Explore the vast range of titles available.

There has been an unprecedented interest in the modulatory effects of intranasal oxytocin on human social cognition and behaviour, however as yet no study has actually demonstrated that this modality of administration increases concentrations of the peptide in the brain as well as blood in humans. Here using combined blood and cerebrospinal fluid (CSF) sampling in subjects receiving either 24 IU of oxytocin (n = 11) or placebo (n = 4) we have shown that oxytocin levels significantly increased in both plasma and CSF. However, whereas oxytocin plasma concentrations peaked at 15 min after intranasal administration and decreased after 75 min, CSF concentrations took up to 75 min to reach a significant level. Moreover, there was no correlation (r = <0.10) between oxytocin plasma and CSF concentrations. Together, these data provide crucial insights into the plasma and CSF kinetics of intranasally administered oxytocin.

The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado–Joseph Disease (MJD) or spinocerebellar ataxia 3 (SCA3) is the most common autosomal dominant form, caused by the expansion of CAG repeats within the ataxin-3 (ATXN3) gene. This mutation results in the expression of an abnormal protein containing long polyglutamine (polyQ) stretches that confers a toxic gain of function and leads to misfolding and aggregation of ATXN3 in neurons. As a result of the neurodegenerative process, SCA3 patients are severely disabled and die prematurely. Several screening approaches, e.g., druggable genome-wide and drug library screenings have been performed, focussing on the reduction in stably overexpressed ATXN3(polyQ) protein and improvement in the resultant toxicity. Transgenic overexpression models of toxic ATXN3, however, missed potential modulators of endogenous ATXN3 regulation. In another approach to identify modifiers of endogenous ATXN3 expression using a CRISPR/Cas9-modified SK-N-SH wild-type cell line with a GFP-T2A-luciferase (LUC) cassette under the control of the endogenous ATXN3 promotor, four statins were identified as potential activators of expression. We here provide an overview of the high throughput screening approaches yet performed to find compounds or genomic modifiers of ATXN3(polyQ) toxicity in different SCA3 model organisms and cell lines to ameliorate and halt SCA3 progression in patients. Furthermore, the putative role of cholesterol in neurodegenerative diseases (NDDs) in general and SCA3 in particular is discussed.

ObjectivesParkinson’s disease (PD) is the second most common neurodegenerative disorder and is further associated with progressive cognitive decline. In respect to motor phenotype, there is some evidence that akinetic-rigid PD is associated with a faster rate of cognitive decline in general and a greater risk of developing dementia.The objective of this study was to examine cognitive profiles among patients with PD by motor phenotypes and its relation to cognitive function.MethodsDemographic, clinical and neuropsychological cross-sectional baseline data of the DEMPARK/LANDSCAPE study, a multicentre longitudinal cohort study of 538 patients with PD were analysed, stratified by motor phenotype and cognitive syndrome. Analyses were performed for all patients and for each diagnostic group separately, controlling for age, gender, education and disease duration.ResultsCompared with the tremor-dominant phenotype, akinetic-rigid patients performed worse in executive functions such as working memory (Wechsler Memory Scale-Revised backward; p=0.012), formal-lexical word fluency (p=0.043), card sorting (p=0.006), attention (Trail Making Test version A; p=0.024) and visuospatial abilities (Leistungsprüfungssystem test 9; p=0.006). Akinetic-rigid neuropsychological test scores for the executive and attentive domain correlated negatively with non-tremor motor scores. Covariate-adjusted binary logistic regression analyses showed significant odds for PD-mild cognitive impairment for not-determined as compared with tremor-dominant (OR=3.198) and akinetic-rigid PD (OR=2.059). The odds for PD-dementia were significant for akinetic-rigid as compared with tremor-dominant phenotype (OR=8.314).ConclusionThe three motor phenotypes of PD differ in cognitive performance, showing that cognitive deficits seem to be less severe in tremor-dominant PD. While these data are cross-sectional, longitudinal data are needed to shed more light on these differential findings.

Purpose Magnetic resonance-guided focused ultrasound (MRgFUS) systems are increasingly used to non-invasively treat tremor; consensus on imaging follow-up is poor in these patients. This study aims to elucidate how MRgFUS lesions evolve for a radiological readership with regard to clinical outcome. Methods MRgFUS-induced lesions and oedema were retrospectively evaluated based on DWI, SWI, T2-weighted and T1-weighted 3-T MRI data acquired 30 min and 3, 30 and 180 days after MRgFUS ( n  = 9 essential tremor, n  = 1 Parkinson’s patients). Lesions were assessed volumetrically, visually and by ADC measurements and compared with clinical effects using non-parametric testing. Results Thirty minutes after treatment, all lesions could be identified on T2-weighted images. Immediate oedema was rare ( n  = 1). Lesion volume as well as oedema reached a maximum on day 3 with a mean lesion size of 0.4 ± 0.2 cm 3 and an oedema volume 3.7 ± 1.2 times the lesion volume. On day 3, a distinct diffusion-restricted rim was noted that corresponded well with SWI. Lesion shrinkage after day 3 was observed in all sequences. Lesions were no longer detectable on DWI in n  = 7/10, on T2-weighted images in n  = 4/10 and on T1-weighted images in n  = 4/10 on day 180. No infarcts or haemorrhage were observed. There was no correlation between lesion size and initial motor skill improvement ( p  = 0.99). Tremor reduction dynamics correlated strongly with lesion shrinkage between days 3 and 180 ( p  = 0.01, R  = 0.76). Conclusion In conclusion, cerebral MRgFUS lesions variably shrink over months. SWI is the sequence of choice to identify lesions after 6 months. Lesion volume is arguably associated with intermediate-term outcome.

