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- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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- van Kuilenburg, Andre B. P., et al.
(författare)
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Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 380:15, s. 1433-1441
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Tidskriftsartikel (refereegranskat)abstract
- We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5′ untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.
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| 7. |
- Geraghty, S, et al.
(författare)
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Practice patterns in haemophilia A therapy - global progress towards optimal care
- 2006
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 12:1, s. 75-81
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Tidskriftsartikel (refereegranskat)abstract
- This paper reports the findings of a global survey of practice patterns for the management of patients with haemophilia A. A total of 147 haemophilia treatment centres worldwide responded to the questionnaire, supplying data for 16 115 patients with haemophilia A. From these responses, 38% (range: 25-48%) of patients were under 18 years old. Almost half (47%) of patients were reported to have mild or moderate haemophilia A, 48% had severe haemophilia A (no inhibitor) and 5% were inhibitor patients. Less than half of patients with severe haemophilia A received prophylactic therapy (37%, excluding inhibitor patients) and 54% received on-demand treatment; the remaining 9% were inhibitor patients. Primary prophylaxis rates for severe haemophilia ranged from 73% in Sweden to 17% in the USA. Most respondents (80%) ranked infrequent bleeds as one of the top five reasons for not administering prophylactic treatment, followed by venous access (60%) and cost (45%). Of patients with severe haemophilia (non-inhibitor), 32% on primary prophylaxis and 27% on secondary prophylaxis had indwelling catheters. Risk of infection and the patient's inability to maintain the line were the key concerns cited by nurses relating to venous access. The mean ratio of nurses to patients with haemophilia A was 1:69 and nurses felt that they were either fully (26%) or mostly (45%) autonomous in assessment and treatment decisions. Results from this current survey suggest that worldwide research should be continued so as to improve outcomes through the identification of optimal treatment protocols for the management of haemophilia A.
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| 8. |
- Lanigan, Fiona, et al.
(författare)
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Delineating Transcriptional Networks of Prognostic Gene Signatures Refines Treatment Recommendations for Lymph Node-negative Breast Cancer Patients.
- 2015
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X. ; 282:18, s. 3455-3473
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Tidskriftsartikel (refereegranskat)abstract
- The majority of women diagnosed with lymph node-negative breast cancer are unnecessarily treated with damaging chemotherapeutics following surgical resection. This highlights the importance of understanding and more accurately predicting patient prognosis. Here, we define the transcriptional networks regulating well-established prognostic gene expression signatures. We find that the same set of transcriptional regulators consistently lie upstream of both 'prognosis' and 'proliferation' gene signatures, suggesting that a central transcriptional network underpins a shared phenotype within these signatures. Strikingly, the master transcriptional regulators within this network predict recurrence risk for lymph node-negative breast cancer better than currently used multi-gene prognostic assays, particularly in lymph node-negative, estrogen receptor-positive patients. Simultaneous examination of p16(INK) (4A ) expression, which predicts tumors that have bypassed cellular senescence, revealed that intermediate levels of p16(INK) (4A) correlate with an intact pRB pathway and improved survival. A combination of these master transcriptional regulators and p16(INK) (4A) , termed the OncoMasTR score, stratifies tumours based on their proliferative and senescence capacity, facilitating a clearer delineation of lymph node-negative breast cancer patients at high risk of recurrence, and thus requiring chemotherapy. Furthermore, OncoMasTR accurately classifies over 60% of patients as 'low risk', an improvement on existing prognostic assays, which has the potential to reduce overtreatment in early-stage patients. Taken together, this study provides new insights into the transcriptional regulation of cellular proliferation in breast cancer and provides an opportunity to enhance and streamline breast cancer prognosis. This article is protected by copyright. All rights reserved.
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- Geraghty, Keith J, et al.
(författare)
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Cognitive behavioural therapy in the treatment of chronic fatigue syndrome : A narrative review on efficacy and informed consent
- 2018
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Ingår i: Journal of Health Psychology. - : Sage Publications. - 1359-1053 .- 1461-7277. ; 23:1, s. 127-138
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive behavioural therapy is increasingly promoted as a treatment for chronic fatigue syndrome. There is limited research on informed consent using cognitive behavioural therapy in chronic fatigue syndrome. We undertook a narrative review to explore efficacy and to identify the salient information that should be disclosed to patients. We found a complex theoretical model underlying the rationale for psychotherapy in chronic fatigue syndrome. Cognitive behavioural therapy may bring about changes in self-reported fatigue for some patients in the short term, however there is a lack of evidence for long-term benefit or for improving physical function and cognitive behavioural therapy may cause distress if inappropriately prescribed. Therapist effects and placebo effects are important outcome factors.
