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Evaluation of intestinal biopsy tissue preservation methods to facilitate large-scale mucosal microbiota research
Get PDFBACKGROUND: Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation ('flash freezing') limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions.METHODS: We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene).FINDINGS: Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions.INTERPRETATION: Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples.FUNDING: Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255).</p
An unusual case of a monorchid horse with an abdominally retained testicle: Monorchid cryptorchid horse
No full textIntroduction: Monorchidism is a rarely described condition in the horse and is not to be confused with cryptorchidism. The diagnosis is challenging and confirmed by surgery and histology in combination with hormonal assays. This report describes, to the best of the author’s knowledge, the first case of monorchidism and abdominal cryptorchidism of the developed testicle in a horse. Methods: An Irish Cob underwent laparoscopic castration for removal of bilateral cryptorchid testicles. At surgery, the horse was diagnosed as a monorchid with the testicle retained intra-abdominally. Histopathological, hormonal, molecular and cytogenetic analysis was performed. This included measuring testosterone and anti-Mullerian hormone (AMH) in serum blood, isolating genomic DNA from EDTA- and heparin-treated blood, PCR amplification of the SRY gene, metaphase chromosome preparation, and DAPI banding before metaphase analysis with fluorescence in situ hybridisation (FISH) analysis. Results: The horse was positive for the SRY gene and had a mosaic 63,X/64,XY karyotype with the aneuploid cells being present in only 2% of metaphases. FISH showed that the missing sex chromosome of the aneuploid cell line was the Y chromosome embedded in micronuclei. An abnormal high rate of micronuclei (6.6%) was observed indicating genotoxic events and/or genome instability. Hormonal assay results confirmed that AMH was not significantly increased, suggesting that no further testicular tissue was present. Histopathology was consistent with testicular tissue displaying a Sertoli cell-only pattern with bipolar ductal structures. Conclusion: The exact causes of monorchidism and cryptorchidism are unclear, but the elevated rate of micronuclei is clear evidence for genome instability which might have been involved in the failure of normal testicular development and descent. Future cases could further clarify the disease mechanism based on this report.</p
Post-Hospitalisation COVID-19 Rehabilitation (PHOSP-R):A randomised controlled trial of exercise-based rehabilitation
No full textOBJECTIVE: Post-COVID syndrome involves prolonged symptoms with multi-system and functional impairment lasting at least 12 weeks after acute COVID-19. We aimed to determine the efficacy of exercise-based rehabilitation interventions, either face-to-face or remote, compared to usual care in individuals experiencing Post-COVID syndrome following a hospitalisation of acute COVID-19.DESIGN: This single-blind randomised controlled trial compared two COVID exercise-based rehabilitation interventions (face-to-face or remote) to usual care in participants with Post-COVID syndrome following a hospitalisation. The interventions were either a face-to-face or remote eight-week program of individually prescribed exercise and education. The primary outcome was the change in Incremental Shuttle Walking Test (ISWT) following eight weeks of intervention (either face-to-face or remote) compared to usual care. Other secondary outcomes were measured including health related quality of life (HRQoL), and exploratory outcomes included lymphocyte immunotyping.RESULTS: 181 participants (55% male, mean [sd] age 59 [12] years, length of hospital stay 12 [19] days) were randomised. There was an improvement in the ISWT distance following face-to-face rehabilitation (mean 52 [95% CI 19 to 85]m, p=0·002) and remote rehabilitation (mean 34 [95% CI 1 to 66]m, p=0·047) compared to usual care alone. There were no differences between groups for HRQoL of self-reported symptoms. Analysis of immune markers revealed significant increases in naïve and memory CD8+ T cells following face-to-face rehabilitation versus usual care alone (p<0·001, n=31).CONCLUSION: Exercise-based rehabilitation improved short-term exercise capacity in Post-COVID syndrome following an acute hospitalisation and showed potential for beneficial immunomodulatory effects.</p
The crux of decisions about who requires high-security care: A systematic analysis of referrals to the State Hospital
No full textThere has been limited study to date into the specific patient factors that influence decisions about an individual's need for high-security psychiatric care. Admission to high-security services requires careful assessment and consideration to ensure patients receive the least restrictive care justified, and those who are most likely to benefit from it are admitted. This retrospective case-control study describes the demographic, clinical and risk characteristics of referrals made to the State Hospital in Scotland during a 12-month period, and delineates differences between referrals that were accepted and rejected for admission. It updates the methods of a previous study undertaken at the State Hospital. Six variables differentiated rejected and accepted referrals in univariate analyses. Multivariate logistic regression found that a model with only the individual's age, whether they were prescribed antipsychotic medication at the time of referral, and whether they had a history of violent convictions, best predicted referral outcome. The findings support the conclusion that it is not only an individual's risk of violence or the severity of their mental illness in isolation, but the combination of these factors that is deemed to necessitate high-security care within a stratified forensic mental health system
Experimental governance in China:models of stakeholder interaction and evolution of the low-carbon cities pilot programme
