Early pregnancy sex steroids during primiparous pregnancies and maternal breast cancer: a nested case-control study in the Northern Sweden Maternity Cohort.
Pregnancy and parity are associated with subsequent breast cancer risk. Experimental and epidemiologic data suggest a role for pregnancy sex steroid hormones. We conducted a nested case-control study in the Northern Sweden Maternity Cohort (1975-2007). Eligible women had provided a blood sample in the first 20 weeks of gestation during a primiparous pregnancy leading to a term delivery. The current study includes 223 cases and 417 matched controls (matching factors: age at and date of blood collection). Estrogen receptor (ER) and progesterone receptor (PR) status was available for all cases; androgen receptor (AR) data were available for 41% of cases (n = 92). Sex steroids were quantified by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression. Higher concentrations of circulating progesterone in early pregnancy were inversely associated with ER+/PR+ breast cancer risk (ORlog2: 0.64 (0.41-1.00)). Higher testosterone was positively associated with ER+/PR+ disease risk (ORlog2: 1.57 (1.13-2.18)). Early pregnancy estrogens were not associated with risk, except for relatively high estradiol in the context of low progesterone (split at median, relative to low concentrations of both; OR: 1.87 (1.11-3.16)). None of the investigated hormones were associated with ER-/PR- disease, or with AR+ or AR+/ER+/PR+ disease. Consistent with experimental models, high progesterone in early pregnancy was associated with lower risk of ER+/PR+ breast cancer in the mother. High circulating testosterone in early pregnancy, which likely reflects nonpregnant premenopausal exposure, was associated with higher risk of ER+/PR+ disease.


Early detection of COPD patients' symptoms with personal environmental sensors: a remote sensing framework using probabilistic latent component analysis with linear dynamic systems.
In this study, we present a cohort study involving 106 COPD patients using portable environmental sensor nodes with attached air pollution sensors and activity-related sensors, as well as daily symptom records and peak flow measurements to monitor patients' activity and personal exposure to air pollution. This is the first study which attempts to predict COPD symptoms based on personal air pollution exposure. We developed a system that can detect COPD patients' symptoms one day in advance of symptoms appearing. We proposed using the Probabilistic Latent Component Analysis (PLCA) model based on 3-dimensional and 4-dimensional spectral dictionary tensors for personalised and population monitoring, respectively. The model is combined with Linear Dynamic Systems (LDS) to track the patients' symptoms. We compared the performance of PLCA and PLCA-LDS models against Random Forest models in the identification of COPD patients' symptoms, since tree-based classifiers were used for remote monitoring of COPD patients in the literature. We found that there was a significant difference between the classifiers, symptoms and the personalised versus population factors. Our results show that the proposed PLCA-LDS-3D model outperformed the PLCA and the RF models between 4 and 20% on average. When we used only air pollutants as input, the PLCA-LDS-3D forecasting results in personalised and population models were 48.67 and 36.33% accuracy for worsening of lung capacity and 38.67 and 19% accuracy for exacerbation of COPD patients' symptoms, respectively. We have shown that indicators of the quality of an individual's environment, specifically air pollutants, are as good predictors of the worsening of respiratory symptoms in COPD patients as a direct measurement.


Severe COVID-19 during pregnancy in Sweden, Norway, and Denmark.
Pregnancy is a risk factor for severe coronavirus disease 2019 (COVID-19) and adverse pregnancy outcomes. We aimed to explore maternal characteristics, pregnancy outcomes, vaccination status, and virus variants among pregnant women admitted to intensive care units (ICU) with severe COVID-19. We identified pregnant women admitted to ICU in Sweden (n = 96), Norway (n = 31), and Denmark (n = 16) because of severe COVID-19, from national registers and clinical databases between March 2020 and February 2022 (Denmark), August 2022 (Sweden), or December 2022 (Norway). Their background characteristics, pregnancy outcome, and vaccination status were compared with all birthing women and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test-positive pregnant women during the same time period. We calculated the number admitted to ICU per 10 000 birthing and per 1000 SARS-CoV-2 test-positive women during the Index, Alpha, Delta, and Omicron periods. Women admitted to ICU had a higher mean body mass index, were more often of non-Scandinavian origin, had on average lower education and income levels, had a higher proportion of chronic and pregnancy-related conditions, delivered preterm, had neonates with low Apgar scores, and had more infants admitted to neonatal care, compared with all birthing and test-positive pregnant women. Of those admitted to ICU, only 7% had been vaccinated before admission. Overall, the highest proportion of women admitted to ICU per birthing was during the Delta period (4.1 per 10 000 birthing women). In Norway, the highest proportion admitted to ICU per test-positive pregnant women was during the Delta period (17.8 per 1000 test-positive), whereas the highest proportion of admitted per test-positive in Sweden and Denmark was seen during the Index period (15.4 and 8.9 per 1000 test-positive, respectively). Admission to ICU because of COVID-19 in pregnancy was a rare event in the Scandinavian countries, but women who were unvaccinated, of non-Scandinavian origin, and with lower socio-economic status were at higher risk of admission to ICU. In addition, women admitted to ICU for COVID-19 had higher risk of adverse pregnancy outcomes.


DOTS in primary care units in the city of Rio de Janeiro, Southeastern Brazil.
To describe the implantation and the effects of directly-observed treatment short course (DOTS) in primary health care units. Interviews were held with the staff of nine municipal health care units (MHU) that provided DOTS in Rio de Janeiro City, Southeastern Brazil, in 2004-2005. A dataset with records of all tuberculosis treatments beginning in 2004 in all municipal health care units was collected. Bivariate analyses and a multinomial model were applied to identify associations between treatment outcomes and demographic and treatment process variables, including being in DOTS or self-administered therapy (SAT). From 4,598 tuberculosis cases treated in public health units administrated by the municipality, 1,118 (24.3%) were with DOTS and 3,480 (75.7%) with SAT. The odds of DOTS were higher among patients with age under 50 years, tuberculosis relapse and prior history of default or treatment failure. The odds of death were 52.0% higher among patients on DOTS as compared to SAT. DOTS modality including community health workers (CHWs) showed the highest treatment success rate. A reduction of 21.0% was observed in the odds of default (vs. cure) among patients on DOTS as compared to patients on SAT, and a reduction of 64.0% among patients on DOTS with CHWs as compared to those without CHWs. Patients with a "low compliance profile" were more likely to be included in DOTS. This strategy improves the quality of care provided to tuberculosis patients, although the proposed goals were not achieved.


HPV Virus Transcriptional Status Assessment in a Case of Sinonasal Carcinoma.
Human Papilloma Virus (HPV) can play a causative role in the development of sinonasal tract malignancies. In fact, HPV may be the most significant causative agent implicated in sinonasal tumorigenesis and is implicated in as many as 21% of sinonasal carcinomas. To date, there are no definitive, reliable and cost-effective, diagnostic tests approved by the FDA for the unequivocal determination of HPV status in head and neck cancers. We followed an exhaustive algorithm to correctly test HPV infection, including a sequential approach with p16INK4a IHC, viral DNA genotyping and in situ hybridization for E6/E7 mRNA. Here, we report a case of sinonasal carcinoma with discordant results using HPV test assays. The tumor we describe showed an irregular immunoreactivity for p16INK4a, and it tested positive for HPV DNA; nevertheless, it was negative for HR-HPV mRNA. We discuss the possible meaning of this discrepancy. It would be advisable to test HPV transcriptional status of sinonasal carcinoma on a diagnostic routine basis, not only by p16INK4a IHC assay, but also by HPV DNA genotyping and HR-HPV mRNA assessment.


Ultra-high density electrodes improve detection, yield, and cell type specificity of brain recordings.
To study the neural basis of behavior, we require methods to sensitively and accurately measure neural activity at single neuron and single spike resolution. Extracellular electrophysiology is a principal method for achieving this, but it has biases in the neurons it detects and it imperfectly resolves their action potentials. To overcome these limitations, we developed a silicon probe with significantly smaller and denser recording sites than previous designs, called Neuropixels Ultra (NP Ultra). This device measures neuronal activity at ultra-high densities (>1300 sites per mm, 10 times higher than previous probes), with 6 μm center-to-center spacing and low noise. This device effectively comprises an implantable voltage-sensing camera that captures a planar image of a neuron's electrical field. We introduce a new spike sorting algorithm optimized for these probes and use it to find that the yield of visually-responsive neurons in recordings from mouse visual cortex improves ~3-fold. Recordings across multiple brain regions and four species revealed a subset of unexpectedly small extracellular action potentials not previously reported. Further experiments determined that, in visual cortex, these do not correspond to major subclasses of interneurons and instead likely reflect recordings from axons. Finally, using ground-truth identification of cortical inhibitory cell types with optotagging, we found that cell type was discriminable with approximately 75% success among three types, a significant improvement over lower-resolution recordings. NP Ultra improves spike sorting performance, sampling bias, and cell type classification.


Intracellular flow cytometric analysis of primary cultured breast tumor cells.
Cell lines are traditionally used as tools for in vitro studies of breast cancer. It is highly debatable however, because of the genetic drift that occurs in such long term cultures how representative these cell lines are of breast cancer in vivo. For this reason primary cultures are generally regarded as a better model. Here we have used a primary culture technique (Int. J. Cancer, 66 (1996) 551; Br. J. Cancer, 78 (1998) 1421) to obtain primary breast cancer cells from 13 breast cancer biopsies. We then describe the development and use of methodology to confirm the purity of the cultures. The acquisition of a highly pure population of epithelial cells was confirmed by flow cytometric analysis of intracellular vimentin and cytokeratin 19. The methodology described will have many applications in studies requiring a highly pure population of epithelial breast cancer cells, as well as wide use in other cancers.


Using stable isotopes in mangrove fisheries research--a review and outlook.
Mangrove forests are important coastal wetlands in most of the tropics, but their importance to fisheries is poorly understood. Rationales for conserving these ecosystems are partly based on ideas that mangroves are important to food webs that support fisheries. Here we review use of stable isotopes to test the strength of the mangrove forest-fish connection, suggesting that a dual focus on both food web ecology and habitat use may be most profitable in future studies of this type.


