Subjective Cognitive Complaints in Participants of the Healthy Brain Ageing Study (HeBA)

Subjective cognitive complaints (SCC) have the potential for earlier detection of Alzheimer’s disease and Parkinson’s disease. Currently, the results of the completed online survey in the frame of the HeBA study reveal that 23% of the Luxembourgish participants have SCC with the SCC group having a higher prevalence rate of depression

Luxembourg Parkinson’s study -comprehensive baseline analysis of Parkinson’s disease and atypical parkinsonism

BackgroundDeep phenotyping of Parkinson’s disease (PD) is essential to investigate this fastest-growing neurodegenerative disorder. Since 2015, over 800 individuals with PD and atypical parkinsonism along with more than 800 control subjects have been recruited in the frame of the observational, monocentric, nation-wide, longitudinal-prospective Luxembourg Parkinson’s study.ObjectiveTo profile the baseline dataset and to explore risk factors, comorbidities and clinical profiles associated with PD, atypical parkinsonism and controls.MethodsEpidemiological and clinical characteristics of all 1,648 participants divided in disease and control groups were investigated. Then, a cross-sectional group comparison was performed between the three largest groups: PD, progressive supranuclear palsy (PSP) and controls. Subsequently, multiple linear and logistic regression models were fitted adjusting for confounders.ResultsThe mean (SD) age at onset (AAO) of PD was 62.3 (11.8) years with 15% early onset (AAO < 50 years), mean disease duration 4.90 (5.16) years, male sex 66.5% and mean MDS-UPDRS III 35.2 (16.3). For PSP, the respective values were: 67.6 (8.2) years, all PSP with AAO > 50 years, 2.80 (2.62) years, 62.7% and 53.3 (19.5). The highest frequency of hyposmia was detected in PD followed by PSP and controls (72.9%; 53.2%; 14.7%), challenging the use of hyposmia as discriminating feature in PD vs. PSP. Alcohol abstinence was significantly higher in PD than controls (17.6 vs. 12.9%, p = 0.003).ConclusionLuxembourg Parkinson’s study constitutes a valuable resource to strengthen the understanding of complex traits in the aforementioned neurodegenerative disorders. It corroborated several previously observed clinical profiles, and provided insight on frequency of hyposmia in PSP and dietary habits, such as alcohol abstinence in PD.Clinical trial registration: clinicaltrials.gov, NCT05266872

Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

Angiosarcoma in chronic lymphoedema: a case of Stewart-Treves syndrome

peer reviewedThe Stewart-Treves Syndrome is defined as an angiosarcoma (very aggressive malignant tumor originating from endothelial cells) appearing in a specific clinical setting. This tumor develops in patients suffering from chronic lymphedema of the upper limb following mastectomy and axillary lymph node dissection for breast cancer. The diagnosis relies on medical history, clinical examination and a histological assesment (biopsy or resection). This syndrome represents a rare clinical entity. Unfortunately, the prognosis is poor. A large surgical resection is the treatment of choice if the patient is a candidate for a surgical resection with a curative intent Radiotherapy is sometimes used as a palliative local treatment. Chemotherapy is only used in more advanced cases, not curable by surgery alone

JNK/ROS signaling pathway is responsible for induction of autophagy in HDAC5 depleted cancer cells

Introduction: Histone deacetylases (HDAC) is a family of eighteen enzymes which modulates the acetylation level of histones and non-histone proteins to regulate gene expression and chromatin structure. Broad spectrum inhibitors of these enzymes such as SAHA can inhibit tumor growth both in vitro and in vivo and are currently used as anti-cancer agents in clinic. For many years, we are investigating the specific role of individual HDAC members in cancer biology and we have recently demonstrated that depletion of HDAC5 using siRNA technology triggered cancer cells to both autophagy and apoptosis (ref papier). The study of autophagy in cancer is a new research field that has recently generated tremendous attention due to the recognition that autophagy can have either pro-survival or pro-death functions depending on its level of activation. In addition, more and more studies indicate that a complex relationship exists between autophagy and apoptosis, and that the interplay between these two processes determines whether a cell will live or die. Aims: The goal of this study is to further understand the role of autophagy induced by HDAC5 depletion. Current investigations include determining the molecular mechanisms by which HDAC5 depletion induces autophagy and exploring regulatory relationship between autophagy and apoptosis on cancer cell death in absence of HDAC5. Results: The set up of the autophagy in absence of HDAC5 was demonstrated by the conversion of LC3 and development of autophagosomes by electronic microscopy. Transcriptomic study demonstrated a deregulation of a set of genes involved in ROS detoxification in HDAC5 depleted cancer cells leading to significant increase of ROS levels. Further investigations showed that pretreatment with NAC, a ROS scavenger, effectively blocked the accumulation of ROS and autopahgy triggered by HDAC5 silencing. Moreover, HDAC5 depletion induces activation of JNK, and knockdown of JNK by siRNA inhibited ROS production and autophagy, but antioxidant NAC failed to block JNK activation induced by HDAC5 depletion indicating that JNK activation may be a upstream signaling of ROS and should be a core component in HDAC5 silencing-induced autophagic signaling pathway. Finally, blocking of autophagy induced by HDAC5 silencing with NAC or chloroquine and bafilomycin enhanced pro-apoptotic effect. Conclusion: Autophagy functions as a prosurvival mechanism to mitigate HDAC5 depletion-induced apoptotic cell death, suggesting that targeting autophagy might improve the therapeutic effects of specific HDAC5 inhibition

