High-Frequency Repetitive Transcranial Magnetic Stimulation Can Improve Depression in Parkinson's Disease: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: A recent evidence-based guideline demonstrated that bilateral repetitive transcranial magnetic stimulation (rTMS) over the motor cortex (M1) can improve motor symptoms of Parkinson's disease (PD). We conducted a randomized, double-blind, placebo-controlled study to evaluate the impact of bilateral M1 rTMS on depression in PD. METHODS: Forty-six patients with PD and mild-to-moderate depression were randomly assigned to active (n = 23) and sham (n = 23) rTMS. Two patients in the sham group did not complete the protocol because of reasons unrelated to the study. High-frequency rTMS was applied over the primary motor cortex bilaterally for 10 days. An investigator blinded to the treatment performed three video-taped examinations on each patient: before stimulation (baseline), and 1 day (short-term effect) and 30 days after the treatment session ended (long-term effect). The primary end point was the changes in depression, while secondary end points included health-related quality of life scales and Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: In the actively treated group, not only did the severity of depression improve (from 17 to 7 points, Montgomery-Åsberg Depression Rating Scale, median values, p < 0.001), but also the health-related quality of life (from 25.4 to 16.9 points, PDQ-39 summary index, median values, p < 0.001). Besides, we could also demonstrate an improvement in MDS-UPDRS Motor Examination (from 26 to 20 points, median values, p < 0.05). In the sham-treated group, none of the examined tests and scales improved significantly after treatment. CONCLUSIONS: Our results demonstrate the beneficial effects of high-frequency bilateral M1 rTMS on depression and health-related quality of life in PD. However, this effect of rTMS should also be confirmed in patients with severe depression by further clinical trials.

Amnesia and future thinking: Exploring the role of memory in the quantity and quality of episodic future thoughts.

OBJECTIVES: To examine the impact of memory accessibility on episodic future thinking. DESIGN: Single-case study of neurological patient HCM and an age-matched comparison group of neurologically Healthy Controls. METHODS: We administered a full battery of tests assessing general intelligence, memory, and executive functioning. To assess autobiographical memory, the Autobiographical Memory Interview (Kopelman, Wilson, & Baddeley, 1990. The Autobiographical Memory Interview. Bury St. Edmunds, UK: Thames Valley Test Company) was administered. The Past Episodic and Future Episodic sections of Dalla Barba's Confabulation Battery (Dalla Barba, 1993, Cogn. Neuropsychol., 1, 1) and a specifically tailored Mental Time Travel Questionnaire were administered to assess future thinking in HCM and age-matched controls. RESULTS: HCM presented with a deficit in forming new memories (anterograde amnesia) and recalling events from before the onset of neurological impairment (retrograde amnesia). HCM's autobiographical memory impairments are characterized by a paucity of memories from Recent Life. In comparison with controls, two features of his future thoughts are apparent: Reduced episodic future thinking and outdated content of his episodic future thoughts. CONCLUSIONS: This article suggests neuropsychologists should look beyond popular conceptualizations of the past-future relation in amnesia via focussing on reduced future thinking. Investigating both the quantity and quality of future thoughts produced by amnesic patients may lead to developments in understanding the complex nature of future thinking disorders resulting from memory impairments. PRACTITIONER POINTS: We highlight the clinical importance of examining the content of future thoughts in amnesic patients, rather than only its quantitative reduction. We propose an explanation of how quantitative and qualitative aspects of future thinking could be affected by amnesia. This could provide a useful approach to understand clinical cases of impaired prospection. LIMITATIONS: Systematic group investigations are required to fully examine our hypothesis. Although the current study utilized typical future thinking measures, these may be limited and we highlight the need to develop clinically relevant measures of prospection.

[VALIDATION OF THE HUNGARIAN UNIFIED DYSKINESIA RATING SCALE]. / AZ EGYSÉGESÍTETT DYSKINESIA-PONTOZÓSKÁLA MAGYAR NYELVI VALIDÁCIÓJA.