Zinc coordination to multiple ligand atoms in organic-rich surface soils.
We report on the solid-phase speciation of naturally occurring Zn in metalliferous organic-matter-rich surface soils. Synchrotron-based studies were used to probe elemental distribution and associations in soil particles (micro-XRF) together with the mineralogy (micro-XRD) and Zn bonding environment (Zn-micro-XANES) at the micrometer-scale level. The average bonding environment of Zn was also probed for bulk soils using XANES. We found the distribution of elements within soil particles to be heterogeneous; however, some elements are consistently co-located. While conventional XRD analyses of whole soils did not identify any Zn mineral phase, synchrotron-based-micro-XRD analyses indicated that sphalerite (ZnS) is present in a particle from a wetland soil (soil labeled G3). Linear combination fit (LCF) analyses of XANES spectra collected for bulk soils (Zn-XANES) and microm-regions (Zn-micro-XANES) within soil particles suggest Zn bonds to oxygen-, nitrogen-, and sulfur-functional groups in these sulfur-, nitrogen-, and zinc-rich organic surface soils. The XANES spectra of all bulk soils and of all microm-regions except for the wetland soil (G3), where ZnS was the most significant constituent, were best fitted by the Zn-arginine reference compound and therefore seems to indicate Zn bonding to nitrogen. Thus, these results provide compelling evidence of the formation of highly covalent Zn-organic bonds in the organic-rich surface soils that were studied. This may explain in part why metal partition coefficients (Kd) are generally higher in organic soils, and why the toxic thresholds for total metal concentrations are higher in organic than in mineral soils.


Statistical mutation calling from sequenced overlapping DNA pools in TILLING experiments.
TILLING (Targeting induced local lesions IN genomes) is an efficient reverse genetics approach for detecting induced mutations in pools of individuals. Combined with the high-throughput of next-generation sequencing technologies, and the resolving power of overlapping pool design, TILLING provides an efficient and economical platform for functional genomics across thousands of organisms. We propose a probabilistic method for calling TILLING-induced mutations, and their carriers, from high throughput sequencing data of overlapping population pools, where each individual occurs in two pools. We assign a probability score to each sequence position by applying Bayes' Theorem to a simplified binomial model of sequencing error and expected mutations, taking into account the coverage level. We test the performance of our method on variable quality, high-throughput sequences from wheat and rice mutagenized populations. We show that our method effectively discovers mutations in large populations with sensitivity of 92.5% and specificity of 99.8%. It also outperforms existing SNP detection methods in detecting real mutations, especially at higher levels of coverage variability across sequenced pools, and in lower quality short reads sequence data. The implementation of our method is available from: http://www.cs.ucdavis.edu/filkov/CAMBa/.


Impact of surfactants on the target recognition of Fab-conjugated PLGA nanoparticles.
Targeted drug delivery with nanoparticles (NPs) requires proper surface ligand presentation and availability. Surfactants are often used as stabilizers in the production of targeted NPs. Here, we evaluated the impact of surfactants on ligand functionalization and downstream molecular recognition. Our model system consisted of fluorescent poly(lactic-co-glycolic acid) (PLGA) NPs that were nanoprecipitated in one of a small panel of commonly-used surfactants followed by equivalent washes and conjugation of an engineered Fab antibody fragment. Size, polydispersity index and zeta potential were determined by dynamic light scattering and laser Doppler anemometry, and Fab presence on the NPs was assessed by enzyme-linked immunosorbent assay. Most importantly, Fab-decorated NP binding to the cell surface receptor was monitored by fluorescence-activated cell sorting. 2% polyvinyl alcohol, 1% sodium cholate, 0.5% Pluronic F127 (F127) and 2% Tween-80 were initially tested. Of the four surfactants tested, PLGA NPs in 0.5% F127 and 2% Tween-80 had the highest cell binding. These two surfactants were then retested in two different concentrations, 0.5% and 2%. The Fab-decorated PLGA NPs in 2% F127 had the highest cell binding. This study highlights the impact of common surfactants and their concentrations on the downstream targeting of ligand-decorated NPs. Similar principles should be applied in the development of future targeted nanosystems where surfactants are employed.


Generation of optical carrier suppressed-differential phase shift keying (OCS-DPSK) format using one dual-parallel Mach-Zehnder modulator in radio over fiber systems.
We present and experimentally demonstrate a new method to generate optical carrier suppressed-differential phase-shift keying (OCSDPSK) modulation format in radio over fiber (RoF) systems. In our scheme, a single dual-parallel Mach-Zehnder modulator (DPMZM) is used to produce OCS-DPSK signal based on amplitude shift keying (ASK) to DPSK format conversion by suppressing the spectral tones of an OCS-ASK signal.


The elimination of trachoma as a public health problem in Togo: Successes and challenges.
As of May 2022, 15 countries have declared that they have reached their trachoma elimination targets, but only 13 of them, including Togo, have been validated by the World Health Organization as having eliminated the disease as a public health problem. The aim of this study was to describe the broad interventions that have supported the elimination of trachoma as a public health problem in Togo from its inception in 2006 to the validation of its elimination in 2022. A review and compilation of data and information contained in the country's submission to World Health Organization for validation of trachoma elimination as a public health problem was conducted. Data from national and local surveillance systems and reports on actions taken after achieving the elimination target were also included. Togo has achieved the elimination of trachoma as a public health problem by 2022. The prevalence of follicular trachoma among children aged 1-9 years is <5% in all nationally defined administrative units suspected of having trachoma after stopping mass treatment for at least 2 years. The prevalence of trichiasis among persons aged 15 years and older is less than 0.2% in all administrative units previously endemic for trachoma and evidence of the ability to manage incident cases of emerging trichiasis in the community has been demonstrated. The key of the success in the elimination process was primarily the political commitment of the health authorities with financial and technical support from various international organizations. The elimination of trachoma as a public health problem in Togo is a real success story that can serve as an example for the elimination of other neglected tropical diseases in Africa. But regular monitoring and surveillance is essential to avoid the re-emergence of such disease in the country.


Aging- and injury-related differential apoptotic response in the dentate gyrus of the hippocampus in rats following brain trauma.
The elderly are among the most vulnerable to traumatic brain injury (TBI) with poor functional outcomes and impaired cognitive recovery. Of the pathological changes that occur following TBI, apoptosis is an important contributor to the secondary insults and subsequent morbidity associated with TBI. The current study investigated age-related differences in the apoptotic response to injury, which may represent a mechanistic underpinning of the heightened vulnerability of the aged brain to TBI. This study compared the degree of TBI-induced apoptotic response and changes of several apoptosis-related proteins in the hippocampal dentate gyrus (DG) of juvenile and aged animals following injury. Juvenile (p28) and aged rats (24 months) were subjected to a moderate fluid percussive injury or sham injury and sacrificed at 2 days post-injury. One group of rats in both ages was sacrificed and brain sections were processed for TUNEL and immunofluorescent labeling to assess the level of apoptosis and to identify cell types which undergo apoptosis. Another group of animals was subjected to proteomic analysis, whereby proteins from the ipsilateral DG were extracted and subjected to 2D-gel electrophoresis and mass spectrometry analysis. Histological studies revealed age- and injury-related differences in the number of TUNEL-labeled cells in the DG. In sham animals, juveniles displayed a higher number of TUNEL(+) apoptotic cells located primarily in the subgranular zone of the DG as compared to the aged brain. These apoptotic cells expressed the early neuronal marker PSA-NCAM, suggestive of newly generated immature neurons. In contrast, aged rats had a significantly higher number of TUNEL(+) cells following TBI than injured juveniles, which were NeuN-positive mature neurons located predominantly in the granule cell layer. Fluorescent triple labeling revealed that microglial cells were closely associated to the apoptotic cells. In concert with these cellular changes, proteomic studies revealed both age-associated and injury-induced changes in the expression levels of three apoptotic-related proteins: hippocalcin, leucine-rich acidic nuclear protein and heat shock protein 27. Taken together, this study revealed distinct apoptotic responses following TBI in the juvenile and aged brain which may contribute to the differential cognitive recovery observed.


A new generation videokymography for routine clinical vocal fold examination.
This study aims to introduce a new-generation videokymographic system, which provides simultaneous laryngoscopic and kymographic image, for routine clinical vocal fold examination. The authors explored a new imaging method for diagnosis and evaluation of voice disorders. The new-generation videokymographic system includes two charge-coupled device image sensors, a color area image sensor, and a monochromic high-speed line-scan image sensor. The high-speed line-scan image sensor is used to capture the kymogram, and the color area image sensor is used to obtain the laryngoscopic image. The two images can be displayed simultaneously on a video monitor or stored in a standard video recorder. Three subjects with nonpathologic voice were investigated in detail with the new videokymographic system. The high-quality laryngoscopic image and kymogram can be used directly for clinical purposes with no further postprocessing. The scan position of the kymogram is always indicated in the laryngoscopic image, which provides feedback for the operator to easily locate the expected scanning position. All varieties of vocal fold vibration, including irregular vibrations, phonation onset and offset, can be observed with the presented method. The continuous kymogram of the vocal fold vibration can be retrieved from a kymographic image sequence for quantitative analysis. The new-generation videokymography provides a simple, quick means to investigate vocal fold vibration, especially for voice disorders. It can emerge as an important tool for routine clinical vocal fold examination.


Geometric auxetics.
We formulate a mathematical theory of auxetic behaviour based on one-parameter deformations of periodic frameworks. Our approach is purely geome- tric, relies on the evolution of the periodicity lattice and works in any dimension. We demonstrate its usefulness by predicting or recognizing, without experiment, computer simulations or numerical approximations, the auxetic capabilities of several well-known structures available in the literature. We propose new principles of auxetic design and rely on the stronger notion of expansive behaviour to provide an infinite supply of planar auxetic mechanisms and several new three-dimensional structures.