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| 11. |
- Geraghty, Keith J, et al.
(författare)
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Myalgic encephalomyelitis/chronic fatigue syndrome and the biopsychosocial model : a review of patient harm and distress in the medical encounter
- 2019
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Ingår i: Disability and Rehabilitation. - : Taylor & Francis Group. - 0963-8288 .- 1464-5165. ; 41:25, s. 3092-3102
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Forskningsöversikt (refereegranskat)abstract
- Objective: Despite the growing evidence of physiological and cellular abnormalities in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), there has been a strong impetus to tackle the illness utilizing a biopsychosocial model. However, many sufferers of this disabling condition report distress and dissatisfaction following medical encounters. This review seeks to account for this discord.Methods: A narrative review methodology is employed to synthesize the evidence for potential iatrogenesis.Results: We identify seven potential modalities of iatrogenesis or harm reported by patients:1. difficulties in reaching an acceptable diagnosis;2. misdiagnosis, including of other medical and psychological conditions;3. difficulties in accessing the sick role, medical care and social support;4. high levels of patient dissatisfaction with the quality of medical care;5. negative responses to controversial therapies (cognitive behavioral therapy and graded exercise therapy);6. challenges to the patient narrative and experience;7. psychological harm (individual and collective distress).Conclusion: The biopsychosocial framework currently applied to ME/CFS is too narrow in focus and fails to adequately incorporate the patient narrative. Misdiagnosis, conflict, and harm are observable outcomes where doctors' and patients' perspectives remain incongruent. Biopsychosocial practices should be scrutinized for potential harms. Clinicians should consider adopting alternative patient-centred approaches.
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| 12. |
- Hunt, Joanne, et al.
(författare)
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Long Covid at the crossroads : Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
- 2022
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Ingår i: Journal of Health Psychology. - : Sage Publications. - 1359-1053 .- 1461-7277. ; 27:14, s. 3106-3120
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Tidskriftsartikel (refereegranskat)abstract
- Whilst parallels have been drawn between Long Covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), there is a well-documented history of negative stereotyping and marginalisation of patients with ME/CFS. A socio-politically oriented comparison of scientific, clinical and societal responses to Long Covid and ME/CFS is thus important to prevent similar harms arising among Long Covid patients. We identify four reasons for injustices in the treatment of ME/CFS patients, and discuss the risk of Long Covid following a similar trajectory. We conclude with policy and practice recommendations to help prevent such injustices arising again, including consideration of critical reflexivity in medical education.
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| 13. |
- Johnstone, Devon L., et al.
(författare)
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Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ : Report of seven new subjects and review of the literature
- 2020
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 43:6, s. 1321-1332
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Tidskriftsartikel (refereegranskat)abstract
- We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.
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| 14. |
- Olsson, Mats, 1960, et al.
(författare)
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Telomere length varies substantially between blood cell types in a reptile
- 2020
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Ingår i: Royal Society Open Science. - : The Royal Society. - 2054-5703. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Telomeres are repeat sequences of non-coding DNA-protein molecules that cap or intersperse metazoan chromosomes. Interest in telomeres has increased exponentially in recent years, to now include their ongoing dynamics and evolution within natural populations where individuals vary in telomere attributes. Phylogenetic analyses show profound differences in telomere length across non-model taxa. However, telomeres may also differ in length within individuals and between tissues. The latter becomes a potential source of error when researchers use different tissues for extracting DNA for telomere analysis and scientific inference. A commonly used tissue type for assessing telomere length is blood, a tissue that itself varies in terms of nuclear content among taxa, in particular to what degree their thrombocytes and red blood cells (RBCs) contain nuclei or not. Specifically, when RBCs lack nuclei, leucocytes become the main source of telomeric DNA. RBCs and leucocytes differ in lifespan and how long they have been exposed to 'senescence' and erosion effects. We report on a study in which cells in whole blood from individual Australian painted dragon lizards (Ctenophorus pictus) were identified using flow cytometry and their telomere length simultaneously measured. Lymphocyte telomeres were on average 270% longer than RBC telomeres, and in azurophils (a reptilian monocyte), telomeres were more than 388% longer than those in RBCs. If this variation in telomere length among different blood cell types is a widespread phenomenon, and DNA for comparative telomere analyses are sourced from whole blood, evolutionary inference of telomere traits among taxa may be seriously complicated by the blood cell type comprising the main source of DNA.
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