinusoidally modulated at one of several frequencies. In thalamic neurons, we found that the rate response to the stimulus envelope was also sinusoidal, with an approximately frequency-independent phase advance with respect to the input. Responses in cortex were similar but with a phase shift that was about three times larger, consistent with a larger amount of rate adaptation. These response properties can be described as a linear transformation of the input for which a single parameter quantifies the phase shift as well as the degree of adaptation. These results are reproduced by a model of adapting neurons connected by synapses with short-term plasticity, showing that the observed linear response and phase lead can be built up from a network that includes a sequence of nonlinear adapting elements. Our study elucidates how slowly varying envelope information under passive stimulation is preserved and transformed through the vibrissa processing pathway.
Neural Ensemble Codes for Stimulus Periodicity in Auditory Cortex
Authors: Bizley Jennifer K. , Walker Kerry M. M. , King Andrew J. , Schnupp Jan W. H.
Published: April 2010

We measured the responses of neurons in auditory cortex of male and female ferrets to artificial vowels of varying fundamental frequency (f0), or periodicity, and compared these with the performance of animals trained to discriminate the periodicity of these sounds. Sensitivity tof0was found in all five auditory cortical fields examined, with most of those neurons exhibiting either low-pass or high-pass response functions. Only rarely was the stimulus dependence of individual neuron discharges sufficient to account for the discrimination performance of the ferrets. In contrast, when analyzed with a simple classifier, responses of small ensembles, comprising 3-61 simultaneously recorded neurons, often discriminated periodicity changes as well as the animals did. We examined four potential strategies for decoding ensemble responses: spike counts, relative first-spike latencies, a binary “spike or no-spike” code, and a spike-order code. All four codes represented stimulus periodicity effectively, and, surprisingly, the spike count and relative latency codes enabled an equally rapid readout, within 75 ms of stimulus onset. Thus, relative latency codes do not necessarily facilitate faster discrimination judgments. A joint spike count plus relative latency code was more informative than either code alone, indicating that the information captured by each measure was not wholly redundant. The responses of neural ensembles, but not of single neurons, reliably encodedf0changes even when stimulus intensity was varied randomly over a 20 dB range. Because trained animals can discriminate stimulus periodicity across different sound levels, this implies that ensemble codes are better suited to account for behavioral performance.
Molecular Dissection ofIAin Cortical Pyramidal Neurons Reveals Three Distinct Components Encoded by Kv4.2, Kv4.3, and Kv1.4 α-Subunits
Authors: Norris Aaron J. , Nerbonne Jeanne M.
Published: April 2010

The rapidly activating and inactivating voltage-gated K+(Kv) current,IA, is broadly expressed in neurons and is a key regulator of action potential repolarization, repetitive firing, backpropagation (into dendrites) of action potentials, and responses to synaptic inputs. Interestingly, results from previous studies on a number of neuronal cell types, including hippocampal, cortical, and spinal neurons, suggest that macroscopicIAis composed of multiple components and that each component is likely encoded by distinct Kv channel α-subunits. The goals of the experiments presented here were to test this hypothesis and to determine the molecular identities of the Kv channel α-subunits that generateIAin cortical pyramidal neurons. Combining genetic disruption of individual Kv α-subunit genes with pharmacological approaches to block Kv currents selectively, the experiments here revealed that Kv1.4, Kv4.2, and Kv4.3 α-subunits encode distinct components ofIAthat together underlie the macroscopicIAin mouse (male and female) cortical pyramidal neurons. Recordings from neurons lacking both Kv4.2 and Kv4.3 (Kv4.2−/−/Kv4.3−/−) revealed that, although Kv1.4 encodes a minor component ofIA, the Kv1.4-encoded current was found in all theKv4.2−/−/Kv4.3−/−cortical pyramidal neurons examined. Of the cortical pyramidal neurons lacking both Kv4.2 and Kv1.4, 90% expressed a Kv4.3-encodedIAlarger in amplitude than the Kv1.4-encoded component. The experimental findings also demonstrate that the targeted deletion of the individual Kv α-subunits encoding components ofIAresults in electrical remodeling that is Kv α-subunit specific.
In VivoDeletion of Immunoglobulin Domains 5 and 6 inNeurofascin(Nfasc) Reveals Domain-Specific Requirements in Myelinated Axons
Authors: Thaxton Courtney , Pillai Anilkumar M. , Pribisko Alaine L. , Labasque Marilyne , Dupree Jeffrey L. , Faivre-Sarrailh Catherine , Bhat Manzoor A.
Published: April 2010