Photoinduced Reactivity in a Dispiro-1,2,4-trioxolane: Adamantane Ring Expansion and First Direct Observation of the Long-Lived Triplet Diradical Intermediates.
Dispiro-1,2,4-trioxolane, 1, an ozonide with efficient and broad antiparasitic activity, was synthesized and investigated using matrix isolation FTIR and EPR spectroscopies together with both B3LYP/6-311++G(3df,3dp) and M06-2X/6-311++G(3df,3dp) theoretical methods. Irradiations (λ ≥ 290 nm) of the matrix isolated 1 (Ar or N2) afforded exclusively 4-oxahomoadamantan-5-one, 4, and 1,4-cyclohexanedione, 5. These results suggested that the reaction proceeded via a dioxygen-centered diradical intermediate, formed upon homolytic cleavage of the labile peroxide bond, which regioselectively isomerized to form the more stable (secondary carbon-centered)/oxygen-centered diradical. In situ EPR measurements during the photolysis of 1 deposited in a MeTHF-matrix led to the detection of signals corresponding to two triplet species, one of which was short-lived while the other proved to be persistent at 10 K. These observations strongly support the proposed mechanism for the photogeneration of 4 and 5, which involves intramolecular rearrangement of the intermediate diradical species 2 to afford the triplet diradical 3.


Orchitis: An unusual presentation of polyarteritis nodosa.
Polyarteritis nodosa (PAN), a systemic necrotizing vasculitis with multiorgan development, is generally restricted to the medium-sized muscular arteries. The varied initial clinical presentations of PAN can lead to a delayed diagnosis. We present the case of a middle-aged male patient who presented with an acute onset right-sided testicular pain as the initial clinical symptom with ischemic changes on ultrasonogram, thereby requiring orchiectomy. This was reported to be a case of tubercular epididymo-orchitis. On review, the biopsy revealed features of necrotizing arteritis as seen in PAN with fibrinoid necrosis and giant cells, thus highlighting the fact that vasculitis due to PAN may have a localized presentation at the time of diagnosis. PAN should be distinguished from other causes of epididymo-orchitis and other vasculitis lesions, the most common being tubercular etiology in the Asian population.


Rods and cones in an enantiornithine bird eye from the Early Cretaceous Jehol Biota.
Extant birds have an extensive spectral range of colour vision among vertebrates, but evidence of colour vision among extinct birds has hitherto been lacking. An exceptionally well-preserved extinct enantiornithine fossil bird from the Early Cretaceous Jiufotang Formation (120 Ma) of Liaoning, China, provides the first report of mineralised soft tissue of a bird eye. Cone cells are identified, which have preserved oil droplets falling between wide ranges of size that can be compared with an extant house sparrow. The size distribution of oil droplets of extant birds demonstrates good correlation between size and the detectable wavelength range of the cone cells: UV-sensitive cones contain the smallest oil droplets, while red-sensitive cones possess the largest. The data suggests that this Early Cretaceous bird could have possessed colour vision.


MR imaging of pseudoaneurysms in aortocoronary bypass graft.
Aneurysm formation may complicate aortocoronary saphenous vein bypass grafts. Because of multiplanar imaging capabilities and the potential for flow evaluation, magnetic resonance (MR) is useful as a noninvasive diagnostic technique. Two cases of pseudoaneurysm formation were evaluated by MR and demonstrate the clinical value of this modality.


Dealing with sickness certification - a survey of problems and strategies among general practitioners and orthopaedic surgeons.
In order to get sickness benefit a sick-listed person need a medical certificate issued by a physician; in Sweden after one week of self-certification. Physicians experience sick-listing tasks as problematic and conflicts may arise when patients regard themselves unable to work due to complaints that are hard to objectively verify for the physician. Most GPs and orthopaedic surgeons (OS) deal regularly with sick-listing issues in their daily practice. The aim of this study was to explore perceived problems and coping strategies related to tasks of sickness certification among general practitioners (GP) and orthopaedic surgeons (OS). A cross-sectional study about sickness certification in two Swedish counties, with 673 participating GPs and 149 OSs, who answered a comprehensive questionnaire. Frequencies together with crude and adjusted (gender and working years) Odds ratios were calculated. A majority of the GPs and OSs experienced problems in sickness certification every week. To assess the patient's work ability, to handle situations when they and the patient had different opinions about the need for sickness absence, and to issue prolongation certificates when the previous was issued by another physician were reported as problematic by a majority in both groups. Both GPs and OSs prolonged sickness certifications due to waiting times in health care or at Social Insurance Office (SIO). To handle experienced problems they used different strategies; OSs issued sickness certificates without personal appointment more often than the GPs, who on the other hand reported having contact with SIO more often than the OSs. A higher rate of GPs experienced support from management and had a common strategy for handling sickness certification at the clinic than the OSs. Most GPs and OSs handled sickness certification weekly and reported a variety of problems in relation to this task, generally GPs to a higher extent, and they used different coping strategies to handle the problems.


A computer-aided temporal and dynamic subtraction technique of the liver for detection of small hepatocellular carcinomas on abdominal CT images.
It is often difficult for radiologists to identify small hepatocellular carcinomas (HCCs) due to insufficient contrast enhancement. Therefore, we have developed a new computer-aided temporal and dynamic subtraction technique to enhance small HCCs, after automatically selecting images set at the same anatomical position from the present (non-enhanced and arterial-phase CT images) and previous images. The present study was performed with CT images from 14 subjects. First, we used template-matching based on similarities in liver shape between the present (non-enhanced and arterial-phase CT images) and previous arterial-phase CT images at the same position. Temporal subtraction images were then obtained by subtraction of the previous image from the present image taken at the same position of the liver. Dynamic subtraction images were also obtained by subtraction of non-enhanced CT images from arterial-phase CT images taken at the same position of the liver. Twenty-one of 22 nodules (95.5%) with contrast enhancement were visualized in temporal and dynamic subtraction images. Compared with present arterial-phase CT images, increases of 150% and 140% in nodule-to-liver contrast were observed on dynamic and temporal subtraction images, respectively. These subtraction images may be useful as reference images in the detection of small moderately differentiated HCCs.


Progressive muscle relaxation in cardiac rehabilitation: a pilot study.
Learning to manage stress is an important lifestyle change for participants in cardiac rehabilitation programs. Progressive muscle relaxation (PMR) is one stress management approach that has produced positive benefits among different patient populations. The purpose of this study was to identify the effects of learning and practicing PMR in a population of cardiac rehabilitation patients. Blood pressure and heart rate data, and scores on the Spielberger State-Trait Anxiety Inventory (STAI) were collected from a treatment group and a control group of patients enrolled in phases II and III of cardiac rehabilitation. Analysis of the data revealed positive effects of PMR on the variables heart rate and state of anxiety. In addition, written evaluations of PMR from patients in the treatment group indicated a high degree of subjective satisfaction with PMR as a means to reduce stress in their lives.


Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect.
Transforming growth factor-beta (TGF-beta) inhibits cell cycle progression of many types of human cells by arresting them in the G1 phase of the cell cycle. The arrest is mediated through interactions of various cyclin-dependent protein kinases (CDKs) and their inhibitors. We demonstrate that treatment with TGF-beta induces increased levels of WAF1/Cip1/p21, a potent inhibitor of various cyclin-CDK kinase activities, in two colon cancer cell lines (LS1034 and LS513), which are sensitive to TGF-beta-induced growth arrest. The induction in at least one of these cell lines (LS1034,p53-) is p53-independent. No WAF1 induction was observed after TGF-beta treatment in a third cell line (HT-29), which is completely insensitive to the cytoinhibitory effect of TGF-beta. In both LS513 and LS1034, WAF1 induction correlated with reduced cyclin E-associated kinase activity in vitro and suppression of the retinoblastoma susceptibility gene (Rb) protein phosphorylation in vivo. In addition, WAF1 was physically associated with cyclin E in the two sensitive cell lines. These results suggest that WAF1/Cip1/p21 is a mediator of cellular sensitivity to TGF-beta.


The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier.
Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrix-dependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression.


MicroRNA-124-3p directly targets PDCD6 to inhibit metastasis in breast cancer.
Breast cancer (BC) is the leading cause of cancer-associated mortality among women worldwide, with a poor 5-year survival rate, particularly among patients with metastatic BC. Previous studies have indicated that the dysregulation of microRNAs (miRNAs/miRs) is associated with carcinogenesis and metastasis. Thus, investigating the underlying molecular mechanisms by which miRNAs mediate their effects may aid in the improvement of BC treatment. In the present study, reverse transcription-quantitative polymerase chain reaction analyses were performed to investigate miR-124-3p expression in BC tissues. The expression of miR-124-3p was significantly decreased in primary BC tissues compared with that in adjacent non-tumor tissues. Downregulated miR-124-3p was correlated with lymph node metastasis and a low overall survival time. Wound-healing and Transwell assays revealed that MDA-MB-231 and MCF-7 cell motility was inhibited by miR-124-3p, but was promoted by a miR-124-3p inhibitor. Overexpression of miR-124-3p increased levels of E-cadherin, and decreased levels of N-cadherin and Vimentin, indicating that miR-124-3p inhibits the epithelial-mesenchymal transition. In addition, a bioinformatics analysis and subsequent in vitro experiments identified programmed cell death protein 6 (PDCD6) as a direct target of miR-124-3p. Restoration of PDCD6 expression impaired the metastasis inhibitor role of miR-124-3p by promoting cell invasion. Furthermore, the expression of miR-124-3p was inversely associated with PDCD6 mRNA levels in clinical breast tumors. Taken together, these data suggest that miR-124-3p inhibits tumor metastasis by inhibiting PDCD6 expression, and that the miR-124-3p/PDCD6 signaling axis may be a potential target for novel treatments in patients with advanced BC.


Imaging of idle breast implants with ultrasound-strain elastography- A first experimental study to establish criteria for accurate imaging of idle implants via ultrasound-strain elastography.
To investigate whether there are fundamental sonographic and elastographic criteria to precisely assess different surfaces and fillings of idle breast implants and to determine their most distinctive parameters. This was a comparative study of different unused breast implant materials, neighter in animals nor in humans. This knowledge should be transferred in vivo to develop an objective measurement tool. Nine idle breast implants-silicone and polyurethane (PU)-were examined in an experimental study by using ultrasound B-mode with tissue harmonic imaging (THI), speckle reduction imaging (SRI, level 0-4), cross-beam (CB, low, medium, high), photopic and the colour coded ultrasound-strain elastography with a multifrequency probe (9-15 MHz).Using a standardised protocol the implants' centre as well as the edge were analysed by one experienced examiner. Two independent readers performed analysis and evaluation. For image interpretation a score was created (score 0:inadequate image, score 5:best image quality). The highest score result for the centre was achieved by using ultrasound with B-mode in addition with CB level medium, SRI level 2, THI and photopic (mean:3.22±SD:1.56), but without any statistic significant difference (t-value = 0.71). With elastography the implants' edge in general was represented without disruptive artefacts (3.89±0.60) with statistic significant difference (t-value = 5.29). Implants filled with inner cohesive silicone gel II° showed best imaging conditions for their centre via ultrasound (5±0) as well as for their edge via elastography (4.50±0.71). Ultrasound-strain elastography and high resolution ultrasound represent a valuable measurement tool to evaluate different properties of idle breast implants. These modified ultrasound examinations could be an additional help for clinical investigations and be correlated with Baker's Classification.


