Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia.

Neurodegenerative and psychiatric disorders including Alzheimer's, Parkinson's or Huntington's diseases and schizophrenia have been associated with a deficit in glutathione (GSH). In particular, a polymorphism in the gene of glutamate cysteine ligase modulatory subunit (GCLM) is associated with schizophrenia. GSH is the most important intracellular antioxidant and is necessary for the removal of reactive by-products generated by the utilization of glucose for energy supply. Furthermore, glucose metabolism through the pentose phosphate pathway is a major source of NADPH, the cofactor necessary for the regeneration of reduced glutathione. This study aims at investigating glucose metabolism in cultured astrocytes from GCLM knockout mice, which show decreased GSH levels. No difference in the basal metabolism of glucose was observed between wild-type and knockout cells. In contrast, glycogen levels were lower and its turnover was higher in knockout astrocytes. These changes were accompanied by a decrease in the expression of the genes involved in its synthesis and degradation, including the protein targeting to glycogen. During an oxidative challenge induced by tert-Butylhydroperoxide, wild-type cells increased their glycogen mobilization and glucose uptake. However, knockout astrocytes were unable to mobilize glycogen following the same stress and they could increase their glucose utilization only following a major oxidative insult. Altogether, these results show that glucose metabolism and glycogen utilization are dysregulated in astrocytes showing a chronic deficit in GSH, suggesting that alterations of a fundamental aspect of brain energy metabolism is caused by GSH deficit and may therefore be relevant to metabolic dysfunctions observed in schizophrenia.

Federalism and democracy. The case of minority nations: a federalist deficit

In this chapter, after pointing out the different logics that lie behind the familiar ideas of democracy and federalism, I have dealt with the case of plurinational federal democracies. Having put forward a double criterion of an empirical nature with which to differentiate between the existence of minority nations within plurinational democracies (section 2), I suggest three theoretical criteria for the political accommodation of these democracies. In the following section, I show the agonistic nature of the normative discussion of the political accommodation of this kind of democracies, which bring monist and pluralist versions of the demos of the polity into conflict (section 3.1), as well as a number of conclusions which are the result of a comparative study of 19 federal and regional democracies using four analytical axes: the uninational/plurinational axis; the unitarianism-federalism axis; the centralisation-decentralisation axis; and the symmetry-asymmetry axis (section 3.2). This analysis reveals shortcomings in the constitutional recognition of national pluralism in federal and regional cases with a large number of federated units/regions with political autonomy; a lower degree of constitutional federalism and a greater asymmetry in the federated entities or regions of plurinational democracies. It also reveals difficulties to establish clear formulas in these democracies in order to encourage a “federalism of trust” based on the participation and protection of national minorities in the shared government of plurinational federations/regional states. Actually, there is a federal deficit in this kind polities according to normative liberal-democratic patterns and to what comparative analysis show. Finally, this chapter advocates the need for a greater normative and institutional refinement in plurinational federal democracies. In order to achieve this, it is necessary to introduce a deeper form of “ethical” pluralism -which displays normative agonistic trends, as well as a more “confederal/asymmetrical” perspective, congruent with the national pluralism of these kind of polities.

Gamma Knife radiosurgery in benign skull base tumors after planned subtotal resection: preliminary results in combined approaches