The formation of paranodal axo-glial junctions is critical for the rapid and efficient propagation of nerve impulses. Genetic ablation of genes encoding the critical paranodal proteins Caspr, contactin (Cont), and the myelinating glia-specific isoform of Neurofascin (NfascNF155) results in the disruption of the paranodal axo-glial junctions, loss of ion channel segregation, and impaired nerve conduction, but the mechanisms regulating their interactions remain elusive. Here, we report that loss of immunoglobulin (Ig) domains 5 and 6 in NfascNF155in mice phenocopies complete ablation of NfascNF155. The mutant mice lack paranodal septate junctions, resulting in the diffusion of Caspr and Cont from the paranodes, and redistribution of the juxtaparanodal potassium channels toward the nodes. Although critical for NfascNF155function, we find that Ig5-6 are dispensable for nodal NfascNF186function. Moreover,in vitrobinding assays using Ig5-6 deletion constructs reveal their importance for the association of NfascNF155with Cont. These findings provide the first molecular evidence demonstrating domain-specific requirements controlling the association of the paranodal tripartite complexin vivo. Our studies further emphasize thatin vivostructure/function analysis is necessary to define the unique protein–protein interactions that differentially regulate the functions of Neurofascins during axonal domain organization.
HLA-DR genotypes influence age at disease onset in children and juveniles with type 1 diabetes mellitus
Authors: Awa W L , Boehm B O , Kapellen T , Rami B , Rupprath P , Marg W , Becker M , Holl R W
Published: April 2010

Objective

To investigate HLA-DR genotype in association with chronological age or calendar year of disease onset and the time trend of genotype frequencies from 1969 to 2009. Additionally, to examine genotype frequency in relation to B-cell-, islet cell antibodies (ICA)-, autoantibodies to insulin-, insulinoma antigen 2 (IA2)-, glutamic acid decarboxylase-antibody positivity, thyroid antibody positivity, thyroid diseases or coeliac antibody positivity. Genotype associations with gender and ethnicity are also analyzed.

Subjects and methods

HLA-typed children and juveniles (n=1445) aged ≤20 years at disease onset from the German/Austrian DPV-database were examined.χ2statistics and mixed hierarchical logistic regression models were used to compare genotype frequencies and establish associations with age at disease manifestation, autoimmune antibodies/diseases, ethnicity and time trend.

Results

Subjects aged <6 years predominantly carried the genotype HLA-DR3/4 (25.2%), whereas in subjects aged >12 years the most prevalent HLA-DR genotype was X/X (18.1%). IA2 positivity was associated with HLA-DR4/X and HLA-DR3/4 positivity (P=0.011), and hypothyroidism was linked to HLA-DR4/4 (P=0.0103). More females carried the HLA-DR4/4 genotype (18.2 vs 12.7%P=0.0048) or were thyroid antibody positive (24.5 vs 14.7%P=0.0001). Larger numbers of <6 year olds were coeliac antibody positive than >12 year olds (14.8 vs 9.1%P=0.0037). No associations between migration background and B-cell-, thyroid- or coeliac-antibody positivity, and no time trend were found.

Conclusion

HLA-DR genotype associated with age at disease onset, ICA positivity and hypothyroidism; female gender with thyroid antibody positivity and low age of diabetes onset with coeliac antibody positivity.
Historical approaches to Merseybeat
Authors: Inglis Ian
Published: April 2010

This article examines the connections between place and sound with a particular concentration upon Liverpool and ‘Merseybeat’. The article examines the ways in which accounts of the city’s musical sound in the early 1960s have been presented in journalistic and critical reception of Liverpool’s popular music. It considers the assumptions behind those accounts, assesses the validity of the explanations they offer and traces the evolution of academic, journalistic and populist discourses about Merseybeat. The contributions can be organized into three categories (delivery, affinity and diversity) which are broadly distinctive perspectives that usefully indicate the different ways in which the sound of Merseybeat has been approached.
The Theological Bearing of Puranic Stories
Authors: Gielen Joris
Published: April 2010