No full textThe Low-Carbon City Pilot (LCCP) programme is a crucial part of China's strategy to combat climate change, serving as a governance paradigm through experimental policy pilots. Existing literature on experimental governance predominantly focused on democratic countries. Attention to Chinese experimentalism is growing but little attention has been paid to thoroughly exploring innovation processes through interactions between local governments and other stakeholders. Drawing on primary data from 21 interviews and secondary data from national and provincial policy documents, this study uncovers four distinct models of stakeholder interaction and identifies three different pathways in the evolution of the LCCP programme. The analysis focuses on evolving interactions between niche innovation and existing regimes; learning processes within these experimental stages; and how low-carbon experimental innovations have facilitated local government reform. The research reveals that China's LCCP programme has promoted a shift from passive to active interactions between niche innovations and regimes, a transition in the learning process from unidirectional to multidimensional, and ultimately, the transformation of low-carbon industries. In summary, this paper helps deepen the understanding of Chinese experimentalism, expands the application of the Strategic Niche Management Framework in the Chinese context, and expose processes of stakeholder interaction in low-carbon urban policy innovation.</p
Effects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levels
No full textBackgroundHuR/ELAV1, a ubiquitous RNA-binding protein, belongs to the RNA-binding protein family and is crucial for stabilizing and regulating the translation of various mRNA targets, influencing gene expression. Elevated HuR levels are associated with multiple disorders, including cancer and neurodegenerative diseases. Despite the identification of small molecule inhibitors targeting HuR, their detailed characterization remains limited. Recently, Eltrombopag, an FDA-approved drug for immune thrombocytopenic purpura and chemotherapy-induced thrombocytopenia, emerged as a potential HuR inhibitor. However, the specific molecular pathways influenced by both HuR and Eltrombopag are not fully understood.ResultsOur study demonstrates that Eltrombopag operates via HuR inhibition, affecting gene expression regulation at the posttranscriptional level. We show that both HuR knockout and Eltrombopag treatment modulate iron metabolism by decreasing ferritin heavy chain (FTH1) and light chain (FTL) synthesis while increasing the expression of iron-regulatory protein 2 (IRP2), a key regulator of ferritin translation. Additionally, HuR inhibition reduces the levels of glycoprotein hormones, alpha polypeptide (CGA), a marker associated with hormone-induced tumors, suggesting a potential use of Eltrombopag in treatment of cancers overexpressing CGA. We observed that the main of control is manifested at the level of translation inhibition, with proteasome-mediated regulation also playing an important role.ConclusionsThese findings uncover novel posttranscriptional mechanisms governed by HuR and its inhibitor, elucidating pathways relevant to HuR-mediated regulation and molecular therapies aimed at targeting this protein
The Development of a Canine Single-chain Phage Antibody Library to Isolate Recombinant Antibodies for use in Translational Cancer Research
No full textThe development of canine immunotolerant monoclonal antibodies can accelerate the invention of new medicines for both canine and human diseases. A methodology was developed to clone the naïve, somatically mutated variable domain repertoire from canine B-cell mRNA using 5’RACE PCR. A set of degenerate primers were then designed and used to clone variable domain genes into archival “holding” plasmid libraries. These archived variable domain genes were then combinatorially ligated to produce a scFv M13 phage library. Next-generation long-read and short-read DNA sequencing methodologies were developed to annotate features of the cloned library including CDR diversity and IGHV/IGKV/IGLV subfamily distribution. A synthetic IgG was developed from this scFv library to the canine immune checkpoint receptor PD-1. This synthetic platform can be used to clone and annotate archived antibody variable domain genes for use in perpetuity in order to develop improved preclinical models for the treatment of complex human disease
The menstrual cycle an overlooked vital sign in psychiatry?
Get PDFWe argue that psychiatry has overlooked a significant modifiable risk factor for mental illness in female patients: cyclical symptoms associated with the menstrual cycle. Premenstrual dysphoric disorder has recently been included in the International Classification of Diseases-11, while there is growing evidence that menstrual cycle stage can impact mental health symptoms transdiagnostically and influence important outcomes such as suicide or admission to hospital. Intervention is possible using existing widely available hormonal treatments. Asking patients about the relationship between their menstrual cycle and mental health is an opportunity to improve diagnosis and treatment that should no longer be neglected.</p
A model of the mechanisms underpinning unconventional aqueous humor outflow
Get PDFPURPOSE: To develop a mathematical model of the unconventional outflow pathway.METHODS: The unconventional pathway is modeled as having two key components: the uveo-vortex and the trans-scleral pathways. The uveo-vortex pathway is modeled using Starling's law and the trans-scleral flow using predominately hydrostatic forces. We include transcytosis from the choriocapillaris (CC) and collapsibility of the suprachoroidal space (SCS) as particular features. There is considerable uncertainty in a number of model parameter values, and we identify the most significant ones using sensitivity analysis.RESULTS: The model successfully generates a fluid flow from anterior to posterior in the choroidal tissue and the SCS, which also demonstrates many of the known physiological features, including the insensitivity of the unconventional flow to fluctuations in the IOP, albumin removal by the trans-scleral flow, and the CC as a net absorber of fluid from, and supplier of albumin to, the choroidal tissue. The model supports the two previously proposed mechanisms of the action of prostaglandin F2α analogues.CONCLUSIONS: We have developed a theoretical model of the unconventional aqueous outflow pathway that successfully captures its physiological features and elucidates the actions of prostaglandin F2α analogues and other drugs.</p
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