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The COVID-19 pandemic impact on continuity of care provision on rare brain diseases and on ataxias, dystonia and PKU. A scoping review
Get PDFOne of the most relevant challenges for healthcare providers during the COVID– 19 pandemic has been assuring the continuity of care to patients with complex health needs such as people living with rare diseases (RDs). The COVID–19 pandemic accelerated the healthcare sector’s digital transformation agenda. The delivery of telemedicine services instead of many face-to-face procedures has been expanded and, many healthcare services not directly related to COVID-19 treatments shifted online remotely. Many hospitals, specialist centres, patients and families started to use telemedicine because they were forced to. This trend could directly represent a good practice on how care services could be organized and continuity of care could be ensured for patients. If done properly, it could boast improved patient outcomes and become a post COVID-19 major shift in the care paradigm. There is a fragmented stakeholders spectrum, as many questions arise on: how is e-health interacting with ‘traditional’ healthcare providers; about the role of the European Reference Networks (ERNs); if remote care can retain a human touch and stay patient centric. The manuscript is one of the results of the European Brain Council (EBC) Value of Treatment research project on rare brain disorders focusing on progressive ataxias, dystonia and phenylketonuria with the support of Academic Partners and in collaboration with European Reference Networks (ERNs) experts, applying empirical evidence from different European countries. The main purpose of this work is to investigate the impact of the COVID-19 pandemic on the continuity of care for ataxias, dystonia and phenylketonuria (PKU) in Europe. The analysis carried out makes it possible to highlight the critical points encountered and to learn from the best experiences. Here, we propose a scoping review that investigates this topic, focusing on continuity of care and novel methods (e.g., digital approaches) used to reduce the care disruption. This scoping review was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) standards. This work showed that the implementation of telemedicine services was the main measure that healthcare providers (HCPs) put in place and adopted for mitigating the effects of disruption or discontinuity of the healthcare services of people with rare neurological diseases and with neurometabolic disorders in Europe
Ultrasonographyc analysis of mesencephalic nuclei in patients with Parkinson's disease with and without depressive symptoms
No full textParkinsonova bolest druga je neurodegenerativna bolest iza Alzheimerove demencije te je rana dijagnostika važan faktor koji doprinosi pravovremenom liječenju a time i poboljšanju kvalitete života bolesnika.
Ovim istraživanjem analizirano je značenje nalaza TCD-a u PB-i kao i premotoričkim simptomima, prvenstveno depresiji.
Osnovna hipoteza istraživanja bila je da ultrazvučna analiza mezencefaličkih jezgara može dati različiti rezultat u bolesnika s depresijom u sklopu PB-i u odnosu na bolesnike bez depresije, što može doprinijeti u prepoznavanju ranog nemotoričkog znaka PB-i.
Istraživanje je provedeno na 150 bolesnika s PB-i, 52 bolesnika s depresijom te 100 kontrola ( ispitanici bez simptoma PB-i ili depresije). Kod svih ispitanika izvršena je analiza bazalnih ganglija TCD-om ( Aloka prosound α-10) u jednom navratu.
Stupanj bolesti u PD-a određen je UPDRS i H&Y skalom dok je stupanj depresije u svim ispitanim skupinama određen BECK-ovom skalom.
Rezultati su pokazali značajnu razliku nalaza TCD-a prvenstveno na nivou bazalnih ganglija između bolesnika s PB-i s i bez depresije kao i između oboljelih od PB-i i velikog depresivnog poremećaja. Utvrdili smo da površina SN korelira s rezultatom BDI, što je rezultat viši veća je površina SN koja se do sada smatrala stabilnim ( nepromjenjivim) markerom PB-i. Depresivni PB ispitanici imaju klinički zahvaćeniju nedominantnu stranu tijela što može poslužiti kao svojevrsni prediktor kasnije depresije u ranoj fazi bolesti. Iako je povišen broj patoloških nalaz SN u velikom depresivnom poremećaju taj je broj viši u PB-i što odgovara ranijim istraživanjima. Također je više patoloških nalaza SN kao i NL u skupini depresivnih PB prema skupini velikog depresivnog poremećaja dok razlike u nalazu NR nismo dokazali.
Dokazali smo korelaciju nalaza TCD-a sa stupnjem bolesti u depresivnoj podskupini PB-i što predstavlja novinu u odnosu na prethodne studije što svakako zahtijeva daljnja istraživanja.Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's dementia.
