Austria E-mail Research Articles

Clinico-pathological correlations in neurodegeneration

During the last years, Acta Neuropathologica has published a number of cluster fascicles focused on special neuropathological subjects, e.g., Alzheimer, Lewy body and prion diseases, brain tumor diagnosis, and animal models of nervous system diseases. Knowledge about clinicopathological correlations in neurodegenerative disorders has been widened, but also obscured by the rapid progress of clinical and basic sciences in detecting essential molecular and genetic backgrounds of these devastating disorders, leading to considerable changes in their traditional classifications and demonstrating multiple, often clinically similar, but biologically different subgroups. The classification of neurodegenerative diseases, previously based on the anatomical systems involved, has progressively been replaced by biologically and genetically defined groups, both promoting and obscuring the clinicians’ views and making exact clinical diagnoses occasionally difficult without molecular pathological background. Neuropathologists as clinical neuroscientists are at the forefront of correlating histological and molecular changes in the brain with neurological features. Accordingly, the idea of reviewing the clinico-pathological correlations of the major neurodegenerative diseases, which should be of interest to both clinicians and basic neuroscientists, was born at the XVIIth International Congress of Neuropathology in Salzburg, Austria, in September 2010. Manuel F. Casanova and colleagues present a critical review of the neuroimaging and morphological correlates of behavioral and psychological symptoms in dementia (BPSD), a subject hitherto rarely discussed in this global form. The review of the literature indicates that BPSD are the expression of regional rather than diffuse brain pathology: psychotic symptoms in demented patients are preferentially associated with the involvement of frontal and/or limbic regions, visual hallucinations with damage to the occipital lobes, apathy with the anterior cingulate gyrus, while white matter lesions appear to be significant for depression. However, BPSD may not be explained by neuropathological findings alone, but are influenced by genetic, neurochemical, environmental, personality, social, and other factors that need further elucidation. Keith A. Josephs and coworkers, based on the pooled data from a number of large clinico-pathological studies, review the neuropathological background of phenotypical variability in frontotemporal dementias (FTD) that currently are classified into three main groups based on the major protein deposits in the brain; frontotemporal lobar degeneration (FTLD)-tau, -TDP, and -FUS. These groups and their specific pathology underly a number of clinical syndromes and the relationships of which are critically discussed. Although strong relationships were identified between FTD with motor neuron disease and FTLD-TDP; semantic dementia and FTLD-TDP, FTLD-tau, and progressive supranuclear palsy (PSP); and the corticobasal syndrome with FTLD-tau, other clinico-pathological relationships are still not clear, although there are some associations between clinical phenotypes and FTLD pathologies. While there remain diagnostic challenges, clinical diagnosis may often predict molecular pathology. Richard Reynolds’ group, based on the broad experience of the UKMS Tissue Bank, present a profound and critical K. A. Jellinger (&) Institute of Clinical Neurobiology, Kenyongasse 18, 1070 Vienna, Austria e-mail: kurt.jellinger@univie.ac.at

New knowledge about CT usage and dose optimisation in children, but a major question is still unanswered

During the last few years, we have seen some worrying articles describing both the significant increase in CT usage in adults and children and estimations of considerable cancer risk from CT in children. The articles by Brenner et al. [1–3] in particular have sparked new awareness and concerns regarding radiation dose. Currently, an article or report on these issues appears in a scientific journal, in a newspaper or on TV almost monthly. This places enormous responsibility on those radiologists who provide CT to children and adolescents. Paediatric radiologists not only have to promote the enormous advances of CT for disease management in childhood, they also need to make every effort to highlight to radiologists, imaging technicians and clinicians in all subspecialties that, before any use of CT in children, two main criteria must be fulfilled: justification, and optimisation of radiation protection. The articles by Pearce et al. [4] and by Goo [5] in this issue of Pediatric Radiology reflect this continuously increasing awareness, and the concerns within and outside the radiological community regarding the increasing number of CT scans in children and the corresponding substantial radiation exposure. While a number of previous publications have described trends in the use of CT primarily in adult populations, very little has been published regarding temporal trends and other patterns of CT usage in young people. The article by Pearce et al. [4] describes patterns in CT usage among young people aged less than 22 years in Northern England from 1993 to 2002. The results show that the number of CT studies increased, in particular in the years 1997–2000. This was around the time of the introduction to clinical practice of helical CT and multidetector CT. These important technical advances improved the overall performance of CT, in particular speed, facilitating large area scans within seconds and multiphase studies. As a result, CT has become an indispensable part of medical imaging. These important technical inceptions and trends in the late 1990s may be the reason for the observed increase in the number of CTs per patient in this study (the median doubled from 1 in 1993 to 2 in 1999). Since we know very little about the utilisation of CT in young populations around the world, it is indeed crucial to report such trends and patterns. Beyond the necessary description of trends in the use of CT in children and young adults, research on optimisation of paediatric CT techniques, particularly of radiation dose, is of major importance. The article by Goo [5] is an example of this important research. This describes an individualised approach that does not rely on age and body weight but rather on cross-sectional area and the mean density of a specific body region to achieve uniform image noise in contrast-enhanced paediatric chest CT. Individualised volume CT dose can thereby be determined. This interesting approach allows a high degree of tailored CT technique in children. On the other hand, it illustrates that paediatric CT is indeed a challenge. The complexity of the technique and approach described leads to a discussion of whether high-quality paediatric CT is perhaps best performed exclusively in dedicated centres R. Fotter (*) Department of Paediatric Radiology, University Hospital, Medical University Graz, Auenbruggerplatz 34, Graz, Styria 8036 Austria e-mail: richard.fotter@medunigraz.at

