Innovazioni nel campo dell'ElettroEncefalografia

Il funzionamento del cervello umano, organo responsabile di ogni nostra azione e pensiero, è sempre stato di grande interesse per la ricerca scientifica. Dopo aver compreso lo sviluppo dei potenziali elettrici da parte di nuclei neuronali in risposta a stimoli, si è riusciti a graficare il loro andamento con l'avvento dell'ElettroEncefaloGrafia (EEG). Tale tecnologia è entrata a far parte degli esami di routine per la ricerca di neuropsicologia e di interesse clinico, poiché permette di diagnosticare e discriminare i vari tipi di epilessia, la presenza di traumi cranici e altre patologie del sistema nervoso centrale. Purtroppo presenta svariati difetti: il segnale è affetto da disturbi e richiede un'adeguata elaborazione tramite filtraggio e amplificazione, rimanendo comunque sensibile a disomogeneità dei tessuti biologici e rendendo difficoltoso il riconoscimento delle sorgenti del segnale che si sono attivate durante l'esame (il cosiddetto problema inverso). Negli ultimi decenni la ricerca ha portato allo sviluppo di nuove tecniche d'indagine, di particolare interesse sono la ElettroEncefaloGrafia ad Alta Risoluzione (HREEG) e la MagnetoEncefaloGrafia (MEG). L'HREEG impiega un maggior numero di elettrodi (fino a 256) e l'appoggio di accurati modelli matematici per approssimare la distribuzione di potenziale elettrico sulla cute del soggetto, garantendo una migliore risoluzione spaziale e maggior sicurezza nel riscontro delle sorgenti neuronali. Il progresso nel campo dei superconduttori ha reso possibile lo sviluppo della MEG, che è in grado di registrare i deboli campi magnetici prodotti dai segnali elettrici corticali, dando informazioni immuni dalle disomogeneità dei tessuti e andando ad affiancare l'EEG nella ricerca scientifica. Queste nuove tecnologie hanno aperto nuovi campi di sviluppo, più importante la possibilità di comandare protesi e dispositivi tramite sforzo mentale (Brain Computer Interface). Il futuro lascia ben sperare per ulteriori innovazioni.

The microtubule plus-end localization of Aspergillus dynein is important for dynein-early-endosome interaction but not for dynein ATPase activation

Cytoplasmic dynein in filamentous fungi accumulates at microtubule plus-ends near the hyphal tip, which is important for minus-end-directed transport of early endosomes. It was hypothesized that dynein is switched on at the plus-end by cargo association. Here, we show in Aspergillus nidulans that kinesin-1-dependent plus-end localization is not a prerequisite for dynein ATPase activation. First, the Walker A and Walker B mutations in the dynein heavy chain AAA1 domain implicated in blocking different steps of the ATPase cycle cause different effects on dynein localization to microtubules, arguing against the suggestion that ATPase is inactive before arriving at the plus-end. Second, dynein from kinA (kinesin 1) mutant cells has normal ATPase activity despite the absence of dynein plus-end accumulation. In kinA hyphae, dynein localizes along microtubules and does not colocalize with abnormally accumulated early endosomes at the hyphal tip. This is in contrast to the colocalization of dynein and early endosomes in the absence of NUDF/LIS1. However, the Walker B mutation allows dynein to colocalize with the hyphal-tip-accumulated early endosomes in the kinA background. We suggest that the normal ability of dyenin to interact with microtubules as an active minus-end-directed motor demands kinesin-1-mediated plus-end accumulation for effective interactions with early endosomes.