Aim: The management of large lesions of the skull base, such as vestibular schwanommas (VS), meningiomas (MEN) or pituitary adenomas (PA), is challenging, with microsurgery remaining the main treatment option. Planned subtotal resection is now being increasingly considered to reduce the risk of neurological deficits following complete resection. The residual part of the tumor can then be treated with Gamma Knife Radiosurgery (GKR) to achieve long-term growth control. Methods: This case series documents early results with planned subtotal resection followed by GKR in Lausanne University Hospital, between July 2010 and March 2012. There were 24 patients who underwent surgery, with 22 having already undergone GKR and 2 waiting for GKR. We analyzed clinical symptoms for all patients, as well as audiograms, ophthalmological and endocrinological tests, when indicated. Results: Nine patients had VS surgery (mean diameter 35 mm; range 30-44.5) through a retrosigmoid approach. There were no post-operative facial nerve deficits. Of the 3 patients whom had useful hearing pre-operatively, this improved in 2 and remained stable in 1. Four patients with clinoid MEN (mean diameter 26.5 mm; range 17-42) underwent subtotal resection of the tumor, and the component in the cavernous sinus was later treated with GKR. The visual status remained stable in 3 patients and one had complete visual recovery. 4 patients underwent subtotal resection of petro-clival MEN (mean diameter 36 mm; range 32-42): 3 had House-Brackmann (HB) grade 2 facial function that recovered completely; one continues to have HB grade 4 facial deficit following surgery. Of the 7 patients with PA (mean diameter 34.5 mm; range 20-54.5), 2 had acromegaly, the others were non functional PA. Six patients underwent trans-sphenoidal surgery, while one patient had a transcavernous sinus resection of the tumor (with prior staged trans-sphenoidal surgery). Visual status improved in 3 patients while the others remained stable. Two patients had transient diabetes insipidus following surgery. Up to now, no additional deficit or worsening has been reported after GKR. Conclusions: Our data suggest that planned subtotal resection has an excellent clinical outcome with respect to preservation of cranial nerves, and other neurological functions, and a good possibility of recovery of many of the pre-operative cranial nerve dysfunctions. The results in terms of tumor control following GKR need further long-term evaluation.

Debt and deficit fluctuations and the structure of bond markets

This paper tests for the market environment within which US fiscal policyoperates, that is we test for the incompleteness of the US government bondmarket. We document the stochastic properties of US debt and deficits andthen consider the ability of competing optimal tax models to account forthis behaviour. We show that when a government pursues an optimal taxpolicy and issues a full set of contingent claims, the value of debthas the same or less persistence than other variables in the economyand declines in response to higher deficit shocks. By contrast, ifgovernments only issue one-period risk free bonds (incomplete markets),debt shows more persistence than other variables and it increases inresponse to expenditure shocks. Maintaining the hypothesis of Ramseybehavior, US data conflicts.

Combined approach for the management of large vestibular schwannomas: Planned subtotal resection followed by gamma knife surgery in a series of 20 consecutive cases.

INTRODUCTION: The management of large lesions of the skull base, such as vestibular schwannomas (VS) is challenging. Microsurgery remains the main treatment option. Combined approaches (planned subtotal resection followed by gamma knife surgery (GKS) for residual tumor long-term control) are being increasingly considered to reduce the risk of neurological deficits following complete resection. The current study aims to prospectively evaluate the safety-efficacy of combined approach in patients with large VS. MATERIALS AND METHODS: We present our experience with planned subtotal resection followed by gamma knife surgery (GKS) in a consecutive a series of 20 patients with large vestibular schwannomas, treated between 2009 and 2014 in Lausanne University Hospital, Switzerland. Clinical and radiological data and audiograms were prospectively collected for all patients, before and after surgery, before and after GKS, at regular intervals, in dedicated case-report forms. Additionally, for GKS, dose-planning parameters were registered. RESULTS: Twenty patients (6 males and 14 females) with large VS had been treated by this approach. The mean age at the time of surgery was 51.6years (range 34.4-73.4). The mean presurgical diameter was 36.7 (range 26.1-45). The mean presurgical tumor volume was 15.9cm(3) (range 534.9). Three patients (15%) needed a second surgical intervention because of high volume of the tumor remnant considered too large for a safe GKS. The mean follow-up after surgery was 27.2months (range 6-61.3). The timing of GKS was decided on the basis of the residual tumor shape and size following surgery. The mean duration between surgery and GKS was 7.6months (range 413.9, median 6months). The mean tumor volume at the time of GKS was 4.1cm(3) (range 0.5-12.8). The mean prescription isodose volume was 6.3cm(3) (range 0.8-15.5). The mean number of isocenters was 20.4 (range 11-31) and the mean marginal prescription dose was 11.7Gy (range 11-12). We did not have any major complications in our series. Postoperative status showed normal facial nerve function (House-Brackmann grade I) in all patients. Six patients with useful pre-operative hearing (GR class 1) underwent surgery with the aim to preserve cochlear nerve function; of these patients, 5 (83.3%) of them remained in GR class 1 and one (16.7%) lost hearing (GR class 5). Two patients having GR class 3 at baseline remained in the same GR class, but the tonal audiometry improved in one of them during follow-up. Eleven patients (57.8%) were in GR class 5 preoperatively; one patient improved hearing after surgery, passing to GR class 3 postoperatively. Following GKS, there were no new neurological deficits, with facial and hearing function remaining identical to that after surgery. CONCLUSION: Our data suggest that planned subtotal resection followed by GKS has an excellent clinical outcome with respect to retaining facial and cochlear nerve function. This represents a paradigm shift of the treatment goals from a complete tumor excision perspective to that of a surgery designed to preserve neural functions. As long-term results emerge, this approach of a combined treatment (microsurgery and GKS) will most probably become the standard of care in the management of large vestibular schwanomma.

