bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting the receptor activator of nuclear factor‐κB (RANK) ligand in prostate cancer bone metastases
Authors: Saad Fred , Markus Richard , Goessl Carsten
Published: April 2008

Newly formed bone in the typically osteoblastic bone metastases from prostate cancer shows characteristics of woven bone, e.g. marked defects in mineralization and microstructure. Adding to the reduced mechanical strength of prostate cancer bone metastasis is an increasingly recognized osteolytic component. The existence of osteoclasts in osteoblastic bone metastases and concomitant increases in urine or serum markers for bone resorption are reported in affected patients. Pathologically increased osteoclastic bone resorption is a key mediator of the clinical complications from bone metastases, among them fractures, spinal cord compression and bone pain. The receptor activator of nuclear factor (NF)‐κB ligand (RANKL) pathway has been identified as the main driving force for osteoclastogenesis and resulting bone resorption. Emerging data indicate that bone marrow‐derived RANKL might also constitute a chemoattractant factor for RANK‐expressing tumour cells that is likely to contribute to the pathogenesis of bone metastases, including those arising from prostate cancer. Cumulative evidence supports RANKL inhibition as a therapeutic goal for the treatment and prevention of bone metastases from prostate cancer.
The Origins and Influence of Land Property Rights in Vietnam
Authors: Hare Denise
Published: April 2008

Vietnam's 1993 Land Law was intended not only to increase the security of farmers’usage rights to their land, but also to facilitate land transfers. Despite potential benefits, the actual issuance of land‐use rights certificates to farmers (as specified by the law) proceeded rather slowly in some regions. This article seeks to identify factors that explain the emergence of this form of property right as well as to measure its effect on agricultural production. The results suggest that the certificate's direct contribution may be rather small in the absence of the appropriate supporting conditions and institutions.
Impact of a commercial destocking relief intervention in Moyale district, southern Ethiopia
Authors: Abebe Dawit , Cullis Adrian , Catley Andy , Aklilu Yacob , Mekonnen Gedlu , Ghebrechirstos Yodit
Published: April 2008

A commercial destocking intervention was piloted in southern Ethiopia during the drought of early 2006. The intervention led to the purchase of an estimated 20,000 cattle valued at USD 1.01 million. On average, destocked households received USD 186 from the sale of cattle—approximately 5,405 households were involved. In terms of aid investment, the approximate cost—benefit ratio was 41:1. During the drought, income from destocking accounted for 54.2 per cent of household income (n = 114 households), and was used to buy food, care for livestock, meet various domestic expenses, support relatives, and either pay off debts or augment savings. Seventy‐nine per cent of the income derived from destocking was used to buy local goods or services. Expenditure on livestock care amounted to 36.5 per cent of local spending, and included the private transportation of livestock to better grazing areas. The buoyant livestock export trade was considered to be an important driver of commercial destocking, demonstrating a positive link between livestock and meat exports, and pastoral vulnerability during drought.
What Do Cross-National Comparisons of Personality Traits Tell Us?
Authors: Heine Steven J. , Buchtel Emma E. , Norenzayan Ara
Published: April 2008

Much research contrasts self-reported personality traits across cultures. We submit that this enterprise is weakened by significant methodological problems (in particular, the reference-group effect) that undermine the validity of national averages of personality scores. In this study, behavioral and demographic predictors of conscientiousness were correlated with different cross-national measures of conscientiousness based on self-reports, peer reports, and perceptions of national character. The predictors correlated strongly with perceptions of national character, but not with self-reports and peer reports. Country-level self- and peer-report measures of conscientiousness failed as markers of between-nation differences in personality.
Hedonic and Instrumental Motives in Anger Regulation
Authors: Tamir Maya , Mitchell Christopher , Gross James J.
Published: April 2008

What motivates individuals to regulate their emotions? One answer, which has been highlighted in emotion-regulation research, is that individuals are motivated by short-term hedonic goals (e.g., the motivation to feel pleasure). Another answer, however, is that individuals are motivated by instrumental goals (e.g., the motivation to perform certain behaviors). We suggest that both answers have merit. To demonstrate the role instrumental goals may play in emotion regulation, we pitted short-term hedonic motives and instrumental motives against each other, by testing whether individuals were motivated to experience a potentially useful, albeit unpleasant, emotion. We found that (a) individuals preferred activities that would increase their level of anger (but not their level of excitement) when they were anticipating confrontational, but not nonconfrontational, tasks and that (b) anger improved performance in a confrontational, but not a non-confrontational, task. These findings support a functional view of emotion regulation, and demonstrate that in certain contexts, individuals may choose to experience emotions that are instrumental, despite short-term hedonic costs.
The Sunny Side of Fairness
Authors: Tabibnia Golnaz , Satpute Ajay B. , Lieberman Matthew D.
Published: April 2008

Little is known about the positive emotional impact of fairness or the process of resolving conflict between fairness and financial interests. In past research, fairness has covaried with monetary payoff, such that the mental processes underlying preference for fairness and those underlying preference for greater monetary outcome could not be distinguished. We examined self-reported happiness and neural responses to fair and unfair offers while controlling for monetary payoff. Compared with unfair offers of equal monetary value, fair offers led to higher happiness ratings and activation in several reward regions of the brain. Furthermore, the tendency to accept unfair proposals was associated with increased activity in right ventrolateral prefrontal cortex, a region involved in emotion regulation, and with decreased activity in the anterior insula, which has been implicated in negative affect. This work provides evidence that fairness is hedonically valued and that tolerating unfair treatment for material gain involves a pattern of activation resembling suppression of negative affect.
It Takes Two
Authors: Zaki Jamil , Bolger Niall , Ochsner Kevin
Published: April 2008

