The impact of age on endothelial dysfunction measured by peripheral arterial tonometry in a healthy population-based cohort - the Malmö offspring study.

BACKGROUND/AIMS: The reactive hyperaemia index (RHI) assesses endothelial function, with a proposed cut-off of <1.67 for prevalent endothelial dysfunction (ED). However, uncertainties remain about whether this cut-off is age-dependent and applicable in healthy individuals. We aimed to explore ED in relation to age within a large population-based cohort of young to middle-aged, healthy individuals. METHODS: Within the Malmö Offspring Study, a total of 1812 subjects (50.9% women, mean age 48 ± 11 years) were included. Post-occlusion/pre-occlusion ratio of the pulsatile signal amplitudes in the non-dominant upper arm was used to calculate RHI by EndoPat®. ED was defined as RHI < 1.67. Multivariable regression models were used to explore associations between ED and age. RESULTS: Prevalent ED was found in 534 (29.5%) participants. In subjects aged ≤30 years, ED was present in 47.4% compared to 27.6% in subjects ≥30 years (p < 0.001). In multivariable logistic regression analyses, ED was associated with younger age (p < 0.001), higher BMI (p < 0.001) and current smoking (p < 0.001). No sex differences were observed. CONCLUSION: In a large healthy population, RHI < 1.67, an early marker of endothelial dysfunction, was more prevalent in younger individuals, implying that RHI might not be a suitable measure of endothelial function in individuals under 30 years of age. Our findings suggest that low RHI in young, healthy individuals may not necessarily indicate true ED but rather an artefact of the limited ability of young and healthy arteries to dilate post-occlusion. Therefore, the term "pseudo-ED" may be applicable to young individuals with low RHI values.

What is the context?The endothelium is a thin layer of cells that lines the inside of blood vessels, and its proper function is crucial for the maintenance of vascular health. Endothelial dysfunction (ED) is an early marker of cardiovascular disease and is characterised by impaired dilation of blood vessels, which can lead to reduced blood flow and increased risk of heart attacks and strokes. The reactive hyperaemia index (RHI) is a widely used non-invasive test that measures endothelial function by evaluating the dilation of blood vessels in response to temporary occlusion.What is new?This study aimed to investigate the relationship between age and ED in a large population-based cohort of young to middle-aged healthy individuals. The results showed that prevalent ED was more common in younger individuals, with 47.4% of participants aged ≤30 years having ED, compared to 27.6% in those ≥30 years. The study also found that ED was associated with higher BMI and current smoking, but no sex differences were observed.What is the impact?The findings suggest that the proposed RHI cut-off of <1.67 for prevalent ED may not be applicable to individuals under the age of 30, as young and healthy arteries may have limited ability to dilate post-occlusion, resulting in low RHI values that do not necessarily indicate true ED. Therefore, the term "pseudo-ED" may be more appropriate for young individuals with low RHI values.

Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons. RESULTS: Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5-Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk. CONCLUSION: Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.

Chronic opioid use before and after exercise therapy and patient education among patients with knee or hip osteoarthritis.

OBJECTIVE: To investigate changes in opioid use after supervised exercise therapy and patient education among knee or hip osteoarthritis patients with chronic opioid use. METHOD: In this cohort study, we linked data from the Good Life with osteoArthritis in Denmark register (GLA:D®; standardised treatment program for osteoarthritis; January 2013 to November 2018) with national health registries. Among 35,549 patients, 1,262 were classified as chronic opioid users based on amount and temporal distribution of dispensed opioids the year before the intervention. We investigated changes in opioid use, measured as mg oral morphine equivalents (OMEQs), from the year before the intervention to the year after using generalized estimating equations. RESULTS: We found a 10% decrease in mg OMEQs from the year before to the year after the intervention (incidence rate ratio [IRR]: 0.90, 95% confidence interval [CI]: 0.86, 0.94). Additional analyses suggested this decrease to be mainly attributable to regulatory actions targeting opioid prescribing during the study period (IRR among patients participating in the intervention before: 0.98 [95% CI: 0.89, 1.07] vs after: 0.83 [0.74, 0.93] regulatory actions). In a random general population sample of matched chronic opioid users, a similar opioid use pattern was observed over time, further supporting the impact of regulatory actions on the opioid use in the study population. CONCLUSION: Among patients with knee or hip osteoarthritis and chronic opioid use, a standardised treatment program did not change opioid use when regulatory changes in opioid prescribing were taken into account.

