Replicative DNA polymerase δ but not ε proofreads errors in Cis and in Trans.

It is now well established that in yeast, and likely most eukaryotic organisms, initial DNA replication of the leading strand is by DNA polymerase ε and of the lagging strand by DNA polymerase δ. However, the role of Pol δ in replication of the leading strand is uncertain. In this work, we use a reporter system in Saccharomyces cerevisiae to measure mutation rates at specific base pairs in order to determine the effect of heterozygous or homozygous proofreading-defective mutants of either Pol ε or Pol δ in diploid strains. We find that wild-type Pol ε molecules cannot proofread errors created by proofreading-defective Pol ε molecules, whereas Pol δ can not only proofread errors created by proofreading-defective Pol δ molecules, but can also proofread errors created by Pol ε-defective molecules. These results suggest that any interruption in DNA synthesis on the leading strand is likely to result in completion by Pol δ and also explain the higher mutation rates observed in Pol δ-proofreading mutants compared to Pol ε-proofreading defective mutants. For strains reverting via AT→GC, TA→GC, CG→AT, and GC→AT mutations, we find in addition a strong effect of gene orientation on mutation rate in proofreading-defective strains and demonstrate that much of this orientation dependence is due to differential efficiencies of mispair elongation. We also find that a 3'-terminal 8 oxoG, unlike a 3'-terminal G, is efficiently extended opposite an A and is not subject to proofreading. Proofreading mutations have been shown to result in tumor formation in both mice and humans; the results presented here can help explain the properties exhibited by those proofreading mutants.

Different roles of eukaryotic MutS and MutL complexes in repair of small insertion and deletion loops in yeast.

DNA mismatch repair greatly increases genome fidelity by recognizing and removing replication errors. In order to understand how this fidelity is maintained, it is important to uncover the relative specificities of the different components of mismatch repair. There are two major mispair recognition complexes in eukaryotes that are homologues of bacterial MutS proteins, MutSα and MutSß, with MutSα recognizing base-base mismatches and small loop mispairs and MutSß recognizing larger loop mispairs. Upon recognition of a mispair, the MutS complexes then interact with homologues of the bacterial MutL protein. Loops formed on the primer strand during replication lead to insertion mutations, whereas loops on the template strand lead to deletions. We show here in yeast, using oligonucleotide transformation, that MutSα has a strong bias toward repair of insertion loops, while MutSß has an even stronger bias toward repair of deletion loops. Our results suggest that this bias in repair is due to the different interactions of the MutS complexes with the MutL complexes. Two mutants of MutLα, pms1-G882E and pms1-H888R, repair deletion mispairs but not insertion mispairs. Moreover, we find that a different MutL complex, MutLγ, is extremely important, but not sufficient, for deletion repair in the presence of either MutLα mutation. MutSß is present in many eukaryotic organisms, but not in prokaryotes. We suggest that the biased repair of deletion mispairs may reflect a critical eukaryotic function of MutSß in mismatch repair.

In vivo bypass of 8-oxodG.

8-oxoG is one of the most common and mutagenic DNA base lesions caused by oxidative damage. However, it has not been possible to study the replication of a known 8-oxoG base in vivo in order to determine the accuracy of its replication, the influence of various components on that accuracy, and the extent to which an 8-oxoG might present a barrier to replication. We have been able to place a single 8-oxoG into the Saccharomyces cerevisiae chromosome in a defined location using single-strand oligonucleotide transformation and to study its replication in a fully normal chromosome context. During replication, 8-oxoG is recognized as a lesion and triggers a switch to translesion synthesis by Pol η, which replicates 8-oxoG with an accuracy (insertion of a C opposite the 8-oxoG) of approximately 94%. In the absence of Pol η, template switching to the newly synthesized sister chromatid is observed at least one third of the time; replication of the 8-oxoG in the absence of Pol η is less than 40% accurate. The mismatch repair (MMR) system plays an important role in 8-oxoG replication. Template switching is blocked by MMR and replication accuracy even in the absence of Pol η is approximately 95% when MMR is active. These findings indicate that in light of the overlapping mechanisms by which errors in 8-oxoG replication can be avoided in the cell, the mutagenic threat of 8-oxoG is due more to its abundance than the effect of a single lesion. In addition, the methods used here should be applicable to the study of any lesion that can be stably incorporated into synthetic oligonucleotides.

