| 1. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 6. |
- Wiessner, M., et al.
(author)
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Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
- 2021
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:5, s. 1422-1434
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Journal article (peer-reviewed)abstract
- Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays. © 2021 The Author(s).
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| 7. |
- Callaway, EM, et al.
(author)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Journal article (peer-reviewed)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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| 8. |
- Dramburg, S, et al.
(author)
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EAACI Molecular Allergology User's Guide 2.0
- 2023
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In: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - 1399-3038. ; 3434 Suppl 28, s. e13854-
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Journal article (peer-reviewed)
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| 9. |
- Matricardi, PM, et al.
(author)
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EAACI Molecular Allergology User's Guide
- 2016
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In: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Wiley. - 1399-3038. ; 2727 Suppl 23, s. 1-250
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Journal article (peer-reviewed)
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| 10. |
- Lam, MT, et al.
(author)
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A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function
- 2019
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 216:12, s. 2778-2799
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Journal article (peer-reviewed)abstract
- Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.
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| 14. |
- Schäbitz, A., et al.
(author)
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Spatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases
- 2022
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Abundant heterogeneous immune cells infiltrate lesions in chronic inflammatory diseases and characterization of these cells is needed to distinguish disease-promoting from bystander immune cells. Here, we investigate the landscape of non-communicable inflammatory skin diseases (ncISD) by spatial transcriptomics resulting in a large repository of 62,000 spatially defined human cutaneous transcriptomes from 31 patients. Despite the expected immune cell infiltration, we observe rather low numbers of pathogenic disease promoting cytokine transcripts (IFNG, IL13 and IL17A), i.e. >125 times less compared to the mean expression of all other genes over lesional skin sections. Nevertheless, cytokine expression is limited to lesional skin and presented in a disease-specific pattern. Leveraging a density-based spatial clustering method, we identify specific responder gene signatures in direct proximity of cytokines, and confirm that detected cytokine transcripts initiate amplification cascades of up to thousands of specific responder transcripts forming localized epidermal clusters. Thus, within the abundant and heterogeneous infiltrates of ncISD, only a low number of cytokine transcripts and their translated proteins promote disease by initiating an inflammatory amplification cascade in their local microenvironment.
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| 19. |
- Sitbon, Olivier, et al.
(author)
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Selexipag for the Treatment of Pulmonary Arterial Hypertension
- 2015
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 373:26
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Journal article (peer-reviewed)abstract
- BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).
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| 20. |
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| 21. |
- Damineli, Augusto, et al.
(author)
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The Long-term Spectral Changes of Eta Carinae : Are they Caused by a Dissipating Occulter as Indicated by CMFGEN Models?
- 2023
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In: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 954
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Journal article (peer-reviewed)abstract
- Eta Carinae (η Car) exhibits a unique set of P Cygni profiles with both broad and narrow components. Over many decades, the spectrum has changed-there has been an increase in observed continuum fluxes and a decrease in Fe II and H I emission-line equivalent widths. The spectrum is evolving toward that of a P Cygni star such as P Cygni itself and HDE 316285. The spectral evolution has been attributed to intrinsic variations such as a decrease in the mass-loss rate of the primary star or differential evolution in a latitudinal-dependent stellar wind. However, intrinsic wind changes conflict with three observational results: the steady long-term bolometric luminosity; the repeating X-ray light curve over the binary period; and the constancy of the dust-scattered spectrum from the Homunculus. We extend previous work that showed a secular strengthening of P Cygni absorptions by adding more orbital cycles to overcome temporary instabilities and by examining more atomic transitions. CMFGEN modeling of the primary wind shows that a time-decreasing mass-loss rate is not the best explanation for the observations. However, models with a small dissipating absorber in our line of sight can explain both the increase in brightness and changes in the emission and P Cygni absorption profiles. If the spectral evolution is caused by the dissipating circumstellar medium, and not by intrinsic changes in the binary, the dynamical timescale to recover from the Great Eruption is much less than a century, different from previous suggestions.
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| 25. |
- Donati, Mauro, 1966, et al.