Neutral Cholesterol Ester Hydrolases in Macrophages: Still a Matter of Debate

HomeCirculation ResearchVol. 108, No. 10Neutral Cholesterol Ester Hydrolases in Macrophages: Still a Matter of Debate Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBNeutral Cholesterol Ester Hydrolases in Macrophages: Still a Matter of Debate Dagmar Kratky Dagmar KratkyDagmar Kratky Institute of Molecular Biology and Biochemistry Medical University of Graz Graz, Austria E-mail (Kratky) Search for more papers by this author Originally published13 May 2011https://doi.org/10.1161/CIRCRESAHA.111.245829Circulation Research. 2011;108:e13To The Editor:In a recent study, Igarashi et al1 reported knockdown experiments using adenoviral short hairpin RNA constructs targeting human neutral cholesterol ester hydrolase-1 (NCEH1, originally named KIAA1363) and the potential cholesterol ester hydrolase CES1. The authors concluded that “NCEH1 is the only enzyme that requires attention when dealing with neutral cholesterol ester hydrolase activity in human macrophages,” reinforcing similar observations by the same group on murine macrophages.2 This created a controversy,3 because our group demonstrated identical neutral cholesterol ester hydrolase activity in wild-type and Nceh1 knockout mice,4 which argues against a critical role of NCEH1 as cholesterol ester hydrolase. The validity of our observations was questioned5 by claiming that we failed to present “data demonstrating the clean knockout of KIAA1363 of this model by Western and/or Northern blot analyses.” This is at variance with Figure 4F of our report,4 which demonstrated the lack of NCEH1 in macrophages of Nceh1 knockout mice by Western blotting with a specific anti-NCEH1 antibody. Moreover, Figure 1 of the supplemental material of our study confirmed homologous recombination by Southern blot analysis and PCR. Thus, we provided comprehensive information on the generation of the Nceh1 knockout mice and compelling evidence that we used macrophages from a “complete and clean” Nceh1 knockout mouse model for our cholesterol ester hydrolase activity assays.The major conclusion drawn by Igarashi et al1 that “NCEH1 is quantitatively the most important neutral cholesterol ester hydrolase in human macrophages and atherosclerosis” is insufficiently supported by the data presented. Despite an almost complete knockdown of NCEH1 in human monocyte-derived macrophages, neutral cholesterol ester hydrolase activity was reduced by only 50%, which leads us to question the conclusion that “NCEH1 is the only enzyme that requires attention when dealing with neutral cholesterol ester hydrolase activity in human macrophages.” In contrast to NCEH1, CES1 knockdown lacked any reduction in cholesterol ester hydrolase activity. Knockdown of CES1, however, was less efficient, and substantial amounts of CES1 protein were present in CES1-silenced macrophages.The claim that NCEH1 (KIAA1363) is the neutral cholesterol ester hydrolase in human1 and murine2 macrophages, therefore, continues to be at variance with observations made by us4 and others.3Dagmar Kratky Institute of Molecular Biology and Biochemistry Medical University of Graz Graz, Austria E-mail [email protected]Sources of FundingD.K. is supported by the Austrian Science Fund (SFB-LIPOTOX F30, DK-MCD, and P19186) and the Austrian Federal Ministry of Science and Research (GEN-AU project GOLD).DisclosuresNone.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.

“There is no dose–response relationship in psychopharmacotherapy” vs “pharmacotherapy in psychiatry is based on ligand–receptor interaction”: a unifying hypothesis and the need for plasma concentration based clinical trials

The main argument against therapeutic drug monitoring (TDM) in psychiatry, which aims at helping the prescribing physician to optimize her/his pharmacotherapy (Baumann et al. 2004), is that “there is no dose–response relationship in psychiatry”. This claim of a lack of any dose–response relationship is voiced, e.g., in a recent meta-analysis (Adli et al. 2005) which suggests that increasing the dose of an antidepressant after an insufficient response to a mid-range dose only led to a clinical improvement in the case of tricyclic antidepressants but not selective serotonin reuptake inhibitors (SSRIs). Consequently, these authors recommend that SSRI dosage may be reduced without loss of efficacy. Internally inconsistent, they also suggest using TDM to monitor the dose—which would be completely unnecessary if no dose response relationship existed. In the same vein, Rasmussen and Brosen (2000) summarize their review of the literature as follows: “In several studies there has not been found a clear relationship between clinical efficacy and plasma concentration, nor any threshold that defines toxic concentrations. The available data do not suggest that any benefit be obtained from routine monitoring of SSRI plasma levels.” In contrast, TDM is based on the implicit assumption that all pharmacotherapies are based on ligand–receptor interaction, i.e., show a range of concentrations in which the therapeutic effect is a linear function of the concentration of the ligand (i.e., the medication). As we will show in the following, both positions are correct and only very little additional information is necessary to reconcile both positions in a unifying hypothesis that, if implemented in future clinical trials, may lead to a considerable saving both in costs and patient risk. An impressive amount of data from randomized controlled clinical trials indeed shows that clinical effect is most often not linearly correlated with dose. This lack of a dose–response relationship can be plausibly explained if one considers that for all psychopharmacologic medications so far investigated, the plasma level—after the extracellular space in the brain the second-best pharmacokinetic compartment to correlate concentration with effect—varies up to 20-fold among subjects/patients at each administered daily dose. Figure 1 gives the respective data (Tanum et al. 2010) for the selective serotonin reuptake inhibitor (SSRI) citalopram, arguably one of the most prescribed antidepressants worldwide; Fig. 2 the data for the partial D2 receptor agonist aripiprazol (Grunder et al. 2008); and Fig. 3 our own (C.H.) data on the SSRI paroxetine. To emphasize again, this is not an effect restricted to the compounds shown in this Commentary. The up to 20-fold interindividual variation of plasma levels at each single dose is a phenomenon that has been observed for all psychopharmacological medications so far. With a 20-fold interindividual variation in plasma levels after a single dose, it is not surprising that data based on dose and not on plasma level yield dose–response relationships that V. Eggart :G. Zernig (*) Experimental Psychiatry Unit, Center of Psychiatry and Psychotherapy, Department of General Psychiatry and Social Psychiatry, Medical University Innsbruck, Innrain 66 a, room 35-G1-010, A-6020, Innsbruck, Austria e-mail: gerald.zernig@me.com

Localized giant inflammatory polyp of the colon in a patient without inflammatory bowel disease

Dear Editor, Gastrointestinal polyps are classified as neoplastic polyps, such as adenoma or polypoid adenocarcinoma, and non-neoplastic polyps of which inflammatory polyps may be regarded as a distinct entity [1]. Within the colon, inflammatory polyps have mainly been described to occur against a background of inflammatory bowel disease (IBD). Rarely, these lesions lead to stenosis, thereby mimicking a malignant tumor [2, 3]. But inflammatory polyps may also be observed in patients without history of IBD [4]. An asymptomatic 45-year-old male underwent routine colonoscopy because of a family history of colorectal cancer. There was no history of IBD. During colonoscopy, an irregular polypoid mass was detected at the hepatic flexure. Repeated biopsies showed chronic inflammation without evidence of malignancy. Prompted by the patient's positive family history and the suspicious endoscopic appearance of the lesion, a right-sided hemicolectomy was performed. On gross inspection, an irregular villous polyp, measuring 4 cm in largest diameter was found. The lesion showed circumferential growth and extended with small polyps of gradually decreasing size into the neighboring normal mucosa (Fig. 1a). Histological examination revealed irregular villous-like projections of the mucosa (Fig. 1b). The crypt architecture was markedly distorted, and the lamina propria contained a dense mixed inflammatory infiltrate. Crypt abscesses as well as hyperplastic lymphoid follicles were frequently observed, while epithelial dysplasia was lacking (Fig. 1c). One slide showed a circumscribed superficial ulcer which was bordered by unspecific granulation tissue. The nonpolypoid mucosa of the resection specimen was entirely normal, without signs of inflammation, particularly IBD. Finally, a diagnosis of “localized giant inflammatory polyp” was made. Localized giant pseudopolyps were first described in 1968 [5]. These lesions are almost invariably associated with IBD [2, 3]. Our case, however, clearly demonstrates that these lesions may also occur in patients without history of IBD. Moreover, the flat mucosa of the resection specimen was entirely normal, lacking signs of chronic inflammation. There is only a single report in the literature illustrating a case similar to ours. Tan et al. [4] reported upon a 64-year-old male without history of IBD who E.-M. Wolf : C. Strasser : E. Spuller : C. Langner (*) Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria e-mail: cord.langner@medunigraz.at

