The large mitochondrial genomes of angiosperms are unusually dynamic because of recombination activities involving repeated sequences. These activities generate subgenomic forms and extensive genomic ...variation even within the same species. Such changes in genome structure are responsible for the rapid evolution of plant mitochondrial DNA and for the variants associated with cytoplasmic male sterility and abnormal growth phenotypes. Nuclear genes modulate these processes, and over the past decade, several of these genes have been identified. They are involved mainly in pathways of DNA repair by homologous recombination and mismatch repair, which appear to be essential for the faithful replication of the mitogenome. Mutations leading to the loss of any of these activities release error-prone repair pathways, resulting in increased ectopic recombination, genome instability, and heteroplasmy. We review the present state of knowledge of the genes and pathways underlying mitochondrial genome stability.
The incidence of placenta accreta spectrum is rising. Management is most commonly with cesarean hysterectomy. These deliveries often are complicated by massive hemorrhage, urinary tract injury, and ...admission to the intensive care unit. Up to 60% of patients require transfusion of ≥4 units of packed red blood cells. There is also a significant risk of death of up to 7%.
The purpose of this study was to assess the outcomes of patients with antenatal diagnosis of placenta percreta that was managed with delayed hysterectomy as compared with those patients who underwent immediate cesarean hysterectomy.
We performed a retrospective study of all patients with an antepartum diagnosis of placenta percreta at our large academic institution from January 1, 2012, to May 30, 2018. Patients were treated according to standard clinical practice that included scheduled cesarean delivery at 34–35 weeks gestation and intraoperative multidisciplinary decision-making regarding immediate vs delayed hysterectomy. In cases of delayed hysterectomy, the hysterotomy for cesarean birth used a fetal surgery technique to minimize blood loss, with a plan for hysterectomy 4–6 weeks after delivery. We collected data regarding demographics, maternal comorbidities, time to interval hysterectomy, blood loss, need for transfusion, occurrence of urinary tract injury and other maternal complications, and maternal and fetal mortality rates. Descriptive statistics were performed, and Wilcoxon rank-sum and chi-square tests were used as appropriate.
We identified 49 patients with an antepartum diagnosis of placenta percreta who were treated at Vanderbilt University Medical Center during the specified period. Of these patients, 34 were confirmed to have severe placenta accreta spectrum, defined as increta or percreta at the time of delivery. Delayed hysterectomy was performed in 14 patients: 9 as scheduled and 5 before the scheduled date. Immediate cesarean hysterectomy was completed in 20 patients: 16 because of intraoperative assessment of resectability and 4 because of preoperative or intraoperative bleeding. The median (interquartile range) estimated blood loss at delayed hysterectomy of 750 mL (650–1450 mL) and the sum total for delivery and delayed hysterectomy of 1300 mL (70 –2150 mL) were significantly lower than the estimated blood loss at immediate hysterectomy of 3000 mL (2375–4250 mL; P<.01 and P=.037, respectively). The median (interquartile range) units of packed red blood cells that were transfused at delayed hysterectomy was 0 (0–2 units), which was significantly lower than units transfused at immediate cesarean hysterectomy (4 units 2–8.25 units; P<.01). Nine of 20 patients (45%) required transfusion of ≥4 units of red blood cells at immediate cesarean hysterectomy, whereas only 2 of 14 patients (14.2%) required transfusion of ≥4 units of red blood cells at the time of delayed hysterectomy (P=.016). There was 1 maternal death in each group, which were incidences of 7% and 5% in the delayed and immediate hysterectomy patients, respectively.
Delayed hysterectomy may represent a strategy for minimizing the degree of hemorrhage and need for massive blood transfusion in patients with an antenatal diagnosis of placenta percreta by allowing time for uterine blood flow to decrease and for the placenta to regress from surrounding structures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Au Canada, 45 % des nouveaux cas de cancer et 63 % des décès dus au cancer se produisent chez les Canadiens de 70 ans et plus. Ces personnes âgées et leurs familles ont des préoccupations et des ...besoins particuliers, mais qui demeurent souvent mal reconnus et satisfaits. Or, le nombre de personnes âgées au Canada devrait plus que doubler au cours des 25 prochaines années. Nous devons donc intégrer à notre pratique en oncologie, de même qu’aux politiques, à la recherche et à la formation, une meilleure compréhension du vieillissement, et développer des modèles de soins optimisés et adéquats pour les personnes âgées. Le groupe d’intérêt sur l’oncologie et le vieillissement de l’Association canadienne des infirmières en oncologie (ACIO) est une initiative incitant les infirmières du domaine à se pencher sur ces questions. Nous résumons ici les faits saillants de l’atelier qui a donné le coup d’envoi à ce groupe lors de la conférence annuelle de l’ACIO en 2015 et rappelons les priorités et problèmes liés à la pratique qui ont été relevés pendant les échanges avec les participants. Nous relatons également la façon dont le groupe d’intérêt a évolué depuis sa création et listons les objectifs qui orienteront les prochaines étapes.