In Western indological literature the term ‘theology’ is often used to analyse descriptions of Hindu gods and their attributes. Western scholars have likewise retrieved a theology focusing on Radha in various texts, notably in the Brahma-vaivarta-purana. In this purana a feminine theology is said to have been developed. The aim of the present study was to assess whether a feminine theology is present in the Brahma-vaivarta-purana and to evaluate whether our understanding of the purana as a theological or non-theological text could enhance our understanding of Hinduism. Both predicates ‘feminine’ and ‘theological’ are problematic with regard to the purana. The purana can only with difficulty be called feminine because women are not always respectfully approached and Radha is not consistently portrayed as superior or equal to Krsna. Since the purana links Radha with the theologically important functions of creation and redemption, the text seems theological. Yet logical inconsistencies make the term theology also unsuitable for the purana. If this purana and other similar texts are not theology, they cannot be used to solve theological problems like the relationship between divine nature and ethics. Hence, there is no contradiction between Radha’s elevated position in some texts and a secondary treatment of women.
Qualidade de vida, gestão do trabalho e plano de carreira como tecnologista em saúde na atenção básica do Sistema Único de Saúde em São Paulo, Brasil
Authors: Lacaz Francisco Antonio de Castro , Vieira Nelson Passagem , Cortizo Carlos Tato , Junqueira Virgínia , Santos Ana Paula Lopes dos , Santos Fabio Souza
Published: April 2010

O artigo trata do conceito de qualidade de vida no/do trabalho, articulando-o com a gestão do trabalho em saúde com base na avaliação de um instrumento de gestão do trabalho: o Plano de Carreiras, Cargos e Salários (PCCS). Objetiva-se analisá-lo como tecnologia de gestão do trabalho na atenção básica do Sistema Único de Saúde (SUS). São discutidos os PCCS de três municípios de São Paulo, Brasil: São Paulo, Guarulhos e Campinas, conforme diretriz emanada do Conselho Nacional de Saúde em 2006, mediante pesquisa de caráter qualitativo desenvolvida em 2007-2008. Retrata resultados de investigação realizada em oito municípios, considerando a visão do gestor, dos usuários representados nos Conselhos de Saúde e de sindicalistas e trabalhadores representantes dos trabalhadores de saúde que foram entrevistados. Conclui-se que a temática é incipiente como política pública de gestão, sendo matéria de pouco domínio seja dos usuários, seja dos sindicalistas e trabalhadores do setor saúde nos municípios estudados, situados dentre os mais populosos e "municípios-polo" de regiões de saúde.
Desafios à coordenação dos cuidados em saúde: estratégias de integração entre níveis assistenciais em grandes centros urbanos
Authors: Almeida Patty Fidelis de , Giovanella Lígia , Mendonça Maria Helena Magalhães de , Escorel Sarah
Published: April 2010

O artigo analisa o desenvolvimento de instrumentos de coordenação desde a Estratégia Saúde da Família aos demais níveis do sistema de saúde com foco em medidas pró-coordenação vinculadas à "integração entre níveis assistenciais". Os resultados obtidos em estudos de casos realizados em quatro grandes centros urbanos apontaram que estão presentes mecanismos de integração entre níveis assistenciais, indicando preocupação com a garantia de atenção integral. As principais estratégias identificadas foram: criação e fortalecimento de estruturas regulatórias no interior das Secretarias Municipais de Saúde e nas unidades de saúde da família com descentralização de funções para o nível local, organização dos fluxos, prontuários eletrônicos e ampliação da oferta de serviços especializados municipais. Contudo, a falta de integração entre diferentes prestadores, a insuficiência de fluxos formais para atenção hospitalar e a ausência de políticas para média complexidade foram apontadas como entraves à garantia do cuidado integral, tornando incompleto o processo de integração da rede.
Avaliação do rastreamento do câncer do colo do útero na Estratégia Saúde da Família no Município de Amparo, São Paulo, Brasil
Authors: Vale Diama Bhadra Andrade Peixoto do , Morais Sirlei Siani , Pimenta Aparecida Linhares , Zeferino Luiz Carlos
Published: April 2010

A mortalidade por câncer do colo uterino não está reduzindo. A terrritorialização e o cadastramento das famílias pela Estratégia Saúde da Família (ESF) favorece que se identifique as mulheres que nunca fizeram o exame citológico ou que estão há mais de três anos sem fazê-lo. Este estudo analisou se o rastreamento do câncer do colo uterino em Amparo, Estado de São Paulo, Brasil, avançou no sentido de seguir as recomendações vigentes ao longo de sete anos da ESF. A periodicidade anual manteve-se alta, com discreta tendência ao espaçamento dos controles. A distribuição de exames tendeu a aumentar no grupo etário 40-59 anos e a diminuir no grupo etário com mais de 60 anos, e a cobertura anual tendeu a diminuir. Os percentuais de exames em excesso variaram de 61,2% a 65,5%. Concluindo, a qualificação do rastreamento do câncer do colo do útero foi discreta e não modificou o padrão oportunístico dos controles. Considerando que os agentes comunitários de saúde podem atuar no sentido de aumentar a cobertura dessas ações, é fundamental capacitá-los para tal.
Análise espacial dos riscos à saúde associados à incineração de resíduos sólidos: avaliação preliminar
Authors: Gouveia Nelson , Prado Rogério Ruscitto do
Published: April 2010

