| 1. |
- Chelban, V., et al.
(författare)
-
PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation
- 2019
-
Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 86:2, s. 225-240
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240. © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
|
|
| 2. |
- Blondelle, J., et al.
(författare)
-
Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism
- 2019
-
Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2:178
-
Tidskriftsartikel (refereegranskat)abstract
- Biological roles of obscurin and its close homolog Obsl1 (obscurin-like 1) have been enigmatic. While obscurin is highly expressed in striated muscles, Obsl1 is found ubiquitously. Accordingly, obscurin mutations have been linked to myopathies, whereas mutations in Obsl1 result in 3M-growth syndrome. To further study unique and redundant functions of these closely related proteins, we generated and characterized Obsl1 knockouts. Global Obsl1 knockouts are embryonically lethal. In contrast, skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts. Only deletion of both proteins and removal of their functional redundancy revealed their roles for sarcolemmal stability and sarcoplasmic reticulum organization. To gain unbiased insights into changes to the muscle proteome, we analyzed tibialis anterior and soleus muscles by mass spectrometry, uncovering additional changes to the muscle metabolism. Our analyses suggest that all obscurin protein family members play functions for muscle membrane systems.
|
|
| 3. |
|
|
| 4. |
- Farr, W. J., et al.
(författare)
-
Current issues and challenges in research on virtual reality therapy for children with neurodisability
- 2016
-
Ingår i: Proceedings of the 11th International Conference in Disability, Virtual Reality and Associated Technologies, Los Angeles, California, USA, 20-22 September, 2016. - 9780704915473
-
Konferensbidrag (refereegranskat)abstract
- A PICO (population, intervention, comparison, outcome) approach is adopted to discuss issues and challenges in virtual reality therapy research in community health settings. Widespread variation within and between populations, e.g. co-morbid conditions, complicates treatment fidelity and applicability. Interventions require flexible dose and frequency to fit into children’s family circumstances, with clearly employed specialist paediatric research staff. Comparisons require adaptation to digital technology, and keep pace with development. Outcomes may overstate the impact of virtual reality therapy and technological novelty, while not fully unpacking hidden digital effects. A wide set of agreed, flexible, and patient-centred outcome measures are required to establish positive clinical baseline.
|
|
| 5. |
- Farr, W., et al.
(författare)
-
Therapeutic potential and ownership of commercially available consoles in children with cerebral palsy
- 2017
-
Ingår i: British Journal of Occupational Therapy. - : Sage Publications. - 0308-0226 .- 1477-6006. ; 80:2, s. 108-116
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction:We conducted a survey amongst families of children with cerebral palsy to ascertain the ownership and therapeutic use and potential of commercial games consoles to improve motor function.Method:Three hundred families in South East England were identified through clinical records, and were requested to complete an anonymised questionnaire.Results: A total of 61 families (20% response) returned a completed questionnaire with 41 (68%) identified males and 19 (32%) identified females with cerebral palsy, with a mean age of 11 years 5 months (SD 3Y 7M). The large majority of families, 59 (97%), owned a commercial console and the child used this for 50-300 minutes a week. Returns by severity of motor impairment were: Gross Motor Function Classification System I (22%), II (32%), III (13%), IV (15%), V (18%). Consoles were used regularly for play across all Gross Motor Function Classification System categories.Conclusion: The potential of games consoles, as home-based virtual reality therapy, in improving the motor function of children with cerebral palsy should be appropriately tested in a randomised controlled trial. Wide ownership, and the relative ease with which children engage in the use of commercially-based virtual reality therapy systems, suggests potential as a means of augmenting therapy protocols, taking advantage of interest and participation patterns of families.
|
|
| 6. |
- Limpert, S., et al.
