Non-invasive brain stimulation for Parkinson's disease: Clinical evidence, latest concepts and future goals: A systematic review.

Parkinson's disease (PD) is becoming a major public-health issue in an aging population. Available approaches to treat advanced PD still have limitations; new therapies are needed. The non-invasive brain stimulation (NIBS) may offer a complementary approach to treat advanced PD by personalized stimulation. Although NIBS is not as effective as the gold-standard levodopa, recent randomized controlled trials show promising outcomes in the treatment of PD symptoms. Nevertheless, only a few NIBS-stimulation paradigms have shown to improve PD's symptoms. Current clinical recommendations based on the level of evidence are reported in Table 1 through Table 3. Furthermore, novel technological advances hold promise and may soon enable the non-invasive stimulation of deeper brain structures for longer periods

Obstacle stepping in patients with Parkinson's disease: Complexity does influence performance

Patients with Parkinson's disease (PD) have difficulties in performing complex bimanual movements. Here we have examined acquisition and performance of a bilateral obstacle stepping task to see whether these difficulties are also present during bipedal movements. Subjects had to minimize foot clearance when repeatedly stepping on a treadmill over randomly approaching obstacles on either side. The subjects had full vision and received acoustic feedback information about task performance. Foot clearance improved in healthy and PD subjects during the acquisition of the task. However, PD subjects showed a slower improvement and achieved a poorer performance level. Thus, in contrast to unilateral obstacle stepping, where no deficits in performance after task repetition were found in PD subjects, bilateral obstacle stepping was poorer in these subjects compared to healthy subjects. The present results extend findings from upper to lower limb movements, namely that PD subjects have difficulties in the performance of bilateral motor task

Spatiotemporal parameters during turning gait maneuvers of different amplitudes in young and elderly healthy adults: A descriptive and comparative study.

Turning during walking adds complexity to gait and has been little investigated until now. Research question What are the differences in spatiotemporal parameters between young and elderly healthy adults performing quarter-turns (90°), half-turns (180°) and full-turns (360°)? The spatiotemporal parameters of 10 young and 10 elderly adults were recorded in a laboratory while turning at 90°, 180° and 360°. Two-way mixed ANOVA were performed to determine the effect of age and turning amplitude. Elderly were slower and needed more steps and time to perform turns of larger amplitude than young adults. Cadence did not differ across age or across turning amplitude. Generally, in the elderly, the spatial parameters were smaller and the temporal parameters enhancing stability (i.e., double-support phase and stance/cycle ratio) were larger, especially for turns of larger amplitudes. In elderly adults, the variability of some spatial parameters was decreased, whereas the variability of some temporal parameters was increased. Stride width of the external leg showed the most substantial difference between groups. Most parameters differed between turning at 90° and turning at larger amplitudes (180°, 360°). Significance This study extends the characterization of turning biomechanics with respect to ageing. It also suggested paying particular attention to the turning amplitude. Finally, the age-related differences may pave the way for new selective rehabilitation protocols in the elderly

Genotype–phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype-phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype-phenotype correlations encouraging further analyses

Measurements of thorium and uranium daughters in radioenvironmental samples using γγ-coincidence spectrometry

We present the performance of a γγ-coincidence spectrometer for measuring the activities of thorium and uranium daughters in environmental samples. The spectrometer consists of two NaI(Tl) detectors facing each other inside a low-background passive shield. We present coincidence gating schemes for achieving the best signal-to-noise ratios, coincidence detection efficiencies, background levels, and minimum detectable activities. The spectrometer is simulated using Geant4 to correct sample efficiencies for self-absorption effects. The device is used to measure thorium and uranium daughter activities in Brazil nuts, potting mix, and magazine paper. Our results for Brazil nuts agree with some, but not all, previous measurements. Thorium or uranium daughter activities have previously not been reported for commercial potting mix. For magazine paper, our measured activities are lower than most previously determined values

The use of visual methods to explore how children construct and assign meaning to the ''self'' within two urban communities in the Western Cape, South Africa

This study aimed to explore how children construct and assign meaning to the ''self'' within two urban communities of Cape Town in South Africa. Using a child participation methodological framework data were collected using Photovoice and community maps with 54 participants between the ages of 9 and 12. Feelings of safety, social connectedness, and children's spaces were found to be central to the ways in which the participants constructed and assigned meaning to the ''self.'' The study provides implications for intervention programmes aimed at improving children's well-being to be inclusive of activities aimed at improving children's self-concept, including the construction of safe spaces for children to play, learn, and form meaningful relationships

