bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidural analgesia for tracheo‐oesophageal fistula repair
Authors: Krishnan K. , Marcus R.
Published: November 2006

Introduction:  Traditionally neonates undergoing surgical repair of tracheo‐oesophageal fistula (TOF) would receive opioid analgesia and be returned ventilated to a neonatal intensive care unit (ICU). It has been shown that the use of epidural analgesia can reduce the need for postoperative ventilation (1). In recent years it has been the practice in our institution to use epidural analgesia for these neonates where possible. This is an audit of our recent experience.

Methods:  We retrospectively identified cases of TOF repair at our institution from January 2002 to September 2005. The notes of these neonates were reviewed for the following information: birth weight, gestational age, co‐existing congenital anomalies, preoperative respiratory function, operation duration, postoperative analgesia, ICU admission and duration of stay in ICU.

Results:  Thirty‐five TOF repairs were identified. One neonate was excluded as he had concomitant abdominal surgery. Of the 34 remaining, 30 sets of notes were reviewed. The outcome for these neonates is shown in the diagram. Of the 10 neonates who did not receive an epidural, a reason was found in eight cases: three were already ventilated, two had abnormal coagulation, two had coexisting congenital heart disease and one had recurrent apnoeas. Only three of the 20 neonates with an epidural required postoperative ventilation, one for metabolic acidosis, one for lung collapse and one for inadequate respiratory effort. All three remained on ICU for <24 h. The median PICU stay for those neonates who did not receive an epidural was 4 days (range 2–11 days). The group who received epidural analgesia was more mature (38.7 weeks c.f. 35.3 weeks gestational age) and heavier (2.9 kg c.f. 2.3 kg) than the group who did not. The mean operative time (including bronchoscopy and surgery) was 2.8 h in the epidural group and 3.3 h in the nonepidural group.

Conclusion:  Mature neonates presenting for TOF repair can be managed with epidural analgesia, usually removing the need for postoperative ventilation and an ICU bed. There is a group of smaller, less mature neonates that did not receive epidural analgesia, we cannot determine from this audit whether any of these would have benefited from epidural analgesia.

Reference  1 Bosenberg AT, Wiersma R, Hadley GP. Esophageal atresia: caudo‐thoracic epidural anesthesia reduces the need for post‐operative ventilatory support. Pediatr Surg Int 1992; 7: 289–291.
Serial measurement of leak conductance around uncuffed endotracheal tubes in children after cardiopulmonary bypass
Authors: Murphy T.W.G. , Reay C.A. , Sims A.J. , Smith J.H.
Published: November 2006

Introduction:  Judging the correctness of the fit of an uncuffed tube in the trachea is an imprecise process that may rely on detecting a just‐audible leak (1). An optimal fit would allow adequate ventilation whilst minimising trauma to the subglottis. If ventilation is prolonged, the fit of the tube in the trachea might vary. We believe that the leak of gas around an uncuffed tube may be evaluated to give an indication of the ‘goodness’ of fit.

Methods:  In the laboratory we developed a technique for quantifying the leak around the tracheal (TT) tube in ventilated children from continuous measurements of airway pressure and inspiratory and expiratory flow acquired from a ventilator. We obtained ethical approval to study 20 children who were ventilated on our PICU after undergoing cardiac surgery on cardiopulmonary bypass. Recordings were made for sequences of 100 breaths at intervals of approximately 4 h during the time that the child was ventilated. Audible leak was graded as ‘none’, ‘minute’, ‘moderate’ or ‘large’ by the anaesthetist responsible for each patient. We calculated the leak conductance (in l.s.–1 cmH2O–1) for each recording and plotted it against time for each patient. We calculated the average leak conductance from the normalised area under this curve to account for irregular sampling, and used this quantity (2) to compare patients who were grouped according to grade of audible leak.

Results:  A total of 286 recordings were collected from 20 patients (age range 5–1356 days, mean age 193 days, weight range 3.0–12.4 kg, mean weight 5.5 kg). Eleven recordings were rejected due to failure or artefact, and two patients were excluded due to insufficient data (two or fewer recordings). Five patients were graded with moderate or large audible leak and the mean leak conductance for this group (mean 360 l.s –1 cmH2O–1) significantly exceeded the leak conductance for the remaining 13 patients with no leak or minute leak (mean 125 l.s –1 cmH2O–1)) with P < 0.05.

Discussion:  We have demonstrated that the physical characteristics of a leak around an uncuffed ET tube can be quantified (3) and that, in this small study, serial measurement of leak conductance is consistent with qualitative audible assessment of leak.

Conclusion:  Leak conductance may provide an objective method for analysing the leak around an uncuffed TT tube and thereby the fit of the tube in the subglottis. We believe that this technique, if adapted, may be useful in the clinical setting.

References  1 Fine GF, Borland LM. The future of the cuffed endotracheal tube. Pediatr Anesth 2004; 14: 38–42.