Although current theories suggest that affective empathy (perceivers' experience of social targets' emotions) should contribute to empathic accuracy (perceivers' ability to accurately assess targets' emotions), extant research has failed to consistently demonstrate a correspondence between them. We reasoned that prior null findings may be attributable to a failure to account for the fundamentally interpersonal nature of empathy, and tested the prediction that empathic accuracy may depend on both targets' tendency to express emotion and perceivers' tendency to empathically share that emotion. Using a continuous affect-rating paradigm, we found that perceivers' trait affective empathy was unrelated to empathic accuracy unless targets' trait expressivity was taken into account: Perceivers' trait affective empathy predicted accuracy only for expressive targets. These data suggest that perceivers' self-reported affective empathy can indeed predict their empathic accuracy, but only when targets' expressivity allows their thoughts and feelings to be read.
Bayesian Non‐Parametric Estimation of Smooth Hazard Rates for Seismic Hazard Assessment
Authors: ROCCA LUCA LA
Published: April 2008

Abstract.  Hazard rate estimation is an alternative to density estimation for positive variables that is of interest when variables are times to event. In particular, it is here shown that hazard rate estimation is useful for seismic hazard assessment. This paper suggests a simple, but flexible, Bayesian method for non‐parametric hazard rate estimation, based on building the prior hazard rate as the convolution mixture of a Gaussian kernel with an exponential jump‐size compound Poisson process. Conditions are given for a compound Poisson process prior to be well‐defined and to select smooth hazard rates, an elicitation procedure is devised to assign a constant prior expected hazard rate while controlling prior variability, and a Markov chain Monte Carlo approximation of the posterior distribution is obtained. Finally, the suggested method is validated in a simulation study, and some Italian seismic event data are analysed.
A List Sequential Sampling Method Suitable for Real‐Time Sampling
Authors: BONDESSON LENNART , THORBURN DANIEL
Published: April 2008

Abstract.  A flexible list sequential πps sampling method is introduced and studied. It can reproduce any given sampling design without replacement, of fixed or random sample size. The method is a splitting method and uses successive updating of inclusion probabilities. The main advantage of the method is in real‐time sampling situations where it can be used as a powerful alternative to Bernoulli and Poisson sampling and can give any desired second‐order inclusion probabilities and thus considerably reduce the variability of the sample size.
The disappearance of the ancient landscape and the climatic anomaly of the early Middle Ages: a question to be pursued
Authors: Cheyette Fredric L.
Published: April 2008

Archaeological surveys and rescue archaeology have now dated the disappearance of occupied sites in late antiquity with considerable precision, especially in the Rhône valley and northern Gaul. Landscape archaeology has shown a conversion from arable to pasture and reforestation during the same period. Recent studies of the climate of the first millennium show that this was also an extended period of wet and cold climate. How these phenomena were connected is an important research question. A preliminary suggestion made here is that since reversion from arable to pasture affected regions as far apart as Italy and Poland it cannot simply be ascribed to the political and fiscal dislocation of the ancient world, but should be understood as one effect of the climatic anomaly.
Frankish military duty and the fate of Roman taxation
Authors: Goffart Walter
Published: April 2008

Frankish kings exacted unpaid military service from their subjects in both Merovingian and Carolingian times. The basis for this right has long been uncertain. A study of the term ‘manse’ as a Carolingian measure of assets brings to light the ostensibly hidden property on whose basis Franks went to war. This military duty reached back to the origins of the Frankish kingdom, when a large share of Roman taxes was awarded in individual allotments to soldiers obligated to serve, otherwise unpaid, when summoned, and heavily fined if they did not. Both demesne and tributary manses – contributory units – were the main part of state resources applied to military costs. They cannot be simply envisaged as components of an agricultural scheme (grand domaine). A tax‐like military obligation was one among several institutions actively surviving from the fifth century to the ninth, and it suggests that Frankish government was more law‐based and administrative than is often allowed.
Tradition as a governing theme in the writings of John Cassian
Authors: Casiday Augustine
Published: April 2008

John Cassian has been criticized in recent scholarship for historical inaccuracy – but it is not self‐evident that his works were intended as histories in the sense that is supposed by that criticism. Instead, Cassian presents himself as the promoter of key traditions. This paper describes of Cassian's own thinking about ‘tradition’ as a key theme in his works. To that end, it aims to redress scholarly misgivings about the worth of Cassian's writings by taking them as the transmission of identifiable traditions into early to mid‐fifth‐century Gaul (rather than as documentary evidence for late fourth‐century Egyptian monasticism).
Presence of residual basal cell carcinoma in re‐excised specimens is more probable when deep and lateral margins were positive
Authors: Fernandes JD , De Lorenzo Messina MC , De Almeida Pimentel ER , Castro LGM
Published: April 2008