BACKGROUND: The Unified Dyskinesia Rating Scale (UDysRS) was published in 2008. It was designed to be simultaneous valid, reliable and sensitive to therapeutic changes. The Movement Disorder Society organizing team developed guidelines for the development of official non-English translations consisting of four steps: translation/back-translation, cognitive pretesting, large field testing, and clinimetric analysis. The aim of this paper was to introduce the new UDysRS and its validation process into Hungarian. METHODS: After the translation of UDysRS into Hungarian and back-translated into English, it was reviewed by the UDysRS translation administration team. Subsequent cognitive pretesting was conducted with ten patients. For the large field testing phase, the Hungarian official working draft version of UDysRS was tested with 256 patients with Parkinson's disease having dyskinesia. Confirmatory factor analyses (CFA) determined whether the factor structure for the valid Spanish UDysRS could be confirmed in data collected using the Hungarian Official Draft Version. To become an official translation, the Comparative Fit Index (CFI) had to be ≥ 0.90 compared to the Spanish-language version. RESULTS: For the Hungarian UDysRS the CFI was 0.98. CONCLUSION: The overall factor structure of the Hungarian version was consistent with that of the Spanish version based on the high CFIs for the UDysRS in the CFA; therefore, this version was designated as the Official Hungarian Version Of The UDysRS.

Doublesex and mab-3-related transcription factor 5 promotes midbrain dopaminergic identity in pluripotent stem cells by enforcing a ventral-medial progenitor fate.

Understanding the control of cell-fate choices during embryonic stem cell (ESC) differentiation is crucial for harnessing strategies for efficient production of desired cell types for pharmaceutical drug screening and cell transplantation. Here we report the identification of the zinc finger-like doublesex and mab-3-related transcription factor 5 (Dmrt5) as a marker for mammalian ventral-medial mesencephalic neuroepithelium that give rise to dopamine neurons. Gain- and loss-of-function studies in ESC demonstrate that Dmrt5 is critically involved in the specification of ventral-medial neural progenitor cell fate and the subsequent generation of dopamine neurons expressing essential midbrain characteristics. Genome-wide analysis of Dmrt5-mediated transcriptome changes and expression profiling of ventral-medial and ventral-lateral mesencephalic neuroepithelium revealed suppressive and inductive regulatory roles for Dmrt5 in the transcription program associated with the ventral-medial neural progenitor fates. Together, these data identify Dmrt5 as an important player in ventral mesencephalic neural fate specification.

[VALIDATION OF THE HUNGARIAN MDS-UPDRS: WHY DO WE NEED A NEW PARKINSON SCALE?]. / AZ MDS-UPDRS MAGYAR VALIDáCIóJA: MIéRT SZüKSéGES UJABB PARKINSON-PONTOZOSKáLA?

BACKGROUND: The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been published in 2008 as the successor of the original UPDRS. The MDS-UPDRS organizing team developed guidelines for the development of official non-English translations consisting of four steps: translation/back-translation, cognitive pretesting, large field testing, and clinimetric analysis. The aim of this paper was to introduce the new MDS-UPDRS and its validation process into Hungarian. METHODS: Two independent groups of neurologists translated the text of the MDS-UPDRS into Hungarian and subsequently back-translated into English. After the review of the back-translated English version by the MDS-UPDRS translation administration team, cognitive pretesting was conducted with ten patients. Based on the results of the initial cognitive pretesting, another round was conducted. For the large field testing phase, the Hungarian official working draft version of MDS-UPDRS was tested with 357 patients with Parkinson's disease (PD). Confirmatory factor analyses (CFA) determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Hungarian Official Draft Version. To become an official translation, the Comparative Fit Index (CFI) had to be ≥ 0.90 compared to the English-language version. RESULTS: For all four parts of the Hungarian MDS-UPDRS, the CFI was ≥ 0.94. CONCLUSION: The overall factor structure of the Hungarian version was consistent with that of the English version based on the high CFIs for all the four parts of the MDS-UPDRS in the CFA; therefore, this version was designated as the "OFFICIAL GUNGARIAN VERSION OF THE MDS-UPDRS'.