2 Matthews JNS et al. Analysis of serial measurements in medical research. BMJ 1990; 300: 230–235.

3 Smith JH et al. Leak resistance around uncuffed endotracheal tubes. Pediatr Anesth 2005; 15: 805–806.
Saving the sphincter in rectal cancer: are we prepared to change practice?
Authors: Wallace M. H. , Glynne‐Jones R.
Published: November 2006

Total mesorectal excision and preoperative radiation with or without chemotherapy has led to a reduction in local recurrence rates in patients with rectal cancer. This article examines the effect such treatment has on the rate of sphincter preservation in patients with rectal cancers close to the anal sphincter mechanism and looks at the evidence for changing clinical practice.
A New Approach for Health Monitoring of Structures: Terrestrial Laser Scanning
Authors: Park H. S. , Lee H. M. , Adeli Hojjat , Lee I.
Published: November 2006

Abstract:  A new approach is presented for health monitoring of structures using terrestrial laser scanning (TLS). Three‐dimensional (3D) coordinates of a target structure acquired using TLS can have maximum errors of about 10 mm, which is insufficient for the purpose of health monitoring of structures. A displacement measurement model is presented to improve the accuracy of the measurement. The model is tested experimentally on a simply supported steel beam. Measurements were made using three different techniques: (1) linear variable displacement transducers (LVDTs), (2) electric strain gages, and (3) a long gage fiber optic sensor. The maximum deflections estimated by the TLS model are less than 1 mm and within 1.6% of those measured directly by LVDT. Although GPS methods allow measurement of displacements only at the GPS receiver antenna location, the proposed TLS method allows measurement of the entire building's or bridge's deformed shape, and thus a realistic solution for monitoring structures at both structure and member level. Furthermore, it can be used to create a 3D finite element model of a structural member or the entire structure at any instance of time automatically. Through periodic measurements of deformations of a structure or a structural member and performing inverse structural analyses with the measured 3D displacements, the health of the structure can be monitored continuously.
A Genetic Algorithm Approach for Optimizing Traffic Control Signals Considering Routing
Authors: Teklu Fitsum , Sumalee Agachai , Watling David
Published: November 2006

Abstract:  It is well known that coordinated, area‐wide traffic signal control provides great potential for improvements in delays, safety, and environmental measures. However, an aspect of this problem that is commonly neglected in practice is the potentially confounding effect of drivers re‐routing in response to changes in travel times on competing routes, brought about by the changes to the signal timings. This article considers the problem of optimizing signal green and cycle timings over an urban network, in such a way that the optimization anticipates the impact on traffic routing patterns. This is achieved by including a network equilibrium model as a constraint to the optimization. A Genetic Algorithm (GA) is devised for solving the resulting problem, using total travel time across the network as an illustrative fitness function, and with a widely used traffic simulation‐assignment model providing the equilibrium flows. The procedure is applied to a case study of the city of Chester in the UK, and the performance of the algorithms is analyzed with respect to the parameters of the GA method. The results show a better performance of the signal timing as optimized by the GA method as compared to a method that does not consider rerouting. This improvement is found to be more significant with a more congested network whereas under a relatively mild congestion situation the improvement is not very clear.
Optimal Design of Scissor‐Link Foldable Structures Using Ant Colony Optimization Algorithm
Authors: Kaveh A. , Shojaee S.
Published: November 2006

Abstract: In this article, the Ant Colony Optimization (ACO) algorithm is employed to size optimization of scissor‐link foldable structures. The advantage of using ACO lies in the fact that the discrete spaces can be optimized with no complexity. The algorithm selects the optimum cross‐sections from the available sections list. Elastic behavior is assumed for the formulation of the problem. In addition to strength constraints, the displacement constraints are considered for design. Here, the displacement method is used for analysis employing a special 3‐node beam known as a uniplet. Two design examples are presented to demonstrate the performance of the algorithm.
THE CONFESSING ANIMAL IN FOUCAULT AND WITTGENSTEIN
Authors: Plant Bob
Published: November 2006

In The History of Sexuality, Foucault maintains that “Western man has become a confessing animal” (1990, 59), thus implying that “man” was not always such a creature. On a related point, Wittgenstein suggests that “man is a ceremonial animal” (1996, 67); here the suggestion is that human beings are, by their very nature, ritualistically inclined. In this paper I examine this crucial difference in emphasis, first by reconstructing Foucault's “genealogy” of confession, and subsequently by exploring relevant facets of Wittgenstein's later thinking. While there are significant correlations between Foucault and Wittgenstein, an important disparity emerges in relation to the question of the “natural.” By critically analyzing this, I show how Wittgenstein's minimal naturalism provides an important corrective to Foucault's more extravagant claims. By implication, we see why any radical relativist, historicist, and/or constructivist position becomes untenable on Wittgensteinian grounds, even though Wittgenstein himself is often read as promoting such views.
“NOT ETHICS, NOT ETHICS ALONE, BUT THE HOLY”
Authors: Caruana John
Published: November 2006

While much has been written about Levinas's conception of ethics, very little has been said about the connection between ethics and holiness in his work. Yet, throughout much of his corpus, Levinas consistently links the two. The first part of my article addresses the important distinction that Levinas establishes between the sacred (le sacré) and holiness (la sainteté). According to Levinas, several influential thinkers conflate these two categories. Holiness, Levinas suggests, represents a kind of antidote to the sacred. The second part examines the various ways that holiness is manifest in ethicality. The key, I suggest, for properly understanding the link between ethical regard and sanctification revolves around an appreciation of Levinas's frequent appeal to the notion of straightforwardness (droiture). For Levinas, the complex relations that bind the self, Other, and God, involve essential conditions of rectitude and uprightness.
THE RELIGIOUS ETHICS IMPLICIT IN SCHLEIERMACHER'S DOCTRINE OF CREATION
Authors: Crossley John P.
Published: November 2006