Local heating of human skin causes hyperemia without mediation by muscarinic cholinergic receptors or prostanoids.
Local changes in surface temperature have a powerful influence on the perfusion of human skin. Heating increases local skin blood flow, but the mechanisms and mediators of this response (thermal hyperemia response) are incompletely elucidated. In the present study, we examined the possible dependence of the thermal hyperemia response on stimulation of muscarinic cholinergic receptors and on production of vasodilator prostanoids. In 13 male healthy subjects aged 20-30 yr, a temperature-controlled chamber was positioned on the volar face of one forearm and used to raise surface temperature from 34 to 41 degrees C. The time course of the resulting thermal hyperemia response was recorded with a laser-Doppler imager. In one experiment, each of eight subjects received an intravenous bolus of the antimuscarinic agent glycopyrrolate (4 microg/kg) on one visit and saline on the other. The thermal hyperemia response was determined within the hour after the injections. Glycopyrrolate effectively inhibited the skin vasodilation induced by iontophoresis of acetylcholine but did not influence the thermal hyperemia response. In a second experiment, conducted in five other subjects, 1 g of the cyclooxygenase inhibitor aspirin administered orally totally abolished the vasodilation induced in the skin by anodal current but also failed to modify the thermal hyperemia response. The present study excludes the stimulation of muscarinic receptors and the production of vasodilator prostaglandins as essential and nonredundant mechanisms for the vasodilation induced by local heating in human forearm skin.


[Molecular aspects in the pathogenesis of nodules and adenomas of the thyroid gland].
Recent advances in thyroid research are reviewed which reflect fundamental changes in understanding of the pathogenesis of thyroid adenomas, and of clonal and polyclonal goiter nodules. It is generally accepted that chronic iodine deficiency leads to the development of a diffuse homogeneous goiter. However, low iodine supply does not explain generation and growth of thyroid nodules and the characteristic functional heterogeneity of most nodular goiters. Molecular analyses of recent years have revealed that thyroid adenomas and most nodules in goiters, even if morphologically heterogeneous, are clonal and thus true benign tumors. This has been demonstrated in areas both with iodine deficiency and with sufficient iodine supply. However, in areas with iodine deficiency, chronic stimulation accelerates the genesis of nodules and adenomas. The molecular pathogenesis of these tumors is still unknown. Only in a subgroup of toxic adenomas mutations of the TSH receptor and the Gs-alpha gene have recently been found that may explain the genesis of these tumors and the development of hyperthyroidism in patients with these adenomas.


Complete decongestive physiotherapy with and without pneumatic compression for treatment of lipedema: a pilot study.
Lipedema is a disproportional obesity for which evidence-based treatment is not currently available. We studied whether complete decongestive physiotherapy (CDP) alone or combined with intermittent pneumatic compression (IPC) could improve the treatment outcome in women with lipedema using a prospective, randomized trial. Eleven patients received CDP (60 min) and thirteen CDP (30 min) plus IPC (30 min) once daily in a 5-day-course. Subsequent to drainage, all subjects received multilayered compression bandaging, physical exercise and skin care. Treatment efficacy was evaluated by limb volume reduction. Both groups achieved significant reductions in mean lower extremity volume (p < 0.05). The addition of IPC is safe, although it provides no synergistic benefit to CDP in leg volume reduction under these study conditions.


Pheromone routing protocol on a scale-free network.
This paper proposes a routing strategy for network systems based on the local information of "pheromone." The overall traffic capacity of a network system can be evaluated by the critical packet generating rate R(c). Under this critical generating rate, the total packet number in the system first increases and then decreases to reach a balance state. The system behaves differently from that with a local routing strategy based on the node degree or shortest path routing strategy. Moreover, the pheromone routing strategy performs much better than the local routing strategy, which is demonstrated by a larger value of the critical generating rate. This protocol can be an alternation for superlarge networks, in which the global topology may not be available.


Economic Burden of Fungal Diseases in the United States.
We conservatively estimated the US economic burden of fungal diseases as $11.5 billion in 2019: direct medical costs ($7.5 billion), productivity loss due to absenteeism ($870 million), and premature deaths ($3.2 billion). An alternative "value of statistical life" approach yielded >$48 billion. These are likely underestimates given underdiagnosis and underreporting.


The association between non-alcoholic fatty liver disease and insulin resistance in 20 obese children and adolescents.
To investigate whether there are correlations between non-alcoholic fatty liver disease (NAFLD) and insulin resistance in obese children. For the first time, we present clinical data of 20 obese children with NAFLD, including an oral glucose tolerance test. Twenty obese children were diagnosed as having NAFLD by abdominal ultrasonography. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (gamma-GT) were reported. Insulin sensitivity was evaluated by oral glucose tolerance test, oral glucose insulin sensitivity (OGIS) and homeostasis is model assessment (HOMA) index. All parameters were compared to 20 obese age- and sex-matched patients without NAFLD. With 81% the prevalence of insulin resistance according to HOMA or OGIS criteria was high in the NAFLD-patients compared to the other group with 63%. Statistically significant differences between both groups were found for mean serum ALT levels, mean glucose levels after 30, 60 and 90 minutes and mean insulin levels after 60 minutes of the glucose tolerance test. The high prevalence of insulin resistance we found in children with NAFLD confirms the suggestion that there may be an association between insulin resistance and NAFLD in obese children and indicates that markers of insulin sensitivity could be useful screening parameters for NAFLD.


Autonomic origin of heart rate fluctuations at the onset of muscular exercise.
The time courses of the heart rate (HR) changes were studied in six healthy male subjects who performed step changes from rest to light dynamic leg exercise (50 W) in the sitting position during a) control, b) parasympathetic blockade (atropine, 2-2.5 mg iv), c) beta-adrenergic blockade (propranolol, 10 mg iv), and d) during combined blockade with both drugs. During the control and beta-blockade experiments all subjects showed an immediate, rapid increase in HR, reaching a peak value after about 10 s, whereafter an equally rapid transient drop by 10-20 beats/min took place reaching the lowest values about 17 s after the onset of work. HR then again increased to reach a steady-state level within 60-90 s. In the atropine experiments this response pattern was not evident at all, whereas in the experiments with combined blockade it could be distinguished to a small, but significant degree. It is concluded that the observed fluctuations of HR at the onset of light dynamic exercise can be explained by a rapid vagal withdrawal, followed by a transient increase in vagal tone.


District versus academic hospitals: differences in the clinical characteristics of patients with atrial fibrillation without valvular heart disease treated with oral anticoagulants
INTRODUCTION Atrial fibrillation (AF) is the most common cardiac arrhythmia with a significant risk of morbidity and mortality. Non-vitamin K antagonist oral anticoagulants are the first‑line drugs in stroke prevention in patients with AF. Oral anticoagulant (OAC) therapy may differ between medical centers. OBJECTIVES We compared the clinical characteristics of AF patients treated with OAC in a district and an academic hospital. PATIENTS AND METHODS We analyzed 3528 patients from the multicenter retrospective CRAFT study: 2666 patients from the academic hospital and 862 patients from the district hospital. Their baseline clinical characteristics were compared. RESULTS Patients treated in the district hospital were older (mean [SD] age, 73.9 [10.3] years vs 66.0 [13.4] years; P <0.001) and more likely female (49.1% vs 37.4%; P <0.001). Patients treated in the academic hospital more frequently had paroxysmal AF, while those in the district hospital, permanent AF. The latter group was also more likely to have comorbidities and a higher frequency of previous bleeding episodes or anemia. The groups did not differ regarding kidney function. In both groups, patients were significantly more likely to be on rivaroxaban than on dabigatran. The group treated in the district hospital were at higher risk of thromboembolic events than the other gruop (mean [SD] CHA2DS2VASc score, 4.6 [1.7] vs 3.05 [2.0]; P <0.001), as well as of hemorrhagic events (mean [SD] HASBLED score, 0.6 [0.7] vs 0.4 [0.6]; P <0.001). CONCLUSIONS Patients with AF treated with OACs in the district and academic hospitals have different clinical characteristics. Patients treated in the district hospital were older, had more comorbidities, more frequently had permanent AF, and were at higher risk of thromboembolic and bleeding events than patients treated in the academic hospital.


Brachial Neuritis With Phrenic Nerve Involvement in a Patient With a Possible Connective Tissue Disease.
Background. Brachial neuritis (BN) is a rare inflammatory condition of peripheral nerves, usually involving the cervicobrachial plexus. These patients present with sudden onset of shoulder and arm pain that evolves into muscle weakness and atrophy.. Case Report. A 33-year-old woman presented with a 1-month history of diffuse pain in her thorax. She had no trauma or inciting incident prior to the onset of this pain and was initially treated for muscle spasms. The patient was seen in the emergency room multiple times and was treated with several courses of antibiotics for pneumonia on the basis of clinical symptoms and abnormal x-rays. The pleuritic chest pain persisted for at least 4 months, and the patient was eventually admitted for worsening pain and dyspnea. On physical examination, crackles were heard at both lung bases, and chest inspection revealed increased expansion in the upper thorax but poor expansion of the lower thorax and mild paradoxical respiration. "Sniff" test revealed no motion of the left hemidiaphragm and reduced motion on the right hemidiaphragm. Her computed tomography scan revealed bilateral atelectasis, more severe at the left base. She reported no symptoms involving her joints or skin or abdomen. Her presentation and clinical course are best explained by BN with a bilateral diaphragmatic weakness. However, she had a positive ANA, RF, anti-RNP antibody, and anti SS-A. Conclusion. Patients with BN can present with diffuse thoracic pain, pleuritic chest pain, and diaphragmatic weakness. Our patient may represent a case of connective tissue disease presenting with brachial plexus neuritis.