Mismatch repair-dependent mutagenesis in nondividing cells.

Mismatch repair (MMR) is a major DNA repair pathway in cells from all branches of life that removes replication errors in a strand-specific manner, such that mismatched nucleotides are preferentially removed from the newly replicated strand of DNA. Here we demonstrate a role for MMR in helping create new phenotypes in nondividing cells. We show that mispairs in yeast that escape MMR during replication can later be subject to MMR activity in a replication strand-independent manner in nondividing cells, resulting in either fully wild-type or mutant DNA sequence. In one case, this activity is responsible for what appears to be adaptive mutation. This replication strand-independent MMR activity could contribute to the formation of tumors arising in nondividing cells and could also contribute to mutagenesis observed during somatic hypermutation of Ig genes.

A stake in the game: Can radiographer image interpretation improve X-ray quality? A scoping review.

BACKGROUND: Image quality is an important factor in imaging optimisation and diagnosis. Many determinants of image quality are controlled by the radiographer; therefore, radiographer-led strategies may be key to improving X-ray image quality. This review examines the literature on radiographer-led diagnostic evaluation to establish its potential to improve X-ray image quality. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews and the Joanna Briggs Institute Manual for Evidence Synthesis Scoping Review were used to review studies relevant to the impact of radiographer-led diagnostic evaluation on image quality. CINHAL, Embase, Scopus, Web of Science and Medline databases were searched for relevant articles. Search terms synonymous with radiographer, commenting, and image quality were used and studies that examined any type of radiographer-led image interpretation and its relationship to image quality in X-ray based modalities were reviewed. RESULTS: Fourteen studies that met the inclusion criteria were reviewed. All the studies reviewed unanimously reported a positive association between radiographer image interpretation and image quality in X-ray based modalities. Five emerging themes were identified to be responsible for the improvement in image quality: increased understanding of image quality requirements, improved technical skills, enhanced ability to utilise supplementary imaging and repeats, collaborative upskilling of colleagues, and a complementary interaction between diagnostic and radiographic skills that serves to enhance image quality. CONCLUSIONS: The findings demonstrate that radiographer image interpretation is a useful strategy to optimise the quality of X-ray examinations. IMPLICATIONS FOR PRACTICE: The findings highlight a new avenue to improve X-ray quality in the clinical environment and support evidence-based uptake of preliminary image evaluation systems. These findings also support the integration of radiographer commenting alongside technical image quality in teaching curricula.

Measurement of muon capture on the proton to 1% precision and determination of the pseudoscalar coupling gP.

The MuCap experiment at the Paul Scherrer Institute has measured the rate Λ(S) of muon capture from the singlet state of the muonic hydrogen atom to a precision of 1%. A muon beam was stopped in a time projection chamber filled with 10-bar, ultrapure hydrogen gas. Cylindrical wire chambers and a segmented scintillator barrel detected electrons from muon decay. Λ(S) is determined from the difference between the µ(-) disappearance rate in hydrogen and the free muon decay rate. The result is based on the analysis of 1.2 × 10(10) µ(-) decays, from which we extract the capture rate Λ(S) = (714.9 ± 5.4(stat) ± 5.1(syst)) s(-1) and derive the proton's pseudoscalar coupling g(P)(q(0)(2) = -0.88 m(µ)(2)) = 8.06 ± 0.55.

Can simulation-based education or other education interventions replace clinical placement in medical radiation sciences? A narrative review.