There is a religious ethics implicit in Schleiermacher's doctrine of creation based on the universal feeling of absolute dependence “prior to” its being informed by any historical tradition. The “highest good” which fundamentally characterizes his religious ethics is found at the intersection of God and the World. The “original perfection of man” and the “original perfection of the world” come together when human life in the world is fully informed by the feeling of absolute dependence. Although Schleiermacher did not develop his religious ethics to the same extent as his philosophical and Christian ethics, it should still be of interest to ethicists in many religious traditions, as it establishes contours and sets limits for the ethics of any monotheistic religious tradition.
RELIGIONIS CAUSA
Authors: Van Eijnatten Joris
Published: November 2006

The claim is widespread that the preservation, or reintroduction, of Western traditions of holy war in the post‐Reformation period was due mostly to Protestantism, especially in its Calvinist variety. This paper makes a case for examining the thought of a much broader selection of minor intellectuals on just and holy war than is usually done, and to do so in other national contexts than exclusively the English Puritan one. To test the apparently widespread view that, historically, Calvinism has had a particular proclivity for holy war, the article treats theological justifications of war in seventeenth‐ and eighteenth‐century Dutch moral theology. Showing that a full‐blown concept of “holy war” was largely absent from Dutch theological thought, it falsifies the assumption that historical Calvinism (or Protestantism in general) is inherently belligerent. The paper demonstrates that justifications of violencereligionis causaand ideological motives for war have always been contingent, not on religions, but on the historical contexts in which those religions operate.
AN ENGAGED BUDDHIST RESPONSE TO JOHN RAWLS'S THE LAW OF PEOPLES
Authors: King Sallie B.
Published: November 2006

In The Law of Peoples, John Rawls proposes a set of principles for international relations, his “Law of Peoples.” He calls this Law a “realistic utopia,” and invites consideration of this Law from the perspectives of non‐Western cultures. This paper considers Rawls's Law from the perspective of Engaged Buddhism, the contemporary form of socially and politically activist Buddhism. We find that Engaged Buddhists would be largely in sympathy with Rawls's proposals. There are differences, however: Rawls builds his view from the idea of independent nation–states, while the Buddhists see the world more in terms of a single humankind, the members being highly interdependent with one another, and also with the physical world. The Buddhists would also push harder than Rawls for global structures building multilateralism, restrict more severely justifications for war and behavior in war, stress economic justice more heavily, and insist on all the human rights in the Universal Declaration of Human Rights.
Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review
Authors: Noël B
Published: November 2006

Background  Statins have been increasingly associated with drug‐induced autoimmune reactions, including lupus erythematosus.

Objective  To identify and determine the clinical and biological characteristics of statin‐induced autoimmune reactions.

Material and methods  The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin‐induced autoimmune diseases. The keywords used were statins, 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis.

Results  Twenty‐eight cases of statin‐induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8 ± 18 months; range 1 month−6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy.

Conclusion  Long‐term exposure to statins may be associated with drug‐induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.
The autologous serum skin test in a cohort of chronic idiopathic urticaria patients compared to respiratory allergy patients and healthy individuals
Authors: Guttman‐Yassky Emma , Bergman Reuven , Maor Carcom , Mamorsky Merav , Pollack Shimon , Shahar Eduardo
Published: November 2006

Background  A positive autologous serum skin test (ASST) is considered to reflect the presence of anti‐FceRI and/or anti‐IgE autoantibodies that are capable of activating mast and basophil cell degranulation. The ASST is regarded as a reliable in vivo test in chronic idiopathic urticaria (CIU) patients, with diagnostic, therapeutic and prognostic implications. However, positive ASST results have also occasionally been demonstrated in patients with other diseases and in healthy subjects.

Objective  To evaluate the specificity and sensitivity of the ASST in a cohort of CIU patients compared to a cohort of respiratory‐allergic patients and a group of normal individuals.

Methods  ASST was performed in a cohort of 116 subjects, 47 subjects with seasonal allergic rhinitis, 32 respiratory‐symptom‐free CIU patients, and 37 healthy individuals.

Results  The results were compared statistically to those of the CIU patients. The intradermal injection of autologous serum induced a weal and flare reaction in 17/32 (53.1%) CIU patients; 14/47 (29.8%) patients with seasonal allergic rhinitis (P = 0.06) and in 15/37 (40.5%) of the healthy controls (P = 0.34). The sensitivity and specificity of the ASST in the CIU patients and the seasonal allergic rhinitis patients was 53 and 28%, respectively. When comparing the CIU patients with the healthy controls the sensitivity and specificity was 55 and 31%, respectively. The positive and negative predictive values of the ASST when comparing CIU patients with healthy controls were 53 and 59.5%, respectively. The positive and negative predictive values of the ASST in the CIU patients compared to seasonal allergic rhinitis patients were 53 and 70%, respectively.

Conclusion  The relatively low sensitivity and specificity of the ASST in the CIU patients compared to the seasonal allergic rhinitis patients and healthy controls warrants a more critical interpretation of the ASST in chronic idiopathic urticaria.
Digital computer analysis of dermatoscopical images of 260 melanocytic skin lesions; perimeter/area ratio for the differentiation between malignant melanomas and melanocytic nevi
Authors: Fikrle T , Pizinger K
Published: November 2006

Background  Digital computer analysis of dermatoscopical images has been reported to facilitate the differential diagnosis of pigmented skin lesions in recent years.