(författare)
-
Reversible electron-hole separation in a hot carrier solar cell
- 2015
-
Ingår i: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- Hot-carrier solar cells are envisioned to utilize energy filtering to extract power from photogenerated electron-hole pairs before they thermalize with the lattice, and thus potentially offer higher power conversion efficiency compared to conventional, single absorber solar cells. The efficiency of hot-carrier solar cells can be expected to strongly depend on the details of the energy filtering process, a relationship which to date has not been satisfactorily explored. Here, we establish the conditions under which electron-hole separation in hot-carrier solar cells can occur reversibly, that is, at maximum energy conversion efficiency. We thus focus our analysis on the internal operation of the hot-carrier solar cell itself, and in this work do not consider the photon-mediated coupling to the Sun. After deriving an expression for the voltage of a hot-carrier solar cell valid under conditions of both reversible and irreversible electrical operation, we identify separate contributions to the voltage from the thermoelectric effect and the photovoltaic effect. We find that, under specific conditions, the energy conversion efficiency of a hot-carrier solar cell can exceed the Carnot limit set by the intradevice temperature gradient alone, due to the additional contribution of the quasi-Fermi level splitting in the absorber. We also establish that the open-circuit voltage of a hot-carrier solar cell is not limited by the band gap of the absorber, due to the additional thermoelectric contribution to the voltage. Additionally, we find that a hot-carrier solar cell can be operated in reverse as a thermally driven solid-state light emitter. Our results help explore the fundamental limitations of hot-carrier solar cells, and provide a first step towards providing experimentalists with a guide to the optimal configuration of devices.
|
|
| 7. |
- Briel, J W, et al.
(författare)
-
Prevalence and risk factors for ischemia, leak, and stricture of esophageal anastomosis: Gastric pull-up versus colon interposition
- 2004
-
Ingår i: Journal of the American College of Surgeons. - : Ovid Technologies (Wolters Kluwer Health). - 1879-1190 .- 1072-7515. ; 198:4, s. 536-541
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Reports of esophageal anastomotic complications often involve more gastric than colonic reconstructions and are incomplete because of fragmented followup by physicians unfamiliar with the surgical procedure. STUDY DESIGN: Three hundred ninety-three consecutive esophagectomy patients had prevalence and risk factors determined for graft ischemia and anastomotic leak; 363 of these patients followed for more than I month (median 15 months) had prevalence and risk factors determined for anastomotic stricture. RESULTS: Conduit ischemia occurred in 36 (9.2%) and anastomotic leak in 43 patients (10.9%). Risk factor for ischemia was comorbid conditions requiring therapy (Odds ratio [OR]: 2.2 [95% CI 1.1-4.3]), and for leak were ischemia (OR: 5.5 [95% CI 2.5-12. 1]), neoadjuvant therapy (OR: 2.2 [95% CI 1.1-4-5]), and comorbid conditions (OR: 2.1 [95% Cl 1.1-3.9]). A stricture developed in 80 patients (22.0%). Risk factors were ischemia (OR: 4.4 [95% Cl 2.0-9.6]), anastomotic leak (OR: 3.8 [95% C11.9-7.6]), and increasing preoperative weight (p = 0.022). The prevalence of ischemia was similar after gastric (10.4%) versus colonic (7.4%) reconstruction; leak and stricture were more common (14.3% versus 6.1%, p = 0.013, 31.3% versus 8.7%, p < 0.000 1, respectively) and strictures were more severe (11.2% versus 2%, p = 0.00 1) after gastric pull-up. Patients free of ischemia and leak who developed stricture were more likely to have had a gastric pull-up (25% versus 7%, p < 0. 000 1). Dilatation was effective treatment in 93% of patients. CONCLUSIONS: After esophagectomy 10% of patients will develop conduit ischemia or an anastomotic leak and 22% will develop anastornotic stricture. Anastomotic leak and strictures are more common and the strictures are more severe after gastric pull-up compared with colon interposition. Dilatation is a safe and effective treatment.
|
|
| 8. |
- Shribman, Samuel, et al.
(författare)
-
Plasma Neurofilament Light as a Biomarker of Neurological Involvement in Wilson's Disease.
- 2021
-
Ingår i: Movement disorders : official journal of the Movement Disorder Society. - : Wiley. - 1531-8257. ; 36:2, s. 503-508
-
Tidskriftsartikel (refereegranskat)abstract
- Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end-organ damage.To identify a biomarker for neurological involvement in WD.Neuronal and glial-specific proteins were measured in plasma samples from 40 patients and 38 age-matched controls. Patients were divided into neurological or hepatic presentations and those with recent neurological presentations or deterioration associated with non-adherence were subcategorized as having active neurological disease. Unified WD Rating Scale scores and copper indices were recorded.Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients.NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments. © 2020 University College London. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
|
|