The antigenic structure of the human glycoprotein hormone alpha-subunit. I. Characterization of anti-alpha monoclonal antibodies.
The glycoprotein hormones CG, LH, FSH, and TSH are composed of two noncovalently linked subunits, alpha and beta. The beta-subunit confers hormone specificity, while the alpha-subunit is homologous within a species. To help in determining the antigenic structure of the common alpha-subunit, six monoclonal antibodies (mAbs) to the free or heterodimeric alpha-subunit of human (h) gonadotropic hormones have been prepared and, along with two previously isolated mAbs, have been characterized for binding specificity to alpha- and beta-subunits and the human glycoprotein hormones, CG, LH, FSH, and TSH. Each mAb was derived from hybidomas of FO myeloma cells fused with spleen cells from mice immunized with free alpha-subunit, hCG or hFSH. mAbs A101, A102, and E512 were specific for the alpha-subunit but showed the highest affinity for the intact hormone; K2.18, K94.6, E501, E502, and E511 were specific for free alpha. All of the antibodies inhibited binding of 125I-hCG to luteal membrane receptor, and 125I-labeled mAbs did not recognize hCG/receptor complex. Characterization by two-site binding assays using alpha, hCG, or hFSH as antigen revealed that all the mAbs bind to unique sites on alpha which may be overlapping, and which are modified in the intact hormone. The antigenic sites for mAbs E502, E511, and K2.18 are at least partially linear because they bind to reduced, carboxymethylated alpha.


Problems experienced by young men and attitudes to help-seeking in a rural Irish community.
Suicide is now the commonest cause of death among young Irish males. The literature identifies a wide range of contributory risk factors in suicide. However, a number of realities have frustrated clinicians' efforts in the area, including the reluctance of young males to engage in mental health services. In this study, we sought to explore the problems experienced by young men in a rural setting and their attitudes towards seeking help. Focus groups were employed to generate themes for a qualitative and quantitative questionnaire which was administered to a community sample of 71 young men (22.4% of the total number of males aged 16-30 years in the area) and 79 key informants. The questionnaires contained demographic items and examined available social outlets, types and extent of difficulties experienced by young men and perceptions of and access to potential sources of support. Both young men and key informants reported that peer pressure and alcohol misuse are areas of most difficulty, that friends and family are the preferred sources of support and that young men view much existing professional help as unacceptable. This study provides a basis for the next stage in the research cycle and also supports the viability of building a partnership between the health services and the local community in developing future suicide prevention strategies for young men.


Complete Genome Sequence of Enterococcus faecalis Siphophage Sigurd.
Enterococcus faecalis is associated with antibiotic-resistant infections, and this study presents E. faecalis siphophage Sigurd. The 41,811-bp Sigurd genome is divided into two arms defined by long convergent predicted transcription units that are separated by a bidirectional rho-independent terminator. Sigurd has a small terminase that is closely related to Bacillus subtilis cos phage phi105.


Exploring the causes of augmentation in restless legs syndrome.
Long-term drug treatment for Restless Legs Syndrome (RLS) patients can frequently result in augmentation, which is the deterioration of symptoms with an increased drug dose. The cause of augmentation, especially derived from dopamine therapy, remains elusive. Here, we review recent research and clinical progress on the possible mechanism underlying RLS augmentation. Dysfunction of the dopamine system highly possibly plays a role in the development of RLS augmentation, as dopamine agonists improve desensitization of dopamine receptors, disturb receptor interactions within or outside the dopamine receptor family, and interfere with the natural regulation of dopamine synthesis and release in the neural system. Iron deficiency is also indicated to contribute to RLS augmentation, as low iron levels can affect the function of the dopamine system. Furthermore, genetic risk factors, such as variations in the BTBD9 and MEIS1 genes, have been linked to an increased risk of RLS initiation and augmentation. Additionally, circadian rhythm, which controls the sleep-wake cycle, may also contribute to the worsening of RLS symptoms and the development of augmentation. Recently, Vitamin D deficiency has been suggested to be involved in RLS augmentation. Based on these findings, we propose that the progressive reduction of selective receptors, influenced by various pathological factors, reverses the overcompensation of the dopamine intensity promoted by short-term, low-dose dopaminergic therapy in the development of augmentation. More research is needed to uncover a deeper understanding of the mechanisms underlying the RLS symptom and to develop effective RLS augmentation treatments.


Helicobacter pylori infection with intestinal metaplasia: An independent risk factor for colorectal adenomas.
To explore the association between Helicobacter pylori (H. pylori) infection status, intestinal metaplasia (IM), and colorectal adenomas. We retrospectively reviewed 1641 individuals aged ≥ 40 years who underwent physical examination, laboratory testing, 13C-urea breath testing, gastroscopy, colonoscopy, and an interview to ascertain baseline characteristics and general state of health. Histopathological results were obtained by gastric and colorectal biopsies. The prevalence of H. pylori infection and adenomas was 51.5% (845/1641) and 18.1% (297/1641), respectively. H. pylori infection was significantly correlated with an increased risk of colorectal adenomas (crude OR = 1.535, 95%CI: 1.044-1.753, P = 0.022; adjusted OR = 1.359, 95%CI: 1.035-1.785, P = 0.028). Individuals with IM had an elevated risk of colorectal adenomas (crude OR = 1.664, 95%CI: 1.216-2.277, P = 0.001; adjusted OR = 1.381, 95%CI: 0.998-1.929, P = 0.059). Stratification based on H. pylori infection stage and IM revealed that IM accompanied by H. pylori infection was significantly associated with an increased risk of adenomas (crude OR = 2.109, 95%CI: 1.383-3.216, P = 0.001; adjusted OR = 1.765, 95%CI: 1.130-2.757, P = 0.012). H. pylori-related IM is associated with a high risk of colorectal adenomas in Chinese individuals.


A prediction model on rockburst intensity grade based on variable weight and matter-element extension.
Rockburst is a common dynamic disaster in deep underground engineering. To accurately predict rockburst intensity grade, this study proposes a novel rockburst prediction model based on variable weight and matter-element extension theory. In the proposed model, variable weight theory is used to optimize the weights of prediction indexes. Matter-element extension theory and grade variable method are used to calculate the grade variable interval corresponding to the classification standard of rockburst intensity grade. The rockburst intensity grade of Engineering Rock Mass is predicted by rock burst intensity level variable and the interval. Finally, the model is tested by predicting the rockburst intensity grades of worldwide several projects. The prediction results are compared with the actual rockburst intensity grades and the prediction results of other models. The results indicate that, after using variable weight theory and grade variable method, the correct rate of prediction results of matter-element extension model is improved, and the safety of the prediction results is also enhanced. This study provides a new way to predict rock burst in underground engineering.


A proteomic glimpse into human ureter proteome.
Urine has evolved as one of the most important biofluids in clinical proteomics due to its noninvasive sampling and its stability. Yet, it is used in clinical diagnostics of several disorders by detecting changes in its components including urinary protein/polypeptide profile. Despite the fact that majority of proteins detected in urine are primarily originated from the urogenital (UG) tract, determining its precise source within the UG tract remains elusive. In this article, we performed a comprehensive analysis of ureter proteome to assemble the first unbiased ureter dataset. Next, we compared these data to urine, urinary exosome, and kidney mass spectrometric datasets. Our result concluded that among 2217 nonredundant ureter proteins, 751 protein candidates (33.8%) were detected in urine as urinary protein/polypeptide or exosomal protein. On the other hand, comparing ureter protein hits (48) that are not shown in corresponding databases to urinary bladder and prostate human protein atlas databases pinpointed 21 proteins that might be unique to ureter tissue. In conclusion, this finding offers future perspectives for possible identification of ureter disease-associated biomarkers such as ureter carcinoma. In addition, the ureter proteomic dataset published in this article will provide a valuable resource for researchers working in the field of urology and urine biomarker discovery. All MS data have been deposited in the ProteomeXchange with identifier PXD002620 (http://proteomecentral.proteomexchange.org/dataset/PXD002620).


Lung function and respiratory symptoms among female hairdressers in Palestine: a 5-year prospective study.
Hairdressers are exposed to chemicals at the workplace which are known to cause respiratory symptoms and asthma. This study aimed to examine changes in self-reported respiratory symptoms over 5 years, as well as to examine the lung function decline and determine whether it is within the expected range, to assess the dropout rate and reasons for leaving the profession, and to examine the associations between occupational factors and lung function changes at follow-up. Prospective study. Female hairdressing salons in Hebron city, Palestine. 170 female hairdressers who participated in a baseline survey in 2008 were followed up in 2013. A total of 161 participants participated in 2013. Change in reported respiratory symptoms and change in lung function over follow-up. Dropout from the profession and reasons for it. Differences between current and former hairdressers in respiratory symptoms and lung function at follow-up. Ambient air ammonia levels in 13 salons. Current hairdressers reported more respiratory symptoms in 2013 compared with baseline. Former hairdressers reported fewer symptoms at follow-up. At follow-up, current hairdressers showed a significant decrease in forced vital capacity of 35 mL/year (95% CI 26 to 44 mL/year) and of 31 mL/year (95% CI 25 to 36 mL/year) for forced expiratory volume in 1 s (FEV1). 28 (16%) of the hairdressers quit the job during the 5-year follow-up, 8 (28%) because of health problems. Hairdressers who had been working for 4 years or more at baseline showed a stronger decline in FEV1 compared with those who worked less than 4 years (difference 13, 95% CI 1 to 25). Current hairdressers developed more respiratory symptoms and larger lung function decline than former hairdressers during follow-up. Few hairdressers left their profession because of respiratory health problems. Working for more years is associated with lung function decline among current hairdressers.