Reinforcement learning in dendritic structures

The discovery of binary dendritic events such as local NMDA spikes in dendritic subbranches led to the suggestion that dendritic trees could be computationally equivalent to a 2-layer network of point neurons, with a single output unit represented by the soma, and input units represented by the dendritic branches. Although this interpretation endows a neuron with a high computational power, it is functionally not clear why nature would have preferred the dendritic solution with a single but complex neuron, as opposed to the network solution with many but simple units. We show that the dendritic solution has a distinguished advantage over the network solution when considering different learning tasks. Its key property is that the dendritic branches receive an immediate feedback from the somatic output spike, while in the corresponding network architecture the feedback would require additional backpropagating connections to the input units. Assuming a reinforcement learning scenario we formally derive a learning rule for the synaptic contacts on the individual dendritic trees which depends on the presynaptic activity, the local NMDA spikes, the somatic action potential, and a delayed reinforcement signal. We test the model for two scenarios: the learning of binary classifications and of precise spike timings. We show that the immediate feedback represented by the backpropagating action potential supplies the individual dendritic branches with enough information to efficiently adapt their synapses and to speed up the learning process.

Reinforcement learning in dendritic structures

The discovery of binary dendritic events such as local NMDA spikes in dendritic subbranches led to the suggestion that dendritic trees could be computationally equivalent to a 2-layer network of point neurons, with a single output unit represented by the soma, and input units represented by the dendritic branches. Although this interpretation endows a neuron with a high computational power, it is functionally not clear why nature would have preferred the dendritic solution with a single but complex neuron, as opposed to the network solution with many but simple units. We show that the dendritic solution has a distinguished advantage over the network solution when considering different learning tasks. Its key property is that the dendritic branches receive an immediate feedback from the somatic output spike, while in the corresponding network architecture the feedback would require additional backpropagating connections to the input units. Assuming a reinforcement learning scenario we formally derive a learning rule for the synaptic contacts on the individual dendritic trees which depends on the presynaptic activity, the local NMDA spikes, the somatic action potential, and a delayed reinforcement signal. We test the model for two scenarios: the learning of binary classifications and of precise spike timings. We show that the immediate feedback represented by the backpropagating action potential supplies the individual dendritic branches with enough information to efficiently adapt their synapses and to speed up the learning process.

Early occurrence of lung adenocarcinoma and breast cancer after radiotherapy of a chest wall sarcoma in a patient with a de novo germline mutation in TP53

We report a 26-year-old female patient who was diagnosed within 4 years with chest sarcoma, lung adenocarcinoma, and breast cancer. While her family history was unremarkable, DNA sequencing of TP53 revealed a germline de novo non-sense mutation in exon 6 p.Arg213X. One year later, she further developed a contralateral ductal carcinoma in situ, and 18 months later a jaw osteosarcoma. This case illustrates the therapeutic pitfalls in the care of a young cancer patient with TP53 de novo germline mutations and the complications related to her first-line therapy. Suggestion is made to use the less stringent Chompret criteria for germline TP53 mutation screening. Our observation underlines the possibly negative effect of radiotherapy in generating second tumors in patients with a TP53 mutation. We also present a review of six previously reported cases, comparing their cancer phenotypes with those generally produced by TP53 mutations.

The Constitutional-Judicial Control of the Legislative and Executive Powers in Central and Eastern European Countries