Multicolour correlative imaging using phosphor probes

Correlative light and electron microscopy exploits the advantages of optical methods, such as multicolour probes and their use in hydrated live biological samples, to locate functional units, which are then correlated with structural details that can be revealed by the superior resolution of electron microscopes. One difficulty is locating the area imaged by the electron beam in the much larger optical field of view. Multifunctional probes that can be imaged in both modalities and thus register the two images are required. Phosphor materials give cathodoluminescence (CL) optical emissions under electron excitation. Lanthanum phosphate containing thulium or terbium or europium emits narrow bands in the blue, green and red regions of the CL spectrum; they may be synthesised with very uniform-sized crystals in the 10- to 50-nm range. Such crystals can be imaged by CL in the electron microscope, at resolutions limited by the particle size, and with colour discrimination to identify different probes. These materials also give emissions in the optical microscope, by multiphoton excitation. They have been deposited on the surface of glioblastoma cells and imaged by CL. Gadolinium oxysulphide doped with terbium emits green photons by either ultraviolet or electron excitation. Sixty-nanometre crystals of this phosphor have been imaged in the atmospheric scanning electron microscope (JEOL ClairScope). This probe and microscope combination allow correlative imaging in hydrated samples. Phosphor probes should prove to be very useful in correlative light and electron microscopy, as fiducial markers to assist in image registration, and in high/super resolution imaging studies

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

Differential contributions of subthalamic beta rhythms and 1/f broadband activity to motor symptoms in Parkinson's disease.

Excessive beta oscillatory activity in the subthalamic nucleus (STN) is linked to Parkinson's Disease (PD) motor symptoms. However, previous works have been inconsistent regarding the functional role of beta activity in untreated Parkinsonian states, questioning such role. We hypothesized that this inconsistency is due to the influence of electrophysiological broadband activity -a neurophysiological indicator of synaptic excitation/inhibition ratio- that could confound measurements of beta activity in STN recordings. Here we propose a data-driven, automatic and individualized mathematical model that disentangles beta activity and 1/f broadband activity in the STN power spectrum, and investigate the link between these individual components and motor symptoms in thirteen Parkinsonian patients. We show, using both modeled and actual data, how beta oscillatory activity significantly correlates with motor symptoms (bradykinesia and rigidity) only when broadband activity is not considered in the biomarker estimations, providing solid evidence that oscillatory beta activity does correlate with motor symptoms in untreated PD states as well as the significant impact of broadband activity. These findings emphasize the importance of data-driven models and the identification of better biomarkers for characterizing symptom severity and closed-loop applications

Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose

N.R.J. was supported by a Diabetes UK RW and JM Collins Studentship (12/0004601). J.B. was supported by a European Foundation for the Study of Diabetes (EFSD) Albert Renold Young Scientist Fellowship and a Studienstiftung des deutschen Volkes PhD Studentship. D.T. was supported by an Advanced Grant from the European Research Commission (268795). G.A.R. was supported by Wellcome Trust Senior Investigator (WT098424AIA) and Royal Society Wolfson Research Merit Awards, and by MRC Programme (MR/J0003042/1), Biological and Biotechnology Research Council (BB/J015873/1), and Diabetes UK Project (11/0004210) grants. G.A.R. and M.W. acknowledge COST Action TD1304 Zinc-Net. D.J.H. was supported by Diabetes UK R.D. Lawrence (12/0004431), EFSD/Novo Nordisk Rising Star and Birmingham Fellowships, a Wellcome Trust Institutional Support Award, and an MRC Project Grant (MR/N00275X/1) with G.A.R. D.J.H and G.A.R. were supported by Imperial Confidence in Concept (ICiC) Grants. J.F. was supported by an MRC Programme grant (MR/L02036X/1). L.P. provided human islets through collaboration with the Diabetes Research Institute, IRCCS San Raffaele Scientific Institute (Milan), within the European islet distribution program for basic research supported by JDRF (1-RSC-2014-90-I-X). P.M. and M.B. were supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 155005 (IMIDIA), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution, and by the Italian Ministry of University and Research (PRIN 2010-2012). D.B. and E.B. provided human islets through the European Consortium for Islet Transplantation sponsored by JDRF (1-RSC-2014-100-I-X)