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Contains fulltext : 51161.pdf (Publisher’s version ) (Open Access) Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.

To be able to treat prolonged epileptic crises practical, safe and effective rescue medication is needed. Today, the standard treatment in community healthcare is rectal diazepam. The introduction of a buccal solution of midazolam opens up a new perspective in their treatment.To evaluate the cost-effectiveness of buccal midazolam with respect to rectal diazepam for children diagnosed with epilepsy who present prolonged convulsive seizures in the community setting in Spain.The study produces a model of its cost-effectiveness from the perspective of the Spanish National Health System (SNS), with the outcomes presented in terms of cost-quality adjusted life years. Data were collected from different sources, including estimations regarding the clinical effectiveness from a clinical trial, from a Delphi panel in Spain and from a national survey carried out on parents of children with epilepsy in order to determine the current practices.Treatment with buccal midazolam produces a saving in costs in comparison to rectal diazepam. The amount saved by the Spanish SNS comes to 5,484 euros per patient per year. Treatment with buccal midazolam offers an improved health-related quality of life. This, together with the savings in costs, means that there is a dominance of buccal midazolam over rectal diazepam in all the settings that have been examined.The results obtained with the model show that buccal midazolam is more cost-effective than rectal diazepam due to a reduction in the need to call out ambulances and for stays in hospital, as well as an improved health-related quality of life.Coste-efectividad de una solucion bucal de midazolam en el tratamiento de las crisis convulsivas prolongadas en el entorno ambulatorio en España.Introduccion. El tratamiento de las crisis epilepticas prolongadas requiere disponer de una medicacion de rescate comoda, segura y efectiva. Actualmente, el tratamiento estandar en la comunidad es el diacepam rectal. La introduccion de una solucion bucal de midazolam abre una perspectiva nueva en el tratamiento. Objetivo. Evaluar el coste-efectividad del midazolam bucal respecto al diacepam rectal para los niños con un diagnostico de epilepsia que presentan crisis convulsivas prolongadas en la comunidad en España. Materiales y metodos. Modelo coste-efectividad desde la perspectiva del Sistema Nacional de Salud (SNS) español, con resultados presentados en terminos de costes y años de vida ajustados por calidad. Los datos se obtuvieron de varias fuentes, incluidas las estimaciones de efectividad clinica de un ensayo clinico, de un panel Delphi en España y de una encuesta nacional a padres de niños con epilepsia para determinar las practicas actuales. Resultados. El tratamiento con midazolam bucal produce un ahorro de costes en comparacion con el diacepam rectal. El ahorro para el SNS español es de 5.484 euros por paciente al año. El tratamiento con midazolam bucal ofrece una mejora en la calidad de vida relacionada con la salud. Esto, unido al ahorro de costes, hace que el midazolam bucal sea dominante frente al diacepam rectal en todos los escenarios examinados. Conclusion. Los resultados del modelo muestran que el midazolam bucal es mas coste-efectivo que el diacepam rectal debido a una reduccion en la necesidad de llamadas a la ambulancia y estancias en el hospital, asi como a una mejora en la calidad de vida relacionada con la salud.

Item does not contain fulltext Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch-Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch-Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine-guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch-Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine-guanine phosphoribosyltransferase deficiency. 01 maart 2010

As the substance, in its garbha-ālaya (matrix-store) aspects, sets itself forth towards the actualization of its potentialities and as the sphere of “determination” comes about, the endless ever-remaining groundlessness of the undetermined comes to manifest itself entitatively. This is the stringent result of the potential relation of the undetermined to the determined becoming actual. As the “undetermined” aspect of the essence becomes the ever-present, all-encompassing, all-pervading medium of “determination,” the “undetermined” itself becomes entitatively manifest as an aspect of total reality, in a way similar to the “hemp” which becomes manifest as an entitative aspect of the “rope.” The “undetermined,” as becoming “manifest” in this way, is called parinispanna, or the “perfected” or absolute Nature. Being an “entitative manifestation,” pariniṣpanna becomes also a dimension for “cognitive manifestation” in individual consciousness. The “entitative manifestation” of the undetermined as actually positing itself as the substratum of the determined, will become “cognitive manifestation” through the individual mental event of samādhi (highest state of abstract, “empty mind”-concentration), as will be seen later.