From EU-SoilHydroGrids to HU-SoilHydroGrids: A leap forward in soil hydraulic mapping.

Spatially explicit, quantitative information on soil hydraulic properties is required in various modelling schemes. At European scale, EU-SoilHydroGrids proved its applicability in a number of studies, in ecological predictions, geological and hydrological hazard assessment, agri-environmental models, among others. Inspired by its continental antecedent, an analogous, but larger scale, national, 3D soil hydraulic database was elaborated for the territory of Hungary (HU-SoilHydroGrids) supported by various improvements (i-iv) in the computation process. Pedotransfer functions (PTFs) were built in the form of i) advanced machine learning methods and ensemble models, and trained on the ii) national soil hydrophysical dataset. The set of predictors used in PTFs was supplemented by iii) additional environmental auxiliary variables. Spatial layers of the soil hydraulic parameters were generated using iv) 100 m resolution information on primary soil properties, namely DOSoReMI.hu. HU-SoilHydroGrids provides information on the most frequently required soil hydraulic properties (water content at saturation, field capacity and wilting point, saturated hydraulic conductivity and van Genuchten parameters for the description of the moisture retention curve) with national coverage at 100 m spatial resolution down to 2 m depth for six GSM standard depth layers. The HU-SoilHydroGrids has significantly lower squared error in the case of describing the moisture retention curve and hydraulic conductivity than the EU-SoilHydroGrids. The derived 3D soil hydraulic database (ver1.0) is presently available in National Laboratory for Water Science and Water Safety for project partners in order to test its functional performance in describing hydrological and ecological processes.

The Role of Urban Cemeteries in Ecosystem Services and Habitat Protection.

Cemeteries, like urban public parks, are an important part of the urban ecosystem, providing semi-natural habitats for many plant and animal species as well as a wide range of ecosystem services: they improve air quality, reduce the urban heat island phenomenon and provide aesthetic and recreational value. This paper explores the role of the cemeteries in the green infrastructure network beyond their sacred and memorial role and their importance as a habitat for urban flora and fauna. In our study, we compared two large public cemeteries of Budapest (Nemzeti Sírkert/National Graveyard and Új Köztemeto/New Public Cemetery) with the Zentralfriedhof Wien (Central Cemetery of Vienna), the latter of which has been forward-looking in terms of green infrastructure development and habitat creation in the past years. Our goal was to determine which maintenance technologies and green space development methods are most beneficial in terms of sustainable habitat creation and the use of appropriate plant species in public cemeteries.

DOCU-CLIM: A global documentary climate dataset for climate reconstructions.

Documentary climate data describe evidence of past climate arising from predominantly written historical documents such as diaries, chronicles, newspapers, or logbooks. Over the past decades, historians and climatologists have generated numerous document-based time series of local and regional climates. However, a global dataset of documentary climate time series has never been compiled, and documentary data are rarely used in large-scale climate reconstructions. Here, we present the first global multi-variable collection of documentary climate records. The dataset DOCU-CLIM comprises 621 time series (both published and hitherto unpublished) providing information on historical variations in temperature, precipitation, and wind regime. The series are evaluated by formulating proxy forward models (i.e., predicting the documentary observations from climate fields) in an overlapping period. Results show strong correlations, particularly for the temperature-sensitive series. Correlations are somewhat lower for precipitation-sensitive series. Overall, we ascribe considerable potential to documentary records as climate data, especially in regions and seasons not well represented by early instrumental data and palaeoclimate proxies.

SenseCam as a rehabilitation tool in a child with anterograde amnesia.