With this study we emphasized the importance of the TCS in PD and premotor symptoms especially depression.
The hypothesis was that TCS of mesencephalic nuclei can distinguish patients with depression in PD from those without it as an early (nonmotor) sign of iPD.
Our research was conducted on 150 PD patients, 52 major depression patients, and 100 individuals without signs of iPD or depression.
TCS was performed once on Aloka prosound α-10 ultrasound. For disease severity in PD we used UPDRS and H&Y scales, and for depression BECK Depression Inventory Scale.
Our result showed a significant difference at the level of basal ganglia between PD patients with and without depression. We have established a correlation between the size of SN and BDI score (higher the BDI score, larger the size of SN). This result confronts all the studies so far because the size of SN was considered to be the stable marker of PD. Depressed PD patients have predominantly affected the nondominant side of the body that can stand as a predictor of depression later on as the disease progresses. We found more pathological findings of SN in major depression but this number is still higher in PD that correlates with earlier studies. We also found more pathological findings of SN and NL in depressed PD patients than in major depression, without difference in NR findings.
We have shown correlation between disease severity and TCS findings in depressed PD patients that confront with the majority of previous studies that demands further research
Učinak toksina botulinuma tipa – A na nemotoričke simptome u bolesnika s fokalnom distonijom
Get PDFBackground: Traditionally, isolated adult-onset cervical dystonia (IAOCD) is considered as a ‘pure’ motor disorder. However, non-motor symptoms (NMS) are increasingly recognized as a part of IOACD phenotype. Cognitive functions in IAOCD were rarely investigated and poorly understood making this issue still a matter of debate. The aim of this prospective study was to investigate, for the first time, the effect of acute and long-term therapeutic applications (more than one year) of botulinum toxin type-A (BoNT-A) on NMS and cognitive functions in IAOCD patients previously not treated with BoNT-A. Design/Methods: The study included 51 IAOCD patients (29 females and 22 males) and 90 (50 female i 40 males) age, gender and education matched healthy controls. Questionnaires used in this study included: Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Beck Depression Inventory – Second Edition (BDI-II), Beck Anxiety Inventory (BAI), Starkstein Apathy Scale (AS), Pitsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), Short Form-36 Health Survey (SF-36). Cognitive functions were assessed using Cogtest®, a computerized neurocognitive battery set of 5 tests: Auditory Number Sequencing (ANS), Spatial Working Memory (SWM), Strategic Target Detection (STD), Continuous Performance Test – Flanker version (Flanker CPT) and Tower of London (ToL). All of the above mentioned investigations were performed prior to initial BoNT-A application (first test). The follow-up was performed after 4 month (second test) and 12 to 16 months after initial BoNT-A application (third test). During the follow-up period the patients received 3 BoNT-A applications.
Results: On initial investigation 46 (90,2%) IAOCD patients had at least one psychiatric disorder in comparison to 36 (40%) healthy controls. Mean BDI-II score, BAI score and AS score were significantly higher in IAOCD patients than in healthy controls (12,59 ± 6,28 vs. 6,11 ± 4,26, p0,05). However, IAOCD patients had worse performance in STD, ToL, and Flanker CPT test (p<0,05). IAOCD patients had significantly reduced quality of life (QoL) determined by SF-36 questionnaire. During follow-up period, we found no significant difference in total BDI-II, BAI, AS, PSQI and FSS score between all three tests. Still, no difference in total AS score on third test was observed between IAOCD and control group, and improvement in total PSQI score was observed in second and third test when compared to initial one. Significant pain amelioration, unrelated to improvement of motor symptoms, was observed during follow-up period. Long-term BoNT-A applications had no effect on cognitive performance as measured by ANS, SWM, Flanker CPT and ToL test. Significant improvement was detected in variables of strategic efficiency and total perseverative errors of STD test, designed for evaluation of complex attention and processing speed. Improvement of QoL was observed in two SF-36 domains: bodily pain and general health perception.