In the past chapters sporadic allusion has been made to the process of “complementarity” as it deploys itself within the infinitesimal realm of subatomic structures. Quantum mechanics and the relativity theory have confirmed that no component of the atom can be adequately understood or explained except through the “totality” of its relations to all other components. Buddhism purports that this claim must be evinced also in regard to the macrocosmic universe and to the human consciousness which this universe houses. As language embodiments of a self-expressing reality, no Buddhist school, no Buddhist founder, no Buddhist thinker can be thoroughly understood except within the “totality” of their relations to one another and within the process of complementarity which has produced a historical view of existence such as that which is called Buddhism. No singular milestone in the history of Buddhist thought - including the Buddha himself - can be considered a totalitarian source of authority in the expression of truth. The “totalitarian” attitude is the disease of dismembered perspectives, each one claiming apodicticity for its own cornered vision.

The function is the “self-manifesting” activity of the essence or substance. In the terminology of the “Awakening of Faith” the function is also called the “permeation” (hsun-hsi; Jap: kunjū). As such it represents universal action which consequently must be considered as primordial karma. The givenness of a universal, primordial “agency” was assumed by the previous pre-totalistic doctrine of causation, but not dialectically accounted for.

This chapter is not primarily meant to offer a detailed exposition of Hīnayāna pluralism and phenomenalism. As already stated, we purport only to prepare the reader in an understanding of the basic presuppositions which underlie the developments of totalistic Buddhism. The present exposition is therefore confined to the essential notions of causality in Hīnayāna and more specifically in the Sarvāstivāda conception of existence.

As already suggested, nirmāṇa-kāya translates as the “body of transformation”:6 this meaning connotes primarily the “this-worldly” body of any sentient being who has achieved final enlightenment. Buddhahood had its first historical, natural manifestation in the body of Gautama, later called also Śākyamuni after his enlightenment at Bodhigayā in 528 b.c. As the historical founder of Buddhism, Śākyamuni represents the nirmāṇa-kāya manifestation par excellence. In his unique vocation as founder of Buddhism and its saṃgha (the first community of Buddhist followers), Śākyamuni constitutes the nirmāṇa-kāya in its “singular” historical manifestation. As for the innumerable sentient beings that followed his path and attained individual Buddhahood - which include all the historical figures involved in the progression and formulation of the religious and philosophical doctrines of Buddhism - they can be designated as the nirmāṇa-kāya in its “plural” manifestation. Thus, this “plurality” sets itself forth historically as the antithetic overcoming of the original “singularity”. As a result of the historical reliance of the plural manifestations on the original dharma (law and doctrine) of Śākyamuni, the “collective” historical manifestations develop in the form of Buddhist religious and philosophical schools. This last aspect, which overrides the opposition between the “singular” and the “plural,” establishes such “collective” manifestations as they deploy themselves within a historical process of dialectics.

The “subject-object” correlation as basic to the constitution of individual consciousness is pre-posited by the parikalpita moment of the “entitative manifestations” as a state of mutual exclusion. The “cognitive manifestations” will show the process of “individual consciousness” as it sets itself forth.

As the historical manifestation of Buddhahood through the nirmāṇa-kāya attains its summit in the collective accomplishments of Buddhist thought (the schools), the first stage of the “ontological” (i.e., entitative and cognitive) self-expression of the state of “knowledge” (shih-chueh) reaches its highest boundary in its motion of “within-this-world” expansion. At “this side” of the boundary, however, the dynamics of the nirmāṇa-body continues uninterruptedly its further deployment of “natural” (this-worldly) manifestations. Thus this boundary sets up the distinction between the “natural” (this-worldly) and “preternatural” (other-worldly) functions of the state of knowledge. It is at this point that the nirmāṇa-kāya subsumes the complementary positing of its “other,” namely the saṃbhoga-kāya. In this sense, “preternatural” or “supraterrestrial” Buddhahood seems to stand in opposition to the “natural” or “terrestrial.”

