The partial skeleton of a 22-24-year old female from Liushui, Southern Silk Road, Xinjiang (China) was analyzed using morphological and biochemical methods. The most striking finding in this ...individual of a Late Bronze Age mounted nomadic population was the complete ossification of the caudal vertebral column including parts of the ligaments of this region due to chronic tuberculosis (Pott's disease). The morphological diagnosis is definitely confirmed by the results of the proteomic analysis. The bacterial protein Ag85 and, for the first time in archaeological skeletal remains, also ESAT-6 was detected, which are typical for Mycobacterium tuberculosis. Extremely intense physical stress aggravated the pathological kyphosis primarily caused by the tuberculous process and promoted dislocation of the caudal thoracic versus the lumbar vertebrae. The fate of this young female suffering from tuberculosis and the consequences of this extreme physical stress characterize the harsh living conditions of typical prehistoric population of mounted nomadic pastoralists.
Infection-related diabetes can arise as a result of virus-associated β-cell destruction. Clinical data suggest that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the ...coronavirus disease 2019 (COVID-19), impairs glucose homoeostasis, but experimental evidence that SARS-CoV-2 can infect pancreatic tissue has been lacking. In the present study, we show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human β-cells express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 full-body postmortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.
The generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment.
We designed a straightforward ...approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny.
Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro
but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids.
Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.
Although alterations in gut microbiota composition during acute colitis have been repeatedly observed, associated functional changes and the recovery from dysbiosis received little attention. In this ...study, we investigated structure and function of the gut microbiota during acute inflammation and recovery in a dextran sodium sulfate (DSS)-colitis mouse model using metatranscriptomics, bacterial 16S rRNA gene amplicon sequencing and monitoring of selected host markers. Parallel to an increase of host markers of inflammation during acute colitis, we observed relative abundance shifts and alterations in phylotype composition of the dominant bacterial orders Clostridiales and Bacteroidales, and an increase of the low abundant Enterobacteriales, Deferribacterales, Verrucomicrobiales and Erysipelotrichales. During recovery, the microbiota began to resume, but did not reach its original composition until the end of the experiment. Microbial gene expression was more resilient to disturbance, with pre-perturbation-type transcript profiles appearing quickly after acute colitis. The decrease of Clostridiales during inflammation correlated with a reduction of transcripts related to butyrate formation, suggesting a disturbance in host-microbe signalling and mucosal nutrient provision. The impact of acute inflammation on the Clostridiales was also characterized by a significant downregulation of their flagellin-encoding genes. In contrast, the abundance of members of the Bacteroidales increased along with an increase in transcripts related to mucin degradation. We propose that acute inflammation triggered a selective reaction of the immune system against flagella of commensals and temporarily altered murine microbiota composition and functions relevant for the host. Despite changes in specific interactions, the host-microbiota homeostasis revealed a remarkable ability for recovery.
Exact measurement of renal function is essential for the treatment of patients. Elevated serum-creatinine levels, while established, are influenced by other parameters and show a significant ...time-lag. This drives the search for novel biomarkers of renal function and injury. Beside Lipocalin-2 and kidney-injury-molecule-1 (KIM-1), the endogenous opioid precursor proenkephalin-A (Penk) has recently emerged as a promising marker for renal function. But the cellular origin and regulation of Penk outside the brain has not yet been investigated in depth.
This study characterizes the cellular origin of Penk expression with high-resolution in situ hybridization in two models of renal fibrosis in mice and human tissue.
Interstitial cells are the main expression site for renal Penk. This classifies Penk as biomarker for interstitial damage as opposed to tubular damage markers like Lipocalin-2 and KIM-1. Furthermore, our data indicate that renal Penk expression is not regulated by classical profibrotic pathways.
This study characterizes changing Penk expression in the kidneys. The similarity of Penk expression across species gives rise to further investigations into the function of Penk in healthy and injured kidneys.
Penk is a promising biomarker for interstitial renal damage that warrants further studies to utilize its predictive potential.
Clinical significance
Knowledge of real-time renal function is essential for proper treatment of critically ill patients and in early diagnosis of acute kidney injury (AKI). Proenkephalin-A has been measured in a number of patient cohorts as a highly accurate and predictive biomarker of renal damage.