Determination of the analytical performances of an in-line Raman spectroscopic method monitoring a hot-melt extrusion process

Mycomel

Global approach for the validation of an in-line Raman spectroscopic method to determine the API content in real-time during a hot-melt extrusion process

Since the Food and Drug Administration (FDA) published a guidance based on the Process Analytical Technology (PAT) approach, real-time analyses during manufacturing processes are in real expansion. In this study, in-line Raman spectroscopic analyses were performed during a Hot-Melt Extrusion (HME) process to determine the Active Pharmaceutical Ingredient (API) content in real-time. The method was validated based on a univariate and a multivariate approach and the analytical performances of the obtained models were compared. Moreover, on one hand, in-line data were correlated with the real API concentration present in the sample quantified by a previously validated off-line confocal Raman microspectroscopic method. On the other hand, in-line data were also treated in function of the concentration based on the weighing of the components in the prepared mixture. The importance of developing quantitative methods based on the use of a reference method was thus highlighted. The method was validated according to the total error approach fixing the acceptance limits at ± 15% and the α risk at ± 5%. This method reaches the requirements of the European Pharmacopeia norms for the uniformity of content of single-dose preparations. The validation proves that future results will be in the acceptance limits with a previously defined probability. Finally, the in-line validated method was compared with the off-line one to demonstrate its ability to be used in routine analyses

Development of an analytical method for crystalline content determination in amorphous solid dispersions produced by Hot-Melt Extrusion using transmission Raman spectroscopy: A feasibility study.

The development of a quantitative method determining the crystalline percentage in an amorphous solid dispersion is of great interest in the pharmaceutical field. Indeed, the crystalline Active Pharmaceutical Ingredient transformation into its amorphous state is increasingly used as it enhances the solubility and bioavailability of Biopharmaceutical Classification System class II drugs. One way to produce amorphous solid dispersions is the Hot-Melt Extrusion (HME) process. This study reported the development and the comparison of the analytical performances of two techniques, based on backscattering and transmission Raman spectroscopy, determining the crystalline remaining content in amorphous solid dispersions produced by HME. Principal Component Analysis (PCA) and Partial Least Squares (PLS) regression were performed on preprocessed data and tended towards the same conclusions: for the backscattering Raman results, the use of the DuoScan™ mode improved the PCA and PLS results, due to a larger analyzed sampling volume. For the transmission Raman results, the determination of low crystalline percentages was possible and the best regression model was obtained using this technique. Indeed, the latter acquired spectra through the whole sample volume, in contrast with the previous surface analyses performed using the backscattering mode. This study consequently highlighted the importance of the analyzed sampling volume.Mycomel

A simple calibration approach based on film-casting for confocal Raman microscopy to support the development of a Hot-Melt Extrusion process

When developing a new formulation, the development, calibration and validation steps of analytical methods based on vibrational spectroscopy are time-consuming. For each new formulation, real samples must be produced and a “reference method” must be used in order to determine the Active Pharmaceutical Ingredient (API) content of each sample. To circumvent this issue, the paper presents a simple approach based on the film-casting technique used as a calibration tool in the framework of hot-melt extrusion process. Confocal Raman microscopic method was successfully validated for the determination of itraconazole content in film-casting samples. Then, hot-melt extrusion was carried out to produce real samples in order to confront the results obtained with confocal Raman microscopy and Ultra High Performance Liquid Chromatography (UHPLC). The agreement between both methods was demonstrated using a comparison study based on the Bland and Altman’s plot

Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production.

peer reviewedWolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1E864K line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, a collapse of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na+/K+ATPase β1 subunit, a key protein for the maintenance of the EP. Overall, our data support a key role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na+/K+ATPase β1 subunit