Up to the advent of the integrationist and totalistic schools, the dharma-kāya was understood to be the all-pervading undifferentiated and universal nature of Tathatā as “explicitly” possessed in the state of Buddhahood. On this basis the dharma-kāya has been often equated with a state of indetermination, non-form and non-individuality. Interpreted in this way, the dharma-kāya - although representing a universal and all-pervasive aspect of reality - would oppose the states of form and individuation proper to the parikalpita and to the paratantra levels of entitative manifestation. A pure state of undifferentiated samādhi would make it cognitively manifest to the individual. But for the individual, an ontological integration into the dharma-kāya would mean a traceless reabsorption into a primordial state of total indetermination to the point of non-return, so to speak. This state could be considered to be a mere negative state of freedom from objective form and from subjective individuality. This imperfect conception of the dharma-kāya would be as such the basis for the subtle and latent duality which still lurks within the state of bodhisattvahood, as explained above. Needless to say, this is not the notion of totalistic dharma-kāya-hood as propounded by the “Awakening of Faith” and by the Hua-yen doctrine.

Tathatā (Thusness) has been referred to as the “essence of all phases and aspects of existence in their totality.”5 The Chinese t’i (body) translates here as the primal “body of existence,” suggesting the universal substratum that underlies all “aspects of embodiment in their totality.” Later in the text the word tzu-t’i (Jap: jitai) is used as connoting the sheer potentiality to act which resides in the “hidden” essence of all existence. It is in this sense that t’i is translated now as the substance, namely, as the “hidden” aspect of an ever-self-disclosing and self-embodying Tathatā. Thus substance connotes Tathatā, i.e., the essence in its aspect of primordial “non-manifestation”: substance is the essence as unmanifested. As such, however, the unmanifested is there to manifest itself, that is, the essence of the unmanifested is to manifest itself. The truth of this statement implies, therefore, the inherent and essential ordination of Tathatā to act towards manifestation. In view of this ordination to act, the substance can be envisioned as connoting three complementary aspects: (I) the substance “as such”; (II) the substance “as agent”; (III) the substance “as patient.”

Essential to our exposition of Buddhist totalism (represented best by the Huayen school of China and its Japanese counterpart, the Kegon school) is the doctrine of the already mentioned text, namely, the “Awakening of Faith in Mahāyāna.” We shall rely heavily on it and our main task will be to restructure the vein of its thinking into the triadic sequence of “complementarity” that we are about to present in the subsequent chapters of this book. Needless to say, equally important are the doctrines propounded by such a great master of Hua-yen, like Hsien-shou Fa-tsang.1 we shall also rely frequently on the Laṅkāvatāra-sūtra, for though this is not a text which explicitly advocates a clear-cut doctrine of “causation-by-Tathatā” it does represent, however, a very significant stage of transition that bridges early subjective idealism and totalism.

Our effort to detect a pervading “unity-in-the-difference” throughout the apparently disparate and mutually opposing doctrines of the various Buddhist schools is not original. The Hua-yen tradition, together with all the integrationist tendencies of Mahāyāna (Tendai, Shingon, Amidism, etc.), made a point of showing the dialectical vertebration of all the Buddhist theoretical differences in some sort of monolithic historical framework. Thus Hegel’s attempts to sense the heartbeat of “complementarity” in the cultural veins of history had more than one forerunner in the progressive, totalistic conceptions of Buddhism. The ever-moving history of art, religion and philosophy embodies that dialectical pulse which, according to Hegel, “beats” already through the sheer conceptual veins of pure thought itself. We are about to show, however, that the great difference between the Hegelian concept of dialectics and that of the “totalistic” schools of Buddhism lies precisely in the still-intermediating character of the historical events that belong to the nirmāṇa-kāya manifestations. The completion of the dialectical process, which begins in the garbha-ālaya notion of potentiality, takes place beyond the historical accomplishments of the human Spirit; for the totalistic realization of Tathatā transcends the collective, historicistic notion of the Hegelian “absolute spirit.”