The present study identifies Penk as a biomarker for interstitial damage in contrast to the tubular biomarkers such as Lipocalin-2 or KIM-1.
Our data show that Penk is regulated independently of classical profibrotic or proinflammatory pathways, indicating it might be more robust against extra-renal influences.
Data presented in this study provide fundamental information about cell type-specific localization and regulation of the potential new biomarker Penk across species as foundation for further research.
Introduction
Despite the benefits associated with weight reduction, the anatomical and functional changes of bariatric surgery may favor the development of undesirable side effects such as the ...appearance of gastrointestinal symptoms (GIS). The aim of this study was to evaluate the effects of using probiotics in individuals with GIS 1 year after being submitted to Roux-en-Y Gastric Bypass (RYGB).
Materials and Methods
This is an experimental, prospective, randomized, cross-over, triple-blind, placebo-controlled study, carried out with patients 1 year after being submitted to RYGB and who reported at least one moderate GIS. Subjects were randomized into two groups and completed the two research periods: in one they received placebo capsules, in the other 50 billion CFU of probiotics (
Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus plantarum, Bifidobacterium bifidum
and
Lactobacillus gasseri)
, both for 8 weeks, with 8 weeks of wash-out period in between, and were evaluated for the presence of Small Intestine Bacterial Overgrowth (SIBO) and GIS, through the Hydrogen breath test and Gastric Symptom Rating Scale (GSRS) questionnaire.
Results
Of a total of 56 participants, 47 individuals completed the study. No significant effects were observed in neither the gastrointestinal symptoms or in the prevalence of SIBO with the use of probiotics.
Conclusion
Supplementation of the probiotics chosen for this study does not seem to alleviate GIS or influence the improvement of SIBO in symptomatic patients after 1 year of RYGB.
Graphical Abstract
Intellectual conflicts of interest (COI), like financial COI, may threaten the validity and trustworthiness of clinical practice guidelines (CPGs). However, comparatively little is known about ...intellectual COI in CPGs. This study sought to estimate the prevalence of intellectual COI and corresponding management strategies among cardiology and pulmonology CPGs.
We conducted a retrospective document review of CPGs published by cardiology or pulmonology professional societies from the United States, Canada, or Europe from 2018 to 2019 available via the Emergency Care Research Institute, Guidelines International Network, or Medscape databases. We assessed the percentage of authors with an intellectual COI, defined as i) authorship on a study reviewed by the CPG, ii) authorship of a prior editorial related to a CPG recommendation, or iii) authorship of a prior related CPG. Management strategies assessed included use of GRADE methodology, inclusion of a methodologist, and recusals due to intellectual COI. Outcomes were assessed overall and compared between cardiology and pulmonology CPGs.
Among the 39 CPGs identified (14 cardiology, 25 pulmonology), there were a total of 737 authors, of whom 473 (64%) had at least one intellectual COI. Among all CPGs, a median of 67% (Interquartile Range 50%-76%) of authors had at least one intellectual COI, and COI was more prevalent among cardiology compared with pulmonology CPGs (84% vs 57%, p<0.001). There was variable use of management strategies among the CPGs, including use of GRADE methodology (64% of CPGs), inclusion of a methodologist (49%), and recusals due to intellectual COI (0%).
Intellectual conflicts of interest appear to be highly prevalent and under-reported among cardiology and pulmonology CPGs, which may threaten their validity. Greater attention to and improved management of intellectual COI by CPG-producing organizations is needed.
Abstract
Background
During HIV retesting in antenatal and preexposure prophylaxis (PrEP) care, discrepant results occur, but guidelines are lacking.
Methods
In a Kenyan trial implementing antenatal ...PrEP, if 1 test is reactive, a second is performed; if discrepant, both are repeated; if persistently discrepant, DNA polymerase chain reaction (PCR) is performed.
Results
Among 4451 women, 23 265 HIV retesting sessions were performed; 14 (0.06%, 95% confidence interval, 0.03%–0.10%) had discrepant results among 10 individuals; in all 10 initial cases, PCR was negative.
Conclusions
Discrepant rapid tests are an expected, rare, and important challenge for antenatal care HIV retesting, with and without PrEP.
Clinical Trials Registration
NCT03070600.
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