Objective  The aim of our study was to perform digital computer analysis of a set of different melanocytic lesions and compare the objective results.

Methods  The set of 260 melanocytic lesions (150 excised difficult cases (46 melanomas, 47 atypical nevi, 57 common nevi and 110 unexcised common nevi) was automatically analysed by the digital dermatoscopical system microDERM. We searched for differences in asymmetry, size, compactness and colour distribution. Perimeter/area ratio was calculated.

Results  The perimeter/area ratio was detected as the most important criterion for differentiation between malignant and benign melanocytic lesions (sensitivity 91.3% and specificity 90.7% for malignant melanomas vs. all benign nevi; sensitivity 91.3% and specificity 80.8% for melanomas vs. clinically atypical nevi). Differences in size of the lesion, shape and asymmetry of colour were found and statistically verified. Using step‐wise logistic regression the formula for calculation of probability of malignant nature of every analysed lesion was constructed.

Conclusion  The perimeter/area ratio is a simple parameter for the differential diagnosis of melanocytic skin lesions.
Vascular adhesion protein‐1 (VAP‐1) is overexpressed in psoriatic patients
Authors: Madej A , Reich A , Orda A , Szepietowski JC
Published: November 2006

Background  Vascular adhesion protein (VAP)‐1 is an adhesion molecule with an enzymatic activity that partakes in the migration process of lymphocytes.

Objectives  The aim of this study was to investigate the expression of VAP‐1 in the skin and serum of psoriatic patients.

Material and methods  Seventy‐one patients suffering from psoriasis aged between 23 and 89 years were included in the study. The mean psoriasis severity assessed according to the psoriasis area and severity index was 14.2 ± 9.6 points. The soluble VAP‐1 serum concentration was evaluated by ELISA and VAP‐1 expression in the skin (nine patients) immunohistochemically.

Results  The serum concentration of soluble VAP‐1 was significantly higher in psoriatic patients than in healthy controls (403.4 ± 130.8 ng/mL vs. 246.4 ± 68.0 ng/mL; P < 0.0001). No significant relationships were found between sVAP‐1 concentration and studied clinical parameters, except the presence of pruritus. Mean number of VAP‐1 positive vessels in psoriatic skin, both lesional (19.8 ± 1.4) and non‐lesional (9.4 ± 1.4), was significantly higher than in healthy skin (5.4 ± 1.5; P < 0.005). Lesional psoriatic skin demonstrated significantly more VAP‐1 positive vessels than non‐lesional skin (P < 0.01).

Conclusions  Significant overexpression of VAP‐1 in both lesional and non‐lesional psoriatic skin and higher serum level of soluble VAP‐1 in psoriatic patients may indicate the role of VAP‐1 in chronic inflammation occurring in psoriasis. However, because of lack of correlation between soluble VAP‐1 serum levels and psoriasis severity this hypothesis needs further investigation.
Dual alteration of limbic dopamine D1 receptor‐mediated signalling and the Akt/GSK3 pathway in dopamine D3 receptor mutants during the development of methamphetamine sensitization
Authors: Chen Pei‐Chun , Lao Chu‐Lan , Chen Jin‐Chung
Published: November 2006

The central dopamine system plays significant roles in motor activity and drug‐induced behavioural sensitization. Our goal was to determine the significance of dopamine D3 receptors in the development of behavioural sensitization to methamphetamine, assessed with D3 receptor mutant mice. The absence of D3 receptors significantly increased the behavioural responses to acute methamphetamine and evoked a faster rate of behavioural sensitization to chronic methamphetamine. In addition, both D3 receptor protein and mRNA levels in the limbic forebrain decreased in sensitized wild‐type mice. Further analyses indicated that D1‐dependent behavioural sensitization and the number of limbic D1 receptors increased in sensitized D3 mutants as compared with sensitized wild‐type mice. Consistent with this finding, we observed higher levels of D1 receptor‐evoked cAMP accumulation and basal phosphoDARPP‐32/Thr34 in the limbic forebrain of D3 mutants than wild‐type mice and the difference was more pronounced after chronic methamphetamine treatment. We also observed an increase in phospho‐extracellular signal‐regulated kinase 2 but a decrease in phosphoAkt/Ser473 and phosphoglycogen synthase kinase 3 (GSK3)‐α/β in the limbic forebrain of D3 mutants compared with wild‐type mice after methamphetamine treatment. The convergent results implicate D3 receptors as a negative regulator of the development of methamphetamine sensitization. A compensatory up‐regulation of D1 receptor‐mediated signals, in addition to an altered Akt/GSK3 pathway, could contribute to the accelerated development of behavioural sensitization.
Identification and characterization of novel activity‐dependent transcription factors in rat cortical neurons
Authors: Sun Woong , Choi Sang‐Hyun , Park Soon Kwon , Kim Soon Jung , Noh Mi Ra , Kim Eun Hae , Kim Hyun Ju , Kim Hyun
Published: November 2006