We present the case of a 13-year-old boy, CJ, with profound episodic memory difficulties following the diagnosis of a metastatic intracranial germ cell tumour and subsequent treatment with radiotherapy and chemotherapy. At the core of this study is the first application of SenseCam to a child with severe memory impairment. CJ was taken for a walk while he was wearing SenseCam. This included visiting four different locations. We manipulated the number of locations he could review on SenseCam "films" and then tested recognition memory (forced choice) for both reviewed and non-reviewed locations. We also collected his justifications for the choices he made. Our results indicate that repeated viewings of SenseCam images support the formation of personal semantic memories. Overall our results suggest that the use of SenseCam in memory rehabilitation extends beyond supporting episodic memory and recollection, and supports the feasibility of its use with children who have marked memory difficulties.

Author Correction: Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates.

The original version of this Article contained an error in the hyperlink for the online repository http://mulvdb.org which was incorrectly given as http://mulv.lms.mrc.ac.uk. This has been corrected in both the PDF and HTML versions of the Article.

Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates.

Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of murine leukemia virus-driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel statistical approaches for identifying selected mutations and yields a high-resolution, genome-wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening of two BCL2 transgenic models confirmed known drivers of human non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features independently of local variance in mutation density also provides support for weakly evidenced cancer genes. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset.

Minimal clinically important difference on the Motor Examination part of MDS-UPDRS.

BACKGROUND: Recent studies increasingly utilize the Movement Disorders Society Sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS). However, the minimal clinically important difference (MCID) has not been fully established for MDS-UPDRS yet. OBJECTIVE: To assess the MCID thresholds for MDS-UPDRS Motor Examination (Part III). METHODS: 728 paired investigations of 260 patients were included. At each visit both MDS-UPDRS and Clinician-reported Global Impression-Improvement (CGI-I) scales were assessed. MDS-UPDRS Motor Examination (ME) score changes associated with CGI-I score 4 (no change) were compared with MDS-UPDRS ME score changes associated with CGI-I score 3 (minimal improvement) and CGI-I score 5 (minimal worsening). Both anchor- and distribution-based techniques were utilized to determine the magnitude of MCID. RESULTS: The MCID estimates for MDS-UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening. CONCLUSIONS: MCID is the smallest change of scores that are clinically meaningful to patients. These MCID estimates may allow the judgement of a numeric change in MDS-UPDRS ME on its clinical importance.

Subjective experience of episodic memory and metacognition: a neurodevelopmental approach.

Episodic retrieval is characterized by the subjective experience of remembering. This experience enables the co-ordination of memory retrieval processes and can be acted on metacognitively. In successful retrieval, the feeling of remembering may be accompanied by recall of important contextual information. On the other hand, when people fail (or struggle) to retrieve information, other feelings, thoughts, and information may come to mind. In this review, we examine the subjective and metacognitive basis of episodic memory function from a neurodevelopmental perspective, looking at recollection paradigms (such as source memory, and the report of recollective experience) and metacognitive paradigms such as the feeling of knowing). We start by considering healthy development, and provide a brief review of the development of episodic memory, with a particular focus on the ability of children to report first-person experiences of remembering. We then consider neurodevelopmental disorders (NDDs) such as amnesia acquired in infancy, autism, Williams syndrome, Down syndrome, or 22q11.2 deletion syndrome. This review shows that different episodic processes develop at different rates, and that across a broad set of different NDDs there are various types of episodic memory impairment, each with possibly a different character. This literature is in agreement with the idea that episodic memory is a multifaceted process.

Benefits and limitations of errorless learning after surviving pediatric brain tumors: a case study.