Alzheimer's Disease in the Danish Malnutrition Period 1999-2007.
Several studies published over the last few years have shown that malnutrition is a risk factor for developing and worsening Alzheimer's disease (AD) and that a balanced diet can delay the onset of the disease. During the period from January 1999 to January 2007, a statistically significant increase in the number of deaths related to malnutrition was found among the elderly in Denmark. Many more may have been suffering from malnutrition, but not to such a degree that it led to their deaths. The aim of this study is to examine whether or not the effect of the malnutrition period can be seen in the number of AD-related deaths. All Danes listed in the National Death Register from 1994 to 2012 where included in this study. Regression analyses based on the Expansion Method were used. We found a sudden statistically significant rise in the number of deaths from AD associated with the period when the general nutritional state among the elderly in Denmark worsened (from 1999 to 2007). The study concludes that the malnutrition period resulted in an excess death rate from Alzheimer's disease. All in all, a total of 345 extra lives were lost, and many might have developed AD earlier than they otherwise would, due to malnutrition.


ARRDC3 suppresses colorectal cancer progression through destabilizing the oncoprotein YAP.
Although colorectal cancer (CRC) is a prevalent malignancy of the digestive system, the underlying mechanisms of CRC tumorigenesis are still elusive. Arrestin-related domain-containing protein-3 (ARRDC3) has been reported to promote lysosome-mediated protein degradation. In the present study, we find that the expression of ARRDC3 is downregulated in CRC specimens. Mechanistically, we reveal that ARRDC3 binds and decreases expression of the oncoprotein YAP, the cotranscription factor of the Hippo pathway. The regulation of the Hippo pathway by ARRDC3 is conserved from Drosophila to mammals. Furthermore, we demonstrate that ARRDC3 plays an anti-oncogenic role in CRC progression by promoting YAP degradation. Finally, we show that ARRDC3 increases the sensitivity of CRC cells toward chemotherapeutic drugs. Taken together, our findings point to ARRDC3 as a potential target for CRC treatment.


Psoriasis patients show signs of insulin resistance.
Recent observations suggest that psoriasis is a risk factor for the development of coronary artery calcification which in turn represents an indicator for atherosclerosis. To clarify a possible pathogenetic link between psoriasis and atherosclerosis, we studied the metabolic state of patients with psoriasis. Thirty-nine consecutive patients with moderate-to-severe plaque-type psoriasis were enrolled in the study. Detailed information was obtained on the patients' clinical picture and history of psoriasis, smoking habits and medication. The body mass index (BMI) of the patients was calculated. Laboratory investigations focused on values for inflammation, lipid profile and multiple cytokines. The intima-media thickness of the carotid artery was measured by ultrasound, and an oral glucose tolerance test was performed to calculate the homeostasis model assessment of insulin resistance (HOMA). Numerous well-recognized correlations such as between BMI and HOMA (P < 0.02) as well as BMI and vessel wall thickness (P < 0.05) were successfully reproduced, thus confirming consistency of our dataset. With regard to psoriasis, we observed a significant correlation between the Psoriasis Area and Severity Index (PASI) score and insulin secretion. Moreover, the PASI score was significantly correlated with serum resistin levels--a cytokine known to be increased in insulin resistance. Taken together, several measurements indicative of insulin resistance were found to be significantly correlated with the PASI score. The concept of insulin resistance as a consequence of chronic inflammation and possible pathogenetic cause for comorbidities known to be associated with psoriasis is supported by these data. Our findings validate further studies on larger cohorts as well as interventional studies.


Simultaneous acquisition of neuronal morphology and cytoarchitecture in the same Golgi-stained brain.
Acquiring an accurate orientation reference is a prerequisite for precisely analysing the morphological features of Golgi-stained neurons in the whole brain. However, the same reflective imaging contrast of Golgi staining for morphology and Nissl staining for cytoarchitecture leads to the failure of distinguishing soma morphology and simultaneously co-locate cytoarchitecture. Here, we developed the dual-mode micro-optical sectioning tomography (dMOST) method to simultaneously image the reflective and fluorescent signals in three dimensions. We evaluated the feasibility of real-time fluorescent counterstaining on Golgi-stained brain tissue. With our system, we acquired whole-brain data sets of physiological and pathological Golgi-stained mouse model brains with fluorescence-labelled anatomical annotation at single-neuron resolution. We also obtained the neuronal morphology of macaque monkey brain tissue using this method. The results show that real-time acquisition of the co-located cytoarchitecture reference in the same brain greatly facilitates the precise morphological analysis of Golgi-stained neurons.


Genomic variation of adenovirus type 5 isolates recovered from bone marrow transplant recipients.
We characterized the genomic variation of adenovirus type 5 isolates recovered from bone marrow transplant recipients in Seattle between 1976 and 1982. By restriction endonuclease analysis, we identified three new adenovirus genomic variants, each associated with a single invasive adenovirus infection. In addition, we were able to obtain suggestive evidence for a nosocomial spread of a particular group of isolates within this population. This study demonstrates that the technique of restriction endonuclease analysis is an important epidemiological tool for investigating viral infections.


Human autoantibody silencing by immunoglobulin light chains.
Several newly arising human antibodies are polyreactive, but in normal individuals the majority of these potentially autodestructive antibodies are removed from the repertoire by receptor editing or B cell deletion in the bone marrow. To determine what proportion of naturally arising autoantibodies can be silenced by immunoglobulin (Ig) light chain receptor editing, we replaced the light chains in 12 such antibodies with a panel of representative Igkappa and Iglambda chains. We found that most naturally arising autoantibodies are readily silenced by light chain exchange. Thus, receptor editing may account for most autoreactive antibody silencing in humans. Light chain complementarity determining region (CDR) isoelectric points did not correlate with silencing activity, but Iglambda genes were more effective than Igkappa genes as silencers. The greater efficacy of Iglambda chains as silencer of autoreactivity provides a possible explanation for the expansion and altered configuration of the Iglambda locus in evolution.


Bisamides derived from azulene-1,3- and -5,7-dicarboxylic acids as new building blocks for anion receptors.
Bisamides based on the azulene moiety were investigated as building blocks for anion receptors. In the course of these studies, derivatives of azulene-1,3- and -5,7-dicarboxylic acid were synthesized and thoroughly characterized. The anion affinities of the derivatives based on functionalization in the five-membered ring and in the seven-membered ring were determined by (1)H NMR titration. The structural analysis of these building blocks was performed by X-ray diffractometry, molecular modelling and 2D NMR spectroscopy. The five-membered ring derivatives are easy to obtain, offer a binding site preorganized in the syn-syn conformation and bind anions with a strength similar to those of pyrrole-based analogues. There is also strong evidence for aromatic CH...anion interactions. The ligands substituted at the 5- and 7-positions offer a binding cleft with an uncommon geometry that originates from the seven-membered ring and seems to be complementary to the chloride anion.


Evolutionary and mechanistic drivers of laterality: A review and new synthesis.
Laterality, best understood as asymmetries of bilateral structures or biases in behaviour, has been demonstrated in species from all major vertebrate classes, and in many invertebrates, showing a large degree of evolutionary conservation across vertebrate groups. Despite the establishment of this phenomenon in so many species, however, the evolutionary and mechanistic study of laterality is uneven with numerous areas in this field requiring greater attention. Here, I present a partial review of how far the study of laterality has come, outlining previous pioneering work, I discuss the hypothesized costs and benefits of a lateralized brain and the suggested path of the evolution of laterality for populations and individuals. I propose an expansion of laterality research into areas that have been touched upon in the past but require stronger evidence from which the field will greatly benefit. Namely, I suggest a continuation of the phylogenetic approach to investigating laterality to better understand its evolutionary path; and a further focus on mechanistic drivers, with special attention to genetic and environmental effects. Putting together the puzzle of laterality using as many pieces as possible will provide a stronger understanding of this field, allowing us to continue to expand the field in novel ways.


MiR-195-5p inhibits the development of chronic obstructive pulmonary disease via targeting siglec1.
Chronic obstructive pulmonary disease (COPD), characterized by chronic inflammation, is a recognized global health crisis. Sialic acid-binding immunoglobulin-like lectin 1 (siglec1 or CD169), mainly expressed in macrophages and dendritic cells, is markedly upregulated after encountering pathogens or under acute/chronic inflammation conditions. However, it is rarely reported that whether siglec1 plays a role in the development of COPD. In this study, we found that siglec1 had higher expression in the lungs from COPD rats and in peripheral blood mononuclear cells (PBMCs) from COPD patients. Knockdown of siglec1 in vivo and in vitro dramatically decreased pro-inflammatory cytokines production in pulmonary macrophages and alleviated pulmonary inflammatory responses in COPD rats as well as inactivated nuclear factor kappa B (NF-κB) signaling. In addition, we identified a new microRNA, miR-195-5p, which has never explored in COPD, was lower expressed in COPD rats and PBMC of COPD patients, and could negatively modulate siglec1 expression in macrophages. Moreover, overexpression of miR-195-5p via miR-195-5p mimics in vitro and in vivo could significantly alleviate pro-inflammatory cytokines production in pulmonary macrophages and pulmonary inflammatory responses in COPD rats. Together, our findings suggested that miR-195-5p inhibited the development of COPD via targeting siglec1, which might become a therapeutic target to improve COPD.


Misspecified poisson regression models for large-scale registry data: inference for 'large n and small p'.
Poisson regression is an important tool in register-based epidemiology where it is used to study the association between exposure variables and event rates. In this paper, we will discuss the situation with 'large n and small p', where n is the sample size and p is the number of available covariates. Specifically, we are concerned with modeling options when there are time-varying covariates that can have time-varying effects. One problem is that tests of the proportional hazards assumption, of no interactions between exposure and other observed variables, or of other modeling assumptions have large power due to the large sample size and will often indicate statistical significance even for numerically small deviations that are unimportant for the subject matter. Another problem is that information on important confounders may be unavailable. In practice, this situation may lead to simple working models that are then likely misspecified. To support and improve conclusions drawn from such models, we discuss methods for sensitivity analysis, for estimation of average exposure effects using aggregated data, and a semi-parametric bootstrap method to obtain robust standard errors. The methods are illustrated using data from the Danish national registries investigating the diabetes incidence for individuals treated with antipsychotics compared with the general unexposed population.