Using gene chip analyses, we have identified novel neuronal activity‐dependent genes. Application of 25 mm KCl to mature (14‐day culture) rat cortical neurons resulted in more than 1.5‐fold induction of 19 genes and reduction of 42 genes among 1200 neural genes. Changes in the overall gene expression profiles appeared to be related to the reduction of excitability and induction of cellular survival signals. Among the genes identified, three transcriptional modulators [encoding Cbp/p300‐interacting transactivator with ED‐rich tail 2 (CITED2), CCAAT/enhancer binding protein β (C/EBPβ) and neuronal orphan receptor‐1, (NOR1)] were newly identified as activity‐dependent transcription factors, and two of these (CITED2 and NOR1) were found to be influenced by electroconvulsive shock (ECS). NOR1 was induced in specific brain regions by behavioral activation, such as exposure to a novel environment. Because the brain regions that exhibited the induction of these newly identified neuronal activity‐dependent transcriptional modulators were distinct from those showing the induction of previously identified activity‐dependent genes such as c‐fos, these genes might be useful markers for mapping neuronal activity in vivo.
Phosphorylation by extracellular signal‐regulated kinase of a multidomain adaptor protein, vinexin, at synapses
Authors: Ito Hidenori , Usuda Nobuteru , Atsuzawa Kimie , Iwamoto Ikuko , Sudo Kaori , Katoh‐Semba Ritsuko , Mizutani Kosuke , Morishita Rika , Deguchi Takashi , Nozawa Yoshinori , Asano Tomiko , Nagata Koh‐ichi
Published: November 2006

Vinexin is an adaptor protein that is supposed to play pivotal roles in cell adhesion, cytoskeletal organization and signaling. At least three splice variants, vinexinα, β and γ, have so far been reported. In spite of the possible importance of vinexin, the properties and functions of vinexin in neuronal cells are almost unknown. Here we show that vinexin isoforms are expressed in rat brain in a developmental stage‐dependent manner, and that vinexinα is relatively abundant in the telencephalon regions of the adult rat brain. An immunohistochemical study showed the localization of vinexinα in neurons and glia in the rat brain. In primary cultured rat hippocampal neurons, vinexin was found to be present at synapses and filopodia in growth cones by immunofluorescent analyses. Biochemical fractionation revealed the distribution of vinexin in synaptosomes. Nerve terminal localization of vinexin was confirmed by electron microscopy. Vinexinβ is reported to be phosphorylated by extracellular signal‐regulated kinase (ERK) at Ser189, which is equivalent to Ser593 of vinexinα. We thus constructed a site‐ and phosphorylation state‐specific antibody to monitor the ERK‐mediated phosphorylation of vinexin. In immunofluorescent analyses, the phosphorylation was observed at synapses formed among cultured rat hippocampal neurons and it was reduced by treatment of the cells with PD98059. In an immunoelectron microscopic examination, the phosphorylation signal was mainly detected on the postsynaptic side of synapses in the rat hippocampal neurons. As active ERK was co‐localized with vinexin in synapses, the ERK signal is likely to be involved in the regulation of vinexin‐dependent cellular processes in synapses. On the other hand, the phosphorylation was hardly detected in neurons cultured for 3 days, suggesting the presence of a yet unidentified regulatory mechanism of vinexin at the growth cone.
Striatal susceptibility to a dopaminergic neurotoxin is independent of sex hormone effects on cell survival and DAT expression but is exacerbated by central aromatase inhibition
Authors: McArthur Simon , Murray Hilary E. , Dhankot Alihusein , Dexter David T. , Gillies Glenda E.
Published: November 2006

The aim of this study was to investigate further the hormone‐dependent processes underlying sex differences in neurotoxic responses within the rat nigrostriatal dopaminergic (NSDA) pathway after partial lesioning with 6‐OHDA, a state thought to mimic the early stages of Parkinson's disease where, in humans and animal models alike, males appear to be more susceptible. Contrary to our hypotheses, hormone manipulations (gonadectomy ± oestrogen or androgen treatment) failed to alter survival of tyrosine hydroxylase immunoreactive cells in the substantia nigra pars compacta (SNc) after lesioning; this indicates that, unlike inherent sex differences in toxin‐induced striatal dopamine depletion, sex differences in cell loss were not hormonally generated, and that hormone‐dependent changes in dopamine depletion can occur independently of cell survival. In addition, hormonally induced changes in striatal expression of the dopamine transporter (DAT), an important factor for 6‐OHDA toxicity, did not correlate with hormonal influences on striatal dopamine loss and, in males, central inhibition of aromatase prior to 6‐OHDA infusion exacerbated striatal dopamine loss with no effect on SNc tyrosine hydroxylase‐immunoreactive survival, suggesting locally generated oestrogen is neuroprotective. These results support the novel view that sex steroid hormones produced peripherally and centrally play a significant, sex‐specific role within the sexually dimorphic NSDA pathway to modulate plastic, compensatory responses aimed at restoring striatal dopamine functionality, without affecting cell loss.
Melatonin prevents glutamate‐induced oxytosis in the HT22 mouse hippocampal cell line through an antioxidant effect specifically targeting mitochondria
Authors: Herrera Federico , Martin Vanesa , García‐Santos Guillermo , Rodriguez‐Blanco Jezabel , Antolín Isaac , Rodriguez Carmen
Published: November 2006