In order to quantify presence of residual BCC in patients with histologic positive margins after the first excison and to correlate the presence of residual tumor in re‐excised lesions with the location of the positive margin on the first excision, a retrospective evaluation of 2053 surgically treated BCC was performed. Only 38.3% of the re‐excised lesions showed residual tumor. In the group of re‐excised lesions where residual BCC was found, 13% had lateral positive margin in the first excision, 39% had deep positive margin and 48% had both lateral and deep positive margins. In the group of re‐excised lesions where no residual BCC was found, 49% of the primary excised lesions had lateral positive margin, 32% had deep positive margin and 19% had both deep and lateral positive margins. The association between residual tumor and positive margins was statistically significant (p = 0.01). Our findings confirm that presence of residual tumour is more likely when both lateral and deep margins are compromised.
A study on serum IgE and clinical symptomatology of atopy in patients suffering from the lysosomal storage disorder Fabry disease
Authors: Möhrenschlager M , Ollert M , Ring J
Published: April 2008

Background  Lysosomal storage disorders may impair intracellular lysosomal processing of antigen with consequences for antibody production [e.g. immunoglobulin E (IgE)] and atopic disease status.

Aims  Serum concentration of total IgE as well as clinical symptoms of atopic disorders as an indirect consequence of lysosomal impairment of antigen processing were studied in male and female Fabry disease (FD) patients with and without replacement of the missing lysosomal enzyme, α‐galactosidase A (α‐Gal A).

Methods  Observational study in 31 adult FD patients with measurements of total serum IgE concentration. Questionnaire‐derived data were obtained for atopic eczema (AE) skin lesions, allergic rhinoconjunctivitis (RCA) and allergic asthma (AA) at present or in the past.

Results  Among 12 FD males under enzyme replacement therapy (ERT), 2 showed total IgE concentrations above 100 kU/L. Clinical symptoms for AA were found in 2, RCA and AE in 1, respectively. Among 10 FD females under ERT, 4 showed total IgE concentrations above 100 kU/L. Clinical symptoms for AA were found in 4, RCA in 2 and AE in 2. Among 9 females without ERT, 2 showed total IgE concentrations above 100 kU/L. Clinical symptoms for AA were found in 2, RCA in 2 and AE in none.

Conclusions  FD patients may demonstrate an increased total serum IgE concentration and may show symptoms of atopic disorders (AA, RCA, AE) in a prevalence rate comparable to international experience for individuals without FD. There was no difference between patients with and without ERT. Lack of detection of AE in females without ERT is suggested to be caused by the small sample size. FD patients without any α‐Gal A activity prior to initiation of ERT should be in the focus of future studies.
Opposed bilateral transposition flap: a simple and effective way to close large defects, especially of the limbs
Authors: Verdolini R , Dhoat S , Bugatti L , Filosa G
Published: April 2008

Background  Excision of large tumours, particularly of the limbs, can be challenging because of problems related to wound repair. This is especially true of the lower legs, where skin is often tight and difficult to mobilize. Closure by flap, which would represent the first choice for defects usually between 12–15 mm to 38–40 mm diameter, is at risk of developing complications, such as end‐flap necrosis or dehiscence due to skin tension. For larger defects, usually more than 40 to 45 mm diameter, grafting still remains the only realistic option in the majority of cases, with all the various problems associated with this procedure, such as lengthy healing times and the risk of developing leg ulcers, above all in elderly patients with impaired blood circulation. Second intention healing implies extraordinarily long healing times with often unacceptable delays in normal ambulation and activity.

Objective  To find an alternative to the usual repair techniques and to try to reduce the risk of complications.

Conclusions  We developed a relatively simple but effective technique for the closure of large wounds resulting from the excision of tumours. Our technique consists of two longitudinal, parallel, transposition flaps obtained from two opposite sides of the wound, with major axes orientated in the cephalic‐caudal direction. The two flaps are then rotated around two fulcra placed at two extremes of the wound by approximately 90°. This relatively simple technique has never caused any of the ordinarily associated problems in terms of necrosis or ulcer development. In addition, dehiscence of sutures never occurred, given the fact that suture tension is minimal. Quick healing has resulted in the majority of cases, avoiding all the problems associated with grafting or other traditional flap techniques.
Reconstructing phylogenies and phenotypes: a molecular view of human evolution
Authors: Bradley Brenda J.
Published: April 2008

This review broadly summarizes how molecular biology has contributed to our understanding of human evolution. Molecular anthropology began in the 1960s with immunological comparisons indicating that African apes and humans were closely related and, indeed, shared a common ancestor as recently as 5 million years ago. Although initially dismissed, this finding has proven robust and numerous lines of molecular evidence now firmly place the human‐ape divergence at 4–8 Ma. Resolving the trichotomy among humans, chimpanzees and gorillas took a few more decades. Despite the readily apparent physical similarities shared by African apes to the exclusion of modern humans (body hair, knuckle‐walking, thin tooth enamel), the molecular support for a human–chimpanzee clade is now overwhelming. More recently, whole genome sequencing and gene mapping have shifted the focus of molecular anthropology from phylogenetic analyses to phenotypic reconstruction and functional genomics. We are starting to identify the genetic basis of the morphological, physiological and behavioural traits that distinguish modern humans from apes and apes from other primates. Most notably, recent comparative genomic analyses strongly indicate that the marked differences between modern humans and chimpanzees are likely due more to changes in gene regulation than to modifications of the genes themselves, an idea first proposed over 30 years ago. Almost weekly, press releases describe newly identified genes and regulatory elements that seem to have undergone strong positive selection along the human lineage. Loci involved in speech (e.g. FOXP2), brain development (e.g. ASPM), and skull musculature (e.g. MYH16) have been of particular interest, but some surprising candidate loci (e.g. those involved in auditory capabilities) have emerged as well. Exciting new research avenues, such as the Neanderthal Genome Project, promise that molecular analyses will continue to provide novel insights about our evolution. Ultimately, however, these molecular findings can only be understood in light of data from field sites, morphology labs, and museum collections. Indeed, molecular anthropology depends on these sources for calibrating molecular clocks and placing genetic data within the context of key morphological and ecological transitions in human evolution.
A natural history of the human mind: tracing evolutionary changes in brain and cognition
Authors: Sherwood Chet C. , Subiaul Francys , Zawidzki Tadeusz W.
Published: April 2008