This project looked at the nature, contents, methods, means and legal and political effects of the influence that constitutional courts exercise upon the legislative and executive powers in the newly established democracies of Central and Eastern Europe. The basic hypothesis was that these courts work to provide a limitation of political power within the framework of the principal constitutional values and that they force the legislature and executive to exercise their powers and duties in strict accordance with the constitution. Following a study of the documentary sources, including primarily the relevant constitutional and statutory provisions and decisions of constitutional courts, Mr. Cvetkovski prepared a questionnaire on various aspects of the topics researched and sent it to the respective constitutional courts. A series of direct interviews with court officials in six of the ten countries then served to clarify a large number of questions relating to differences in procedures etc. that arose from the questionnaires. As a final stage, the findings were compared with those described in recent publications on constitutional control in general and in Central and Eastern Europe in particular. The study began by considering the constitutional and political environment of the constitutional courts' activities in controlling legislative and executive powers, which in all countries studied are based on the principles of the rule of law and the separation of powers. All courts are separate bodies with special status in terms of constitutional law and are independent of other political and judicial institutions. The range of matters within their jurisdiction is set by the constitution of the country in question but in all cases can be exercised only with the framework of procedural rules. This gives considerable significance to the question of who sets these rules and different countries have dealt with it in different ways. In some there is a special constitutional law with the same legal force as the constitution itself (Croatia), the majority of countries allow for regulation by an ordinary law, Macedonia gives the court the autonomy to create and change its own rules of procedure, while in Hungary the parliament fixes the rules on procedure at the suggestion of the constitutional court. The question of the appointment of constitutional judges was also considered and of the mechanisms for ensuring their impartiality and immunity. In the area of the courts' scope for providing normative control, considerable differences were found between the different countries. In some cases the courts' jurisdiction is limited to the normative acts of the respective parliaments, and there is generally no provision for challenging unconstitutional omissions by legislation and the executive. There are, however, some situations in which they may indirectly evaluate the constitutionality of legislative omissions, as when the constitution contains provision for a time limit on enacting legislation, when the parliament has made an omission in drafting a law which violates the constitutional provisions, or when a law grants favours to certain groups while excluding others, thereby violating the equal protection clause of the constitution. The control of constitutionality of normative acts can be either preventive or repressive, depending on whether it is implemented before or after the promulgation of the law or other enactment being challenged. In most countries in the region the constitutional courts provide only repressive control, although in Hungary and Poland the courts are competent to perform both preventive and repressive norm control, while in Romania the court's jurisdiction is limited to preventive norm control. Most countries are wary of vesting constitutional courts with preventive norm control because of the danger of their becoming too involved in the day-to-day political debate, but Mr. Cvetkovski points out certain advantages of such control. If combined with a short time limit it can provide early clarification of a constitutional issue, secondly it avoids the problems arising if a law that has been in force for some years is declared to be unconstitutional, and thirdly it may help preserve the prestige of the legislation. Its disadvantages include the difficulty of ascertaining the actual and potential consequences of a norm without the empirical experience of the administration and enforcement of the law, the desirability of a certain distance from the day-to-day arguments surrounding the political process of legislation, the possible effects of changing social and economic conditions, and the danger of placing obstacles in the way of rapid reactions to acute situations. In the case of repressive norm control, this can be either abstract or concrete. The former is initiated by the supreme state organs in order to protect abstract constitutional order and the latter is initiated by ordinary courts, administrative authorities or by individuals. Constitutional courts cannot directly oblige the legislature and executive to pass a new law and this remains a matter of legislative and executive political responsibility. In the case of Poland, the parliament even has the power to dismiss a constitutional court decision by a special majority of votes, which means that the last word lies with the legislature. As the current constitutions of Central and Eastern European countries are newly adopted and differ significantly from the previous ones, the courts' interpretative functions should ensure a degree of unification in the application of the constitution. Some countries (Bulgaria, Hungary, Poland, Slovakia and Russia) provide for the constitutional courts' decisions to have a binding role on the constitutions. While their decisions inevitably have an influence on the actions of public bodies, they do not set criteria for political behaviour, which depends rather on the overall political culture and traditions of the society. All constitutions except that of Belarus, provide for the courts to have jurisdiction over conflicts arising from the distribution of responsibilities between different organs and levels in the country, as well for impeachment procedures against the head of state, and for determining the constitutionality of political parties (except in Belarus, Hungary, Russia and Slovakia). All the constitutions studied guarantee individual rights and freedoms and most courts have jurisdiction over complaints of violation of these rights by the constitution. All courts also have some jurisdiction over international agreements and treaties, either directly (Belarus, Bulgaria and Hungary) before the treaty is ratified, or indirectly (Croatia, Czech Republic, Macedonia, Romania, Russia and Yugoslavia). In each country the question of who may initiate proceedings of norm control is of central importance and is usually regulated by the constitution itself. There are three main possibilities: statutory organs, normal courts and private individuals and the limitations on each of these is discussed in the report. Most courts are limited in their rights to institute ex officio a full-scale review of a point of law, and such rights as they do have rarely been used. In most countries courts' decisions do not have any binding force but must be approved by parliament or impose on parliament the obligation to bring the relevant law into conformity within a certain period. As a result, the courts' position is generally weaker than in other countries in Europe, with parliament remaining the supreme body. In the case of preventive norm control a finding of unconstitutionality may act to suspend the law and or to refer it back to the legislature, where in countries such as Romania it may even be overturned by a two-thirds majority. In repressive norm control a finding of unconstitutionality generally serves to take the relevant law out of legal force from the day of publication of the decision or from another date fixed by the court. If the law is annulled retrospectively this may or may not bring decisions of criminal courts under review, depending on the provisions laid down in the relevant constitution. In cases relating to conflicts of competencies the courts' decisions tend to be declaratory and so have a binding effect inter partes. In the case of a review of an individual act, decisions generally become effective primarily inter partes but is the individual act has been based on an unconstitutional generally binding normative act of the legislature or executive, the findings has quasi-legal effect as it automatically initiates special proceedings in which the law or other regulation is to be annulled or abrogated with effect erga omnes. This wards off further application of the law and thus further violations of individual constitutional rights, but also discourages further constitutional complaints against the same law. Thus the success of one individual's complaint extends to everyone else whose rights have equally been or might have been violated by the respective law. As the body whose act is repealed is obliged to adopt another act and in doing so is bound by the legal position of the constitutional court on the violation of constitutionally guaranteed freedoms and rights of the complainant, in this situation the decision of the constitutional court has the force of a precedent.

