Evaluation of Spectral X-Ray Imaging for Panoramic Dental Images Based on a Simulation Framework.

Modern photon counting detectors allow the calculation of virtual monoenergetic or material decomposed X-ray images but are not yet used for dental panoramic radiography systems. To assess the diagnostic potential and image quality of photon counting detectors in dental panoramic radiography, ethics approval from the local ethics committee was obtained for this retrospective study. Conventional CT scans of the head and neck region were segmented into bone and soft tissue. The resulting datasets were used to calculate panoramic equivalent thickness bone and soft tissue images by forward projection, using a geometry like that of conventional panoramic radiographic systems. The panoramic equivalent thickness images were utilized to generate synthetic conventional panoramic radiographs and panoramic virtual monoenergetic radiographs at various energies. The conventional, two virtual monoenergetic images at 40 keV and 60 keV, and material-separated bone and soft tissue panoramic equivalent thickness X-ray images simulated from 17 head CTs were evaluated in a reader study involving three experienced radiologists regarding their diagnostic value and image quality. Compared to conventional panoramic radiographs, the material-separated bone panoramic equivalent thickness image exhibits a higher image quality and diagnostic value in assessing the bone structure p < . 001 and details such as teeth or root canals p < . 001 . Panoramic virtual monoenergetic radiographs do not show a significant advantage over conventional panoramic radiographs. The conducted reader study shows the potential of spectral X-ray imaging for dental panoramic imaging to improve the diagnostic value and image quality.

Acetylcholinesterase Activity Influenced by Lipid Membrane Area and Surface Acoustic Waves.

According to the current model of nerve propagation, the function of acetylcholinesterase (AChE) is to terminate synaptic transmission of nerve signals by hydrolyzing the neurotransmitter acetylcholine (ACh) in the synaptic cleft to acetic acid (acetate) and choline. However, extra-synaptic roles, which are known as 'non-classical' roles, have not been fully elucidated. Here, we measured AChE activity with the enzyme bound to lipid membranes of varying area per enzyme in vitro using the Ellman assay. We found that the activity was not affected by density fluctuations in a supported lipid bilayer (SLB) induced by standing surface acoustic waves. Nevertheless, we found twice as high activity in the presence of small unilamellar vesicles (SUV) compared to lipid-free samples. We also showed that the increase in activity scaled with the available membrane area per enzyme.

A National Registry Study of Patient and Renal Survival in Adult Nephrotic Syndrome.

INTRODUCTION: We aimed to determine the mortality rate, cause of death, and rate of end-stage kidney disease (ESKD) in adults with nephrotic syndrome (NS). METHODS: We conducted a national registry-based study, including all 522 adults who had a kidney biopsy for NS in Scotland in 2014-2017. We linked the Scottish Renal Registry to death certificate data. We performed survival and Cox proportional hazards analyses, accounting for competing risks of death and ESKD. We compared mortality rates with those in the age- and sex-matched general population. RESULTS: A total of 372 patients had primary NS; 150 had secondary NS. Over a median follow-up of 866 days, 110 patients (21%) died. In patients with primary NS, observed versus population 3-year mortality was 2.1% (95% CI 0.0%-4.6%) versus 0.9% (0.8%-1.0%) in patients aged <60 years and 24.9% (18.4%-30.8%) versus 9.4% (8.3%-10.5%) in those aged ≥60 years. In secondary NS, this discrepancy was 17.1% (5.6%-27.2%) versus 1.1% (0.9%-1.2%) in <60-year-olds and 49.4% (36.6%-59.7%) versus 8.1% (6.6%-9.6%) in ≥60-year-olds. In primary NS, cardiovascular causes accounted for 28% of deaths, compared with 18% in the general population. Eighty patients (15%) progressed to ESKD. Incidence of ESKD by 3 years was 8.4% (95% CI 4.9%-11.7%) in primary and 35.1% (24.3%-44.5%) in secondary NS. Early remission of proteinuria and the absence of early acute kidney injury (AKI) were associated with lower rates of death and ESKD. CONCLUSIONS: Adults with NS have high rates of death and ESKD. Cardiovascular causes account for excess mortality in primary NS.

Coronary Artery Disease in Patients Presenting With Acute Ischemic Stroke or Transient Ischemic Attack and Elevated Troponin Levels.