Cobra venom cytotoxins; apoptotic or necrotic agents?
Organs homeostasis is controlled by a dynamic balance between cell proliferation and apoptosis. Failure to induction of apoptosis has been implicated in tumor development. Cytotoxin-I (CTX-I) and cytotoxin-II (CTX-II) are two physiologically active polypeptides found in Caspian cobra venom. Anticancer activity and mechanism of cell death induced by these toxins have been studied. The toxins were purified by different chromatographic steps and their cytotoxicity and pattern of cell death were determined by MTT, LDH release, acridine orange/ethidium bromide (AO/EtBr) double staining, flow cytometric analysis, caspase-3 activity and neutral red assays. The IC50 of CTX-II in MCF-7, HepG2, DU-145 and HL-60 was 4.1 ± 1.3, 21.2 ± 4.4, 9.4 ± 1.8 μg/mL and 16.3 ± 1.9 respectively while the IC50 of this toxin in normal MDCK cell line was 54.5 ± 3.9 μg/mL. LDH release suddenly increase after a specific toxins concentrations in all cell lines. AO/EtBr double staining, flow cytometric analysis and caspase-3 activity assay confirm dose and time-dependent induction of apoptosis by both toxins. CTX-I and CTX-II treated cells lost their lysosomal membrane integrity and couldn't uptake neutral red day. CTX-I and CTX-II showed significant anticancer activity with minimum effects on normal cells and better IC50 compared to current anticancer drug; cisplatin. They induce their apoptotic effect via lysosomal pathways and release of cathepsins to cytosol. These effects were seen in limited rage of toxins concentrations and pattern of cell death rapidly changes to necrosis by increase in toxin's concentration. In conclusion, significant apoptogenic effects of these toxins candidate them as a possible anticancer agent.


The Extracellular Calcium-Sensing Receptor (CASR) Regulates Gonadotropins-Induced Meiotic Maturation of Porcine Oocytes.
Gonadotropins and epidermal growth factor (EGF) play crucial roles in promoting oocyte maturation. The regulatory network downstream of these key factors is not well understood. The present study was designed to investigate the role of the calcium-sensing receptor (CASR) in porcine oocyte in vitro maturation. CASR expression was up-regulated in oocytes matured in gonadotropin-containing medium. Cortical distribution of CASR was enhanced with gonadotropins but not EGF. Supplementation of a CASR agonist (NPS R-568) in the gonadotropin (FSH and/or LH)-containing maturation medium significantly enhanced oocyte nuclear maturation. Addition of NPS2390, a CASR antagonist, compromised oocyte nuclear maturation. Furthermore, increased cortical distribution and decreased expression of CASR was observed after the NPS R-568 treatment. Oocytes treated with NPS R-568 had higher concentration of CYCLIN B1, decreased reactive oxygen species, and increased glutathione levels, indicative of advanced cytoplasmic maturation. In contrast, NPS2390 treatment compromised oocyte cytoplasmic maturation. A higher blastocyst formation rate after parthenogenetic activation was observed when oocytes were matured in the presence of the CASR agonist, NPS R-568. MAPK3/1 phosphorylation was increased during in vitro maturation and after NPS R-568 treatment, and decreased following CASR antagonist supplementation. Taken together, our data showed that the CASR is a gonadotropin-regulated factor that promotes porcine oocyte maturation in a MAPK-dependent manner.


Minimal inhibitory dosage of rifampicin in intermittent treatment of Mycobacterium leprae infection in mice.
The total minimal inhibitory dose of rifampicin determined in the experimental mouse model, was found to be 10 mg/kg body weight, administered once a week for 6 weeks or once every 2 weeks for 12 weeks. From these and other results it is suggested that administration of RMP in human treatment can be reduced to a total amount of 7.2 either as a 600 mg dose once a week for 12 weeks or as a 900 mg dose once a week for 8 weeks. At present these regimens can only be used as an introductory treatment for multibacillary cases and are still too expensive for developing countries, but their efficacy should be evaluated in the field as sole treatments in tuberculoid cases, since they could signify a substantial economy for the management of the majority of leprosy infections.


Forensic toxicology.
Forensic toxicology has developed as a forensic science in recent years and is now widely used to assist in death investigations, in civil and criminal matters involving drug use, in drugs of abuse testing in correctional settings and custodial medicine, in road and workplace safety, in matters involving environmental pollution, as well as in sports doping. Drugs most commonly targeted include amphetamines, benzodiazepines, cannabis, cocaine and the opiates, but can be any other illicit substance or almost any over-the-counter or prescribed drug, as well as poisons available to the community. The discipline requires high level skills in analytical techniques with a solid knowledge of pharmacology and pharmacokinetics. Modern techniques rely heavily on immunoassay screening analyses and mass spectrometry (MS) for confirmatory analyses using either high-performance liquid chromatography or gas chromatography as the separation technique. Tandem MS has become more and more popular compared to single-stage MS. It is essential that analytical systems are fully validated and fit for the purpose and the assay batches are monitored with quality controls. External proficiency programs monitor both the assay and the personnel performing the work. For a laboratory to perform optimally, it is vital that the circumstances and context of the case are known and the laboratory understands the limitations of the analytical systems used, including drug stability. Drugs and poisons can change concentration postmortem due to poor or unequal quality of blood and other specimens, anaerobic metabolism and redistribution. The latter provides the largest handicap in the interpretation of postmortem results.


Extensive lanthanum deposition in the gastric mucosa: the first histopathological report.
Lanthanum carbonate is one of the new phosphate binders used for the treatment of hyperphosphatemia in patients with chronic kidney disease. It is poorly absorbed from the gastrointestinal tract, forms insoluble complexes within the lumen, and prevents the absorption of dietary phosphate. A 63-year-old female with a 7-year history of peritoneal dialysis, who was treated with lanthanum carbonate for four years, underwent endoscopic submucosal dissection for intramucosal gastric cancer. Resected specimens showed massive accumulation of macrophages containing fine, granular, brown material in the lamina propria. This was confirmed as lanthanum deposition by scanning electron microscopy with energy dispersive x-ray spectroscopy. Although lanthanum may be poorly absorbed, increased tissue accumulation of lanthanum, particularly in the liver and bone, has been reported in animals with chronic kidney disease. This report indicates enhanced gastrointestinal absorption of lanthanum in some patients or conditions, although its clinical significance awaits further studies.


Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development.
The c-Jun amino-terminal kinase (JNK) group of MAP kinases has been identified in mammals and insects. JNK is activated by exposure of cells to cytokines or environmental stress, indicating that this signaling pathway may contribute to inflammatory responses. Genetic and biochemical studies demonstrate that this signaling pathway also regulates cellular proliferation, apoptosis, and tissue morphogenesis. A functional role for JNK is therefore established in both the cellular response to stress and in many normal physiological processes.


Deriving wavelength spectra from fringe images from a fixed-gap single-etalon Fabry-Perot spectrometer.
A new method is described for inferring wavelength spectra from two-dimensional images of Fabry-Perot interference fringes. This new method addresses the practical difficulties that have been previously encountered in determining the fringe image's center, magnification, and distortions accurately enough to fully exploit the spectral resolution provided by the etalon. The method proceeds in two steps. First, the instrument's mapping of image position to interference order is characterized by use of images of a scene illuminated uniformly by a highly monochromatic laser. Then this information is applied to resample two-dimensional images of unknown radiation sources down to sets of one or more one-dimensional wavelength spectra. Discrete cross-correlation techniques are used at both stages of anal-


ICT & OTs: a model of information and communications technology acceptance and utilisation by occupational therapists (part 2).
The research reported in this paper describes the development, empirical validation and analysis of a model of technology acceptance by Australian occupational therapists. The study described involved the collection of quantitative data through a national survey. The theoretical significance of this work is that it uses a thoroughly constructed research model, with one of the largest sample sizes ever tested (n=1605), to extend technology acceptance research into the health sector. Results provide strong support for the model. This work reveals the complexity of the constructs and relationships that influence technology acceptance and highlights the need to include sociotechnical and system issues in studies of technology acceptance in healthcare to improve information system implementation success in this arena. The results of this study have practical and theoretical implications for health informaticians and researchers in the field of health informatics and information systems, tertiary educators, Commonwealth and State Governments and the allied health professions.


Epidermal keratinocytes sense dsRNA via the NLRP3 inflammasome, mediating interleukin (IL)-1β and IL-18 release.
Skin epidermis, in addition to its barrier function, is able to actively sense harmful pathogens using pattern recognition receptors. In immune cells, the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome can mediate innate immunity against viral infection via a mechanism involving viral dsRNA recognition. Epidermal keratinocytes express NLRP3 inflammasome, which can sense contact sensitizers and mite allergens, leading to pro-interleukin (IL)-1β and pro-IL-18 cleavage into their active forms. Skin often faces viral infection. However, it is unknown whether viral dsRNA can be detected by the keratinocyte NLRP3 inflammasome. We transfected polyinosinic:polycytidylic acid (poly I:C), a synthetic viral dsRNA analogue, into cultured primary human keratinocytes at the aid of Lipofectamine 2000, and found that transfected poly I:C activated caspase-1 and induced caspase-1-dependent release of IL-1β and IL-18, which were suppressed on transfection with NLRP3 siRNA. The activation of keratinocyte NLRP3 inflammasome by transfected poly I:C was dependent on dsRNA-induced protein kinase (PKR) activation, and priming with type I interferons upregulated NLRP3 inflammasome activation through promoting PKR activation in poly I:C-transfected keratinocytes. In conclusion, the NLRP3 inflammasome can act as a sensor of dsRNA in epidermal keratinocytes, which may be important in both skin innate immune defense against viral infection and skin inflammation.


Metabolic Inputs into the Epigenome.
A number of molecular pathways play key roles in transmitting information in addition to the genomic sequence-epigenetic information-from one generation to the next. However, so-called epigenetic marks also impact an enormous variety of physiological processes, even under circumstances that do not result in heritable consequences. Perhaps inevitably, the epigenetic regulatory machinery is highly responsive to metabolic cues, as, for example, central metabolites are the substrates for the enzymes that catalyze the deposition of covalent modifications on histones, DNA, and RNA. Interestingly, in addition to the effects that metabolites exert over biological regulation in somatic cells, over the past decade multiple studies have shown that ancestral nutrition can alter the metabolic phenotype of offspring, raising the question of how metabolism regulates the epigenome of germ cells. Here, we review the widespread links between metabolism and epigenetic modifications, both in somatic cells and in the germline.