An off-target scale limits the utility of Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS) as a measure of well-being in public health surveys.

OBJECTIVES: To assess the utility and measurement properties for the well-being scale Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS) in a Swedish general population survey. STUDY DESIGN: A cross-sectional survey study. METHODS: Data were retrieved from the 2018 public health survey in Stockholm County, containing a random sample of 22 856 persons stratified to be representative for the municipalities and districts within the region. The data were analyzed according to Rasch Measurement Theory. RESULTS: Person attribute values are positively skewed (mean 2.32, SD 1.85), with wide gaps in the item threshold attribute values. Overall item fit statistics were acceptable, and person measurement separation reliability was 0.83, indicating three statistically distinct ranges in the estimated well-being values. CONCLUSION: While the SWEMWBS items indicated acceptable fit to the Rasch measurement model, targeting of items to sample is skewed toward lower levels of well-being, and there is a ceiling effect. Thus, we suggest a careful reconsideration of SWEMWBS as a tool for use in general public health surveys, especially for assessing change over time and group differences, as there are large measurement uncertainties for the majority of cases when the population as a whole is sampled. We encourage revisions applying a coherent and comprehensive ordinal construct theory for well-being to fill the gaps in the upper end of the SWEMWBS scales' item thresholds. The addition of more challenging items would improve targeting for population-based surveys, increase reliability, and provide more actionable information that could be useful in improving individuals' well-being.

Control computerized tomography in neoadjuvant chemotherapy for muscle invasive urinary bladder cancer has no value for treatment decisions and low correlation with nodal status.

BACKGROUND: Control computerized tomography (cCT) is routinely used in many cystectomy centres before the final treatment cycle in patients with muscle-invasive urinary bladder cancer (MIBC) undergoing neoadjuvant chemotherapy (NAC). This is for evaluating response or nonresponse to NAC treatment. In a real-world retrospective cohort, we intended to evaluate the frequency of changed individual treatment strategies following cCT and to investigate any discrepancies between cCT-results on nodal staging and final pN-stages. METHODS: We performed a retrospective data-based, multicenter study of 242 MIBC-patients, staged cT2N0M0-cT4aN0M0, having undergone NAC and radical cystectomy (RC) between 2008 and 2019 at four Swedish cystectomy centres. Statistical analysis was performed using IBM SPSS statistics 26. RESULTS: Overall, 139/242 patients were examined with cCT. Six patients were staged as progressive at cCT and 5/139 (3.6%) underwent a change of previously planned treatment strategy. 2/6 patients with suspected progression (33%) did not change strategy and underwent all preplanned NAC-cycles plus RC. Only 1/6 patients assigned as progressive at the cCT, showed progression in the postoperative pathology specimen. In total 133/139 patients were considered being without progress on cCT, yet 28/133 (21%) presented with nodal progression at postoperative pathology examinations. Only 1/29 patients with histopathologically verified nodal dissemination were detected with cCT, thus 28/29 (96.6%) with pN + were undetected. The sensitivity for cCT to predict pTNM was 17% CI [0%-64%] and the specificity was 78% CI [71%-86%]. CONCLUSIONS: CCT prior to the final treatment cycle of NAC in MIBC, leads to a low percentage of treatment strategy changes and cCT cannot accurately predict pN-status.

Role of Aurora B and Haspin kinases in the metaphase Topoisomerase II checkpoint.

DNA Topoisomerase II (TopoII) uses ATP hydrolysis to decatenate chromosomes so that sister chromatids can faithfully segregate in mitosis. When the TopoII enzyme cycle stalls due to failed ATP hydrolysis, the onset of anaphase is delayed, presumably to allow extra time for decatenation to be completed. Recent evidence revealed that, unlike the spindle assembly checkpoint, this TopoII checkpoint response requires Aurora B and Haspin kinases and is triggered by SUMOylation of the C-terminal domain of TopoII.

Gamma-radiation induced synthesis of freestanding nickel nanoparticles.

