| 1. |
- De Luca, Francesca, et al.
(författare)
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Elective one-minute full brain multi-contrast MRI versus brain CT in pediatric patients : a prospective feasibility study
- 2024
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Ingår i: BMC Medical Imaging. - 1471-2342. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Brain CT can be used to evaluate pediatric patients with suspicion of cerebral pathology when anesthetic and MRI resources are scarce. This study aimed to assess if pediatric patients referred for an elective brain CT could endure a diagnostic fast brain MRI without general anesthesia using a one-minute multi-contrast EPI-based sequence (EPIMix) with comparable diagnostic performance. Methods: Pediatric patients referred for an elective brain CT between March 2019 and March 2020 were prospectively included and underwent EPIMix without general anesthesia in addition to CT. Three readers (R1–3) independently evaluated EPIMix and CT images on two separate occasions. The two main study outcomes were the tolerance to undergo an EPIMix scan without general anesthesia and its performance to classify a scan as normal or abnormal. Secondary outcomes were assessment of disease category, incidental findings, diagnostic image quality, diagnostic confidence, and image artifacts. Further, a side-by-side evaluation of EPIMix and CT was performed. The signal-to-noise ratio (SNR) was calculated for EPIMix on T1-weighted, T2-weighted, and ADC images. Descriptive statistics, Fisher’s exact test, and Chi-squared test were used to compare the two imaging modalities. Results: EPIMix was well tolerated by all included patients (n = 15) aged 5–16 (mean 11, SD 3) years old. Thirteen cases on EPIMix and twelve cases on CT were classified as normal by all readers (R1–3), while two cases on EPIMix and three cases on CT were classified as abnormal by one reader (R1), (R1–3, p = 1.00). There was no evidence of a difference in diagnostic confidence, image quality, or the presence of motion artifacts between EPIMix and CT (R1–3, p ≥ 0.10). Side-by-side evaluation (R2 + R4 + R5) reviewed all scans as lacking significant pathological findings on EPIMix and CT images. Conclusions: Full brain MRI-based EPIMix sequence was well tolerated without general anesthesia with a diagnostic performance comparable to CT in elective pediatric patients. Trial registration: This study was approved by the Swedish Ethical Review Authority (ethical approval number/ID Ethical approval 2017/2424-31/1). This study was a clinical trial study, with study protocol published at ClinicalTrials.gov with Trial registration number NCT03847051, date of registration 18/02/2019.
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| 2. |
- Eidhof, Ilse, et al.
(författare)
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Unraveling the brain's response to COVID-19 : How SARS-CoV-2 afflicts dopaminergic neurons
- 2024
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Ingår i: Cell Stem Cell. - 1934-5909 .- 1875-9777. ; 31:2, s. 152-154
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 patients often display dysfunctions of the nervous system, indicating an effect of SARS-CoV-2 on neural cells. Yang et al. now show that human stem-cell-derived dopaminergic neurons are susceptible to SARS-CoV-2, triggering inflammation and senescence. The study further identifies three FDA-approved drugs capable of reversing these cellular phenotypes.
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| 3. |
- Jain, Saumey, et al.
(författare)
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On-Chip Neural Induction Boosts Neural Stem Cell Commitment : Toward a Pipeline for iPSC-Based Therapies
- 2024
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Ingår i: Advanced science (Weinheim, Baden-Wurttemberg, Germany). - : Wiley-VCH Verlagsgesellschaft. - 2198-3844.