Conclusion: Spectrum of IAOCD symptoms includes various NMS such as pain, psychiatric comorbidities, impaired sleep quality, pathological fatigue, and cognitive dysfunction, especially in the domains of attention and executive functioning, thus implicating shared neurobiology of motor symptoms, NMS and cognitive dysfunction. Except for major analgesic effect and mild positive effect on sleep quality and apathy, long-term BoNT-A treatment had no statistically significant impact on other NMS. In addition, long-term BoNT-A application showed modest improvement of attention without any negative implication on other cognitive domains. Finally, we can say that in the dosages applied in this study (150-200U per application), BoNT-A is significantly effective in reducing pain and motor symptoms, probably minimally effective in improvement of sleep quality and apathy, ineffective in reducing anxiety, depression and fatigue. We did not find any negative influence of BoNT-A on cognitive functions with the applied objectivization methods, moreover, a slight improvement in complex attention and processing speed was found
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Genetic mechanisms of lysosomal dysfunction in Parkinson's disease
No full textGlavni patološki znak Parkinsonove bolesti (PB) jest nakupljanje proteina alfa sinukleina (aSyn) što sugerira da neučinkovita razgradnja proteina podložnih agregaciji igra važnu ulogu u patogenezi bolesti. Studije o rijetkim naslijeĊenim oblicima PB ukazale su na smanjenu razgradnju aSyn putem autofagno-lizosomalnog puta (ALP) kao jednog od ključnih mehanizama u podlozi PB. Kako bismo karakterizirali pretpostavljene genetske mehanizme koji dovode do disfunkcije ALP-a u PB, proveli smo opsežnu analizu genetskih varijanti korištenjem ciljanog panela za sekvenciranje pod nazivom LYSOGENE. LYSOGENE panel sadrţži sveobuhvatni skup od 440 ALP srodnih gena, kao i gene prethodno opisane u familijarnim oblicima PB, sinukleinopatijama i drugim neurodegenerativnim bolestima. Identificirali smo značajan broj varijanti ALP gena među PB pacijentima u usporedbi s kontrolnim ispitanicima, s 396 varijanti prisutnih isključivo u PB bolesnika. Ove varijante uključene su u više od 50 bioloških procesa, ponajprije u putovima organizacije lizosoma, transporta organskih tvari, abnormalne mijelinizacije i metabolizma sfingolipida. Suprotno tome, varijante koje su pronađene isključivo u zdravih ispitanika nisu bile povezane sa specifičnim biološkim putovima. Na temelju podataka sekvenciranja, odabrali smo ARSD, GALC i LRBA gene s najviše zastupljenim genetskim varijantama kod pacijenata s PB i istražili njihove učinke na lizosomalno oštećenje, akumulaciju aSyn i neurotoksičnost primjenom SH-SY5Y staničnih linija koje stabilno eksprimiraju ljudski aSyn. Rezultati su uspoređeni s učincima utišavanja ATP13A2 gena za kojeg je opisano da dovodi do nakupljanja aSyn. Naši rezultati snažno upućuju na to da specifične varijante ALP gena mogu doprinijeti lizosomalnoj disfunkciji u PB. Ovim istraživanjem je po prvi puta opisana povezanost utišavanja ARSD i LRBA gena s nakupljanjem aSyn proteina te potvrđena povezanost utišavanja GALC gena s PB. Ovo istraživanje je potvrdilo vezu između lizosomalnog oštećenja i akumulacije aSyn.Accumulation of misfolded proteins in the brain is the main pathological hallmark of neurodegenerative diseases, including Parkinson’s disease (PD), suggesting that inadequate clearance of aggregation-prone proteins plays an important role in the disease pathogenesis. Studies on the rare inherited forms of PD have highlighted disturbed alpha-synuclein clearance through the autophagy-lysosomal pathway (ALP) as a key mechanism leading to PD. In order to characterize the putative underlying genetic mechanisms leading to ALP dysfunction in PD, we performed comprehensive analysis of genetic variants in ALP genes in PD patients using the custom LYSOGENE targeted next-generation sequencing panel, containing a set of 440 ALP related genes, as well as genes previously implicated in familial forms of PD. We identified a significant number of ALP gene variants among PD patients when compared to control subjects. These variants were involved in over 50 biological processes, with the greatest enrichment observed in categories of lysosome organization, organic substance transport, abnormal myelination and sphingolipid metabolism. In contrast, variants found exclusively in healthy subjects were not related to specific biological pathways.