Acute pulmonary edema caused by a multiple sclerosis relapse

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) [1]. In the majority of patients, MS begins with a relapsing–remitting course. It is characterized by unpredictable relapses followed by periods of months to years of clinical remission. MS relapses entail various clinical symptoms depending on the location of the inflammatory lesion within the CNS. Besides the common symptoms of optic neuritis, paresis, paraesthesia, and ataxic gait disorders, in some rare cases a relapse may alter cardiovascular and autonomic function [1]. Clinical studies have shown that acute cerebral lesions (e.g., stroke, hemorrhage) may induce changes in cardiac and respiratory function including hypertension, arrhythmias, myocardial necrosis, and sudden death [2, 3]. Moreover, experimental and clinical studies indicate that damage of the brainstem is likely to cause disturbances in either sympathetic or parasympathetic autonomic function with subsequent cardiac and respiratory dysfunction [4–6]. Neurogenic pulmonary edema (NPE) is usually defined as an acute pulmonary edema occurring shortly after various injuries of the central nervous system [7]. The most important vasomotor centers for NPE development are nuclei of the solitary tract, the dorsal motor vagus nucleus in the medulla oblongata and the medial reticulated nucleus. On the other hand, brainstem damage in the region of the solitary tract nuclei may result in a transient cardiomyopathy [8]. The exact mechanisms remain poorly understood because of the complexity of its pathophysiologic mechanisms, involving both hemodynamic and inflammatory aspects. There are two possible explanations: one presumes that neurological damage directly involves the pulmonary and cardiac vascular bed with disconnection of the central nervous system vasomotor centers. However, there are also data that brainstem dysfunction can cause changes of sympathetic vasomotor tone [7]. This case study describes a rare initial presentation of a MS relapse with pulmonary edema caused by left ventricular failure. A 48-year-old woman, diagnosed with clinically definite relapsing–remitting MS 3 years previously with a preexisting expanded disability status scale (EDSS) of 3.5, presented with increasing dyspnea and cough without chest pain to a department of internal medicine. She was on immunomodulatory treatment with glatiramer acetate. No clinically apparent atherosclerotic disease was known. On admission, laboratory testing showed that high-sensitivity troponin T was slightly elevated. An electrocardiogram showed no signs of myocardial infarction. In a coronary computed tomography angiogram, no significant changes in the coronary arteries were found. The next day, increases in high-sensitivity troponin T, C-reactive protein (CRP), and a massive increase of B-type natriuretic peptide (proBNP) were observed (Table 1). Pulmonary edema was initially not diagnosed (Fig. 1a) and according to the assumption of pneumonia the patient was treated with antibiotic therapy (amoxicillin) and furosemide. Due to the further worsening of respiratory conditions, intubation and mechanical respirator treatment became necessary. An echocardiogram showed acute left ventricular failure with apical wall motion abnormalities and a left ventricular ejection fraction of 35% in this patient without a history of cardiac disease. No abnormalities concerning the right ventricle and the atria were seen. With regard to her P. Wipfler (&) G. Pilz E. Broussalis S. M. Golaszewski A. Kunz E. Trinka J. Kraus Christian-Doppler-Klinik, University Hospital of Neurology, Paracelsus Medical University and Salzburger Landesklinken, Ignaz Harrerstrasse 79, 5020 Salzburg, Austria e-mail: p.wipfler@salk.at

Preface: special section of papers dealing with overdeepened basins and valleys in the alpine realm

Overdeepened basins and valleys are common features in most regions that were glaciated during the Quaternary. Such structures are known from areas formerly covered by the Laurentian and Scandinavian Ice Sheet as well as for some parts of the Alps and their foreland. The phenomenon describes subsurface geomorphic features, erosionally cut into bedrock and later filled up by sediments. These structures can reach a depth of several hundred metres below the present valley floor. The sedimentary fillings of overdeepened basins and valleys are of particular interest for applied geosciences, for example in the context of groundwater resource management and subsurface constructions (i.e. tunnels). Recently, the topic of when and how overdeepening occurred in the past has gained additional attention with regard to the long-term stability of nuclear waste disposals, especially in Switzerland. In this context, it is important to note that relatively little research focussed on this issue during the past three decades. The last overview on the topic was a compilation of papers published in a special issue of the journal Eiszeitalter und Gegenwart in 1979. This special section in the present issue of the Swiss Journal of Geosciences comprises six papers related to the phenomenon of overdeepening in the Alps. The article by F. Preusser, J. Reitner and Ch. Schluchter summarises the areal distribution and geometry, reviews the present knowledge of the age of formation, and discusses possible processes responsible for overdeepened features. P. Jordan analyses the overdeepened structures in the foreland of the Swiss Alps using a Digital Elevation Model of bedrock surface based on outcrop and borehole data. It is shown that overdeepening mainly occurs within the limits of the Last Glaciation Maximum (LGM), but with a few overdeepened valleys and basin reaching beyond. M. Durst Stucki, R. Reber and F. Schlunegger interpret the buried valleys beneath the city of Bern as a network of tunnel valleys originating from subglacial high pressure melt water erosion. Valleys found in the surrounding Molasse uplands are regarded to represent proglacial melt water paths. The subsurface characteristics of three deep valleys from the Eastern Alps are investigated by E. Bruckl, J. Bruckl, W. Chwatal and Ch. Ullrich using different geophysical surveys. The authors conclude that deep erosion is not related to basal shear stress and that glacial confluence situations did in these examples not lead to important overdeepening. Rather, it is suggested that deep erosion was related to high pressured melt water at the glacier bed in settings of already tectonically weakened bedrock. The upper part of the sedimentary filling of the overdeepened Wehntal in northern Switzerland is analysed by F. Anselmetti, R. Drescher-Schneider, H. Furrer, H. R. Graf, S. Lowick, F. Preusser and M. Riedi revealing that it reaches back to at least 180,000 a. It is shown that the penultimate glaciation (pre-dating the Last Interglacial) may have reached the area M. Fiebig (&) Institute of Applied Geology, University of Natural Resources and Life sciences, Peter Jordan-Str. 70, 1190 Vienna, Austria e-mail: markus.fiebig@boku.ac.at