Since the last common ancestor shared by modern humans, chimpanzees and bonobos, the lineage leading toHomo sapienshas undergone a substantial change in brain size and organization. As a result, modern humans display striking differences from the living apes in the realm of cognition and linguistic expression. In this article, we review the evolutionary changes that occurred in the descent ofHomo sapiensby reconstructing the neural and cognitive traits that would have characterized the last common ancestor and comparing these with the modern human condition. The last common ancestor can be reconstructed to have had a brain of approximately 300–400 g that displayed several unique phylogenetic specializations of development, anatomical organization, and biochemical function. These neuroanatomical substrates contributed to the enhancement of behavioral flexibility and social cognition. With this evolutionary history as precursor, the modern human mind may be conceived as a mosaic of traits inherited from a common ancestry with our close relatives, along with the addition of evolutionary specializations within particular domains. These modern human‐specific cognitive and linguistic adaptations appear to be correlated with enlargement of the neocortex and related structures. Accompanying this general neocortical expansion, certain higher‐order unimodal and multimodal cortical areas have grown disproportionately relative to primary cortical areas. Anatomical and molecular changes have also been identified that might relate to the greater metabolic demand and enhanced synaptic plasticity of modern human brain's. Finally, the unique brain growth trajectory of modern humans has made a significant contribution to our species’ cognitive and linguistic abilities.
Locomotion and posture from the common hominoid ancestor to fully modern hominins, with special reference to the last common panin/hominin ancestor
Authors: Crompton R. H. , Vereecke E. E. , Thorpe S. K. S.
Published: April 2008

Based on our knowledge of locomotor biomechanics and ecology we predict the locomotion and posture of the last common ancestors of (a) great and lesser apes and their close fossil relatives (hominoids); (b) chimpanzees, bonobos and modern humans (hominines); and (c) modern humans and their fossil relatives (hominins). We evaluate our propositions against the fossil record in the context of a broader review of evolution of the locomotor system from the earliest hominoids of modern aspect (crown hominoids) to early modernHomo sapiens.While some early East African stem hominoids were pronograde, it appears that the adaptations which best characterize the crown hominoids are orthogrady and an ability to abduct the arm above the shoulder – rather than, as is often thought, manual suspensionsensu stricto. At 7–9 Ma (not much earlier than the likely 4–8 Ma divergence date for panins and hominins, seeBradley, 2008) there were crown hominoids in southern Europe which were adapted to moving in an orthograde posture, supported primarily on the hindlimb, in an arboreal, and possibly forOreopithecus, a terrestrial context. By 7 Ma,Sahelanthropusprovides evidence of a Central African hominin, panin or possibly gorilline adapted to orthogrady, and both orthogrady and habitually highly extended postures of the hip are evident in the arboreal East African protohomininOrrorinat 6 Ma. If the traditional idea that hominins passed through a terrestrial ‘knuckle‐walking’ phase is correct, not only does it have to be explained how a quadrupedal gait typified by flexed postures of the hindlimb could have preadapted the body for the hominin acquisition of straight‐legged erect bipedality, but we would have to accept a transition from stem‐hominoid pronogrady to crown hominoid orthogrady, back again to pronogrady in the African apes and then back to orthogrady in hominins. Hand‐assisted arboreal bipedality, which is part of a continuum of orthograde behaviours, is used by modern orangutans to forage among the small branches at the periphery of trees where the core hominoid dietary resource, ripe fruit, is most often to be found. Derivation of habitual terrestrial bipedality from arboreal hand‐assisted bipedality requires fewer transitions, and is also kinematically and kinetically more parsimonious.
Cranial base evolution within the hominin clade
Authors: Nevell L. , Wood B.
Published: April 2008

The base of the cranium (i.e. the basioccipital, the sphenoid and the temporal bones) is of particular interest because it undergoes significant morphological change within the hominin clade, and because basicranial morphology features in several hominin species diagnoses. We use a parsimony analysis of published cranial and dental data to predict the cranial base morphology expected in the hypothetical last common ancestor of the Pan–Homo clade. We also predict the primitive condition of the cranial base for the hominin clade, and document the evolution of the cranial base within the major subclades within the hominin clade. This analysis suggests that cranial base morphology has continued to evolve in the hominin clade, both before and after the emergence of the genus Homo.
Emotional health in adolescents with and without a history of specific language impairment (SLI)
Authors: Conti‐Ramsden Gina , Botting Nicola
Published: April 2008

Objective:  This study examined the emotional health of adolescents with and without specific language impairment (SLI).