OBJECTIVES: In response to increasing student enrolment and workload pressures from the Covid-19 pandemic, a recent focus on health student preparation programs has been on curricula adaptations and replacement of clinical placement time with alternative education activities. The aim of the narrative review was to explore the current evidence relating to education activities in Medical Radiation Sciences (MRS) used to replace clinical placements or part of clinical placements. Medline, CINAHL and Web of Science databases were used to search for articles published between 2017 and 2022. Data from the literature was summarised into (1) planning and development of clinical replacement learning activities in MRS, (2) evaluation of clinical replacement activities, and (3) benefits and challenges of clinical replacement in MRS. KEY FINDINGS: Planning and development of clinical replacement learning activities in MRSrequires support from a wide range of stakeholders, and evidence from activities already implemented exists. Activities largely encompass an institution-specific focus. Developed clinical replacement activities use a blended approach, with simulation-based education (SBE) as a main teaching platform. Evaluation of clinical replacement activities are largely focused on students' achievement of learning objectives relating to practical and communication skills. Emerging evidence based on small student samples shows that clinical and clinical replacement activities provide similar results in terms of learning objectives. CONCLUSION: Benefits and challenges of clinical replacement in MRS are similar to those presented in the other health professions. The balance between quality and quantity of teaching and learning experiences for clinical skill development in MRS needs to be further investigated. IMPLICATIONS FOR PRACTICE: To meet the dynamic challenges of the health care environment and MRS profession, a major goal in the future will be to affirm the benefit of clinical replacement activities for MRS students.

Measurement of the positive muon lifetime and determination of the Fermi constant to part-per-million precision.

We report a measurement of the positive muon lifetime to a precision of 1.0 ppm; it is the most precise particle lifetime ever measured. The experiment used a time-structured, low-energy muon beam and a segmented plastic scintillator array to record more than 2×10(12) decays. Two different stopping target configurations were employed in independent data-taking periods. The combined results give τ(µ(+)) (MuLan)=2 196 980.3(2.2) ps, more than 15 times as precise as any previous experiment. The muon lifetime gives the most precise value for the Fermi constant: G(F) (MuLan)=1.166 378 8(7)×10(-5) GeV(-2) (0.6 ppm). It is also used to extract the µ(-)p singlet capture rate, which determines the proton's weak induced pseudoscalar coupling g(P).

Experimental investigation of geologically produced antineutrinos with KamLAND.

The detection of electron antineutrinos produced by natural radioactivity in the Earth could yield important geophysical information. The Kamioka liquid scintillator antineutrino detector (KamLAND) has the sensitivity to detect electron antineutrinos produced by the decay of 238U and 232Th within the Earth. Earth composition models suggest that the radiogenic power from these isotope decays is 16 TW, approximately half of the total measured heat dissipation rate from the Earth. Here we present results from a search for geoneutrinos with KamLAND. Assuming a Th/U mass concentration ratio of 3.9, the 90 per cent confidence interval for the total number of geoneutrinos detected is 4.5 to 54.2. This result is consistent with the central value of 19 predicted by geophysical models. Although our present data have limited statistical power, they nevertheless provide by direct means an upper limit (60 TW) for the radiogenic power of U and Th in the Earth, a quantity that is currently poorly constrained.

Hyaline astrocytic inclusions in pediatric epilepsy: report of two cases.

Distinctive hyaline inclusion bodies in the cytoplasm of neocortical astrocytes were observed in surgical resection specimens of a frontal epileptic focus, in 2 patients aged 16 and 10 who had suffered intractable partial seizures since the age of 2 years. One case had minimal neurological impairment and no brain malformation on MRI and recovered completely following surgery. The second case had mental retardation and surgery reduced the frequency and generalization of seizures. In both cases, the astrocytic inclusions were strongly eosinophilic, hyaline and refractile. They were PAS negative. Electron microscopy in the first case, confirmed their granular osmiophilic structure. By immunohistochemistry, the inclusions were strongly positive for filamin in the first case, only some were weakly positive in the second case. They also variably expressed other proteins such as alpha-B-crystallin, GFAP, S-100 protein and cytoglobin. We compare our findings with previously reported cases and discuss the clinical significance of the inclusions and the pathophysiologic relevance of filamin A and other proteins accumulation in astrocytes.

The misinterpretation rates of radiology residents on emergent neuroradiology magnetic resonance (MR) angiogram studies: correlation with level of residency training.

The purpose of this study was to determine the discrepancy rates of radiology residents interpreting emergent neck and Circle of Willis magnetic resonance angiography (MRA) studies and to detect any adverse clinical outcomes. Three hundred seventeen MRA studies given preliminary reading by radiology residents were retrospectively reviewed over a 2-year period. Discrepancies were classified as either false negatives (failure to diagnose abnormalities) or false positives (misinterpreting normal scans as abnormal). The overall discrepancy rate was 12.1% for Circle of Willis MRA and 7.9% for neck MRA. Fourth-year residents had the lowest discrepancy rates (7.7%), but this was not statistically significant. The most common misses were stenosis greater than 70% (n = 9) and aneurysm (n = 12). No adverse clinical outcome was detected mainly due to rapid turnaround time for final reporting.