Neuropathology in Parkinson’s disease with mild cognitive impairment

In a recent paper, Adler et al. [1] reported the neuropathologic findings in eight cases of Parkinson disease with mild cognitive impairment (PD-MC) (6 males, 2 females, mean age 82.8 years, mean PD duration 11.4 years). Four patients each had amnestic MCI memory only, three non-amnestic MCI with frontal executive and one with frontal executive and visuospatial dysfunctions. Using the Unified Lewy Body Staging System (ULBSS [2]), three cases each were brainstem-predominant (stage IIa), and brainstem–limbic predominant (stage III), and two neocortical LB stage (stage IV), while two PD cases with non-amnestic and one with amnestic MCI showed additional multiple brain infarcts. These data suggested a heterogenous neuropathology of PD-MCI, as found in Parkinson disease dementia (PDD). Unfortunately, no assessment of diffuse (amyloid) plaques and cerebral amyloid angiopathy (CAA) was performed, the impact of which on cognitive dysfunction in Lewy body diseases (LBDs) has been shown [7, 8]. Among 233 autopsy-confirmed cases of LBDs in the years 1989–2007 (54.6% cognitively unimpaired, 42% PDD), we found eight cases (3.4%) with PD-MCI (4 females and males each, mean age 76.6 years, mean duration of PD 13.4 years; mini-mental examination scores/ MMSE, 6–4 months prior to death 26–29). Demographic and morphologic findings are summarized in Table 1. Using current definitions of MCI in PD [5], four patients had been diagnosed with amnestic MCI memory only, three with non-amnestic MCI with frontal dysexecution, and one MCI involving multiple domains. Neuropathology revealed two cases in brainstem-predominant stage (Braak et al. [3, 4], ULBSS 2a [2]), five cases in brainstem–limbic predominant stage (Braak et al. [4], ULBSS 3), and one in neocortical LB stage (Braak et al. [5], ULBSS 4). Neuritic Braak stages ranged from I to III (mean 1.3); a few neuritic plaques in cerebral cortex (neocortex and limbic areas) were observed in only two cases (amnestic–memory predominant MCI and MCI multidomains). The severity of amyloid plaques in cerebral cortex, using a five-grading system [6, 7] ranged from 0 to 3? (mean 1.1), involving three cases. No diffuse amyloid plaques were observed in the basal ganglia. Mild to moderate generalized CAA in the meninges was observed in two brains (amnestic and multiple domain MCI, one each). In the case of MCI involving multiple domains, there was a correlation between the intensity of amyloid and neuritic plaques and meningeal CAA, while the other case showed some relations between amyloid plaque load and CAA confirming the suggestion that both amyloid plaque load and CAA may contribute to cognitive impairment in Lewy body disease or PD [7]. Mild lacunar state in striatum or thalamus was detected in three cases (one each with amnestic, non-amnestic, and multiple domains MCI), both without correlation to Lewy body or Alzheimer pathology stages, confirming the absence of correlations between cerebrovascular lesions and the other pathologic or clinical findings in PD [6]. The presently available scarce data in PD-MCI suggest a heterogenous neuropathology simular to those found in MCI cases without PD [9, 11–14], except the scarcity of cerebrovascular pathology and white matter lesions (data not shown) in the present series. MCI stages and their neuropathologic correlations in dementia with Lewy bodies (MCI-DLB [10]), to the best of our knowledge, have not been defined so far. The findings of these two small clinicopathologic cohorts of PD-MCI implicate the necessity for further prospective studies in well documented PD cases with MCI. K. A. Jellinger (&) Institute of Clinical Neurobiology, Kenyongasse 18, 1070 Vienna, Austria e-mail: kurt.jellinger@univie.ac.at

Geography for and with indigenous peoples: indigenous geographies as challenge and invitation

In mid-2006, the International Geographical Union established its Indigenous Peoples’ Knowledges and Rights Commission (IPKRC). Inaugurated at the IGU Regional Conference in Brisbane, Australia, the IPKRC represents an effort by the IGU to engage with the Indigenous issues and the relationships between the discipline and the rights, knowledge and interests of Indigenous peoples in the twenty-first Century. In lateOctober 2007, the IPKRC met jointly with the IGU Commission on Islands at the National Taiwan University in Taipei. That conference brought together more than 60 participants and included 52 formal presentations and papers. This special issue of GeoJournal celebrates that meeting by publishing some of the very best papers from that conference and demonstrates the value of a continuing dialogue between Indigenous peoples and geography. While the value of such dialogue is clear, the challenges facing the IPKRC are no small matter. There are relatively few Indigenous geographers in the discipline, and Indigenous geography has not been a major disciplinary focus. Indigenous issues have often been marginalized in the discipline as they were in the affairs of many settler and colonial societies. Indeed, like many scientific disciplines, contemporary geography has a regrettable colonial legacy to address. Colonial geography facilitated the occupation and possession of Indigenous peoples’ lands, waters and resources by the colonizing ‘other’. Through its contribution to mapping and describing Indigenous peoples’ territories, geography was a powerful handmaiden of the colonial project. In 1984, David Stea and Ben Wisner edited a special issue of Antipode that represented an important opening of the discipline’s reconsideration of its relationships with Indigenous peoples (Stea and Wisner 1984). A decade ago, in the case of Australia, Howitt and Jackson (1998, 155) argued that there had been ‘‘substantial change in the relationship between geography in Australia and indigenous people.’’ They went onto suggest that the relationship between the discipline and Indigenous people was ‘‘of great value to the discipline and the nation as we move towards more equitable and sustainable futures’’ (1998, 155). Similarly in New Zealand, Berg and Kearns argued that there was a ‘‘political edge’’ to the work of many cultural geographers in New Zealand, particularly those ‘‘with interests in Maori issues’’ (1997, 1). More recently, special issues of major journals such as Geografiska Annaler (Series B, Human Geography, 88/3, 2006) K. Frantz (&) Institut fur Geographie, Universitat Innsbruck, Innrain 52, 6020 Innsbruck, Austria e-mail: Klaus.Frantz@uibk.ac.at

Adaptation to climate change: tools and methods

After the Copenhagen Conference in December 2009, it is more obvious than ever that adaptation to climate change is inevitable. Both the scientific and the policy communities will have to devote more attention to the issue of adaptation in the coming years. In this special issue, we focus on the tools and approaches that will be needed to meet the challenge of adaptation to climate change. This special issue is based on papers presented at a session at the Climate Change Congress held in Copenhagen in March 2009, which aimed to synthesize the current state of scientific knowledge on the issue of climate change as an input to the deliberations that were to take place at the end of the same year. Several important questions were addressed in the session and are examined in more detail here: What methods and tools are available to support adaptation decisions and also contribute to sustainable development? What kind of information and what communication channels are needed for adaptation decisions to be made in good time and in the right place? What general approaches to research and development are needed given the wide range of stakeholders to be involved and their diverse interests to be respected in adaptation measures? As pointed out by Banaszak and colleagues (in this issue), different people have different perceptions of the risks that they are facing and this leads to conflicts related to the implementation of adaptation measures. People filter the information that they receive about a risk through preexisting mental models, which cannot be changed easily. Groups of individuals sharing the same models are better able to communicate with each other and share their learning, while communication with groups with a different mental model is more difficult. Extreme events appear to provide opportunities to stimulate changes of mental models. Furthermore, participation both in decision-making and in reaping the benefits of action can also lead to such changes. The topic of ‘‘mental models’’ is also a focus of the paper by Valkering et al. (this issue), who use a multipleperspective approach as part of participatory scenario development. Taking the different perspectives of actors into account can contribute to more robust and flexible strategies for climate change adaptation. Valkering et al. show that during the process, the perspectives can change, for example as a result of context developments or learning among the participants. A change of perspective means that either the participants change their position or the dominance of particular perspectives shifts. An example is presented for climate change adaptation in the Netherlands. The results demonstrate the learning that took place when the perspectives approach was used. A comprehensive approach to provide decision support for adaptation is presented by Daniell and colleagues (in this issue), who note the need for capacity building and coordination over multiple governance levels. In addition to illustrating the variety of multilevel processes and the different actor groups engaged at each level, they also show the multitude of different policy domains that affect the adaptation to climate change (e.g. land use, water, transport and energy policy). Adaptation to climate change requires coordination over multiple levels of governance to arrive at acceptable local, regional and global management J. Jager (&) Vienna, Austria e-mail: jill.jaeger@speed.at