Survivors of childhood brain tumors often acquire complex cognitive difficulties including impairments in attention, processing speed, and different aspects of memory function. These impairments can affect their learning in the real world and in the classroom. However, the efficacy of memory rehabilitation techniques post treatment has not yet been assessed in these patients. We present the case of a 15-year-old boy, C.J., who acquired a profound episodic memory impairment due to a metastatic germ cell tumor and subsequent treatment. The focus of this study was the application of an errorless learning technique to a verbal learning task. We were interested to test whether C.J. would benefit from errorless learning as compared to errorful learning. Results of an experiment and a follow-up study indicated that C.J.'s learning was more efficient under errorless conditions, although access to the information from long-term memory remained cue dependent. Implications for learning with or without the support of episodic memory are discussed, and future directions for memory rehabilitation of brain tumor survivors are outlined.

Familiar ochronotic arthropathy-caused by a gene mutation traced three hundred years.

Authors trace an ochronotic Hungarian family, which moved from Slovakia to Hungary 300 years ago. As the family members lived in a relatively close village community the gene mutation had been survived silently for ages before the clinical symptoms developed. Family tree analysis could detect with the use of allele specific PCR amplification-the p.G161R mutation of the homogentisic acid 1,2-dioxygenase (HGD) gene, which resulted in a specific genotype appearing in the Slovak population. We found a heterozygote member of this family who has children with an alkaptonuria-homozygote and known-heterozygote genotypes so there would be a high risk of alkaptonuria in their offsprings. Therefore genetic counselling is highly recommended to minimize the risk factors.

Estrogen-related receptor beta interacts with Oct4 to positively regulate Nanog gene expression.

Embryonic stem (ES) cell self-renewal is regulated by transcription factors, including Oct4, Sox2, and Nanog. A number of additional transcriptional regulators of ES cell self-renewal have recently been identified, including the orphan nuclear receptor estrogen-related receptor beta (Esrrb). However, the mode of action of Esrrb in ES cells is unknown. Here, using an Oct4 affinity screen, we identify Esrrb as an Oct4 partner protein. Esrrb can interact with Oct4 independently of DNA. Esrrb is recruited near the Oct-Sox element in the Nanog proximal promoter, where it positively regulates Nanog expression. Esrrb recruitment to the Nanog promoter requires both the presence of Oct4 and a degenerate estrogen-related receptor DNA element. Consistent with its role in Nanog regulation, expression of the Esrrb protein within the Oct4-positive ES cell population is mosaic and correlates with the mosaic expression of the Nanog protein. Together with previous reports that Nanog may regulate Esrrb gene expression, our results suggest that Esrrb and Nanog act as part of a feedback regulatory circuit that modulates the fluctuating self-renewal capacity of ES cell populations.

Stimulation of H(2)O(2) generation by calcium in brain mitochondria respiring on alpha-glycerophosphate.

It has been reported recently (Tretter et al., 2007b) that in isolated guinea pig brain mitochondria supported by alpha-glycerophosphate (alpha-GP) reactive oxygen species (ROS) are produced through the reverse electron transport (RET) in the respiratory chain and by alpha-glycerophosphate dehydrogenase (alpha-GPDH). We studied the effect of calcium on the generation of H(2)O(2) as measured by the Amplex Red fluorescent assay in this model. H(2)O(2) production in alpha-GP-supported mitochondria was increased significantly in the presence of 100, 250, and 500 nM Ca(2+), respectively. In addition, Ca(2+) enhanced the membrane potential, the rate of oxygen consumption, and the NAD(P)H autofluorescence in these mitochondria. Direct measurement of alpha-GPDH activity showed that Ca(2+) stimulated the enzyme by decreasing the Km for alpha-GP. In those mitochondria where RET was eliminated by the Complex I inhibitor rotenone (2 microM) or due to depolarization by ADP (1 mM), the rate of H(2)O(2) formation was smaller and the stimulation of H(2)O(2) generation by Ca(2+) was prevented partly, but the stimulatory effect of Ca(2+) was still significant. These data indicate that in alpha-GP-supported mitochondria activation of alpha-GPDH by Ca(2+) leads to an accelerated RET-mediated ROS generation as well as to a stimulated ROS production by alpha-GPDH.

Characteristics of alpha-glycerophosphate-evoked H2O2 generation in brain mitochondria.