Background: There is little information concerning the invasive coronary angiography (ICA) findings of patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) with elevated troponin levels and suspected myocardial infarction (MI). This study analyzed patient characteristics associated with ICA outcomes. Methods: A total of 8,322 patients with AIS or TIA, treated between March 2010 and May 2020, were retrospectively screened for elevated serum troponin I at hospital admission. Patients in whom ICA was performed, due to suspected type 1 MI based on symptoms, echocardiography, and ECG, were categorized according to ICA results (non-obstructive coronary artery disease (CAD): ≥1 stenosis ≥50% but no stenosis ≥80%; obstructive CAD: any stenosis ≥80% or hemodynamically relevant stenosis assessed by FFR/iwFR). Results: Elevated troponin levels were detected in 2,205 (22.5%) patients, of whom 123 (5.6%) underwent ICA (mean age 71 ± 12 years; 67% male). CAD was present in 98 (80%) patients, of whom 51 (41%) were diagnosed with obstructive CAD. Thus, ICA findings of obstructive CAD accounted for 2.3% of patients with troponin elevation and 0.6% of all stroke patients. The clinical hallmarks of myocardial ischemia, including angina pectoris (31 vs. 15%, p < 0.05) and regional wall motion abnormalities (49 vs. 32%, p = 0.07), and increased cardiovascular risk indicated obstructive CAD. While there was no association between lesion site or stroke severity and ICA findings, causal large-artery atherosclerosis was significantly more common in patients with obstructive coronary disease (p < 0.05). Conclusion: The rate of obstructive CAD in patients with stroke or TIA and elevated troponin levels with suspected concomitant type I MI is low. The cumulation of several cardiovascular risk factors and clinical signs of MI were predictive. AIS patients with large-artery atherosclerosis and elevated troponin may represent an especially vulnerable subgroup of stroke patients with risk for obstructive CAD.

Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin.

Inducible nitric oxide synthase (iNOS) plays a crucial role in controlling growth of Mycobacterium tuberculosis (M.tb), presumably via nitric oxide (NO) mediated killing. Here we show that leukocyte-specific deficiency of NO production, through targeted loss of the iNOS cofactor tetrahydrobiopterin (BH4), results in enhanced control of M.tb infection; by contrast, loss of iNOS renders mice susceptible to M.tb. By comparing two complementary NO-deficient models, Nos2-/- mice and BH4 deficient Gch1fl/flTie2cre mice, we uncover NO-independent mechanisms of anti-mycobacterial immunity. In both murine and human leukocytes, decreased Gch1 expression correlates with enhanced cell-intrinsic control of mycobacterial infection in vitro. Gene expression analysis reveals that Gch1 deficient macrophages have altered inflammatory response, lysosomal function, cell survival and cellular metabolism, thereby enhancing the control of bacterial infection. Our data thus highlight the importance of the NO-independent functions of Nos2 and Gch1 in mycobacterial control.

Dictyostelium as a Model to Assess Site-Specific ADP-Ribosylation Events.

The amoeba Dictyostelium discoideum is a single-cell organism that can undergo a simple developmental program, making it an excellent model to study the molecular mechanisms of cell motility, signal transduction, and cell-type differentiation. A variety of human genes that are absent or show limited conservation in other invertebrate models have been identified in this organism. This includes ADP-ribosyltransferases, also known as poly-ADP-ribose polymerases (PARPs), a family of proteins that catalyze the addition of single or poly-ADP-ribose moieties onto target proteins. The genetic tractability of Dictyostelium and its relatively simple genome structure makes it possible to disrupt PARP gene combinations, in addition to specific ADP-ribosylation sites at endogenous loci. Together, this makes Dictyostelium an attractive model to assess how ADP-ribosylation regulates a variety of cellular processes including DNA repair, transcription, and cell-type specification. Here we describe a range of techniques to study ADP-ribosylation in Dictyostelium, including analysis of ADP-ribosylation events in vitro and in vivo, in addition to approaches to assess the functional roles of this modification in vivo.

An adherent tissue-inspired hydrogel delivery vehicle utilised in primary human glioma models.

A physical hydrogel cross-linked via the host-guest interactions of cucurbit[8]uril and utilised as an implantable drug-delivery vehicle for the brain is described herein. Constructed from hyaluronic acid, this hydrogel is biocompatible and has a high water content of 98%. The mechanical properties have been characterised by rheology and compared with the modulus of human brain tissue demonstrating the production of a soft material that can be moulded into the cavity it is implanted into following surgical resection. Furthermore, effective delivery of therapeutic compounds and antibodies to primary human glioblastoma cell lines is showcased by a variety of in vitro and ex vivo viability and immunocytochemistry based assays.

Redundancy between nucleases required for homologous recombination promotes PARP inhibitor resistance in the eukaryotic model organism Dictyostelium.

ADP-ribosyltransferases promote repair of DNA single strand breaks and disruption of this pathway by Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) is toxic to cells with defects in homologous recombination (HR). Here, we show that this relationship is conserved in the simple eukaryote Dictyostelium and exploit this organism to define mechanisms that drive resistance of the HR-deficient cells to PARPi. Dictyostelium cells disrupted in exonuclease I, a critical factor for HR, are sensitive to PARPi. Deletion of exo1 prevents the accumulation of Rad51 in chromatin induced by PARPi, resulting in DNA damage being channelled through repair by non-homologous end-joining (NHEJ). Inactivation of NHEJ supresses the sensitivity of exo1- cells to PARPi, indicating this pathway drives synthetic lethality and that in its absence alternative repair mechanisms promote cell survival. This resistance is independent of alternate-NHEJ and is instead achieved by re-activation of HR. Moreover, inhibitors of Mre11 restore sensitivity of dnapkcs-exo1- cells to PARPi, indicating redundancy between nucleases that initiate HR can drive PARPi resistance. These data inform on mechanism of PARPi resistance in HR-deficient cells and present Dictyostelium as a convenient genetic model to characterize these pathways.