Welcome to ICN 2010

As the President of the Organizing Committee of the XVIIth International Congress of Neuropathology (ICN 2010), I am delighted to be given the opportunity to introduce this issue of ACTA NEUROPATHOLOGICA, to be distributed to participants of ICN 2010. In addition to the book of abstracts, to be printed in a supplementary issue of BRAIN PATHOLOGY, the present series of review articles illustrates well the meeting and its scope. An ICN should be dear to all neuropathologists, as this global event brings together the research and medical-diagnostic aspects of the field in one place only every 4 years. Originally, we expected to attract an attendance of up to 800–1,000 researchers, medical specialists and industry representatives; however, the global crisis seems to have a more profound impact on the number of registrants than we anticipated. This hurts in particular, as we decided to design ICN 2010 as a low-budget, non-profit event, in order to keep costs for attendees as affordable as possible, in particular for young scientists, students and trainees and those from economically disadvantaged countries. Fortunately, however, there is no impact on the quality of scientific presentations and discussions, as also testified by the contributions to this issue of ACTA NEUROPATHOLOGICA. The scientific program of ICN 2010 covers topics that span the whole range of areas of interest for neuropathologists: there is no other event for them that compares with the breadth and depth of information to be gained there. With regard to topics of the submitted abstracts, neurodegeneration and tumours predominate and equal each other, with one-third each. While this is hardly surprising, it may become a matter of concern if neuropathology lessens, or even loses, its grip on the full spectrum of neuropsychiatric diseases that have been in its domain since decades. ICN 2010 tries to counter-balance such trends: while these topics do get the attention they rightly deserve, it is not a neurodegenerationand tumour-only meeting. In particular, invited speakers from neighbouring disciplines provide insight that is difficult if not impossible for neuropathologists to get elsewhere in comparable comprehensiveness. Some of these exemplary invited lectures are published in this journal issue: V. Hugh Perry discusses the contribution of systemic inflammation to neurodegeneration—a major source of orientation in a turf where (neuro)immunologists and neurodegeneration researchers meet—and also come apart. A similar dualistic situation applies to neurodegeneration and cerebrovascular disease; Costantino Iadecola analyses the overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Problems of tumour neuropathology are discussed by Martin van den Bent from a clinician’s perspective, while David Ellison provides data for new classifications of medulloblastoma. In the area of infectious and inflammatory disorders that is of pivotal importance in many parts of the globe, Kum Thong Wong focuses on epidemic viral encephalitis, in particular by the emerging henipaviruses. The group of Tamas Revesz covers the role of brain biopsy in dementia, an issue that reemerges with progress in fine-tuning of neuropathological diagnoses (and possibly also with decline of autopsy rates). Muscle pathology has to remain an intrinsic part of neuropathology; Caroline Sewry updates on the rapid progress in muscular dystrophies that demonstrates how difficult it has become for a neuropathology laboratory to provide state-of-art diagnostic service. With increasing and widespread use of anti-epileptic surgery, there is a need for neuropathologists H. Budka (&) Institute of Neurology, Medical University of Vienna, AKH 4 J, Wahringer Gurtel 18–20, 1097 Vienna, Austria e-mail: herbert.budka@meduniwien.ac.at

Does negative plus negative give positive? The value of combining intradiscal treatment strategies

Combining different treatment strategies is common practice in medical therapy by pharmaceutical agents. Why not do the same in spine surgery? Obviously, any combination of treatments requires rigorous analysis of possible synergistic or antagonistic effects on outcome. Ahn and Lee provide a well-designed prospective study on the combination of percutaneous endoscopic lumbar discectomy with thermal annuloplasty for monoor bisegmental discogenic low back pain. Outcome assessment is based on widely accepted scales, and a follow-up rate of 90% after 2 years is generally considered sufficient for evaluation in spine surgery. The success rate of 70% suggests a considerable value of the proposed combination for discogenic low back pain, although it has dropped from 90% reported in a preceding series of 30 patients presented by the same group in 2009 [4]. Does the combination of two minimally invasive techniques finally offer a surgical solution for discogenic low back pain? We doubt it! The concept of combining a “thermal annuloplasty effect” and a “decompression effect” is not new and has been used since the late 1990s [9]. Intradiscal electrothermal therapy (IDET) has been based on the mechanisms of action proposed by the authors and has also started out with a success rate of 70% [8]. Randomised controlled trials, however, demonstrated that IDET is no better than placebo in the treatment of discogenic low back pain [3, 6]. The selective citation of annuloplasty results as provided in the paper is not scientifically sound. There is no evidence for percutaneous mechanical disc decompression in managing axial low back pain [5]. Thus, both intradiscal decompression and annuloplasty have not demonstrated long-term efficacy according to the pertinent literature. Can we expect that the combination of two ineffective or at least questionable treatment strategies will be effective in the treatment of discogenic low back pain? Does negative plus negative give positive? It cannot be stressed enough that the presented data are not based on a randomised and not even a controlled study. An independent observer does not at all eliminate bias if there is no control group, and telephone interviews as part of the postoperative assessment give limited information. Thus, without further data derived from randomised controlled trials, there is no indication that the proposed treatment works better than standardised conservative care. The authors put great emphasis on the technical aspects of their percutaneous technique: elimination of “inflamed” nucleus tissue, preservation of normal nucleus, thermal modulation along the whole length of the posterior annulus, and so on. However, these considerations are based on unproven assumptions and theoretical pathophysiological speculations. One third of treated segments were classified as Pfirrmann grade 4, in which differentiation of nucleus and annulus is lost by definition [7]. These patients obviously do not have a normal nucleus. What we, however, dislike most about the proposed technique is its destructive nature. Discectomy, be it by open C. Thome (*) Department of Neurosurgery, Medical University Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria e-mail: claudius.thome@uki.at

Cardiac tamponade following pericarditis 18 days after catheter ablation of atrial fibrillation