Circulation patterns and molecular epidemiology of human respiratory syncytial virus over five consecutive seasons in Morocco.
Respiratory syncytial virus (HRSV) is the leading cause of respiratory tract infections in infants and young children. we investigated the prevalence and characteristics of HRSV in Morocco and explored trends in circulating genotypes through partial G gene analysis of HRSV strains prevalent from 2012 to 2017. Respiratory samples were gathered from both outpatients and inpatients meeting ILI or SARI case definitions. The patients' ages varied from 1 month to 99 years old. Nucleic acids were extracted and HRSV type/subtype was detected by RT-qPCR. A subset of positive samples was randomly selected in each epidemic year, the complete viral genome was sequenced, phylogenetic analysis was performed using the MEGA7 program and the genotypes were confirmed. The 3679 specimens were collected from 2012 to 2017, of which 726 (19.7%) were positive for HRSV. The 35% (257/726) of HRSV-positives were of the HRSV-A subtype, while the HRSV-B subtype accounted for 61% (442/726). The co-infection rate was 3.7% (27/726). The virus circulates in a periodic pattern, where epidemics occur during the fall months through early spring. HRSV genotype was confirmed in 127 specimens (56 HRSV-A and 71 HRSV-B). Based on phylogenetic analysis, all HRSV-A were ON1 genotype, and HRSV-B were mostly BA9 genotype. HRSV-B belonging to the BA10 genotype was detected in 2012 exclusively. BA9, BA10, and ON1 were the only HRSV genotypes detected between 2012 and 2017. Variations in the G gene amino acid chain were identified in local strains, which suggests an increased need for continuous genomic surveillance.


Protection from hyperbaric oxidant stress by administration of buthionine sulfoximine.
To explore the role of glutathione in protecting rats from hyperbaric hyperoxia, we administered buthionine sulfoximine (BSO) to block gamma-glutamyl cysteine synthase activity and decrease tissue glutathione synthesis. We then exposed these animals and their vehicle-treated matched controls to 100% oxygen at 4 ATA or room air at 1 ATA. After BSO treatment, glutathione concentrations in air-exposed controls decreased 62% in lung, 76% in liver, 28% in brain, and 62% in plasma. Paradoxically, BSO-treated rats were protected from hyperbaric hyperoxia. The BSO-treated animals seized significantly later and had a markedly prolonged time of survival compared with the vehicle-treated controls. We conclude that BSO treatment protects rats from hyperbaric hyperoxia, despite its effects of lowering plasma and tissue glutathione concentrations. This protection may be related to a direct effect of the compound in decreasing free radical-mediated tissue injury, increasing tissue antioxidant defenses, or increasing seizure threshold.


Tentorial Dural Arteriovenous Fistulas: A Single-Center Cohort of 12 Patients.
Tentorial dural arteriovenous fistulas usually drain into cortical veins and often present with hemorrhage. Treatment goal is occlusion of the draining vein, either by surgery or endovascular techniques. We present the multimodality treatment results of 12 patients with tentorial dural arteriovenous fistulas. Between January 2007 and January 2017, 12 consecutive patients with tentorial dural arteriovenous fistulas were treated. There were 11 men and 1 woman with a mean age of 62 years (range 44-85). Clinical presentation was hemorrhage in 8 (67%), pulsatile tinnitus in 2 (17%) and an incidental finding in 2 (17%). The fistula location was at the tentorium cerebelli in 5 (42%), the torcula Herophilii in 4 (33%) and petroclival in 3 (25%). In 11 patients, arterial embolization with Onyx or PHIL was the primary treatment. Complete obliteration was achieved in one session in 5 (45%) and in 2 sessions in 4 (36%). In 2 patients additional surgery was needed. Primary surgery was performed in 1 patient followed by endovascular coil occlusion via the venous route. One patient with exclusive pial feeders from the posterior inferior cerebellar artery had a clinically silent P3 occlusion during trans arterial embolization. Finally, all 12 fistula were completely occluded, confirmed with angiography after 8-12 weeks. There were no permanent procedural complications. Patients with tentorial dural arteriovenous fistulas were effectively and safely cured with a strategy of endovascular treatment with various techniques and surgery. Surgical and endovascular techniques are complementary in the treatment of these challenging vascular disorders.


IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function.
BackgroundSome clinical features of severe COVID-19 represent blood vessel damage induced by activation of host immune responses initiated by the coronavirus SARS-CoV-2. We hypothesized autoantibodies against angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor expressed on vascular endothelium, are generated during COVID-19 and are of mechanistic importance.MethodsIn an opportunity sample of 118 COVID-19 inpatients, autoantibodies recognizing ACE2 were detected by ELISA. Binding properties of anti-ACE2 IgM were analyzed via biolayer interferometry. Effects of anti-ACE2 IgM on complement activation and endothelial function were demonstrated in a tissue-engineered pulmonary microvessel model.ResultsAnti-ACE2 IgM (not IgG) autoantibodies were associated with severe COVID-19 and found in 18/66 (27.2%) patients with severe disease compared with 2/52 (3.8%) of patients with moderate disease (OR 9.38, 95% CI 2.38-42.0; P = 0.0009). Anti-ACE2 IgM autoantibodies were rare (2/50) in non-COVID-19 ventilated patients with acute respiratory distress syndrome. Unexpectedly, ACE2-reactive IgM autoantibodies in COVID-19 did not undergo class-switching to IgG and had apparent KD values of 5.6-21.7 nM, indicating they are T cell independent. Anti-ACE2 IgMs activated complement and initiated complement-binding and functional changes in endothelial cells in microvessels, suggesting they contribute to the angiocentric pathology of COVID-19.ConclusionWe identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications.FUNDINGBill & Melinda Gates Foundation, Gates Philanthropy Partners, Donald B. and Dorothy L. Stabler Foundation, and Jerome L. Greene Foundation; NIH R01 AR073208, R01 AR069569, Institutional Research and Academic Career Development Award (5K12GM123914-03), National Heart, Lung, and Blood Institute R21HL145216, and Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Science Foundation Graduate Research Fellowship (DGE1746891).


Shortening of HO1 3'UTRs by Alternative Polyadenylation Suppresses Adipogenesis in 3T3-L1.
Appropriately increasing intramuscular fat content can help improve meat quality, so it is necessary to explore the internal molecular mechanism of preadipocyte differentiation. The role of heme oxygenase 1 (HO1) in cell oxidative stress, energy metabolism, cell proliferation, and differentiation has gradually been revealed. Here, we used 3'RACE to identify the full-length 3' untranslated region (3'UTR) of HO1 and found that a very short 3'UTR variant was produced by alternative polyadenylation (APA). HO1 with a long 3'UTR variant was identified as a direct target of miR155-5P and miR377-3P. Our experimental results verified the inhibitory effect of HO1 on preadipocyte differentiation. In addition, our research confirms that by escaping microRNA inhibitory effects, the HO1 3'UTR short variant produced by APA has a higher level of expression. Thus, the HO1 3'UTR short variant has a stronger inhibitory effect on the preadipocyte differentiation than the HO1 3'UTR long variants in 3T3-L1.


Correlation between adenoma detection rate in colonoscopy- and fecal immunochemical testing-based colorectal cancer screening programs.
The adenoma detection rate (ADR) is the main quality indicator of colonoscopy. The ADR recommended in fecal immunochemical testing (FIT)-based colorectal cancer screening programs is unknown. Using the COLONPREV (NCT00906997) study dataset, we performed a post-hoc analysis to determine if there was a correlation between the ADR in primary and work-up colonoscopy, and the equivalent figure to the minimal 20% ADR recommended. Colonoscopy was performed in 5722 individuals: 5059 as primary strategy and 663 after a positive FIT result (OC-Sensor™; cut-off level 15 µg/g of feces). We developed a predictive model based on a multivariable lineal regression analysis including confounding variables. The median ADR was 31% (range, 14%-51%) in the colonoscopy group and 55% (range, 21%-83%) in the FIT group. There was a positive correlation in the ADR between primary and work-up colonoscopy (Pearson's coefficient 0.716; p < 0.001). ADR in the FIT group was independently related to ADR in the colonoscopy group: regression coefficient for colonoscopy ADR, 0.71 (p = 0.009); sex, 0.09 (p = 0.09); age, 0.3 (p = 0.5); and region 0.00 (p = 0.9). The equivalent figure to the 20% ADR was 45% (95% confidence interval, 35%-56%). ADR in primary and work-up colonoscopy of a FIT-positive result are positively and significantly correlated.


Predictive Factors of Prolonged Ventilation Following Cardiac Surgery with Cardiopulmonary Bypass.
In this trial, we initially aimed to investigate the major predictive factors for prolonged mechanical ventilation (PMV) following cardiac surgery with cardiopulmonary bypass (CPB) in our center and, secondarily, we tried to find out the effects of the independent factors on mortality. Between July 2017 and August 2018, 207 patients who underwent cardiac surgery with CPB were retrospectively investigated. The patients were randomly divided into two subgroups according to the duration of ventilator dependence (group 1 <24 hours, n=164, 79%; group 2 >24 hours, n=43, 21%). 207 patients (mean age 59.47±10.56) who underwent cardiac surgery with CPB were enrolled in this study (n=145, 70% of male patients; n=62, 30% of female patients). Amid these patients, 43 (n=43, 20.77%) had prolonged intubation time. After multivariate logistic regression analysis among preoperative factors, female gender (OR=2.321, P=0.028), leukocytosis (OR=1.233, P=0.006), perioperative lactate level (OR=1.224, P=0.027), CPB time (OR=1.012, P=0.012) and postoperative revision for bleeding (OR=23.125, P=0.040) were significantly detected. The effect of predictive factors on mortality after cardiac surgery was determined and found that PMV did not affect hospital mortality (OR=1.979, P=0.420). In our report, we revealed, differently from previous studies, that intraoperative lactate levels which manifest organ perfusion and oxygenation were included and were significantly different in the early extubation group compared to the PMV group. Female gender, preoperative leukocytosis, intraoperative CPB time, lactate levels and postoperative revision for bleeding were the independent predictive factors for PMV. Moreover, PMV did not affect the early-term mortality during hospital stay.