Unilateral carotid granulomatous arteritis and Crohn's disease.

Chronic idiopathic granulomatous arteritis of the large vessels - and, specifically, "Takayasu's arteritis" and "giant cell arteritis" - is an unusual condition that rarely leads to stroke and is only occasionally associated with Crohn's disease. We report here on a unique case of a 56-year-old man with a 25-year history of Crohn's disease who also had a 4-year history of recurrent right-sided ischaemic strokes and partial seizures, and a unilateral progressive retrograde occlusion of the right internal and common carotid arteries. Biopsies of the temporal and carotid arteries showed large-vessel granulomatous arteritis, with features of both giant cell and Takayasu's arteritis.

High-concentration nonavian high-molecular weight hyaluronan injections and time-to-total knee replacement surgery.

Aim: To examine the time-to-total knee replacement (TKR) surgery among patients with high-concentration nonavian high-molecular-weight hyaluronan injection (HMW-HA) compared with those without HA injections. Materials & methods: Using MarketScan® Commercial claims all patients aged 18-64 who underwent TKR surgery between 2008 and 2017 were identified. Time-to-TKR surgery was compared between patients receiving Orthovisc® (Anika Therapeutics Inc. Bedford MA, USA, referred to as nonavian HMW-HA) injections and patients who did not receive an HA injection. Results: The median time-to-TKR surgery was 893 days in the nonavian HMW-HA cohort and 399 days in the non-HA cohort (p < 0.001), a difference of 494 days (16.2 months). Conclusion: This study demonstrates that the time-to-TKR surgery is 16.2 months longer in patients who received treatment with nonavian HMW-HA injections.

Cerebral immunoglobulin light chain amyloid angiopathy-related hemorrhages.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is a common cause of intracerebral hemorrhage (ICH) particularly in elderly patients. In CAA-related hemorrhages, amyloid deposits in the brain vessel walls mainly contain amyloid beta-protein (A-beta). Rarely other forms of amyloid substances have been reported in sporadic CAA-related hemorrhages. METHODS: We report the case of a 44-year-old patient with recurrent ICH who had surgical evacuation of a large frontal hematoma. Following surgery, samples from the hematoma and adjacent cerebral cortex were obtained for histopathological examination. RESULTS: Within the recent hemorrhage, a few arteriolar walls were thickened with an amyloid deposit that was immunostained for immunoglobulin (Ig) M and light chain lambda. In the wall of some vessels, around the amyloid deposits, as well as in the adjacent cerebral cortex, there was an infiltration by monotypic lymphocytes and plasma cells expressing IgM and light chain lambda. No amyloid deposition was found outside the hemorrhage. There was no evidence of multiple myeloma, B-cell malignancy, or systemic amyloidosis. CONCLUSIONS: Recurrent ICH may be due to amyloid deposition of IgM lambda produced by monotypic proliferation of lymphocytes and plasma cells purely localized to the brain.

[Neurenteric cyst of the posterior fossa. Case report and review of the literature]. / Kyste neurentérique de la fosse postérieure. A propos d'un cas, revue de la littérature.

Intracranial neurenteric cysts are rare entities. The term is currently used to describe epithelial cysts that are lined with a presumed endodermal-derived epithelium and are mostly located in the posterior fossa. Preoperative diagnosis is often difficult because of their clinical presentation, which may resemble a subarachnoid hemorrhage, and the radiological aspect, which can mimic vascular pathologies. We describe a posterior fossa neurenteric cyst in a 27-year-old woman, who presented with sudden headache as the only symptom and who was addressed to our hospital for subarachnoid hemorrhage. Diagnostic angiography was negative and MRI revealed a prepontine cystic lesion. The patient underwent a posterolateral approach on the right side, with subtotal resection of the lesion. We discuss the embryologic, diagnostic and therapeutic aspects of these cysts and review the literature.