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Tidskriftsartikel (refereegranskat)abstract
- The clinical translation of induced pluripotent stem cells (iPSCs) holds great potential for personalized therapeutics. However, one of the main obstacles is that the current workflow to generate iPSCs is expensive, time-consuming, and requires standardization. A simplified and cost-effective microfluidic approach is presented for reprogramming fibroblasts into iPSCs and their subsequent differentiation into neural stem cells (NSCs). This method exploits microphysiological technology, providing a 100-fold reduction in reagents for reprogramming and a ninefold reduction in number of input cells. The iPSCs generated from microfluidic reprogramming of fibroblasts show upregulation of pluripotency markers and downregulation of fibroblast markers, on par with those reprogrammed in standard well-conditions. The NSCs differentiated in microfluidic chips show upregulation of neuroectodermal markers (ZIC1, PAX6, SOX1), highlighting their propensity for nervous system development. Cells obtained on conventional well plates and microfluidic chips are compared for reprogramming and neural induction by bulk RNA sequencing. Pathway enrichment analysis of NSCs from chip showed neural stem cell development enrichment and boosted commitment to neural stem cell lineage in initial phases of neural induction, attributed to a confined environment in a microfluidic chip. This method provides a cost-effective pipeline to reprogram and differentiate iPSCs for therapeutics compliant with current good manufacturing practices.
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| 4. |
- Arora, Abishek, et al.
(författare)
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Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Research continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine hydrochloride and zinc deficiency) and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after 5-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. Moreover, fluoxetine exposure elevated several fatty acids when validated using mass spectrometry-based metabolomics. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.
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| 5. |
- Falk, Anna
(författare)
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Depression and delirium in cardiac surgery patients
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Depression is common in persons with cardiac disease, and there is a well-known association between depression and increased cardiovascular morbidity and mortality. Preoperative depression has been associated with postoperative delirium (POD) after general surgery but the association between depression and POD in persons undergoing cardiac surgery is sparsely studied. Postoperative delirium affects a large proportion of patients undergoing cardiac surgery. Delirium phenotypes are commonly divided into hyper- and hypoactive, where hypoactive symptoms (reduced motor activity and withdrawal) often are overlooked due to their discreet character. To our knowledge, there are no studies describing patients’ experiences of hypoactive delirium after cardiac surgery. Although the association between depression and mortality after coronary artery bypass grafting has been confirmed, the association between preoperative depression and long-term survival after cardiac surgery is sparsely studied. The overall aim of this thesis was to contribute to the understanding of the association between depression and delirium, as well as depression and mortality in patients undergoing cardiac surgery. Study I was a systematic literature review and meta-analysis including cohort studies reporting odds ratios (ORs) and 95% confidence intervals (CIs) for POD after cardiac surgery in patients with preoperative depression compared to patients without depression. ORs and 95% CIs for POD were calculated using random-effects models. Seven studies were included with a combined study population of 2066 patients. The pooled prevalence of POD was 26% and preoperative depression was present in 9% of the total study population. All studies showed a positive association between preoperative depression and POD. Patients with depression had a pooled OR of 2.31 (95% CI 1.37–3.90) for POD. Study II was a population-based cohort study including 1120 persons undergoing cardiac surgery from 2013–2016. Preoperative depression was defined by the Patient Health Questionnaire-9, and baseline characteristics were contained in the Swedish Cardiac Surgery Registry. POD was evaluated by assessing medical records. The association between preoperative depression and POD was determined through multivariable logistic regression analysis. A total of 162 patients (14,5%) reported depressive symptoms preoperatively. The incidence of POD was 26%. The overall adjusted odds of delirium were 2.19 times higher in patients with depressive symptoms compared to controls (95% CI 1.43–3.34). Study III was a qualitative descriptive semi-structured interview study aiming to describe cardiac surgery patients' experiences of hypoactive delirium. Twelve cardiac surgery patients with hypoactive symptoms of delirium were purposefully selected. The data were analyzed by qualitative content analysis with an inductive, latent approach. Two themes based on eight sub-themes emerged: “Dream or reality in parallel worlds” included disturbing experiences of existing in parallel realities with cognitive effects, residual nightmares, and illusions that occasionally persisted after hospital discharge. “Managing the state of hypoactive delirium” included experiences of intellectually dealing with hypoactive delirium with assumptions of causes and cures, and through interactions like communicating with others. The delirium experienced by the participants was considerably more extensive than what had been documented in their medical journals, an indication that hypoactive delirium is overlooked. Study IV was a population-based cohort study investigating the same study cohort as in Study II. The vital status at end of the study was collected from the Swedish Cardiac Surgery Registry on December 15, 2022. During a mean follow-up of 7.2 years (maximum 9.2 years), there were 36 deaths in 1129 person-years (PYs) in the depressed group, compared to 160 deaths in 6889 PYs in the non-depressed group. In the adjusted analysis, self-reported depressive symptoms were associated with worse long-term survival (HR=1.66; 95% CI, 1.09-2.54) compared with no reported depressive symptoms. The absolute survival differences (% and 95% CI) between the non-depressed and the depressed patients were -1.9 (-3.9–0.19), -5.7 (-11– -0.01), and -9.7 (-19– -0.4) after one, five, and eight years, respectively. In conclusion, depression is a significant, independent risk factor for POD and worse longterm survival after cardiac surgery. Depression screening is important to identify patients at risk, and delirium assessment tools should be used to detect all kinds of POD.