Radial measures of public services deficit for regional allocation of public funds

The goal of this paper is to present an optimal resource allocation model for the regional allocation of public service inputs. Theproposed solution leads to maximise the relative public service availability in regions located below the best availability frontier, subject to exogenous budget restrictions and equality ofaccess for equal need criteria (equity-based notion of regional needs). The construction of non-parametric deficit indicators is proposed for public service availability by a novel application of Data Envelopment Analysis (DEA) models, whose results offer advantages for the evaluation and improvement of decentralised public resource allocation systems. The method introduced in this paper has relevance as a resource allocation guide for the majority of services centrally funded by the public sector in a given country, such as health care, basic and higher education, citizen safety, justice, transportation, environmental protection, leisure, culture, housing and city planning, etc.

Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia.

Glutathione (GSH) metabolism dysfunction is one risk factor in schizophrenia. A transitory brain GSH deficit was induced in Wistar (WIS) and mutant (ODS; lacking ascorbic acid synthesis) rats using BSO (l-buthionine-(S,R)-sulfoximine) from post-natal days 5-16. When GSH was re-established to physiological levels, juvenile BSO-ODS rats were impaired in the water maze task. Long after treatment cessation, adult BSO-WIS/-ODS rats showed impaired place discrimination in the homing board with distributed visual or olfactory cues. Their accuracy was restored when a single cue marked the trained position. Similarly, more working memory errors were made by adult BSO-WIS in the radial maze when several olfactory cues were present. These results reveal that BSO rats did not suffer simple sensory impairment. They were selectively impaired in spatial memory when the task required the integration of multimodal or olfactory cues. These results, in part, resemble some of the reported olfactory discrimination and cognitive impairment in schizophrenia.

Brain volumetric correlates of autism spectrum disorder symptoms in attention deficit/hyperactivity disorder.

Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children's Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners' ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.

Deficit, human capital and economic growth dynamics

Long-run economic growth arouses a great interest since it can shed light on the income-path of an economy and try to explain the large differences in income we observe across countries and over time. The neoclassical model has been followed by several endogenous growth models which, contrarily to the former, seem to predict that economies with similar preferences and technological level, do not necessarily tend to converge to similar per capita income levels. This paper attempts to show a possible mechanismthrough which macroeconomic disequilibria and inefficiencies, represented by budget deficits, may hinder human capital accumulation and therefore economic growth. Using a mixed education system, deficit is characterized as a bug agent which may end up sharply reducing the resources devoted to education and training. The paper goes a step further from the literature on deficit by introducing a rich dynamic analysis of the effects of a deficit reduction on different economic aspects.Following a simple growth model and allowing for slight changes in the law of human capital accumulation, we reach a point where deficit might sharply reduce human capital accumulation. On the other hand, a deficit reduction carried on for a long time, taking that reduction as a more efficient management of the economy, may prove useful in inducing endogenous growth. Empirical evidence for a sample of countries seems to support the theoretical assumptions in the model: (1) evidence on an inverse relationship betweendeficit and human capital accumulation, (2) presence of a strongly negative associationbetween the quantity of deficit in the economy and the rate of growth. They may prove a certain role for budget deficit in economic growth