Real-world impact of the high concentration non-avian high molecular weight hyaluronan on pain medication use among osteoarthritis patients.

Objective: A prior study found that hyaluronic acid (HA) treatment may help reduce pain medication use (such as steroids, non-steroidal anti-inflammatory drugs [NSAIDs] and opioids) among knee osteoarthritis (OA) patients in the real-world setting. This study aims to update the prior study results to include only the high concentration non-avian high molecular weight hyaluronan (HMW-HA) injectables using data from recent years.Study design: This was a retrospective cohort study utilizing IBM MarketScan Commercial data from 2008 to 2015.Methods: Commercially insured patients between 18 and 64 years of age who received high concentration non-avian HMW-HA (Orthovisc1) between 1 January 2008 and 30 June 2015 were identified. Utilization of three prescription pharmacotherapies commonly used in the treatment for knee OA - NSAIDs, corticosteroid injections and opioids - in the 6 month pre and post periods was assessed. Utilization was measured as number of prescriptions and any prescription (yes/no). The independent variable was receiving the high concentration non-avian HMW-HA injection. Paired sample t-test and McNemar's test were used to assess pre-post changes.Results: The utilization of NSAIDs and steroids prescriptions was reduced significantly during the post period among the study cohort. The proportion of patients filling these prescriptions during the post period was also reduced (p < .001). In addition, the number of patients getting any opioid prescriptions was reduced significantly during the post period (p < .001).Conclusions: Based on this retrospective cohort study, the high concentration non-avian HMW-HA may offer effective pain alleviation among knee OA patients while reducing prescription pain medications such as steroids, NSAIDs and opioids.

Multifocal Epstein-Barr virus-associated smooth muscle tumor in adults with AIDS: case report and review of the literature.

OBJECTIVES: The aim of this study was to provide a systematic review of Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) in human immunodeficiency virus (HIV)-infected adults, focusing on clinical and histopathologic features and outcome. METHODS: A literature search was performed using Medline, Embase and the Cochrane Library. RESULTS: We reviewed 35 cases including our case of a patient with a progressive multifocal EBV-SMT. Patients were mainly men (n = 24) with a mean age of 35.5 years. Median CD4 count was 21/mm(3). Main locations were brain (n = 12), liver (n = 8), spinal cord (n = 7) and adrenal gland (n = 6). The tumors were multifocal in 34% of cases, whereas analysis of clonality showed different clones in tumors from different sites. Treatment included removal surgery in 17 cases and/or radiotherapy in 9 and therapeutic abstention in 4. Mean follow-up after diagnosis was 12.3 months. Nine patients died during this period essentially from opportunistic infection and only 2 from the disease. CONCLUSION: EBV-SMT should be added to the list of virally induced tumors in severely immunocompromised HIV-infected adults. Multifocality of independent tumor clones, especially in liver, brain, spinal cord and adrenal gland, and a slow disease progression seem to be the key features of these tumors, the treatment of which remains poorly defined.

An autopsy case of acute multiple sclerosis (Marburg's type) during pregnancy.

We report a case of a 9-month pregnant woman who presented acute psychiatric and neurological symptoms with extensive involvement of the white matter on MRI and no oligoclonal bands on CSF examination. Despite high doses of intravenous steroids, plasmapheresis and immunosuppressive drugs, a fatal outcome (coma) was noted 8 months later. Neuropathological examination confirmed the diagnosis of Marburg's type of multiple sclerosis showing sharp-edged lesions of demyelination, giant astrocytes, numerous macrophages and little perivascular inflammation. We discuss the definition and limits of the Marburg entity with reference to acute disseminated encephalomyelitis, impact of pregnancy, unusual MRI features, neuropathology and treatment.

[Malignant mixed müllerian tumor of the uterus following tamoxifen for breast cancer: case report]. / Tumeur müllérienne mixte de l'utérus après traitement par tamoxifène pour cancer du sein: à propos d'un cas.

Tamoxifen is an antioestrogen widely used in the breast cancer treatment. Its paradoxical antioestrogenic action on breast and its oestrogenic action on the endometer is well-known. Since 1988, few cases of malignant mixed müllerian tumors following tamoxifen were described. We report a new case of uterine malignant mixed müllerian tumor four years after the end of tamoxifen for breast cancer.