Method:  One hundred and thirty‐nine adolescents with a history of SLI (15;10 years) and a peer group of 124 adolescents with normal language development (NLD) (15;11 years) participated, who were in their final year of compulsory schooling. The risk of emotional difficulties was assessed using the Moods and Feelings Questionnaire (MFQ) and the Child Manifest Anxiety Scale‐R (CMAS‐R). Comprehensive language and cognition data were available for all participants (NLD and SLI) concurrently and also longitudinally for those with SLI.

Results:  A clear increased risk of emotional health symptoms was found for the SLI group on both self‐ and parental‐report. Girls scored less favourably than boys when groups were combined, but these were due to the effect of the NLD group, with no gender differences found in the SLI group. Direct links with language and cognition were not obvious. Instead, more diffuse factors such as family history of emotional health difficulties may warrant further investigation.

Conclusion:  There is a marked higher rate of anxiety and depression symptoms in adolescents with SLI. However, these do not appear to be a direct result of impoverished communicative experiences.
Steroid‐induced sexual differentiation of the developing brain: multiple pathways, one goal
Authors: Schwarz Jaclyn M. , McCarthy Margaret M.
Published: April 2008

Hormone exposure, including testosterone and its metabolite estradiol, induces a myriad of effects during a critical period of brain development that are necessary for brain sexual differentiation. Nuclear volume, neuronal morphology, and astrocyte complexity are examples of the wide range of effects by which testosterone and estradiol can induce permanent changes in the function of neurons for the purpose of reproduction in adulthood. This review will examine the multitude of mechanisms by which steroid hormones induce these permanent changes in brain structure and function. Elucidating how steroids alter brain development sheds light on how individual variation in neuronal phenotype is established during a critical period.
Inflammatory events in hippocampal slice cultures prime neuronal susceptibility to excitotoxic injury: a crucial role of P2X7 receptor‐mediated IL‐1β release
Authors: Bernardino Liliana , Balosso Silvia , Ravizza Teresa , Marchi Nicola , Ku George , Randle John C. , Malva João O. , Vezzani Annamaria
Published: April 2008

We investigated the consequences of transient application of specific stimuli mimicking inflammation to hippocampal tissue on microglia activation and neuronal cell vulnerability to a subsequent excitotoxic insult. Two‐week‐old organotypic hippocampal slice cultures, from 7‐day‐old C57BL/6 donor mice, were exposed for 3 h to lipopolysaccharide (LPS; 10 ng/mL) followed by 3 h co‐incubation with 1 mM ATP, or 100 μM 2′3′‐O‐(4‐benzoyl‐benzoyl) adenosine 5′‐triphosphate triethylammonium, a selective P2X7 receptor agonist. These treatments in combination, but not individually, induced a pronounced activation and apoptotic‐like death of macrophage antigen‐1 (MAC‐1)‐positive microglia associated with a massive release of interleukin (IL)‐1β exceeding that induced by LPS alone. Antagonists of P2X7 receptors prevented these effects. Transient pre‐exposure of slice cultures to a combination of LPS and P2X7 receptor agonists, but not either one or the other alone, significantly exacerbated CA3 pyramidal cell loss induced by subsequent 12 h exposure to 8 μM α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propinate (AMPA). Potentiation of AMPA toxicity was prevented when IL‐1β production or its receptor signaling were blocked by an inhibitor of interleukin‐converting‐enzyme or IL‐1 receptor antagonist during application of LPS + ATP. The same treatments did not prevent microglia apoptosis‐like death. These findings show that transient exposure to specific pro‐inflammatory stimuli in brain tissue can prime neuronal susceptibility to a subsequent excitotoxic insult. P2X7 receptor stimulation, and the consequent IL‐1β release, is mandatory for exacerbation of neuronal loss. These mechanisms may contribute to determine cell death/survival in acute and chronic neurodegenerative conditions associated with inflammatory events.
α2 adrenoreceptor agonist regulates protein kinase C‐induced heat shock protein 27 phosphorylation in C6 glioma cells
Authors: Tanabe Kumiko , Takai Shinji , Matsushima‐Nishiwaki Rie , Kato Kanefusa , Dohi Shuji , Kozawa Osamu
Published: April 2008

Dexmedetomidine (Dexmd), a potent and highly specific α2 adrenoreceptor agonist, is an efficient therapeutic agent for sedation. Dexmd has been recently reported to have a neuroprotective effect. Heat shock protein (HSP) 27, a low‐molecular weight HSP has been shown to be expressed following cerebral ischemia in astrocytes but not in neurons. HSP27 expression is involved in ischemic tolerance of the brain. This study investigated the effect of Dexmd on HSP27 in rat C6 glioma cells. 12‐O‐tetradecanoylphorbol‐13‐actate (TPA), a direct activator of protein kinase C (PKC), stimulated the phosphorylation of HSP27 at Ser82, but not Ser15 in a time‐dependent manner. Prostaglandin (PG) E1 or PGE2 which activates the adenylyl cyclase‐cAMP system as well as forskolin and dibutyryl‐cAMP, suppressed the TPA‐induced phosphorylation of HSP27. Dexmd reversed the suppression of HSP27 phosphorylation by the adenylyl cyclase‐cAMP system. Therefore, these results strongly suggest that Dexmd reverses the suppression of HSP27 phosphorylation by the adenylyl cyclase‐cAMP system activation through the inhibition of its system in C6 cells. α2 Adrenoreceptor agonists may therefore show a neuroprotective effect through the modification of HSP27 phosphorylation induced by PKC activation.
Permeation of blood‐borne IL15 across the blood‐brain barrier and the effect of LPS
Authors: Pan Weihong , Hsuchou Hung , Yu Chuanhui , Kastin Abba J.
Published: April 2008