Based on the NGS data, we selected genes ARSD, GALC and LRBA with the most over-represented genetic variants in PD patients and investigated their effects on lysosomal impairment, alpha-synuclein accumulation and neurotoxicity using SH-SY5Y cell lines stably expressing human alpha-synuclein. The results were compared to the effects of the knock-down of a known lysosome-related gene, ATP13A2, which causes a rare autosomal recessive form of juvenile-onset atypical PD (PARK9). Our knock-down experiments described for the first time the association between ARSD and LRBA genes with the accumulation of aSyn and confirmed the association between GALC gene and PD. This study confirmed a link between lysosomal dysfunction and alpha-synuclein accumulation
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Genetic mechanisms of lysosomal dysfunction in Parkinson's disease
No full textGlavni patološki znak Parkinsonove bolesti (PB) jest nakupljanje proteina alfa sinukleina (aSyn) što sugerira da neučinkovita razgradnja proteina podložnih agregaciji igra važnu ulogu u patogenezi bolesti. Studije o rijetkim naslijeĊenim oblicima PB ukazale su na smanjenu razgradnju aSyn putem autofagno-lizosomalnog puta (ALP) kao jednog od ključnih mehanizama u podlozi PB. Kako bismo karakterizirali pretpostavljene genetske mehanizme koji dovode do disfunkcije ALP-a u PB, proveli smo opsežnu analizu genetskih varijanti korištenjem ciljanog panela za sekvenciranje pod nazivom LYSOGENE. LYSOGENE panel sadrţži sveobuhvatni skup od 440 ALP srodnih gena, kao i gene prethodno opisane u familijarnim oblicima PB, sinukleinopatijama i drugim neurodegenerativnim bolestima. Identificirali smo značajan broj varijanti ALP gena među PB pacijentima u usporedbi s kontrolnim ispitanicima, s 396 varijanti prisutnih isključivo u PB bolesnika. Ove varijante uključene su u više od 50 bioloških procesa, ponajprije u putovima organizacije lizosoma, transporta organskih tvari, abnormalne mijelinizacije i metabolizma sfingolipida. Suprotno tome, varijante koje su pronađene isključivo u zdravih ispitanika nisu bile povezane sa specifičnim biološkim putovima. Na temelju podataka sekvenciranja, odabrali smo ARSD, GALC i LRBA gene s najviše zastupljenim genetskim varijantama kod pacijenata s PB i istražili njihove učinke na lizosomalno oštećenje, akumulaciju aSyn i neurotoksičnost primjenom SH-SY5Y staničnih linija koje stabilno eksprimiraju ljudski aSyn. Rezultati su uspoređeni s učincima utišavanja ATP13A2 gena za kojeg je opisano da dovodi do nakupljanja aSyn. Naši rezultati snažno upućuju na to da specifične varijante ALP gena mogu doprinijeti lizosomalnoj disfunkciji u PB. Ovim istraživanjem je po prvi puta opisana povezanost utišavanja ARSD i LRBA gena s nakupljanjem aSyn proteina te potvrđena povezanost utišavanja GALC gena s PB. Ovo istraživanje je potvrdilo vezu između lizosomalnog oštećenja i akumulacije aSyn.Accumulation of misfolded proteins in the brain is the main pathological hallmark of neurodegenerative diseases, including Parkinson’s disease (PD), suggesting that inadequate clearance of aggregation-prone proteins plays an important role in the disease pathogenesis. Studies on the rare inherited forms of PD have highlighted disturbed alpha-synuclein clearance through the autophagy-lysosomal pathway (ALP) as a key mechanism leading to PD. In order to characterize the putative underlying genetic mechanisms leading to ALP dysfunction in PD, we performed comprehensive analysis of genetic variants in ALP genes in PD patients using the custom LYSOGENE targeted next-generation sequencing panel, containing a set of 440 ALP related genes, as well as genes previously implicated in familial forms of PD. We identified a significant number of ALP gene variants among PD patients when compared to control subjects. These variants were involved in over 50 biological processes, with the greatest enrichment observed in categories of lysosome organization, organic substance transport, abnormal myelination and sphingolipid metabolism. In contrast, variants found exclusively in healthy subjects were not related to specific biological pathways.