Sirs: One year ago, a 68-year-old man was treated with pulmonary vein (PV) isolation for paroxysmal AF. Ostial PV isolation was performed by using the High Density Mesh Ablator Catheter (Bard Electrophysiology, Lowell, MA, USA). The deployed Mesh Ablator was positioned at the anatomical PV ostium. Lesions were created with pulsed RF energy from an RF energy generator (Stockert 1000 XP, Biosense Webster Inc., Diamond Bar, CA, USA). Target temperature was set at 58 C with a maximum energy output of 80 W. After each energy delivery time of 300 s, endocardial electrograms from 10 mm distal to the anatomical PV ostium were obtained with the Mesh Ablator Catheter to confirm circumferential PV isolation. With an energy delivery time of 600 s for each PV, isolation of all PVs could be achieved. Due to AF recurrence, re-ablation was performed 12 months after the first procedure. Before re-ablation, electrical reconnection was documented with a decapolar spiral catheter (Reflexion Spiral Variable Radius Catheter, St. Jude Medical, St. Paul, MN, USA). No PV stenosis was found. For re-ablation, we used a threedimensional mapping system (Ensite NavX, Verismo, St. Jude Medical) for navigation based on a fusion with cardiac computer tomography, and an irrigated-tip ablation catheter (Cool Path, St. Jude Medical) for ablation. To achieve better catheter stability, a steerable sheath (Agilis, St. Jude Medical) was used. The ablation setting consisted of a preselected catheter tip temperature of 42 C, a power of 30 W, and a flow rate of 17 mL/min. Adjacent to the oesophagus visualized with contrast medium swallowed immediately before sedation of the patient, the power was reduced to 25 W. The right sided and the left sided PVs were isolated with a single circumferential antral line and additional ablations at the carina between the superior and inferior PVs, respectively (Fig. 1). After completion of the ablation lines, successful PV isolation was confirmed with the spiral catheter for all PVs. The cumulative RF delivery time was 2,860 s, the procedure time was 230 min. The procedure was completed without any complications. The patient was discharged on a betablocker, an ACE-inhibitor, a proton pump inhibitor and phenprocoumon. The patient was readmitted to hospital 14 days after the second AF ablation because of symptoms suggestive of pericarditis. The leading symptoms consisted of fever up to 38.5 C and chest pain, exacerbated by movement and inspiration. The 12-lead ECG showed non-ischemic STelevation in leads I, II, III, aVL, aVF and V2–V6 (Fig. 2) and blood work showed elevated c-reactive protein and erythrocyte sedimentation rate. A CT scan of the chest and echocardiography revealed no abnormalities. Cardiac enzymes remained negative and the patient was therefore treated with anti-inflammatory drugs. On the fourth day of hospitalization, the patient experienced syncope with subsequent severe cardiogenic shock accompanied by dilated jugular veins associated with not detectable blood pressure. Transthoracic echocardiography performed in the ICU showed significant pericardial effusion. At pericardiocentesis, 400 ml of blood could be removed resulting in restoration of normal blood pressure. Laboratory analyses of the removed blood showed a haemoglobin level comparable to peripheral blood with an oxygen saturation of 91% indicating active bleeding from the left atrium. At this point of time, INR was 1.93 and the T. Lambert (&) C. Steinwender F. Leisch R. Hofmann Cardiovascular Division, City Hospital Linz, Krankenhausstrase 9, 4020 Linz, Austria e-mail: Thomas.lambert@akh.linz.at

Primary leptomeningeal lymphoma of the cauda equina: a rare cause of radiculopathy

Primary leptomeningeal lymphoma (PLML) is a particularly rare neoplasm, accounting for only 7% of all primary central nervous system lymphomas. PLML is defined as a syndrome of lymphomatous meningeal infiltration without identification of systemic lymphoma or parenchymal CNS lymphoma in the clinical course of the disease [6, 12]. The diagnosis is challenging and requires a high index of suspicion. Early diagnosis, however, is crucial as immediate treatment may be beneficial. We here report a case of PLML of the cauda equina to raise awareness for this disorder and reduce the delay to diagnosis in similar cases. A 69-year-old immunocompetent man complained about increasing low back pain and moderate weakness of the left leg, which had slowly developed over 1 year. Neurologic examination and electrodiagnostic studies indicated a left-sided L5–S1 radiculopathy. There was no evidence of polyneuropathy. MRI of the spine, the pelvis, and the brain, including contrast-enhanced sequences, was unremarkable. Routine lumbar puncture yielded normal findings. The patient underwent an extensive laboratory and image work-up to rule out malignant, autoimmune, or infectious disease. Due to negative findings, he was discharged to home. High-resolution, contrast-enhanced MR neurography [7, 10] and a second lumbar tap were performed 36 days later. Analysis of the cerebrospinal fluid (CSF) revealed 0 cells/ll with a normal glucose and protein content and imaging findings were again inconclusive (Fig. 1a and b). Short inversion time inversion recovery (STIR) images, however, then illustrated hyperintensity and contrast enhancement of the left piriformis muscle and the left medial gluteal muscle, suggesting acute denervation (Fig. 1c). Subsequent treatment with intravenous methylprednisolone 10 mg/kg/day for 5 days was without clinical benefit at that point. Only 9 months later, the patient was readmitted with a pronounced flaccid lower extremity paraparesis and severe low back pain. Contrast-enhanced MRI of the lumbar spine then disclosed abnormal thickening and marked linear enhancement coating multiple cauda equina nerve roots highly suggestive of leptomeningeal infiltration by tumor (Fig. 2a–c). Urgent analyses of the CSF revealed elevated protein (439 mg/dl; normal range: 15–45) and a lymphocytic pleocytosis (70 cells/ll) with many atypical cells consistent with lymphoma. A biopsy of an anterior cauda equina nerve root as highlighted by immunohistochemistry with S100 (Fig. 2d) and NSE revealed a massive diffuse interstitial infiltrate of atypical lymphocytic cells, that reached the marginal area of the small specimen with epithelial membrane antigen (EMA) positive cells indicating leptomeningeal infiltration [14]. The cells expressed CD20 and CD79, but were negative for Kl-1, EMA, CD56, M. Beitzke (&) C. Enzinger F. Fazekas Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036 Graz, Austria e-mail: markus.beitzke@klinikum-graz.at

Euroanalysis XV, 2009: The European conference on analytical chemistry

Euroanalysis has become one of the most important broadspectrum analytical conference series covering essentially all aspects of analytical sciences. It is held every 2 years in different European countries and is organized under the umbrella of the Division of Analytical Chemistry (DAC) of the European Association of Chemical and Molecular Sciences (EuCheMS). In 2009 this conference was arranged by the Austrian Society of Analytical Chemistry (ASAC) represented by the chairmen Wolfgang Buchberger and Wolfgang Lindner. Euroanalysis had previously been organized successfully by ASAC in Vienna in 1990. For its return to Austria, Innsbruck had been chosen as the venue, where the convention center ‘Congress Innsbruck’ provided a perfect environment. Despite some fears of negative impacts due to the economic crisis in 2009, the number of participants was as high as in previous conferences of this series. The organizers welcomed approximately 700 delegates from 53 countries with Spain, Austria, Germany, Czech Republic, Russia, and Italy being the top six regarding participants. We were particularly proud to welcome more than 200 students from all over the world, which gave the conference a very dynamic and lively atmosphere. About 60 travel grants were provided as financial support for young analytical chemists. Under the motto “The Impact of Analytical Chemistry on Quality of Life”, 130 lectures and 640 poster presentations resulted in a very attractive program which covered practically all areas of analytical sciences. In accordance with the intentions expressed at the foundation of the Euroanalysis series, the conference gave an excellent overview of the advances in the various areas of analytical sciences and stimulated communication between analytical chemists working in quite diverse fields. This fact was also reflected by the various plenary lectures including “Proteomics—a Tool in Personalized Medicine?” (F. Lottspeich), “The Environmental Challenge for Analytical Sciences” (M. Grasserbauer), “Nanoanalytics—Probing Matter at the Atomic Scale” (H. Fuchs), “Ionics. A New Paradigm in Ion Detection in Solution” (P. K. Dasgupta), “Plus Lucis: Advanced Waveguides for Enhanced Infrared Diagnostics” (B. Mizaikoff), “Microarray Technology—Current Status and Trends” (R. Niessner), “LCxLC: Liquid Chromatography Enters a New Dimension” (P. Schoenmakers), and “New Stationary Phases for Enrichment and Separation Technologies in the -Omics Area—a Challenge in Analytical Separation Science” (G. Bonn). The broad spectrum of technological and thematic issues of the scientific program was covered by triple sessions starting with well-received keynote lectures. In keeping with tradition, we also had a session on education as we regard it as an important aspect of this symposium series. Obviously, modern analytical sciences do not simply aim at providing qualitative and quantitative results but also focus on the development of new strategies for efficient problem solving as well as on interpretation of data obtained by state-of-the-art techniques. The current trend to divide analytical sciences into a range of subdisciplines W. Buchberger (*) Johannes Kepler University Linz, Institute for Analytical Chemistry, Altenberger Strase 69, 4040 Linz, Austria e-mail: Wolfgang.Buchberger@jku.at