A versatile method to produce metallic nickel nanoparticles is demonstrated. Metallic Ni nanoparticles have been synthesized from aqueous solution of NiCl2 using γ-radiation induced reduction. To prevent Ni re-oxidation, post-irradiation treatment was elaborated. Structural and compositional analyses were executed using X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy. These studies reveal that the synthesized material consists of fcc Ni particles having size of 3.47 ± 0.71 nm. The nanoparticles have a tendency to agglomerate to the larger clusters. The latter are partially oxidized to form thin amorphous/poor-crystalline Ni(OH)2/NiO layers at the surface. Magnetization measurements demonstrate that the nanomaterial exhibit ferromagnetic-like behaviour with magnetization 30% lower than that in bulk Ni. The large active surface area (ECSA, 39.2 m2 g-1) and good electrochemical reversibility, confirmed by the electrochemical studies, make the synthesized material a potential candidate as an active component for energy storage devices.

Childhood allergy is preceded by an absence of gut lactobacilli species and higher levels of atopy-related plasma chemokines.

Alterations in the composition and reduced diversity of the infant microbiome are associated with allergic disease in children. Further, an altered microbiota is linked to immune dysregulation, including skewing of different T helper (Th) subsets, which is also seen in atopic individuals. The aim of this study was, therefore, to investigate the associations between gut lactobacilli and Th-related plasma factors in allergy development during childhood. A total of 194 children with known allergy status at 1 year of age were followed to 10 years of age. We used real-time polymerase chain reaction (PCR) to investigate the presence of three lactobacilli species (Lactobacillus casei, L. paracasei, L. rhamnosus) in infant fecal samples (collected between 1 week and 2 months of age) from a subgroup of children. Plasma chemokines and cytokines were quantified at 6 months and at 1, 2, 5 and 10 years of age with Luminex or enzyme-linked immunosorbent assay (ELISA). Fractional exhaled nitrogen oxide (FeNO) was measured and spirometry performed at 10 years of age. The data were analysed by non-parametric testing and a logistic regression model adjusted for parental allergy. An absence of these lactobacilli and higher levels of the chemokines BCA-1/CXCL13, CCL17/TARC, MIP-3α/CCL20 and MDC/CCL22 in plasma at 6 months of age preceded allergy development. The presence of lactobacilli associated with lower levels of atopy-related chemokines during infancy, together with higher levels of interferon (IFN)-γ and lower FeNO during later childhood. The results indicate that the presence of certain lactobacilli species in the infant gut may influence allergy-related parameters in the peripheral immune system, and thereby contribute to allergy protection.

Effect of hysterectomy on pain in women with endometriosis: a population-based registry study.

OBJECTIVE: To assess pain symptoms before and after hysterectomy in women with endometriosis. DESIGN: A population-based registry study. SETTING: Sweden. POPULATION: Women aged 18-45 years who underwent hysterectomy for endometriosis between 2010 and 2015. METHODS: Pain symptoms before hysterectomy and 12 months after surgery were collected from the Swedish National Quality Register for Gynaecological Surgery (GynOp). Pain symptoms were also assessed by follow-up surveys after a median follow-up period of 63 months. MAIN OUTCOME MEASURES: Pelvic or lower abdominal pain after hysterectomy. RESULTS: The study included 137 women. The proportion of women experiencing pain of any severity decreased by 28% after hysterectomy (P < 0.001). The proportion of women with severe pain symptoms decreased by 76% after hysterectomy (P < 0.001). The majority of women (84%) were satisfied with the surgical result. Presence of severe pain symptoms after the hysterectomy was associated with less satisfaction (P < 0.001). Pain symptoms after surgery, patient satisfaction and the patient's perceived improvement were not significantly different between women whose ovarian tissue was preserved and women who underwent bilateral oophorectomy. CONCLUSIONS: We observed a significant, long-lasting reduction in pain symptoms after hysterectomy among women with endometriosis. Hysterectomy, with the possibility of ovarian preservation, may be a valuable option for women with endometriosis who suffer from severe pain symptoms. TWEETABLE ABSTRACT: Hysterectomy is a valuable option for women with endometriosis and severe pain symptoms.

GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia?

Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APα), it's role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APα depend on administration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APα and APα antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials.