Based on the NGS data, we selected genes ARSD, GALC and LRBA with the most over-represented genetic variants in PD patients and investigated their effects on lysosomal impairment, alpha-synuclein accumulation and neurotoxicity using SH-SY5Y cell lines stably expressing human alpha-synuclein. The results were compared to the effects of the knock-down of a known lysosome-related gene, ATP13A2, which causes a rare autosomal recessive form of juvenile-onset atypical PD (PARK9). Our knock-down experiments described for the first time the association between ARSD and LRBA genes with the accumulation of aSyn and confirmed the association between GALC gene and PD. This study confirmed a link between lysosomal dysfunction and alpha-synuclein accumulation
Genetic mechanisms of lysosomal dysfunction in Parkinson's disease
No full textGlavni patološki znak Parkinsonove bolesti (PB) jest nakupljanje proteina alfa sinukleina (aSyn) što sugerira da neučinkovita razgradnja proteina podložnih agregaciji igra važnu ulogu u patogenezi bolesti. Studije o rijetkim naslijeĊenim oblicima PB ukazale su na smanjenu razgradnju aSyn putem autofagno-lizosomalnog puta (ALP) kao jednog od ključnih mehanizama u podlozi PB. Kako bismo karakterizirali pretpostavljene genetske mehanizme koji dovode do disfunkcije ALP-a u PB, proveli smo opsežnu analizu genetskih varijanti korištenjem ciljanog panela za sekvenciranje pod nazivom LYSOGENE. LYSOGENE panel sadrţži sveobuhvatni skup od 440 ALP srodnih gena, kao i gene prethodno opisane u familijarnim oblicima PB, sinukleinopatijama i drugim neurodegenerativnim bolestima. Identificirali smo značajan broj varijanti ALP gena među PB pacijentima u usporedbi s kontrolnim ispitanicima, s 396 varijanti prisutnih isključivo u PB bolesnika. Ove varijante uključene su u više od 50 bioloških procesa, ponajprije u putovima organizacije lizosoma, transporta organskih tvari, abnormalne mijelinizacije i metabolizma sfingolipida. Suprotno tome, varijante koje su pronađene isključivo u zdravih ispitanika nisu bile povezane sa specifičnim biološkim putovima. Na temelju podataka sekvenciranja, odabrali smo ARSD, GALC i LRBA gene s najviše zastupljenim genetskim varijantama kod pacijenata s PB i istražili njihove učinke na lizosomalno oštećenje, akumulaciju aSyn i neurotoksičnost primjenom SH-SY5Y staničnih linija koje stabilno eksprimiraju ljudski aSyn. Rezultati su uspoređeni s učincima utišavanja ATP13A2 gena za kojeg je opisano da dovodi do nakupljanja aSyn. Naši rezultati snažno upućuju na to da specifične varijante ALP gena mogu doprinijeti lizosomalnoj disfunkciji u PB. Ovim istraživanjem je po prvi puta opisana povezanost utišavanja ARSD i LRBA gena s nakupljanjem aSyn proteina te potvrđena povezanost utišavanja GALC gena s PB. Ovo istraživanje je potvrdilo vezu između lizosomalnog oštećenja i akumulacije aSyn.Accumulation of misfolded proteins in the brain is the main pathological hallmark of neurodegenerative diseases, including Parkinson’s disease (PD), suggesting that inadequate clearance of aggregation-prone proteins plays an important role in the disease pathogenesis. Studies on the rare inherited forms of PD have highlighted disturbed alpha-synuclein clearance through the autophagy-lysosomal pathway (ALP) as a key mechanism leading to PD. In order to characterize the putative underlying genetic mechanisms leading to ALP dysfunction in PD, we performed comprehensive analysis of genetic variants in ALP genes in PD patients using the custom LYSOGENE targeted next-generation sequencing panel, containing a set of 440 ALP related genes, as well as genes previously implicated in familial forms of PD. We identified a significant number of ALP gene variants among PD patients when compared to control subjects. These variants were involved in over 50 biological processes, with the greatest enrichment observed in categories of lysosome organization, organic substance transport, abnormal myelination and sphingolipid metabolism. In contrast, variants found exclusively in healthy subjects were not related to specific biological pathways.
Based on the NGS data, we selected genes ARSD, GALC and LRBA with the most over-represented genetic variants in PD patients and investigated their effects on lysosomal impairment, alpha-synuclein accumulation and neurotoxicity using SH-SY5Y cell lines stably expressing human alpha-synuclein. The results were compared to the effects of the knock-down of a known lysosome-related gene, ATP13A2, which causes a rare autosomal recessive form of juvenile-onset atypical PD (PARK9). Our knock-down experiments described for the first time the association between ARSD and LRBA genes with the accumulation of aSyn and confirmed the association between GALC gene and PD. This study confirmed a link between lysosomal dysfunction and alpha-synuclein accumulation
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