Chronic recurrent follicular papules and plaques on the face

Clinical and Experimental DermatologyVolume 35, Issue 1 p. 99-100 Chronic recurrent follicular papules and plaques on the face H. Müller, H. Müller Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, AustriaSearch for more papers by this authorK. Eisendle, K. Eisendle Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, AustriaSearch for more papers by this authorB. Zelger, B. Zelger Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, AustriaSearch for more papers by this author H. Müller, H. Müller Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, AustriaSearch for more papers by this authorK. Eisendle, K. Eisendle Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, AustriaSearch for more papers by this authorB. Zelger, B. Zelger Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, AustriaSearch for more papers by this author First published: 07 December 2009 https://doi.org/10.1111/j.1365-2230.2009.03230.xCitations: 1 Dr Hansgeorg Müller, Department of Dermatology and Venerology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria E-mail: hansgeorg.mueller@uki.at Conflict of interest: none declared. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume35, Issue1January 2010Pages 99-100 RelatedInformation

The relationship between alcohol intake and cellular immune activity in systemic lupus erythematosus may change from inhibitory to stimulatory within 2 months of study: findings from an integrative single-case study

Alcoholic beverages such as beer and wine contain several compounds (e.g. ethanol and antioxidants) that potentially counteract inflammatory diseases such as systemic lupus erythematosus (SLE) [1]. However, evidence on the association between alcohol consumption and SLE disease activity is equivocal. While meta-analyses by Wang et al. revealed that alcohol drinking might be protective in SLE [2], their own most recent empirical work did not support this observation [3]. This inconsistency may arise from the inability of conventional group studies to appropriately handle the subjective and temporal qualities characterizing the association between drinking alcohol and physiological response [4]. In order to better deal with complex psychosomatic features, we have developed an integrative research approach based on extensive single-case studies [5]. Using this approach, it was shown in a 40-year-old patient with SLE that daily alcohol consumption was associated with a decline in levels of urinary neopterin, an immune activation marker and indicator of SLE activity [6], within 24 h after intake [5]. In our second integrative single-case study on a 52-year-old woman with SLE, we investigated—among other topics—the dynamic relations between drinking alcohol, emotional states (mental activity, irritation and mood) and urinary neopterin concentrations [7]. In this study, the patient collected her entire urine and filled out questionnaires for 56 days in 12-h intervals (total of 112 consecutive measurements). Urinary neopterin was analyzed applying HPLC. The patient noted type and quantity of alcohol intake, which was then converted into gram alcohol consumed. Emotional states (mental activity, irritation and mood) were determined using the short form of the Eigenschaftsworterliste [8]. Time series analysis consisted of autoregressive moving average modelling—to control for serial dependencies—and adjusted crosscorrelational analysis [9]. Cross-correlational analyses revealed that the effect that moderate alcohol consumption (sparkling wine, wine and schnapps) had on urinary neopterin levels differed depending on which time series period was statistically analyzed, i.e. the period before or the period after the occurrence of an inflammatory event (acute paranasal sinusitis) which took place halfway through the study period (12-h units 45– 54). Before sinusitis occurred (1–44), increases in alcohol intake were paralleled by decreases in urinary neopterin levels (lag0: r=−0.371; p<0.05), whereas after sinusitis (55–112) increases in alcohol consumption were followed by increases in urinary neopterin concentrations with a temporal delay of 12 h (lag1 : r 1⁄4 þ0:308; p<0.05). Analyses further demonstrated that none of the emotional states measured in this study (i.e. mental activity, irritation and mood) interfered with the associations between alcohol consumption and neopterin. This integrative single-case study showed that the relationship between alcohol intake and cellular immune activity in SLE can change from inhibitory to stimulatory C. Schubert (*) Clinic of Medical Psychology, Department of Psychiatry and Psychotherapy, Innsbruck Medical University, Innsbruck, Austria e-mail: christian.schubert@i-med.ac.at

Sensor devices and biosensors in food analysis

Food is an incredibly complex mixture of mostly natural, but also artificial, substances. Thus food analysis is a very challenging field, especially when dealing with the detection of minor components, for example flavors, vitamins, antioxidants, natural toxins, more or less unwanted toxic heavy metals from soil, herbicide or pesticide residues, etc. Special clinical problems, for example metabolic defects or allergies, often result in the need to detect traces of cross contaminants, etc. Detection of such chemically very different analytes in, for chemists, ‘‘most unfriendly surroundings’’ once needed very tricky and time-consuming methods, and the results obtained were often questionable. Sensor technology currently attracts increasing attention as a successor to conventional analytical techniques in the food industry. The reasons are manyfold and the potential applications widespread, including fermentation and monitoring of production processes and product quality to provide healthy, uncontaminated, high-standard food with long shelf life. For organic components, especially, the development of very selective biosensors has improved food analysis substantially. This does not, however, render careful sample preparation unnecessary and we should never forget that the quality of each result given by the readout depends on this fact. A huge variety of chemical sensors have been invented for food analysis; many are based on electrochemical measurements but optical readout also is becoming increasingly important. Detection methods are not restricted to these two techniques only, so this special issue isrounded off by presenting various miscellaneous methods, for example piezoelectric devices with molecular imprinting. Another very wide field is the use of immobilized antibodies, or any other biorecognitive components, on the sensor devices, selectively locking the material of interest and making it available for further sensing procedures on a transducer which can be either electrochemical or optical. Another advantage is extreme sensitivity, even down to the femtomolar range in special cases. The major drawback of biosensors is often high dependence on certain conditions necessary for biorecognition, for example pH, temperature, or ionic strength of the analyte, a problem that can sometimes be overcome by very careful choice of immobilization techniques, which sometimes also enables reaction even in organic solvents. Biosensors are, furthermore, not restricted to analysis of naturally occurring substances—biorecognition may also be adapted to artificial additives by use of specific antibodies for recognition. Finding appropriate chemical or enzymatic reactions for electrochemical or optical monitoring can be facilitated by use of enzymes obtained from mutated or genetically engineered microorganisms. Optical monitoring combined with high sensitivity occasionally also enables miniaturization and production of microarrays, thus giving such systems a promising future. The here compiled invited reviews and original contributions on sensor devices and biosensors in food analysis should give the reader overviews about sensor types, performance criteria, principal performance characteristics, and possible variations with respect to different analytes. F. Pittner (&) University of Vienna, Vienna, Austria e-mail: Fritz.Pittner@univie.ac.at