The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. SCA3 is the most common form, caused by the expansion of CAG repeats within the ataxin 3 ( ATXN3 ) gene. The mutation results in the expression of an abnormal protein, containing long polyglutamine (polyQ) stretches. The polyQ stretch confers a toxic gain of function and leads to misfolding and aggregation of ATXN3 in neurons. Thus, modulators of ATXN3 expression could potentially ameliorate the pathology in SCA3 patients. Therefore, we generated a CRISPR/Cas9 modified ATXN3-Exon4-Luciferase (ATXN3-LUC) genomic fusion- and control cell lines to perform a reporter cell line-based high-throughput screen comprising 2640 bioactive compounds, including the FDA approved drugs. We found no unequivocal inhibitors of, but identified statins as activators of the LUC signal in the ATXN3-LUC screening cell line. We further confirmed that Simvastatin treatment of wild type SK-N-SH cells increases ATXN3 mRNA and protein levels which likely results from direct binding of the activated sterol regulatory element binding protein 1 (SREBP1) to the ATXN3 promotor. Finally, we observed an increase of normal and expanded ATXN3 protein levels in a patient-derived cell line upon Simvastatin treatment, underscoring the potential medical relevance of our findings.

Emerging evidence suggests an inverse association between cancer and neurodegenerative diseases (NDD). Although phenotypically different, both diseases display a significant imbalance in the ubiquitination/deubiquitination processes. Therefore, we particularly investigated the expression of ubiquitin C-terminal hydrolases (UCHs: UCH-L1, UCH-L3, UCH-L5 and BAP1), a subfamily of deubiquitinating enzymes (DUBs), using publically available datasets (GTEx, TCGA) and observed altered expression of UCH-L1, UCH-L3, UCH-L5 in 17 cancer types. Interestingly, UCH-L1 (known to be enriched in neurons and interacting with the Parkinson’s disease-associated protein α-synuclein) appeared to be a prognostic indicator of unfavorable outcome in endometrial and urothelial cancer, while increased expression of UCH-L3 and UCH-L5 was associated with poor survival in liver and thyroid cancer, respectively. In normal tissues, UCH-L1 was found to be strongly expressed in the cerebral cortex and hypothalamus, while UCH-L3 expression was somewhat higher in the testis. The occurrence of mutation rates in UCHs also suggests that BAP1 and UCH-L5 may play a more dominant role in cancers than UCH-L1 and UCH-L3. We also characterized the functional context and configuration of the repeat elements in the promoter of DUBs genes and found that UCHs are highly discriminatory for catabolic function and are mainly enriched with LINE/CR1 repeats. Regarding the thesis of an inverse association between cancer and NDD, we observed that among all DUBs, UCHs are the one most involved in both entities. Considering a putative therapeutic potential based on presumed common mechanisms, it will be useful to determine whether other DUBs can compensate for the loss of UCH activity under physiological conditions. However, experimental evidence is required to substantiate this argument.

Parkinson disease (PD) is characterized by a pivotal progressive loss of substantia nigra dopaminergic neurons and aggregation of α -synuclein protein encoded by the SNCA gene. Genome-wide association studies identified almost 100 sequence variants linked to PD in SNCA . However, the consequences of this genetic variability are rather unclear. Herein, our analysis on selective single nucleotide polymorphisms (SNPs) which are highly associated with the PD susceptibility revealed that several SNP sites attribute to the nucleosomes and overlay with bivalent regions poised to adopt either active or repressed chromatin states. We also identified large number of transcription factor (TF) binding sites associated with these variants. In addition, we located two docking sites in the intron-1 methylation prone region of SNCA which are required for the putative interactions with DNMT1. Taken together, our analysis reflects an additional layer of epigenomic contribution for the regulation of the SNCA gene in PD.

Multiple lines of evidence suggest a link between environmental toxins and Parkinson's disease (PD). Although numerous studies reported associations of genetic variants in de-toxifying enzymes, i.e. cytochrome genes, with PD. Epigenetic modifications of genes and subsequent altered expression may confer a yet unappreciated level of susceptibility. We present a genome-wide methylation analysis of PD with quantitative DNA methylation levels of 27.500 CpG sites representing 14.495 genes. We found decreased methylation of the cytochrome P450 2E1 gene and increased expression of CYP2E1 messenger RNA in PD patients' brains, suggesting that epigenetic variants of this cytochrome contribute to PD susceptibility.

Little is known about the specific anaesthesiological and multidisciplinary management of high-intensity focused ultrasound (HIFU) in uterine fibroids. This observational single-center study is the first reporting on an interdisciplinary approach to optimize outcome following ultrasound (US)-guided HIFU in German-speaking countries. A sample of forty patients with symptomatic uterine fibroids was treated by HIFU. Relevant treatment parameters such as total treatment time for intervention, anaesthesia, and sonication time as well as total energy, body temperature, peri-interventional medication and complications were analyzed. Interventional variables did not correlate significantly either with opioid dose or with body temperature. The average fibroid volume reduction rate was 37.8% ± 23.5%, 48.5% ± 22.0% and 70.2% ± 25.5% after 3, 6 and 12 months, respectively. No major anaesthesiological complications occurred apart from an epileptic seizure prior to HIFU treatment in one patient. Peri-procedural hyperthermia (> 37.5 °C) occurred in two patients. Post-procedural two patients experienced a sciatic nerve irritation up to one year; one patient with very large treated fibroid experienced strong short-lasting post-procedural pain. There were two complication-free pregnancies of HIFU-treated patients. Multidisciplinary management is crucial to optimize safety and outcome of US-guided HIFU for uterine fibroids. Peri-procedural pain and temperature management are critical points where an adequate collaboration between anesthesiologist and interventionalist is mandatory.