Interleukin15 (IL 15) is a proinflammatory cytokine with elevated concentrations in autoimmune diseases involving the periphery (e.g. rheumatoid arthritis) and CNS (e.g. multiple sclerosis). Its interactions with the blood‐brain barrier (BBB) were studied in normal and lipopolysaccharide (LPS)‐treated mice. 125I‐IL15 remained intact for at least 10 min after i.v. injection and reached CNS parenchyma with regional differences between brain and spinal cord. Both in vivo and in situ brain perfusion of 125I‐IL15 showed that its permeation of the BBB was non‐saturable. LPS induced a significant increase of IL15 uptake by the brain and spinal cord, partly related to a higher general permeability of the BBB. The results suggest that the BBB is an interface for blood‐borne IL15 to interact with the CNS in the basal state and during inflammation.
P2Y receptor mediated inhibitory modulation of noradrenaline release in response to electrical field stimulation and ischemic conditions in superfused rat hippocampus slices
Authors: Csölle Cecília , Heinrich Attila , Kittel Ágnes , Sperlágh Beáta
Published: April 2008

In this study, the inhibitory regulation of the release of noradrenaline (NA) by P2 receptors was investigated in hippocampus slices pre‐incubated with [3H]NA. Electrical field stimulation (EFS; 2 Hz, 240 shocks, and 1 ms) released NA in an outside [Ca2+]‐dependent manner, and agonists of P2Y receptors inhibited the EFS‐evoked [3H]NA release with pharmacological profile similar to that of the P2Y1 and P2Y13 receptor subtypes. This inhibitory modulation was counteracted by bicuculline and 6‐cyano‐2,3‐dihydroxy‐7‐nitro‐quinoxaline + 2‐amino‐5‐phosphonovalerate and 2‐amino‐4‐phosphonobutyrate. In contrast, the excess release in response to 30 min combined oxygen and glucose deprivation was outside [Ca2+] independent, but still sensitive to the inhibition of both facilitatory P2X1 and inhibitory P2Y1 receptors. Whereas mRNA encoding P2Y12 and P2Y13 receptor subunits were expressed in the brainstem, P2Y1 receptor immunoreactivity was localized to neuronal somata and dendrites innervated by the mossy fiber terminals in the CA3 region of the hippocampus, as well as somata of granule cells and interneurons in the dentate gyrus. In summary, in addition to the known facilitatory modulation via P2X receptors, EFS‐evoked [3H]NA outflow in the hippocampus is subject to inhibitory modulation by P2Y1/P2Y13 receptors. Furthermore, endogenous activation of both facilitatory and inhibitory P2 receptors may participate in the modulation of pathological NA release under ischemic‐like conditions.
Retrograde axonal transport and motor neuron disease
Authors: Ström Anna‐Lena , Gal Jozsef , Shi Ping , Kasarskis Edward J. , Hayward Lawrence J. , Zhu Haining
Published: April 2008

Transport of material between extensive neuronal processes and the cell body is crucial for neuronal function and survival. Growing evidence shows that deficits in axonal transport contribute to the pathogenesis of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we review recent data indicating that defects in dynein‐mediated retrograde axonal transport are involved in ALS etiology. We discuss how mutant copper‐zinc superoxide dismutase (SOD1) and an aberrant interaction between mutant SOD1 and dynein could perturb retrograde transport of neurotrophic factors and mitochondria. A possible contribution of axonal transport to the aggregation and degradation processes of mutant SOD1 is also reviewed. We further consider how the interference with axonal transport and protein turnover by mutant SOD1 could influence the function and viability of motor neurons in ALS.
Effect of indomethacin on basal and carbon dioxide stimulated cerebral blood flow in man
Authors: Wennmalm Åke , Eriksson Siw , Wahren John
Published: April 2008

Summary. Cerebral blood flow (CBF) was measured using the nitrous oxide technique in the basal state and following inhalation of CO2 in eight, healthy, awake male volunteers, before and during inhibition of prostaglandin synthesis with indomethacin. Arterial and jugular venous oxygen contents and pCO2 were also analysed. Indomethacin reduced the basal CBF by 35%, from 43 ± 2 to 28 ± 2 ml/100 ml tissue per min, but did not affect the calculated cerebral metabolic rate of oxygen (CMRO2). The reduced CBF was accompanied by an elevation of jugular venous pCO2. Inhalation of 6–7% CO2 increased CBF to 98 ± 17 ml/100 ml tissue per min before indomethacin, compared with only 42 ± 4 ml/100 ml tissue per min after indomethacin. This difference in the hypercapnia induced increase in CBF before and after indomethacin was reflected also by the data on arterio‐venous differences in pCO2.