To Measure the Unmeasurable

In their article Takahido Shien and colleagues from the National Cancer Center Hospital in Tokyo, report their experiences with using clinical and pathological tumor features as predictors of the response of breast tumors to neoadjuvant chemotherapy [1]. Neoadjuvant chemotherapy is widely used to downsize primary tumors and facilitate subsequent resection or breast conservation, both in locally advanced disease and in the earlier stages of operable breast cancer. The overall response rate is usually good (between 70% and 90%), but the extent of the tumor response and shrinkage varies greatly between individual patients. Being able to predict the eventual outcome of neoadjuvant chemotherapy would be of great value in providing information to patients and their physicians about what can be achieved by taking this preoperative approach. Outcome data could allow for informed decision making and balancing potential benefits against side effects and risks. A recent report has been indicated that endocrine responsive and lobular cancers are less likely to respond very well to neoadjuvant chemotherapy [2]. In general, it is agreed that only complete pathological remission (pCR) will lead to an overall survival benefit for the patient [3], and this has blighted the initial enthusiasm over the advantages of neoadjuvant chemotherapy. It is known that partial remissions—i.e., reductions in tumor volume of more than 50%—fail to yield significant longterm benefit [4]; yet, surprisingly, the biology that underlies this observation remains unclear. Shien et al. reported that they found that what they call ‘‘scirrhous-type’’ tumors would less likely show a pCR. For reduction of tumor size (defined as reduction of size by 30% in their article), high-grade tumors and tumors appearing ‘‘localized’’ on computerized tomography (CT) scans were more likely to respond. Scirrhous-type tumors may reflect lobular cancers, which do not respond well to neoadjuvant chemotherapy. High-grade tumors are generally believed to be more sensitive to chemotherapy than low-grade tumors; however, it remains difficult to explain, in terms of tumor biology, what ‘‘localization’’ of the tumor means. The study by Shien et al. reports interesting findings; however, it also has several weaknesses: CT is not widely used on a global basis for tumor evaluation during neoadjuvant treatment because of the radiation involved, and because the accuracy of the scans is often inferior to mammography and magnetic resonance imaging (MRI), both of which are widely accepted imaging techniques [5]. Also, it is well known that response to neoadjuvant chemotherapy will depend on other factors, such as p53 overexpression and the chemotherapy protocol used: for example, clinical experience shows that anthracyclins lead to concentric shrinkage of tumors, whereas taxanes often result in a more scattered pattern of residual tumor [6]. Furthermore, Shien et al. suggest a system of response evaluation based on clinical measurements of tumor sizes. This is obviously scientifically dangerous: not only because the surgeon will often overestimate the actual responses of neoadjuvant treatment during palpation and caliper measurements, but also because a generally accepted, objective measurement system must be established. Surgeons may or may not like the WHO/RECIST response criteria of CR/ PR/NC/PD [7], but it has obvious advantages to avoid reinventing the wheel again and again. M. Gnant (&) Department of Surgery, Medical University of Vienna, Austrian Breast and Colorectal Cancer Study Group, A-1090 Vienna, Waehringer, Guertel 18-20, Austria e-mail: michael.gnant@meduniwien.ac.at

Comments on the paper by E. M. Minicucci et al. “DNA damage in lymphocytes and buccal mucosa cells of children with malignant tumours undergoing chemotherapy”

I read the paper by Minicucci et al. ‘‘DNA damage in lymphocytes and buccal mucosa cells of children with malignant tumours undergoing chemotherapy’’ [1] with great interest because recently I analyzed all available literature sources concerning the influence of chemoand radiotherapies on exfoliated mucosal cells [2]. The problem of possible micronuclei (MN)-inducing activity of antiblastics on epithelial oral mucosa cells has not been studied well. Only four papers were published concerning cancer patients (for review see [2]) and two concerning patients with other diseases treated with cytostatics [3, 4]. It has been shown that in these papers positive effect was registered in some cases. But no firm conclusion could be drawn if chemotherapy induces MN in oral epithelial cells. I think it is because all investigators applied various time points to collect exfoliated epithelial cells after the application of cytostatics. For example, it is practically not clear when the samples of buccal cells were collected by Minicucci et al. [1]. The time factor could play a key role in finding of MN because of kinetics (or the life cycle) of these types of cells. According to Szete et al. [5], the half-life of buccal cells is about 15 days and Kassie et al. [6] showed that MN level is highest 28 days after the effect of mutagen. After that there is an elimination of cells with MN. Hence, collection of oral cells ought to be done not later than 30 days after the last application of cytostatic drug. In my opinion, success of such kind of investigations depends mainly on the study of primary patients (without any treatment which can induce damage of cytogenetic structures) after one cycle of chemotherapy because it is mostly toxic for organism, and it could induce changes in basal cell kinetics. Also, due to this the so-called nuclear anomalies (karyolysis, karyorrhexis, pycnosis) can appear [7]. The evaluation of the so-called nuclear anomalies along with MN will improve the quality of the studies. Minicucci et al. [1] found significantly increased levels of MN in lymphocytes which were collected at the same time as exfoliated cells. It is because, unlike epithelial cells, half-life of lymphocytes is substantially longer (some years) that it is possible to find an increased number of MN in lymphocytes of children under therapy of much longer time than 30 days (the critical time point to register MN in epithelial cells) [8]. It is noteworthy that Torres-Bugarin et al. [7] investigated about 40 patients under antiblastic therapy, and found significantly increased levels of MN in some of them. But among them were subjects after two or even three cycles of therapy. Like Minicucci et al. [1], no firm information was presented as to when the buccal cells were collected. Based on the data presented by the authors, the number of cells with MN only in primary cancer patients treated with three chemotherapeutic schedules was calculated. Totally among them 19 were primary, and MN frequencies were 1.6 ± 0.4% before and 2.6 ± 0.7% after treatment (p [ 0.05, Mann–Whitney test). In ten patients treated with carboplatin ?5-fluorouracil MN numbers were 0.95 ± 0.12% before and 1.35 ± 0.42% after treatment, and in nine patients treated with isophosphamide ? epirubicin the frequencies were 2.9 ± 1.0% (before) and 4.9 ± 1.6% (after treatment) (p [ 0.05 in both cases, Mann–Whitney U test). As can be noted, no significant increase of cells with MN was found also in primary patients after one course of therapy. But the time of cell collection was not clearly indicated by the authors [1]. Ramos-Remus studied and A. Nersesyan (&) Institute of Cancer Research, Vienna, Austria e-mail: armen.nersesyan@meduniwien.ac.at