(author)
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Marginal Bone Preservation in Single-Tooth Replacement: A 5-Year Prospective Clinical Multicenter Study
- 2015
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In: Clinical Implant Dentistry and Related Research. - : Wiley. - 1523-0899. ; 17:3, s. 425-434
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Journal article (peer-reviewed)abstract
- BACKGROUND: Few long-term studies are available comparing immediate and conventional loading protocols of implant-supported single-tooth replacement. PURPOSE: The aim of the present randomized controlled clinical trial was to evaluate prospectively the 5-year clinical and radiological outcome of immediate functional loading implants used in single-tooth replacement. MATERIALS AND METHODS: One hundred fifty-one subjects, who required single-tooth rehabilitation in the area from position 15 to 25 and from 35 to 45, were enrolled in eight private clinics in Italy. A randomization protocol was applied to allocate the implants in three treatment groups: one control group and two test groups. In the control group, implant placement was performed according to a conventional drilling procedure, and the implants were submerged for 3 months before abutment connection and loading. Implants allocated in the test group 1 and 2 followed an immediate functional loading protocol. While in test group 1, implant placement was performed according to conventional drilling procedure, in test group 2, a modified implant installation procedure (osteotome technique) was applied. Clinical and radiographic examinations were performed during the 5-year follow-up, and technical and biological complications were registered. RESULTS: Although four implants (three in the test group 2 and one in the test group 1) were lost in the immediate functional loading groups in the first year of follow-up, no further implant loss occurred in any of the treatment groups in the following monitoring period up to 5 years. No significant differences on marginal bone level changes were observed between the treatment groups. About 52% of all implants showed bone gain in the period from 1-year to 5-year follow-up. The percentage of all implants that in the same interval of time showed bone loss was about 28%. Although few technical complications were recorded in the period of time up to 5 years, implants showing biological complication were 5.7%. CONCLUSION: It is suggested that implants installed with a conventional installation technique together with an immediate functional loading protocol may be considered as a valid treatment alternative in a long-term perspective when used in a single-tooth replacement in an esthetic area.
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| 26. |
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| 27. |
- Jarach, CM, et al.
(author)
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Global Prevalence and Incidence of Tinnitus: A Systematic Review and Meta-analysis
- 2022
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In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:9, s. 888-900
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Journal article (peer-reviewed)abstract
- To date, no systematic review has taken a meta-analytic approach to estimating the prevalence and incidence of tinnitus in the general population.ObjectiveTo provide frequency estimates of tinnitus worldwide.Data SourcesAn umbrella review followed by a traditional systematic review was performed by searching PubMed-MEDLINE and Embase from inception through November 19, 2021.Study SelectionResearch data from the general population were selected, and studies based on patients or on subgroups of the population with selected lifestyle habits were excluded. No restrictions were applied according to date, age, sex, and country.Data Extraction and SynthesisRelevant extracted information included type of study, time and location, end point, population characteristics, and tinnitus definition. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline.Main Outcomes and MeasuresPooled prevalence estimates of any tinnitus, severe tinnitus, chronic tinnitus, and diagnosed tinnitus as well as incidence of tinnitus were obtained using random-effects meta-analytic models; heterogeneity between studies was controlled using the χ2 test, and inconsistency was measured using the I2 statistic.ResultsAmong 767 publications, 113 eligible articles published between 1972 and 2021 were identified, and prevalence estimates from 83 articles and incidence estimates from 12 articles were extracted. The pooled prevalence of any tinnitus among adults was 14.4% (95% CI, 12.6%-16.5%) and ranged from 4.1% (95% CI, 3.7%-4.4%) to 37.2% (95% CI, 34.6%-39.9%). Prevalence estimates did not significantly differ by sex (14.1% [95% CI, 11.6%-17.0%] among male individuals; 13.1% [95% CI, 10.5%-16.2%] among female individuals), but increased prevalence was associated with age (9.7% [95% CI, 7.4%-12.5%] among adults aged 18-44 years; 13.7% [95% CI, 11.0%-17.0%] among those aged 45-64 years; and 23.6% [95% CI, 19.4%-28.5%] among those aged ≥65 years; P &lt; .001 among age groups). The pooled prevalence of severe tinnitus was 2.3% (95% CI, 1.7%-3.1%), ranging from 0.5% (95% CI, 0.3%-0.7%) to 12.6% (95% CI, 11.1%-14.1%). The pooled prevalence of chronic tinnitus was 9.8% (95% CI, 4.7%-19.3%) and the pooled prevalence of diagnosed tinnitus was 3.4% (95% CI, 2.1%-5.5%). The pooled incidence rate of any tinnitus was 1164 per 100 000 person-years (95% CI, 479-2828 per 100 000 person-years).Conclusions and RelevanceDespite the substantial heterogeneity among studies, this comprehensive systematic review on the prevalence and incidence of tinnitus suggests that tinnitus affects more than 740 million adults globally and is perceived as a major problem by more than 120 million people, mostly aged 65 years or older. Health policy makers should consider the global burden of tinnitus, and greater effort should be devoted to boost research on tinnitus.
