| 21. |
- Palmer, Elizabeth E., et al.
(författare)
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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:2, s. 668-697
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Tidskriftsartikel (refereegranskat)abstract
- Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
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| 22. |
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| 23. |
- Laharnar, N., et al.
(författare)
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Overnight pulse wave analysis to assess autonomic changes during sleep in insomnia patients and healthy sleepers
- 2020
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Insomnia has been associated with increased cardiovascular (CV) risk, which may be linked to sympathetic activation. Non-invasive overnight pulse wave analysis may be a useful tool to detect early signs of autonomic changes during sleep in insomniacs. Fifty-two participants (26 men, 37±13 years, BMI: 24±5 kg/m2, 26 insomniacs/ 26 controls) underwent overnight polysomnography with pulse oximetry and pulse wave analysis including pulse rate, vascular stiffness (pulse propagation time, PPT), and a composite cardiac risk index based on autonomic function and overnight hypoxia. We identified two subgroups of insomniacs, with and without objectively disturbed sleep (sleep efficiency SE≤80%, n = 14 vs. SE>80%, n = 12), and observed increased pulse rate and vascular stiffness in insomnia cases when diagnosis was based on both, subjective and objective criteria. Both insomnia groups were associated with higher overnight pulse rate than controls (median/ IQR: low-SE (low sleep efficiency): 67/ 58-70bpm; high-SE: 66/ 63-69bpm; controls: 58/ 52-63bpm; p = 0.01). Vascular stiffness was higher (reduction of PPT) in low-SE insomniacs compared with high-SE insomniacs and controls (169/ 147-232ms; 237/ 215-254ms; 244/ 180-284ms; p = 0.01). The cardiac risk index was increased in low-SE insomniacs (0.2/ 0.0–0.7; 0.0/ 0.0–0.4; 0.0/ 0.0–0.3; p = 0.05). Our results suggest a hyperarousal state in young and otherwise healthy insomniacs during sleep. The increased pulse rate and vascular stiffness in insomniacs with low SE suggest early signs of rigid vessels and potentially, an elevated CV risk. Overnight pulse wave analysis may be feasible for CV risk assessment in insomniacs and may provide a useful tool for phenotyping insomnia in order to provide individualized therapy. © 2020 Laharnar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 24. |
- Naeem, Aishath, et al.
(författare)
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Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance
- 2023
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:9, s. 1929-1943
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Tidskriftsartikel (refereegranskat)abstract
- Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor (BCR) signaling, cell viability, and CCL3/CCL4 chemokine production in both BTK wild-type and C481S mutant CLL cells. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, cell survival, and CCL3/CCL4 chemokine secretion. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability, and cytokine production. We employed longitudinal whole-exome sequencing on 2 patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to noncovalent BTKis.
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| 25. |
- Bott, Lukas Thomas, et al.
(författare)
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Coulomb dissociation of O-16 into He-4 and C-12
- 2023
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Ingår i: NUCLEAR PHYSICS IN ASTROPHYSICS - X, NPA-X 2022. - : EDP Sciences. - 2100-014X. ; 279
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Konferensbidrag (refereegranskat)abstract
- We measured the Coulomb dissociation of O-16 into He-4 and C-12 within the FAIR Phase-0 program at GSI Helmholtzzentrum fur Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section O-16(alpha,gamma)C-12, which is the time reversed reaction to C-12(alpha,gamma)O-16. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the (RB)-B-3 setup were necessary to cope with the high-intensity O-16 beam. All tracking detectors were designed to let the unreacted O-16 ions pass, while detecting the C-12 and He-4.
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| 26. |
- Jacobs, Susan S., et al.
(författare)
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Home oxygen therapy for adults with chronic lung disease an official american thoracic society clinical practice guideline
- 2020
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X. ; 202:10, s. 121-141
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence-based guidelines are needed for effective delivery of home oxygen therapy to appropriate patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Methods: The multidisciplinary panel created six research questions using a modified Delphi approach. A systematic review of the literature was completed, and the Grading of Recommendations Assessment, Development and Evaluation approach was used to formulate clinical recommendations. Recommendations: The panel found varying quality and availability of evidence and made the following judgments: 1) strong recommendations for long-term oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe chronic resting hypoxemia, 2) a conditional recommendation against long-term oxygen use in patients with COPD with moderate chronic resting hypoxemia, 3) conditional recommendations for ambulatory oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe exertional hypoxemia, 4) a conditional recommendation for ambulatory liquidoxygen use in patients who are mobile outside the home and require .3 L/min of continuous-flow oxygen during exertion (very-lowquality evidence), and 5) a recommendation that patients and their caregivers receive education on oxygen equipment and safety (bestpractice statement). Conclusions: These guidelines provide the basis for evidence-based use of home oxygen therapy in adults with COPD or ILD but also highlight the need for additional research to guide clinical practice.
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