OBJETIVO: examinar se as emissões do incinerador de resíduos sólidos Vergueiro estavam associadas a um risco aumentado de câncer entre a população residente em seu entorno. MÉTODO: a área de influência deste incinerador foi delimitada por um raio de 7 km a partir de seu centróide georeferenciado. Os óbitos de indivíduos residentes em distritos administrativos contidos nessa área, no período de 1998 a 2002, por câncer de pulmão, fígado, laringe e linfoma não-Hodgkin em adultos, e por leucemia e todos cânceres combinados em crianças, foram selecionados e geocodificados. A área estudada foi dividida em 7 (sete) anéis concêntricos delimitados por raios de 1 a 7 km a partir do incinerador. A análise da associação entre proximidade residencial ao incinerador e mortalidade por câncer foi baseada na comparação entre número de casos observados e esperados, utilizando-se o teste de Stone para examinar o declínio do risco (razão O/E) com a distância do incinerador. RESULTADOS: a área estudada incluiu 1.599.532 habitantes, sendo 92.894 crianças < 5 anos e 634.993 adultos > 40 anos. Não se observou um gradiente espacial nas razões de mortalidade conforme aumenta a distância do incinerador para nenhuma das causas e morte examinadas. CONCLUSÃO: embora não tenha sido detectado aumento no risco dos cânceres previamente selecionados, é importante monitorar as emissões de incineradores ainda em funcionamento e seus possíveis efeitos na saúde. O estudo da distribuição da morbimortalidade em áreas circunvizinhas a essas instalações pode vir a ser uma opção metodológica para atividades de vigilância.
Confiabilidade dos dados antropométricos obtidos em crianças atendidas na Rede Básica de Saúde de Alagoas
Authors: Lima Maria Amália de Alencar , Oliveira Maria Alice Araújo , Ferreira Haroldo da Silva
Published: April 2010

INTRODUÇÃO: O monitoramento do crescimento infantil constitui-se em importante ferramenta para a construção de indicadores úteis ao planejamento de políticas e ações de atenção à saúde da criança. Para isso é necessário que os dados antropométricos obtidos apresentem satisfatória confiabilidade. OBJETIVO: Investigar a confiabilidade dos dados antropométricos produzidos nos Estabelecimentos de Assistência à Saúde (EAS) do SUS em Alagoas. MÉTODOS: Para composição da amostra, sortearam-se 20 dentre os 102 municípios do Estado. Em seguida, dois EAS por município e, nestes, cerca de dez crianças menores de cinco anos. A amostra foi constituída de 40 EAS e 347 crianças. As medidas antropométricas (peso e estatura) foram aferidas (1) na rotina do serviço (S); (2) pelo pesquisador utilizando equipamento padrão (P) e; (3) pesquisador usando equipamentos do serviço (PS). RESULTADOS: A aplicação do teste Kappa indicou concordância "substancial" (K = 0,69) nas classificações de peso-para-idade (PI) entre S e P e "quase perfeita" (K = 0,83) entre PS e P. Quanto à altura-para-idade (AI), a concordância entre S e P foi "discreta" (K = 0,27), passando a "moderada" (K = 0,56) entre PS e P. O Erro Técnico da Medição segundo faixas etárias (</> 24 meses) indicou problemas na técnica e nos equipamentos. As medidas de peso corporal obtidas em S foram sistematicamente superestimadas (p < 0,05; teste dos sinais), o que determinou baixa sensibilidade e uma elevada taxa de falsos negativos (38,5% para PI e 57,1% para AI). CONCLUSÃO: A baixa confiabilidade observada para a variável altura, desaconselha sua utilização na construção de indicadores de saúde até que os EAS sejam dotados de estadiômetros adequados e pessoal qualificado a utilizá-los. Quanto à variável peso, embora possa ser utilizada, é necessário melhorar sua qualidade por meio da capacitação dos antropometristas e da aquisição e/ou manutenção dos equipamentos.