Genomic Epidemiology as a Public Health Tool to Combat Mosquito-Borne Virus Outbreaks.

Next-generation sequencing technologies, exponential increases in the availability of virus genomic data, and ongoing advances in phylogenomic methods have made genomic epidemiology an increasingly powerful tool for public health response to a range of mosquito-borne virus outbreaks. In this review, we offer a brief primer on the scope and methods of phylogenomic analyses that can answer key epidemiological questions during mosquito-borne virus public health emergencies. We then focus on case examples of outbreaks, including those caused by dengue, Zika, yellow fever, West Nile, and chikungunya viruses, to demonstrate the utility of genomic epidemiology to support the prevention and control of mosquito-borne virus threats. We extend these case studies with operational perspectives on how to best incorporate genomic epidemiology into structured surveillance and response programs for mosquito-borne virus control. Many tools for genomic epidemiology already exist, but so do technical and nontechnical challenges to advancing their use. Frameworks to support the rapid sharing of multidimensional data and increased cross-sector partnerships, networks, and collaborations can support advancement on all scales, from research and development to implementation by public health agencies.

Revealing structural evolution occurring from photo-initiated polymer network formation.

Photopolymerization is a key enabling technology offering spatial and temporal control to allow for future functional materials to be made to meet societal needs. However, gaining access to robust experimental techniques to describe the evolution of nanoscale morphology in photo-initiated polymeric systems has proven so far to be a challenging task. Here, we show that these physical transformations can be monitored and quantified at the nanoscale in situ and in real-time. It is demonstrated that the initial structural features of the liquid precursors significantly affect the final morphology and the physical properties of the resulting solid via the occurrence of local heterogeneities in the molecular mobility during the curing transformation. We have made visible how local physical arrestings in the liquid, associated with both cross-linking and vitrification, determine the length scale of the local heterogeneities forming upon curing, found to be in the 10-200 nm range.

Distribution of bacteria between different milk fractions, investigated using culture-dependent methods and molecular-based and fluorescent microscopy approaches.

AIMS: To develop a protocol for DNA extraction using whole milk and further, to investigate how the use of whole instead of skimmed milk during DNA extraction affected the resulting microbial composition. METHODS AND RESULTS: In a model study, three selected bacterial species (Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 11775 and Lactobacillus reuteri PTA 4659) were added to raw milk and their distribution between different milk fractions was examined by cultivation on selective agar plates. Quantitative real-time PCR (qPCR) assays and Illumina amplicon sequencing were conducted after DNA extraction of whole milk and skimmed milk. In addition, fluorescent microscopy was used to visualize the distribution of Lactobacillus reuteri R2LC mCherry in milk samples with different fat contents. Depending on spike-in bacterial species, recovery rates of 7·4-26·5% of added bacteria were obtained in the fat fraction in culture-based enumeration. qPCR showed a 7-9 fold increase in recovery of spike-in bacteria when the milk fat fraction was combined with the pellet during the DNA extraction step. In the Illumina 16S amplicon approach, relative abundance of six of the top 11 operational taxonomic units identified differed significantly when comparing skimmed milk and whole milk as starting material. Fluorescent microscopy images demonstrated that L. reuteri R2LC mCherry was associated with fat globules in whole milk samples. CONCLUSIONS: This study demonstrates that milk fat harbours bacterial species that might be underestimated when skimmed milk, rather than whole milk, is used for DNA extraction. SIGNIFICANCE AND IMPACT OF THE STUDY: This study emphasizes the importance of using whole instead of skimmed milk for DNA extraction. A protocol for extracting DNA from whole milk is suggested.

Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium.

BACKGROUND: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. PATIENTS AND METHODS: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). RESULTS: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis. CONCLUSIONS: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.

Investigation of self-reported dizziness in the elderly when lying down or turning over in bed, and possible benign paroxysmal positional vertigo.