The pineal hormone melatonin has neuroprotective effects in a large number of models of neurodegeneration. Melatonin crosses the blood–brain barrier, shows a decrease in its nocturnal peaks in blood with age that has been associated with the development of neurodegenerative disorders, and has been shown to be harmless at high concentrations. These properties make melatonin a potential therapeutic agent against neurodegenerative disorders but the pathways involved in such neuroprotective effects remain unknown. In the present report we study the intracellular pathways implicated in the complete neuroprotection provided by melatonin against glutamate‐induced oxytosis in the HT22 mouse hippocampal cell line. Our results strongly suggest that melatonin prevents oxytosis through a direct antioxidant effect specifically targeted at the mitochondria. Firstly, none of the described transducers of melatonin signalling seems to be implicated in the neuroprotection provided by this indole. Secondly, melatonin does not prevent cytosolic GSH depletion‐dependent increase in reactive oxygen species (ROS), but it totally prevents mitochondrial ROS production despite the fact that the latter is much higher than the former. And finally, there is a high correlation between the concentration at which melatonin and closely related indoles exert a direct antioxidant effect in vitro and a neuroprotective effect against glutamate‐induced oxytosis.
Expression and evolution of the mammalian brain gene Ttyh1
Authors: Matthews Clayton A. , Shaw John E. , Hooper Jane A. , Young Ian G. , Crouch Michael F. , Campbell Hugh D.
Published: November 2006

Homologues of the Drosophila melanogaster tweety (tty) gene are present in mammals and Caenorhabditis elegans. The encoded proteins have five predicted membrane‐spanning regions and recent findings suggest that some family members may be chloride channels. Phylogenetic analysis of the tty family including novel members from slime mould Entamoeba and plants has revealed the occurrence of independent gene duplication events in different lineages. expressed sequence tag data indicate that expression of the mammalian Ttyh1 gene is restricted mainly to neural tissue and is up‐regulated in astrocytoma, glioma and several other cancers. In this study, mammalian expression vectors were used to investigate the subcellular localization and the effect of over‐expression of Ttyh1 in human epithelial kidney cells. The results confirm that Ttyh1 is a membrane protein and show that it is deposited on the substratum along the migration paths of motile cells above the α5β1‐integrin complex. The ectopic expression of Ttyh1 also induced long filopodia, which were branched and dynamic in both stationary and migratory cells. The filopodia contained F‐actin and occurred at the ends of microtubules which were polarized towards the membrane. Upon contact with nearby cells some filopodia stabilized and filled with F‐actin, whereas Ttyh1 was highly concentrated at the cell–cell interface. Ttyh1 N‐ and C‐terminal antipeptide antibodies detected Ttyh1 along the axons of neurones in primary rat hippocampal cell cultures, and in situ in whole rat brain slices around the hippocampus and occasionally between cells. These data suggest a role for Ttyh1 in process formation, cell adhesion and possibly as a transmembrane receptor.
24S‐hydroxycholesterol induces cholesterol release from choroid plexus epithelial cells in an apical‐ and apoE isoform‐dependent manner concomitantly with the induction of ABCA1 and ABCG1 expression
Authors: Fujiyoshi Masachika , Ohtsuki Sumio , Hori Satoko , Tachikawa Masanori , Terasaki Tetsuya
Published: November 2006

The release of cholesterol from choroid plexus epithelial cells (CPE) plays an important role in cholesterol homeostasis in the CSF. The purpose of this study was to clarify the molecules involved in cholesterol release in CPE and the regulation mechanisms of the cholesterol release by the liver X receptor (LXR) using a conditionally immortalized CPE line (TR‐CSFB3). The mRNA expression of LXRα, LXRβ and their target genes, ATP‐binding cassette transporter (ABC)A1, ABCG1, ABCG4 and ABCG5, were detected in rat choroid plexus. ABCA1 and ABCG1 protein were detected in the plasma membrane of TR‐CSFB3 cells. Following treatment with 24S‐hydroxycholesterol, an endogenous LXR ligand, the expression of ABCA1 and ABCG1 were induced in TR‐CSFB3 cells. Moreover, apolipoprotein (apo)AI‐ and high‐density lipoprotein (HDL)‐mediated cholesterol release to the apical side of TR‐CSFB3 cells was facilitated by this treatment, whereas that to the basal side was not affected. Following 24S‐hydroxycholesterol treatment, apoE3‐dependent cholesterol release from TR‐CSFB3 cells was enhanced more than the apoE4‐dependent release. These results suggest that LXR activation facilitates cholesterol release into the CSF from CPE through the functional induction of ABCA1 and ABCG1. The difference between apoE3 and apoE4 suggests that the cholesterol release from CPE is related to the development of neurodegenerative diseases.
Dopamine and adult neurogenesis
Authors: Borta Andreas , Höglinger Günter U
Published: November 2006

Dopamine is an important neurotransmitter implicated in the regulation of mood, motivation and movement. We have reviewed here recent data suggesting that dopamine, in addition to being a neurotransmitter, also plays a role in the regulation of endogenous neurogenesis in the adult mammalian brain. In addition, we approach a highly controversial question: can the adult human brain use neurogenesis to replace the dopaminergic neurones in the substantia nigra that are lost in Parkinson's disease?
NO‐cGMP mediated galanin expression in NGF‐deprived or axotomized sensory neurons
Authors: Thippeswamy Thimmasettappa , Haddley Kate , Corness Jacquie D. , Howard Mark R. , McKay Jennifer S. , Beaucourt Stephanie M. , Pope Marion D. , Murphy David , Morris Richard , Hökfelt Tomas , Quinn John P.
Published: November 2006