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| 28. |
- Mobasheri, Ali, et al.
(author)
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A White Paper on Collagen Hydrolyzates and Ultrahydrolyzates : Potential Supplements to Support Joint Health in Osteoarthritis?
- 2021
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In: Current Rheumatology Reports. - : Springer Science and Business Media LLC. - 1523-3774 .- 1534-6307. ; 23:11
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Research review (peer-reviewed)abstract
- Purpose of Review: Osteoarthritis (OA) is the most common forms of arthritis in the general population, accounting for more pain and functional disability than any other musculoskeletal disease. There are currently no approved disease modifying drugs for OA. In the absence of effective pharmacotherapy, many patients with OA turn to nutritional supplements and nutraceuticals, including collagen derivatives. Collagen hydrolyzates and ultrahydrolyzates are terms used to describe collagens that have been broken down into small peptides and amino acids in the presence of collagenases and high pressure. Recent Findings: This article reviews the relevant literature and serves as a White Paper on collagen hydrolyzates and ultrahydrolyzates as emerging supplements often advertised to support joint health in OA. Collagen hydrolyzates have demonstrated some evidence of efficacy in a handful of small scale clinical trials, but their ability to treat and reverse advanced joint disease remains highly speculative, as is the case for other nutritional supplements. Summary: The aim of this White Paper is to stimulate research and development of collagen-based supplements for patients with OA and other musculoskeletal diseases at academic and industrial levels. This White Paper does not make any treatment recommendations for OA patients in the clinical context, but simply aims to highlight opportunities for scientific innovation and interdisciplinary collaboration, which are crucial for the development of novel products and nutritional interventions based on the best available and published evidence.
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| 29. |
- Myatra, Sheila Nainan, et al.
(author)
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Awake proning in patients with COVID-19-related hypoxemic acute respiratory failure: A rapid practice guideline
- 2023
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In: Acta Anaesthesiologica Scandinavica. - : WILEY. - 0001-5172 .- 1399-6576. ; 67:5, s. 569-575
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Journal article (peer-reviewed)abstract
- This rapid practice guideline provides evidence-based recommendations for the use of awake proning in adult patients with acute hypoxemic respiratory failure due to COVID-19. The panel included 20 experts from 12 countries, including one patient representative, and used a strict conflict of interest policy for potential financial and intellectual conflicts of interest. Methodological support was provided by the guidelines in intensive care, development, and evaluation (GUIDE) group. Based on an updated systematic review, and the grading of recommendations, assessment, development, and evaluation (GRADE) method we evaluated the certainty of evidence and developed recommendations using the Evidence-to-Decision framework. We conducted an electronic vote, requiring >80% agreement amongst the panel for a recommendation to be adopted. The panel made a strong recommendation for a trial of awake proning in adult patients with COVID-19 related hypoxemic acute respiratory failure who are not invasively ventilated. Awake proning appears to reduce the risk of tracheal intubation, although it may not reduce mortality. The panel judged that most patients would want a trial of awake proning, although this may not be feasible in some patients and some patients may not tolerate it. However, given the high risk of clinical deterioration amongst these patients, awake proning should be conducted in an area where patients can be monitored by staff experienced in rapidly detecting and managing clinical deterioration. This RPG panel recommends a trial of awake prone positioning in patients with acute hypoxemic respiratory failure due to COVID-19.
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| 30. |
- PAGANELLI, R, et al.