Characteristics of reactive oxygen species (ROS) production in isolated guinea-pig brain mitochondria respiring on alpha-glycerophosphate (alpha-GP) were investigated and compared with those supported by succinate. Mitochondria established a membrane potential (DeltaPsi(m)) and released H(2)O(2) in parallel with an increase in NAD(P)H fluorescence in the presence of alpha-GP (5-40 mm). H(2)O(2) formation and the increase in NAD(P)H level were inhibited by rotenone, ADP or FCCP, respectively, being consistent with a reverse electron transfer (RET). The residual H(2)O(2) formation in the presence of FCCP was stimulated by myxothiazol in mitochondria supported by alpha-GP, but not by succinate. ROS under these conditions are most likely to be derived from alpha-GP-dehydrogenase. In addition, huge ROS formation could be provoked by antimycin in alpha-GP-supported mitochondria, which was prevented by myxothiazol, pointing to the generation of ROS at the quinol-oxidizing center (Q(o)) site of complex III. FCCP further stimulated the production of ROS to the highest rate that we observed in this study. We suggest that the metabolism of alpha-GP leads to ROS generation primarily by complex I in RET, and in addition a significant ROS formation could be ascribed to alpha-GP-dehydrogenase in mammalian brain mitochondria. ROS generation by alpha-GP at complex III is evident only when this complex is inhibited by antimycin.

Correction of severe anaemia using immuno-regulated gene therapy is achieved by restoring the early erythroblast compartment.

Patients with chronic renal failure usually require exogenous erythropoietin (epo) to alleviate anaemia resulting from inadequate epo production by the kidneys. We have recently shown that severe anaemia in genetically manipulated epo-deficient mice (EpoTAg) can be corrected by adoptively transferred epo-producing lymphocytes. The aim of this study was to investigate the precise effects of human epo administration by this route on erythropoietic development in epo-deficient mice. The erythroblast compartments of untreated and treated EpoTAg mice were analysed in comparison with wild-type mice. The early erythroblast population was reduced in the bone marrow of epo-deficient mice, whilst the number of erythroid colony-forming units (CFU-E) was not significantly compromised. This paucity in marrow early erythroblasts was restored to normal values in treated mutant mice. In addition, the early erythroblast population was expanded in the spleens of treated animals. These findings show that the early erythroblasts are important targets of epo and that epo corrects anaemia of epo-deficient mice by restoring marrow function and splenic erythropoiesis.

High incidence of spontaneous disease in an HLA-DR15 and TCR transgenic multiple sclerosis model.

Multiple sclerosis (MS) is thought to involve CD4 T cell recognition of self myelin, many studies focusing on a pathogenic role for anti-myelin, HLA-DR15-restricted T cells. In experimental allergic encephalomyelitis, it is known which epitopes trigger disease and that disease is associated with determinant spread of T cell reactivity. Characterization of these events in human MS is critical for the development of peptide immunotherapies, but it has been difficult to define the role of determinant spread or define which epitopes might be involved. In this study, we report humanized transgenic mice, strongly expressing HLA-DR15 with an MS-derived TCR; even on a RAG-2 wild-type background, mice spontaneously develop paralysis. Disease, involving demyelination and axonal degeneration, correlates with inter- and intramolecular spread of the T cell response to HLA-DR15-restricted epitopes of myelin basic protein, myelin oligodendrocyte glycoprotein, and alphaB-crystallin. Spread is reproducible and progressive, with two of the epitopes commonly described in responses of HLA-DR15 patients. The fact that this pattern is reiterated as a consequence of CNS tissue damage in mice demonstrates the value of the transgenic model in supplying an in vivo disease context for the human responses. This model, encompassing pathologically relevant, spontaneous disease with the presentation of myelin epitopes in the context of HLA-DR15, should offer new insights and predictions about T cell responses during MS as well as a more stringent test bed for immunotherapies.