Leukaemia inhibitory factor (LIF) and nerve growth factor (NGF) are well characterized regulators of galanin expression. However, LIF knockout mice containing the rat galanin 5′ proximal promoter fragment (− 2546 to + 15 bp) driving luciferase responded to axotomy in the same way as control mice. Also, LIF had no effect on reporter gene expression in vitro, neither in the presence or absence of NGF, suggesting that other factors mediate an axotomy response from the galanin promoter. We then addressed the role of nitric oxide (NO) using NGF‐deprived rat dorsal root ganglion (DRG) neuron cultures infected with viral vectors containing the above‐mentioned construct, and also studied endogenous galanin expression in axotomized DRG in vivo. Blocking endogenous NO in NGF‐deprived DRG cultures suppressed galanin promoter activity. Consistent with this, axotomized/NGF‐deprived DRG neurons expressed high levels of neuronal NO synthase (nNOS) and galanin. Further, using pharmacological NOS blockers, or adenoviral vectors expressing dominant‐negative either for nNOS or soluble guanylate cyclase in vivo and in vitro, we show that the NO‐cGMP pathway induces endogenous galanin in DRG neurons. We propose that both LIF and NO, acting at different promoter regions, are important for the up‐regulation of galanin, and for DRG neuron survival and regeneration after axotomy.
Nitric oxide regulates cell survival in purified cultures of avian retinal neurons: involvement of multiple transduction pathways
Authors: Mejía‐García T. A. , Paes‐de‐Carvalho R.
Published: November 2006

Nitric oxide (NO) is an important signaling molecule in the CNS, regulating neuronal survival, proliferation and differentiation. Here, we explored the mechanism by which NO, produced from the NO donor S‐nitroso‐acetyl‐d‐l‐penicillamine (SNAP), exerts its neuroprotective effect in purified cultures of chick retinal neurons. Cultures prepared from 8‐day‐old chick embryo retinas and incubated for 24 h (1 day in culture, C1) were treated or not with SNAP, incubated for a further 72 h (up to 4 days in culture, C4), fixed, and the number of cells estimated, or processed for cell death estimation, by measuring the reduction of the metabolic dye 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT). Experimental cultures were run in parallel but were re‐fed with fresh medium in the absence or presence of SNAP at culture day 3 (C3), incubated for a further 24 h up to C4, then fixed or processed for the MTT assay. Previous studies showed that the re‐feeding procedure promotes extensive cell death. SNAP prevented this death in a concentration‐ and time‐dependent manner through the activation of soluble guanylate cyclase; this protection was significantly reversed by the enzyme inhibitors 1H‐[1,2,4]oxadiazolo‐[4,3‐a]quinoxalin‐1‐one (ODQ) or LY83583, and mimicked by 8‐bromo cyclic guanosine 5′‐phosphate (8Br‐cGMP) (GMP) or 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzyl indazole (YC‐1), guanylate cyclase activators. The effect was blocked by the NO scavenger 2‐phenyl‐4,4,5,5‐tetramethylimidazoline‐1‐oxyl‐3‐oxide (PTIO). The effect of NO was also suppressed by LY294002, Wortmannin, PD98059, KN93 or H89, indicating the involvement, respectively, of phosphatidylinositol‐3 kinase, extracellular‐regulated kinases, calmodulin‐dependent kinases and protein kinase A signaling pathways. NO also induced a significant increase of neurite outgrowth, indicative of neuronal differentiation, and blocked cell death induced by hydrogen peroxide. Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore considered an important mediator of apoptosis and necrosis, as well as boc‐aspartyl (OMe) fluoromethylketone (BAF), a caspase inhibitor, also blocked cell death induced by re‐feeding the cultures. These findings demonstrate that NO inhibits apoptosis of retinal neurons in a cGMP/protein kinase G (PKG)‐dependent way, and strengthens the notion that NO plays an important role during CNS development.
Expression and localization of Parkinson's disease‐associated leucine‐rich repeat kinase 2 in the mouse brain
Authors: Higashi Shinji , Moore Darren J. , Colebrooke Rebecca E. , Biskup Saskia , Dawson Valina L. , Arai Heii , Dawson Ted M. , Emson Piers C.
Published: November 2006

Mutations in the gene encoding leucine‐rich repeat kinase 2 (LRRK2) have been identified as the cause of familial Parkinson's disease (PD) at the PARK8 locus. To begin to understand the physiological role of LRRK2 and its involvement in PD, we have investigated the distribution of LRRK2 mRNA and protein in the adult mouse brain. In situ hybridization studies indicate sites of mRNA expression throughout the mouse brain, with highest levels of expression detected in forebrain regions, including the cerebral cortex and striatum, intermediate levels observed in the hippocampus and cerebellum, and low levels in the thalamus, hypothalamus and substantia nigra. Immunohistochemical studies demonstrate localization of LRRK2 protein to neurones in the cerebral cortex and striatum, and to a variety of interneuronal subtypes in these regions. Furthermore, expression of LRRK2 mRNA in the striatum of VMAT2‐deficient mice is unaltered relative to wild‐type littermate controls despite extensive dopamine depletion in this mouse model of parkinsonism. Collectively, our results demonstrate that LRRK2 is present in anatomical brain regions of direct relevance to the pathogenesis of PD, including the nigrostriatal dopaminergic pathway, in addition to other regions unrelated to PD pathology, and is likely to play an important role in the normal function of telencephalic forebrain neurones and other neuronal populations.
Dichloroacetate causes reversible demyelination in vitro: potential mechanism for its neuropathic effect
Authors: Felitsyn Natalia , Stacpoole Peter W. , Notterpek Lucia
Published: November 2006