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| 6. |
- Mastropasqua, Francesca, et al.
(författare)
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Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.
- 2023
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Ingår i: Biology open. - : The Company of Biologists. - 2046-6390. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level HNRNPU downregulation leads to an increased fraction of neural progenitors in the maturing neuronal population. We conclude that the HNRNPU locus is involved in delayed commitment of neural progenitors to differentiate in cell types with hindbrain profile.
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| 7. |
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| 8. |
- Drouin-Ouellet, Janelle, et al.
(författare)
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Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease
- 2022
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:10, s. 2203-2219
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Tidskriftsartikel (refereegranskat)abstract
- We have developed an efficient approach to generate functional induced dopaminergic (DA) neurons from adult human dermal fibroblasts. When performing DA neuronal conversion of patient fibroblasts with idiopathic Parkinson's disease (PD), we could specifically detect disease-relevant pathology in these cells. We show that the patient-derived neurons maintain age-related properties of the donor and exhibit lower basal chaperone-mediated autophagy compared with healthy donors. Furthermore, stress-induced autophagy resulted in an age-dependent accumulation of macroautophagic structures. Finally, we show that these impairments in patient-derived DA neurons leads to an accumulation of phosphorylated alpha-synuclein, the classical hallmark of PD pathology. This pathological phenotype is absent in neurons generated from induced pluripotent stem cells from the same patients. Taken together, our results show that direct neural reprogramming can be used for obtaining patient-derived DA neurons, which uniquely function as a cellular model to study age-related pathology relevant to idiopathic PD.
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| 9. |
- Eisfeldt, Jesper, et al.
(författare)
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Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:16
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Tidskriftsartikel (refereegranskat)abstract
- Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient's cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient's cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.
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| 10. |
- Schuy, Jakob, et al.
(författare)
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Partial Monosomy 21 Mirrors Gene Expression of Trisomy 21 in a Patient-Derived Neuroepithelial Stem Cell Model
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Induced pluripotent stem cells (iPSCs) from patients are an attractive disease model to study tissues with poor accessibility such as the brain. Using this approach, we and others have shown that trisomy 21 results in genome-wide transcriptional dysregulations. The effects of loss of genes on chromosome 21 is much less characterized. Here, we use patient-derived neural cells from an individual with neurodevelopmental delay and a ring chromosome 21 with two deletions spanning 3.8 Mb at the terminal end of 21q22.3, containing 60 protein-coding genes. To investigate the molecular perturbations of the partial monosomy on neural cells, we established patient-derived iPSCs from fibroblasts retaining the ring chromosome 21, and we then induced iPSCs into neuroepithelial stem cells. RNA-Seq analysis of NESCs with the ring chromosome revealed downregulation of 18 genes within the deleted region together with global transcriptomic dysregulations when compared to euploid NESCs. Since the deletions on chromosome 21 represent a genetic “contrary” to trisomy of the corresponding region, we further compared the dysregulated transcriptomic profile in with that of two NESC lines with trisomy 21. The analysis revealed opposed expression changes for 23 genes on chromosome 21 as well as 149 non-chromosome 21 genes. Taken together, our results bring insights into the effects on the global and chromosome 21 specific gene expression from a partial monosomy of chromosome 21qter during early neuronal differentiation.
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