We conclude that indomethacin inhibits both basal and hypercapnia stimulated CBF in man and suggest that this effect of the drug is due to inhibition of prostaglandin formation. If so, cerebral vascular PG formation plays an important role not only in the maintenance of CBF during normocapnia, but also in the cerebral vasodilation associated with elevated arterial pCO2.
Ventilation/perfusion relationships
Authors: Wagner Peter D.
Published: April 2008

Summary. Over the last 10 years the investigation of V̇A/Q̇ relationships has been significantly advanced as a result of the application of computer‐assisted engineering techniques to the traditional concepts and equations of gas exchange. The price paid for this increase in ability to measure V̇A/Q̇ relationships has been an increase in the complexity of technique, especially as seen by clinicians without a special interest in mathematics. Advances have taken place in the understanding of mechanisms of altered gas exchange in disease, but just as importantly in this author's mind, advances have taken place in our understanding of the problem of indirectly obtaining information from an inaccessible organ. This has been illustrated at some length in this review, and has been applied not only to the newer, more complex approaches to gas exchange, but also to the more traditional methods for assessing gas exchange such as the measurement of venous admixture. Thus, one must have a good understanding of the basic information content of any method before it can be used appropriately.
Increasing glucose intake during total parenteral nutrition increases norepinephrine excretion in trauma and sepsis
Authors: Nordenström Jörgen , Jeevanandam Malayappa , Elwyn David H. , Carpentier Yvon A. , Askanazi Jeffrey , Robin Arnold , Kinney John M.
Published: April 2008

Summary. Total Parenteral Nutrition (TPN) was given to 15 traumatized or infected patients with all of the non‐protein calories, either as intravenous glucose (Glucose System), or as 50% glucose + 50% intravenous fat (Lipid System). Before the administration of TPN, mean urinary excretion of unconjugated norepinephrine was 2–37 ± 0–52 (SEM) μg/kg/day, which is significantly higher than for normal subjects (0–62 ± 0–04 μg/kg/day; n= 56). TPN with the Glucose System for 4–6 days significantly increased the norepinephrine excretion from 1–95 ± 0–47 to 6–77 ± 0–95 μg/kg/day (P < 0.01). When TPN with the Lipid System was given the increase (from 3.05 ± 0.89 to 4.26 ± 0.70 μg/kg/day) was not statistically significant. A modest increase in resting energy expenditure was seen with the Glucose System but not with the Lipid System.

The administration of high glucose loads during TPN, in addition to providing nutritional support, may exert a metabolic stress as reflected by increased metabolic rate and increased catecholamine excretion. These metabolic changes are reduced when intravenous fat emulsions are substituted for a major part of glucose calories.
Continuous monitoring of oxygen tension in human gastrocnemius muscle during exercise
Authors: Holm Sten , Bylund‐Fellenius Ann‐Christin
Published: April 2008

Summary. A technique for continuous monitoring of the intramuscular oxygen tension (i.m. PO2) in human skeletal muscle at rest and during exercise was evaluated. A commercially available oxygen transducer mounted in the tip of a flexible catheter was slightly modified and its characteristics in terms of linearity, response time etc. were investigated in vitro.

The oxygen probe was introduced through a cannula into the gastrocnemius muscle often normal subjects and ten patients with peripheral arterial insufficiency. The i.m. PO2 was continuously monitored at rest as well as during fatiguing leg exercise performed on a foot ergometer. The resting i.m. PO2 was 3.83 ± 0.45 kPa in normal subjects and 3.67 ±0.53 kPa in patients with peripheral arterial insufficiency. During exercise a decrease in the i.m. Po2 was found in both patients and normal subjects. At a work load of 8 kg normal subjects exercised for 8.1 ±0.6 min and the i.m. PO2 decreased to 2.45±0.39 kPa. At the same work load (8 kg) the i.m. PO2 decreased to I ‐22±0–4 kPa in the patients although their exercise time was considerably shorter (2.5 ±0.3 min) because of the development of claudication pain. An increase of the work load to 12 kg in the normals reduced the exercise time to 2.2 ± 0.1 min and provoked a more pronounced decrease in the i.m. PO2 (0.99 ±0.01 kPa). The limitations and advantages of the present technique are discussed in relation to other techniques. The results demonstrate that this technique is suitable for measurements of i.m. PO2 in human skeletal muscle tissue during exercise.
Influence of mixed venous PO2 on diffusion of O2 across the pulmonary blood: gas barrier
Authors: Wagner Peter D.
Published: April 2008

Summary. Analyses of diffusion limitation of pulmonary O2 exchange have stressed that alveolar PO2 (PAO2) is one of the most important factors to consider, but recent reports suggest that PAO2 is important only insofar as it determines the effective slope of the O2 dissociation curve. If this slope is the critical factor, mixed venous PO2 (Pv̄o2) should also be important. This notion was examined in theoretical calculations of oxygenation along the capillary in a homogeneous lung model of normal diffusing capacity. For PAO2= 100 torr, half‐time of rise of PO2, between PV̄O2, and PAO2 (T1/2) increased from 0·09 s (PV̄;O2= 50) to 0·32 s (PV̄;O2=10), while for PAO2= 60, T1/2 increased from 0·18 s (Pv̄O2= 50) to 0·43 s (PV̄;O= 10). At PAO2= 60, diffusion equilibration after 0·75 s was virtually complete if PV̄;O2⋙ 40 torr, but was only 80% complete for PV̄;O2= 10. These calculations show that at any given PAO2, PV̄;O2, has considerable influence on the rate of diffusion equilibration of O2. Thus, situations in which PV̄;O2 is low (e.g. when cardiac output is low in relation to O2 uptake) are associated with considerably increased vulnerability of O2 exchange to diffusion limitation, other factors remaining unchanged.
Metabolic adaptations in post‐exercise recovery
Authors: Krzentowski G. , Pirnay F. , Luyckx A. S. , Pallikarakis N. , Lacroix M. , Mosora F. , Lefèbvre P. J.
Published: April 2008