Dichloroacetate (DCA) is an investigational drug for genetic mitochondrial diseases whose use has been mitigated by reversible peripheral neuropathy. We investigated the mechanism of DCA neurotoxicity using cultured rat Schwann cells (SCs) and dorsal root ganglia (DRG) neurons. Myelinating SC‐DRG neuron co‐cultures, isolated SCs and DRG neurons were exposed to 1–20 mm DCA for up to 12 days. In myelinating co‐cultures, DCA caused a dose‐ and exposure‐dependent decrease of myelination, as determined by immunolabeling and immunoblotting for myelin basic protein (MBP), protein zero (P0), myelin‐associated glycoprotein (MAG) and peripheral myelin protein 22 (PMP22). Partial recovery of myelination occurred following a 10‐day washout of DCA. DCA did not affect the steady‐state levels of intermediate filament proteins, but promoted the formation of anti‐neurofilament antibody reactive whirls. In isolated SC cultures, DCA decreased the expression of P0 and PMP22, while it increased the levels of p75NTR (neurotrophin receptor), as compared with non‐DCA‐treated samples. DCA had modest adverse effects on neuronal and glial cell vitality, as determined by the release of lactate dehydrogenase. These results demonstrate that DCA induces a reversible inhibition of myelin‐related proteins that may account, at least in part, for its clinical peripheral neuropathic effects.
Brain‐derived neurotrophic factor regulates the expression of D1 dopamine receptors
Authors: Do Thuy , Kerr Bredford , Kuzhikandathil Eldo V.
Published: November 2006

We have previously demonstrated that the CAD catecholaminergic neuronal cell line is an appropriate model system to study the regulation of D1 dopamine receptor expression. In this report, we show that brain‐derived neurotrophic factor (BDNF) up‐regulates the expression of D1 dopamine receptor in CAD cells. In addition, by comparing D1 receptor mRNA expression in wild‐type, heterozygous and homozygous trkB knockout mice, we show that TrkB receptor signaling up‐regulates D1 receptor expression in vivo. In CAD cells expressing the TrkB receptor, BDNF increased D1 receptor mRNA in a time‐ and dose‐dependent manner with a fourfold increase in D1 receptor mRNA observed as early as 3 h with 10 ng/mL of BDNF. Using different classes and concentrations of kinase inhibitors, we determined that BDNF‐induced increase of D1 receptor mRNA is mediated by the phosphatidylinositol 3‐kinase signaling pathway. The increase required both new transcription and protein synthesis, as it was blocked by actinomycin D and cyclohexamide, respectively. Promoter deletion analysis identified a D1 promoter region necessary for mediating the effect of BDNF. These results provide novel evidence that D1 dopamine receptor expression is regulated by BDNF and its signaling pathway.
Optimizing Allocation of Management Resources for Wildlife
Authors: MARSH HELENE , DENNIS ANDREW , HINES HARRY , KUTT ALEX , McDONALD KEITH , WEBER ELLEN , WILLIAMS STEPHEN , WINTER JOHN
Published: November 2006

Abstract:  Allocating money for species conservation on the basis of threatened species listings is not the most cost‐effective way of promoting recovery or minimizing extinction rates. Using ecological and social factors in addition to threat categories, we designed a decision‐support process to assist policy makers in their allocation of resources for the management of native wildlife and to clarify the considerations leading to a priority listing. Each species is scored on three criteria at the scale of the relevant jurisdiction: (1) threat category, (2) consequences of extinction, and (3) potential for successful recovery. This approach provides opportunity for independent input by policy makers and other stakeholders (who weight the relative importance of the criteria) and scientists (who score the species against the criteria). Thus the process explicitly separates societal values from the technical aspects of the decision‐making process while acknowledging the legitimacy of both inputs. We applied our technique to two Australian case studies at different spatial scales: the frogs of Queensland (1,728,000 km2; 116 species) and the mammals of the Wet Tropics bioregion (18,500 km2; 96 species). We identified 7 frog and 10 mammal species as priorities for conservation. The frogs included 1 of the 9 species classified as endangered under Queensland legislation, 3 of the 10 species classified as vulnerable, 2 of the 22 species classified as rare, and 1 of the 75 species classified as least concern. The mammals identified included 3 of the 6 species classified as endangered, 1 of the 4 species classified as vulnerable, 5 of the 11 species classified as rare, and 1 of the 75 species classified as least concern. The methods we used to identify species were robust to comparisons across the two taxonomic groups. We concluded that (1) our process facilitates comparisons of data required to make transparent, cost‐effective, and strategic management decisions across taxonomic groups and (2) the process should be used to short‐list species for further discussion rather than for allocating resources per se.