Imaging intact human organs from the organ to the cellular scale in three dimensions is a goal of biomedical imaging. To meet this challenge, we developed hierarchical phase-contrast tomography (HiP-CT), an X-ray phase propagation technique using the European Synchrotron Radiation Facility (ESRF)’s Extremely Brilliant Source (EBS). The spatial coherence of the ESRF-EBS combined with our beamline equipment, sample preparation and scanning developments enabled us to perform non-destructive, three-dimensional (3D) scans with hierarchically increasing resolution at any location in whole human organs. We applied HiP-CT to image five intact human organ types: brain, lung, heart, kidney and spleen. HiP-CT provided a structural overview of each whole organ followed by multiple higher-resolution volumes of interest, capturing organotypic functional units and certain individual specialized cells within intact human organs. We demonstrate the potential applications of HiP-CT through quantification and morphometry of glomeruli in an intact human kidney and identification of regional changes in the tissue architecture in a lung from a deceased donor with coronavirus disease 2019 (COVID-19).
Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis; a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease.
Implementing a policy mandating the submission of a completed reporting guideline checklist for observational studies, RCTs and systematic reviews can increase compliance. We advocate this measure for other journals and for other study types.
Reflective practice is a paper requirement of your career progression in health care. However, if done properly, it can greatly improve your skills as a health care provider. This article provides some structure to reflective practice to allow a health care provider to engage more with reflective practice and get more out of the experience.
BackgroundMicrovascular decompression (MVD) and partial sensory rhizotomy (PSR) provide longstanding pain relief in trigeminal neuralgia (TN). Given their invasiveness, complications can result from such posterior fossa procedures, but the impact of these procedures and their complications on patient-reported outcome measures (PROM), such as quality of life and distress, are not well established.MethodFive years after surgery, patients who underwent first MVD or PSR for TN at one institution, between 1982 and 2002, were sent a self-completion assessment set containing a range of PROMs: the Short Form-12 (SF-12) questionnaire to assess quality of life, the Hospital Anxiety and Depression Scale (HADS) to assess distress, and a questionnaire containing questions about postoperative complications, their severity and impact on quality of life. These findings and demographic data were compared between MVD and PSR.ResultsOne hundred and eighty-one of 245 (73.9%) patients after first MVD and 49 of 60 (81.7%) after PSR responded, and were included in analyses. The mean SF-12 scores of patients after MVD and PSR at five-year follow-up were significantly lower than English age-matched norms. Though there were no differences in SF-12 physical or mental component scores between the two procedures, patients after PSR were more likely to have case-level anxiety (RR = 3.3; 95% CI, 1.1–10.5; p = 0.03), had more postoperative complications, and of greater severity, including pain (RR = 2.52; 95% CI, 1.5–4.1; p < 0.001), numbness (RR = 5.9; 95% CI, 3.8–9.2; p < 0.001), burning sensations (RR = 3.0; 95% CI, 1.5–5.8; p = 0.001) and difficulty in eating (RR = 17.1; 95% CI, 5.6–53.1; p < 0.001), and these had a larger impact on quality of life for PSR compared to MVD.ConclusionsThe quality of life 5 years after MVD or PSR is poorer than in the general population and associated with postoperative complications such as pain, numbness, burning sensation and difficulty in eating. These complications are commoner after PSR than MVD, and this is associated with anxiety in PSR patients at five-year follow-up. However, these differences are not reflected by quality of life scores. Outcome measures need to incorporate patient experience after treatment for TN, and represent patient priorities for quality of life.Electronic supplementary materialThe online version of this article (10.1007/s00701-017-3350-6) contains supplementary material, which is available to authorized users.
Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. Studies implicating the phenotypic consequences of SNX14 mutations to be consequences of subcellular disruption to autophagy and lipid metabolism have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) have also been conducted, demonstrated an important biochemical role during lipid biogenesis. In this study we report the effect of loss of SNX14 in mice, which resulted in embryonic lethality around mid-gestation due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. In contrast to other vertebrates, zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation were both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the consequences of loss of function varies between species. Mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo. Mutations in the human Sorting Nexin 14 (SNX14) gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20; OMIM 616354) 1. These mutations most often lead to complete loss or truncation of the SNX14 protein, resulting in early onset cerebellar atrophy, ataxia, developmental delay, intellectual disability and coarse facial features, with hearing loss, relative macrocephaly and seizures only reported in some patients 1-7. SNX14 is ubiquitously expressed among tissues, accounting for the clinically recognisable syndromic presentation characteristic of SCAR20 1,5,7. SNX14 belongs to the RGS-PX protein family, which includes SNX13, SNX19 and SNX25 8. No mutations in these other members have yet been identified as the cause of human diseases. Inside the cell, SNX14 mutations impact both autophagy and lipid metabolism 1,2,9. The most apparent subcellular phenotype is the accumulation of autolysosomes containing lipids 1,9. SNX14 is localised to the endoplasmic reticulum membrane via its N-terminal transmembrane domain where it is enriched in proximity to lipid
BackgroundThere is currently conflicting evidence surrounding the effects of obesity on postoperative outcomes. Previous studies have found obesity to be associated with adverse events, but others have found no association. The aim of this study was to determine whether increasing body mass index (BMI) is an independent risk factor for development of major postoperative complications.MethodsThis was a multicentre prospective cohort study across the UK and Republic of Ireland. Consecutive patients undergoing elective or emergency gastrointestinal surgery over a 4‐month interval (October–December 2014) were eligible for inclusion. The primary outcome was the 30‐day major complication rate (Clavien–Dindo grade III–V). BMI was grouped according to the World Health Organization classification. Multilevel logistic regression models were used to adjust for patient, operative and hospital‐level effects, creating odds ratios (ORs) and 95 per cent confidence intervals (c.i.).ResultsOf 7965 patients, 2545 (32·0 per cent) were of normal weight, 2673 (33·6 per cent) were overweight and 2747 (34·5 per cent) were obese. Overall, 4925 (61·8 per cent) underwent elective and 3038 (38·1 per cent) emergency operations. The 30‐day major complication rate was 11·4 per cent (908 of 7965). In adjusted models, a significant interaction was found between BMI and diagnosis, with an association seen between BMI and major complications for patients with malignancy (overweight: OR 1·59, 95 per cent c.i. 1·12 to 2·29, P = 0·008; obese: OR 1·91, 1·31 to 2·83, P = 0·002; compared with normal weight) but not benign disease (overweight: OR 0·89, 0·71 to 1·12, P = 0·329; obese: OR 0·84, 0·66 to 1·06, P = 0·147).ConclusionOverweight and obese patients undergoing surgery for gastrointestinal malignancy are at increased risk of major postoperative complications compared with those of normal weight.
The kidney contains a network of lymphatic vessels that clear fluid, small molecules, and cells from the renal interstitium. Through modulating immune responses and via crosstalk with surrounding renal cells, lymphatic vessels have been implicated in the progression and maintenance of kidney disease. In this Review, we provide an overview of the development, structure, and function of lymphatic vessels in the healthy adult kidney. We then highlight the contributions of lymphatic vessels to multiple forms of renal pathology, emphasizing CKD, transplant rejection, and polycystic kidney disease and discuss strategies to target renal lymphatics using genetic and pharmacologic approaches. Overall, we argue the case for lymphatics playing a fundamental role in renal physiology and pathology and treatments modulating these vessels having therapeutic potential across the spectrum of kidney disease.
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