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WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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BACKGROUND AND AIMS: Tumour rupture (TR) signifies stage III disease and requires treatment intensification, which includes radiotherapy. We studied the associations between radiological, surgical and pathology TR in children with Wilms tumour (WT) in a United Kingdom multicentre clinical study. PATIENTS AND METHODS: The IMPORT (Improving Population Outcomes for Renal Tumours of Childhood) study registered 712 patients between 2012 and 2021. Children with TR on central radiology review (CRR) at diagnosis and/or indication of preoperative TR on surgical forms were included. Correlation between radiology/surgery/pathology findings was made. RESULTS: Total 141 patients had TR identified (69 on CRR, 43 on surgical form and 29 on both), and 124/141 had images available for CRR, and 98/124 had features suggestive of TR on diagnostic CRR (63 magnetic resonance imaging/35 computed tomography). TR was limited to the renal fossa in 47/98 (48%) and intraperitoneal in 51/98 (52%). Three of 98(3%) had upfront surgery, and 87/95 (92%) had TR confirmed on post-chemotherapy preoperative scans. Among 80/98 (82%) cases with TR on CRR and available surgical forms, TR was not confirmed on surgery or pathology in 38/80, giving a false-positive rate of 48%. Preoperative TR was indicated on 72 surgical forms, with images available for CRR in 55. Twenty-six of 55 (47%) were false-negative for TR on CRR and of those 10/26 (38%) had TR confirmed on pathology. CONCLUSIONS: Radiology alone should not be used to define TR, as it does not accurately correlate with surgical or pathology findings, and therefore cannot be relied upon for definitive staging and treatment. A multidisciplinary team should take the decision regarding the final abdominal stage and treatment using a multimodality approach considering clinical, radiological, surgical and pathological findings.
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This report describes a 48-year-old man who presented with a month history of weakness and paraesthesia associated with severe pain of all four limbs. Initially diagnosed and treated as Guillain Barre syndrome due to the severity of his extremity weakness, it was later discovered to be eosinophilic granulomatous polyangiitis (EGPA). Mononeuritis multiplex should not be underestimated or overlooked in the setting of diagnosing EGPA and requires prompt treatment with biologics to limit the permanent consequences on patient's quality of life with regard to developing limb weakness and pain. Although peripheral neuropathy, namely, mononeuritis multiplex, is not the most common feature of EGPA, it is important to consider it in order not to delay treatment with biologic agents that as seen in our patient can both halt the progress of the disease as well as give the patient a better quality of life.
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BACKGROUND: Malnutrition is a prevalent issue among older adults in long-term care facilities and is associated with adverse health outcomes and increased healthcare costs. Identifying the predictors of malnutrition in this population is crucial for developing effective intervention strategies. This study aimed to explore the factors contributing to malnourishment among older individuals living in long-term care facilities in Qatar. METHODS: This cross-sectional study included 75 older adults from two long-term care facilities (Rumailah Hospital and Enaya Specialized Care Center) in Qatar. Baseline characteristics, including age, sex, length of stay, mortality, weight, body mass index, co-morbidities, and laboratory parameters, were assessed. Data were analyzed using the most recent version of the SPSS software, version 29. Predictors of malnutrition and mortality were identified using logistic regression analysis. RESULTS: Of the 75 older individuals included in the study, 85% (64) were malnourished. The average age of the participants was 74.89 years, with a standard deviation of 10.21. Of all participants, approximately 61% (46) were males, and 39% (29) were females. Most malnourished older adults were classified as either at "moderate (29.69%)" or "severe risk (37.50%)," according to the Geriatric Nutritional Risk Index. Malnourished participants experienced a significant percentage of weight change within 3 months (14.01 ± 7.89); the only statistically significant predictor of malnutrition was the percentage of weight change within 3 months with an odds ratio (OR) of 4.8 (confidence interval [CI] 1.56-14.75) and p-value of 0.006. Statistically significant predictors of mortality were malnutrition (OR 24.84, CI 1.09-564) and age (OR 1.07, CI 1.00-1.14). CONCLUSIONS: A significant predictor of malnutrition in older adults identified in this study was the sudden and recent change in weight, which can be employed to detect individuals at risk early and guide tailored interventions. Malnutrition is a significant predictor of mortality. Employing a multidimensional strategy to tackle malnutrition can improve outcomes for the older individuals.