Hepatitis A vaccines and the elderly

Hepatitis A virus (HAV) exposure in unprotected adults may cause severe and serious symptoms, with risk of both morbidity and mortality increasing with age. As seroprevalence of HAV is low in industrialised countries, and an increasing number of people, with an increasing median age, travel from areas of low HAV endemicity to high endemicity, pre-travel vaccination is warranted. Vaccination of the elderly against HAV, however, may be associated with reduced seroprotection, since the immune response decreases with age. Studies with monovalent hepatitis A vaccine or combined hepatitis A and B vaccine show good efficacy in adults in general. Few studies have assessed the immune response in older adults. The only prospective study with monovalent hepatitis A vaccine in the elderly showed a reduced seroprotection of approximately 65% after a single primary dose in subjects over the age of 50 years, while seroprotection was 98% in this age group after receiving a booster dose. The only prospective study with combined hepatitis A and B vaccine in younger subjects or older than 40 years showed similar seroprotection (99-100%) against HAV compared to a monovalent vaccine after receiving three doses. As data on seroprotection for HAV in the elderly are limited, further studies are needed to elucidate how optimal protection in the elderly can be achieved. In the mean time, based on the available data, the suggestion is made to screen elderly travellers to areas endemic for HAV for the presence of naturally acquired immunity, and, if found susceptible, be immunised well in advance of their trip, to allow time for post-vaccination antibody testing and/or administration of a second dose of the vaccine.

[Emotion activation in personality disorders]

There are at least six psychotherapeutic treatments of personality disorders having received empirical and clinical validation in terms of their efficacy. These treatments are based on different theoretical models, namely the cognitive-behavioural, psychodynamic and interpersonal models. This article briefly presents these treatments, focusing on the process of therapeutic change. It is assumed that the process of emotional activation is one of the most interesting theoretical psychotherapy ingredient in treatments of these patients. The treatments are discussed regarding this hypothesis and its clinical implications.

Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial

PURPOSE: The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy. PATIENTS AND METHODS: The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2-positive breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF > or = 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction. RESULTS: Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m(2) v 257 mg/m(2)) or epirubicin (480 mg/m(2) v 422 mg/m(2)) and had a lower screening LVEF and a higher body mass index. CONCLUSION: Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.

Cerebellar disorders in childhood: cognitive problems

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.

The Determination of Aluminum in the Presence of Manganese and Iron by the Use of a Mercury Cathode

Since 1880, when Wolcott Gibbs made the suggestion that mercury could be used as a cathode in gravimetric electroanalysis, many articles have appeared in literature either criticizing the method or citing successful results which have been obtained by it.