Summary. To investigate further the hormonal and metabolic adaptations occurring when carbohydrates are ingested after prolonged exercise, we have compared the fate of a 100‐g oral glucose load (using ‘naturally labelled’13C‐glucose) in healthy volunteers after an overnight fast at rest either without previous exercise or after a 3‐h exercise performed on a treadmill at about 50% of the individual V̇o2 max.

In comparison to the control conditions, the oral glucose tolerance test (OGTT) performed in the post‐exercise recovery period was characterized by a greater rise in peripheral blood glucose levels and delayed insulin response. Plasma glucagon values were significantly elevated at the time glucose was given (+48 ±13 pg ml‐1) and at the end of the OGTT. Plasma‐free fatty acid (FFA) levels were 1675 ± 103 μEq 1‐1 when glucose was given, and subsequently reduced to values similar to those observed in the control conditions. Indirect calorimetry indicated that OGTT in post‐exercise recovery was associated with decreased carbohydrate and increased lipid oxidation when compared to control conditions.

Exogenous glucose oxidation was also significantly reduced: 25·1 ± 2·6 vs. 35·9 ± 1·9 g per 7 h. We suggest that the higher plasma glucagon levels and the delayed insulin response played a role in the decreased hepatic glucose retention previously described by others in post‐exercise recovery. Our data also suggest that the higher lipid oxidation rate observed at the time glucose was given in the post‐exercise period could explain, according to the Randle ‘glucose‐fatty acid cycle’, the decreased carbohydrate oxidation and the preferential muscle glycogen repletion already well documented. The reason why the lipid oxidation rate remains increased 3–7 h after glucose ingestion in spite of the fact that FFA levels at that time are similar to those observed in control conditions is still unknown; further kinetic studies are needed to clarify this point.
Adaptation of human skeletal muscle to endurance training of long duration
Authors: Schantz P. , Henriksson J. , Jansson E.
Published: April 2008

Summary. The aim of this study was to examine the adaptive response of skeletal muscle to dynamic training of long duration and low intensity. The response of m. triceps brachii, (TB) and m. quadriceps femoris, vastus lateralis (VL) to training of long duration at an intensity corresponding to approximately 45% of V̇O2, max, has been studied in six subjects. Muscle specimens were taken during training (18.5 miles (30 km)), which involved skiing with a backpack, (6 daydweek, 8 weeks), as well as during a subsequent period of detraining (33 weeks). Increases in oxidative enzyme activities and capillarization during training were limited to the TB. There were parallel increases in citrate synthase (CS) and malate dehydrogenase (MDH) during the first 3 weeks of training (30%). CS then continued to rise (to 90% above pretraining level), while the increase in MDH levelled off. The activity of 3–hydroxyacyl‐CoA‐dehydrogenase (HAD) and the number of capillaries per fibre increased by 50 % and 40 % respectively. A selective decrease (12%) in area of fibre type IIA was noted during training after a 2‐week period of energy deficiency. During the first 6 weeks of detraining, the decrease in CS and HAD (30%) was greater than the decrease in capillaries per fibre (14%).

It is concluded that prolonged duration of training is not, in itself, sufficient to elicit an adaptive response in the leg muscles, while a modest training effect was seen for the arm muscles. The finding emphasizes the importance of adequate intensity in physical training programmes.
Evaluation of the transcutaneous oxygen method used at 37°C for measurement of reactive hyperaemia in the skin
Authors: Ewald Uwe
Published: April 2008

Summary. The transcutaneous oxygen electrode used at an electrode temperature of 35–37°C measures changes in Po2 at the skin surface that are mainly determined by changes in skin blood flow. Simultaneously, information about tissue Po2 in a defined skin area can be obtained by calculation. The reproducibility of this new application of the transcutaneous PO2 technique and factors influencing the recordings were analysed.

Reactive hyperaemia was best recorded at 37°C, where the coefficient of variation (CV) was 14% and the correlation coefficient was 0·90 between duplicate measurements within 15 min (n= 57). The day‐to‐day variation was greater (CV 19–28%). No significant spatial differences in reactive hyperaemia were noted when the distance between the electrodes was no more than 3 cm on the same forearm. A slightly lower reactive hyperaemia was noted when the arm with the electrode was elevated above the level of the heart, as compared with a lower position. Age and sex had significant influence, children (n= 34) exhibiting a greater postocclusive peak tcPo2 response than adults (n= 67). In adults, females (n= 30) showed significantly higher peak tcPo2 values during reactive hyperaemia than males.

This method is a new application of the tcPo2 technique and can be used as a non‐invasive tool for simultaneous blood flow and tissue Po2 studies in microcirculatory research.