Deficit, human capital and economic growth dynamics

Long-run economic growth arouses a great interest since it can shed light on the income-path of an economy and try to explain the large differences in income we observe across countries and over time. The neoclassical model has been followed by several endogenous growth models which, contrarily to the former, seem to predict that economies with similar preferences and technological level, do not necessarily tend to converge to similar per capita income levels. This paper attempts to show a possible mechanismthrough which macroeconomic disequilibria and inefficiencies, represented by budget deficits, may hinder human capital accumulation and therefore economic growth. Using a mixed education system, deficit is characterized as a bug agent which may end up sharply reducing the resources devoted to education and training. The paper goes a step further from the literature on deficit by introducing a rich dynamic analysis of the effects of a deficit reduction on different economic aspects.Following a simple growth model and allowing for slight changes in the law of human capital accumulation, we reach a point where deficit might sharply reduce human capital accumulation. On the other hand, a deficit reduction carried on for a long time, taking that reduction as a more efficient management of the economy, may prove useful in inducing endogenous growth. Empirical evidence for a sample of countries seems to support the theoretical assumptions in the model: (1) evidence on an inverse relationship betweendeficit and human capital accumulation, (2) presence of a strongly negative associationbetween the quantity of deficit in the economy and the rate of growth. They may prove a certain role for budget deficit in economic growth

Syndrome de Cogan : à propos d'un cas et brève revue de la littérature [Cogan's Syndrome]

We report the case of a 20-year-old woman, with no medical history, who in a short period of time developed the association of a bilateral vestibulocochlear deficit and a nonsyphilitic interstitial keratitis, the usual clinical presentation of Cogan's syndrome. This rare disease was named after David Cogan, the ophthalmologist to whom we owe the description of the first series of cases. The precise aetiology of Cogan's syndrome has yet to be defined, but clinical and biological evidence point toward an immunopathological process. Some authors distinguish between a typical and an atypical form of Cogan's syndrome, the former being associated with interstitial keratitis, the latter with other forms of ocular involvement. The diagnosis of Cogan's syndrome is mainly a clinical one, the association of a bilateral vestibulocochlear deficit and a non-syphilitic keratitis being almost specific. Cogan's syndrome is frequently associated with general signs and cardiovascular, neurological, rheumathological and digestive involvement. Laboratory data usually show nonspecific inflammatory signs (elevation of the white cell count and of the erythrocyte sedimentation rate). The mortality of the disease is essentially determined by its cardiovascular involvement, mostly aortic insufficiency, which should therefore actively be sought for in every patient. It is useful to emphasise that the typical form of Cogan's syndrome carries a higher risk regarding the development of aortic insufficiency, whereas the atypical form is more often associated with a systemic vasculitis. Treatment is mandatory, based upon corticosteroids, and must sometimes be intensified by the administration of a steroid-sparing immunosuppressive drug. Although our patient perfectly met the diagnostic criteria of Cogan's syndrome, the vestibular symptoms preceded the visual complaints, the reverse temporal sequence being more often reported in the literature. Systemic signs and cardiovascular involvement are frequently seen in Cogan's syndrome, but were notably absent in our patient. Blood samples showed inflammatory signs, whereas both lumbar puncture and cerebral MRI were normal, which is the usual pattern encountered in Cogan's syndrome. Following the rapid initiation of immunosuppressive therapy (Prednisone), the visual symptoms due to the bilateral keratitis resolved in a matter of days, whereas the vestibulocochlear deficit was only partly - but dramatically - reduced. This is in accordance with literature data, showing that a severe and permanent auditory deficit occurs at some time in the majority of patients suffering from Cogan's syndrome. Tapering off Prednisone unfortunately reactivated the audiovestibular and ocular symptoms of the disease in our patient so that a steroid-sparing immunosuppressive drug had to be added (azathioprine, followed by mycophenolate mofetil because the patient developed hepatic intolerance). Only after these therapeutic measures could the disease be stabilised. With this case report, we would like to emphasise the importance of rapidly identifying the clinical picture of Cogan's syndrome, so that immunosuppressive therapy can be started without delay, which may significantly reduce both morbidity and mortality of this disease.