OBJECTIVES: This study aimed to investigate the rate of dizziness and occurrence of benign paroxysmal positional vertigo in the elderly by physical examination in those reporting dizziness symptoms when lying down or turning over in bed. METHODS: A total of 498 people, aged 70-85 years, were asked to complete a questionnaire regarding dizziness symptoms. Subjects answering that they became dizzy in bed were asked to participate in a physical examination and diagnostic manoeuvres investigating benign paroxysmal positional vertigo. RESULTS: A total of 324 participants (65 per cent) completed the questionnaire. More than one-quarter (29 per cent) reported dizziness and 32 (10 per cent) reported dizziness when turning in bed. Of these 32 persons, 22 (69 per cent) underwent a physical examination. Six participants tested positive for benign paroxysmal positional vertigo. CONCLUSION: Ten per cent of the elderly participants reported positional symptoms, and 6 out of 22 fulfilled diagnostic criteria for benign paroxysmal positional vertigo. Furthermore, benign paroxysmal positional vertigo was established despite a delay between questionnaire completion and investigation, emphasising that this type of dizziness may not be a self-limiting disorder.

Interleukin 4 induces rapid mucin transport, increases mucus thickness and quality and decreases colitis and Citrobacter rodentium in contact with epithelial cells.

Citrobacter rodentium infection is a murine model for pathogenic intestinal Escherichia coli infection. C. rodentium infection causes an initial decrease in mucus layer thickness, followed by an increase during clearance. We aimed to identify the cause of these changes and to utilize this naturally occurring mucus stimulus to decrease pathogen impact and inflammation. We identified that mucin production and speed of transport from Golgi to secretory vesicles at the apical surface increased concomitantly with increased mucus thickness. Of the cytokines differentially expressed during increased mucus thickness, IFN-γ and TNF-α decreased the mucin production and transport speed, whereas IL-4, IL-13, C. rodentium and E. coli enhanced these aspects. IFN-γ and TNF-α treatment in combination with C. rodentium and pathogenic E. coli infection negatively affected mucus parameters in vitro, which was relieved by IL-4 treatment. The effect of IL-4 was more pronounced than that of IL-13, and in wild type mice, only IL-4 was present. Increased expression of Il-4, Il-4-receptor α, Stat6 and Spdef during clearance indicate that this pathway contributes to the increase in mucin production. In vivo IL-4 administration initiated 10 days after infection increased mucus thickness and quality and decreased colitis and pathogen contact with the epithelium. Thus, during clearance of infection, the concomitant increase in IL-4 protects and maintains goblet cell function against the increasing levels of TNF-α and IFN-γ. Furthermore, IL-4 affects intestinal mucus production, pathogen contact with the epithelium and colitis. IL-4 treatment may thus have therapeutic benefits for mucosal healing.

Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3).

BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

On the move through time - a historical review of plant clock research.

The circadian clock is an important regulator of growth and development that has evolved to help organisms to anticipate the predictably occurring events on the planet, such as light-dark transitions, and adapt growth and development to these. This review looks back in history on how knowledge about the endogenous biological clock has been acquired over the centuries, with a focus on discoveries in plants. Key findings at the physiological, genetic and molecular level are described and the role of the circadian clock in important molecular processes is reviewed.

Recycling of MSWI-bottom ash in paved constructions in Sweden - A risk assessment.

This paper presents results from a risk assessment of recycling pre-treated bottom ash from municipal solid waste incineration as a subbase layer in certain asphalt paved constructions in Sweden. Based on a model for assessing environmental and health risks at contaminated areas, previously developed by the Swedish EPA and by the Swedish Geotechnical Institute, target values for total content and porewater concentrations were calculated. Three different construction sizes and geometries were considered; a 1 km long road of 10 and 20 m width, respectively, and an application of 100 × 300 m. Additionally, different technical solutions of the use of bottom as in road embankments were considered. Compared to risk assessments conducted in other countries, target values are generally higher, but in the same order of magnitude. Total lead concentrations in dust potentially emitted during construction and demolition of the bottom ash is identified as a critical factor. It requires particular attention when planning for or carrying out groundwork constructions with pre-treated bottom ash. As exposure to dust and bioavailaibility of lead in bottom ash are likely to be overestimated by the underlying risk model, higher target values for lead in bottom ash should be possible for the envisaged construction purposes without affecting the general risk level. As no data is available on actual dust production and deposition by constructing and demolishing subbase layers of pre-treated bottom ash, this should be a part of future studies in order to narrow down lead target values.

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer.

Tissue-resident memory T (TRM ) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin-expressing TRM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.