(author)
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CD8+ T lymphocytes provide helper activity for IgE synthesis in human immunodeficiency virus-infected patients with hyper-IgE
- 1995
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 181:1, s. 423-428
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Journal article (peer-reviewed)abstract
- Increased levels of serum IgE and eosinophilia have been described in human immunodeficiency virus (HIV) infection, almost exclusively in patients with CD4+ cell count < 200 cells/microliters. IgE production is regulated by CD4+ T helper type 2 (Th-2) lymphocytes, producing interleukin 4 (IL-4) and expressing a ligand for the B cell-specific CD40 molecule (CD40 ligand [L]). A shift to a Th-2-like pattern of cytokine secretion has been postulated to be associated with progression toward acquired immunodeficiency syndrome (AIDS). We studied three AIDS patients with very high levels of IgE and almost complete depletion of CD4+ lymphocytes, suggesting that IgE synthesis could not be driven by CD4+ cells. IgE in vitro synthesis by cells from such patients was, however, inhibited by anti-IL-4. We show that both CD8+ T cell lines and the majority of CD8+ T cells clones derived from these patients produce IL-4, IL-5, and IL-6 in half of the cases together with interferon gamma (IFN-gamma). 44% of CD8+ T cell clones expressed a CD40L, and the supernatants of the clones were capable of inducing IgE synthesis by normal B cells costimulated with anti-CD40. CD8+ T cells in these patients therefore functionally mimic Th-2 type cells and may account for hyper-IgE and eosinophilia in the absence of CD4+ cells. The presence of such CD8+ cells may also provide a source of IL-4 directing the development of predominant Th-2 responses in HIV infection.
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| 31. |
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| 32. |
- Scala, E, et al.
(author)
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Hidradenitis Suppurativa: Where We Are and Where We Are Going
- 2021
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In: Cells. - : MDPI AG. - 2073-4409. ; 10:8
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Journal article (peer-reviewed)abstract
- Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily affecting apocrine gland-rich areas of the body. It is a multifactorial disease in which genetic and environmental factors play a key role. The primary defect in HS pathophysiology involves follicular occlusion of the folliculopilosebaceous unit, followed by follicular rupture and immune responses. Innate pro-inflammatory cytokines (e.g., IL-1β, and TNF-α); mediators of activated T helper (Th)1 and Th17 cells (e.g., IFN-γ, and IL-17); and effector mechanisms of neutrophilic granulocytes, macrophages, and plasma cells are involved. On the other hand, HS lesions contain anti-inflammatory mediators (e.g., IL-10) and show limited activity of Th22 cells. The inflammatory vicious circle finally results in pain, purulence, tissue destruction, and scarring. HS pathogenesis is still enigmatic, and a valid animal model for HS is currently not available. All these aspects represent a challenge for the development of therapeutic approaches, which are urgently needed for this debilitating disease. Available treatments are limited, mostly off-label, and surgical interventions are often required to achieve remission. In this paper, we provide an overview of the current knowledge surrounding HS, including the diagnosis, pathogenesis, treatments, and existing translational studies.
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| 33. |
- Scala, F, et al.
(author)
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Phenotypic variation of transcriptomic cell types in mouse motor cortex
- 2021
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 144-
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Journal article (peer-reviewed)abstract
- Cortical neurons exhibit extreme diversity in gene expression as well as in morphological and electrophysiological properties1,2. Most existing neural taxonomies are based on either transcriptomic3,4 or morpho-electric5,6 criteria, as it has been technically challenging to study both aspects of neuronal diversity in the same set of cells7. Here we used Patch-seq8 to combine patch-clamp recording, biocytin staining, and single-cell RNA sequencing of more than 1,300 neurons in adult mouse primary motor cortex, providing a morpho-electric annotation of almost all transcriptomically defined neural cell types. We found that, although broad families of transcriptomic types (those expressing Vip, Pvalb, Sst and so on) had distinct and essentially non-overlapping morpho-electric phenotypes, individual transcriptomic types within the same family were not well separated in the morpho-electric space. Instead, there was a continuum of variability in morphology and electrophysiology, with neighbouring transcriptomic cell types showing similar morpho-electric features, often without clear boundaries between them. Our results suggest that neuronal types in the neocortex do not always form discrete entities. Instead, neurons form a hierarchy that consists of distinct non-overlapping branches at the level of families, but can form continuous and correlated transcriptomic and morpho-electrical landscapes within families.
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