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NUK, OILJ, UL, UM, UPUK, VSZLJ
Summary
Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more ...clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem‐like cells, a source of post‐treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM‐infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)‐β‐mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single‐cell transcriptomics demonstrated that both tumour and haematopoietic‐derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co‐expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti‐tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.
Our manuscript challenges the current paradigm that Glioblastoma (GBM) is a poor candidate for immunotherapy, therefore impacting on clinical approaches. We identify NK cells as a target for immunosuppression in GBM, with multiple suppressive pathways within GBM human tumours. We also identify a group of GBM patients with higher immunological activity, who will benefit from immunotherapies that target these immunosuppressive pathways.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Plaque control in patients with periodontal disease is critically dependent upon self‐care through specific oral hygiene‐related behaviours.
Objectives
To determine the relationship ...between adherence to oral hygiene instructions in adult periodontal patients and psychological constructs. To determine the effect of interventions based on psychological constructs on oral health‐related behaviour in adult periodontal patients.
Data Sources
The Cochrane Oral Health Group's Trials Register, MEDLINE, EMBASE and PsycINFO.
Study Appraisal and Synthesis Methods
Studies were grouped according to the study design, and appraised using an appropriate methodology, either the Newcastle‐Ottawa assessment for observational studies, or the Cochrane criteria for trials.
Results
Fifteen reports of studies were identified.
Limitations
There was a low risk of bias identified for the observational studies. Older trials suffered from high risk of bias, but more recent trials had low risk of bias. However, the specification of the psychological intervention was generally poor.
Conclusions and Implications of Key Findings
The use of goal setting, self‐monitoring and planning are effective interventions for improving oral hygiene‐related behaviour in patients with periodontal disease. Understanding the benefits of behaviour change and the seriousness of periodontal disease are important predictors of the likelihood of behaviour change.
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BFBNIB, CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains ...poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells.
The interstellar medium of the Milky Way is multiphase, magnetized and turbulent. Turbulence in the interstellar medium produces a global cascade of random gas motions, spanning scales ranging from ...100 parsecs to 1,000 kilometres (ref. 4). Fundamental parameters of interstellar turbulence such as the sonic Mach number (the speed of sound) have been difficult to determine, because observations have lacked the sensitivity and resolution to image the small-scale structure associated with turbulent motion. Observations of linear polarization and Faraday rotation in radio emission from the Milky Way have identified unusual polarized structures that often have no counterparts in the total radiation intensity or at other wavelengths, and whose physical significance has been unclear. Here we report that the gradient of the Stokes vector (Q, U), where Q and U are parameters describing the polarization state of radiation, provides an image of magnetized turbulence in diffuse, ionized gas, manifested as a complex filamentary web of discontinuities in gas density and magnetic field. Through comparison with simulations, we demonstrate that turbulence in the warm, ionized medium has a relatively low sonic Mach number, M(s) ≲ 2. The development of statistical tools for the analysis of polarization gradients will allow accurate determinations of the Mach number, Reynolds number and magnetic field strength in interstellar turbulence over a wide range of conditions.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Coxiella burnetii is an intracellular pathogen that replicates in a lysosome-derived vacuole. The molecular mechanisms used by this bacterium to create a pathogen-occupied vacuole remain largely ...unknown. Here, we conducted a visual screen on an arrayed library of C. burnetii NMII transposon insertion mutants to identify genes required for biogenesis of a mature Coxiella-containing vacuole (CCV). Mutants defective in Dot/Icm secretion system function or the PmrAB regulatory system were incapable of intracellular replication. Several mutants with intracellular growth defects were found to have insertions in genes encoding effector proteins translocated into host cells by the Dot/Icm system. These included mutants deficient in the effector proteins Cig57, CoxCC8 and Cbu1754. Mutants that had transposon insertions in genes important in central metabolism or encoding tRNA modification enzymes were identified based on the appearance filamentous bacteria intracellularly. Lastly, mutants that displayed a multi-vacuolar phenotype were identified. All of these mutants had a transposon insertion in the gene encoding the effector protein Cig2. Whereas vacuoles containing wild type C. burnetii displayed robust accumulation of the autophagosome protein LC3, the vacuoles formed by the cig2 mutant did not contain detectible amounts of LC3. Furthermore, interfering with host autophagy during infection by wild type C. burnetii resulted in a multi-vacuolar phenotype similar to that displayed by the cig2 mutant. Thus, a functional Cig2 protein is important for interactions between the CCV and host autophagosomes and this drives a process that enhances the fusogenic properties of this pathogen-occupied organelle.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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