Undifferentiated head and neck tumors: the contribution of immunohistochemical technique to differential diagnosis.
Undifferentiated head and neck and skull base tumors are not unusual. They can arise in mucosa as well as in salivary glands, soft tissues or lymph nodes. Suitable therapy and prognosis for each case depends upon precise histopathological diagnosis. To evaluate the role of immunohistochemical techniques in determining the conclusive diagnosis. The occurrence of these tumors in our service and the way in which they were distributed according to cell pattern, patient's age and tumor location was also evaluated. Cross-sectional study. Hospital das Clínicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil. 43 biopsies performed between January 1990 and December 1997, diagnosed as undifferentiated head and neck tumors. We applied an immunohistochemical panel in accordance with the avidin-biotin-peroxidase complex method. The final diagnosis was achieved after new analysis in conjunction with biopsies stained using the hematoxylin-eosin technique. This study evaluated undifferentiated tumors in head and neck, and the way in which they were distributed, according to cell pattern, patient's age and tumor location. The most frequent locations for undifferentiated tumors were the lymph nodes, 20.9%; pharynx and neck, 16.3%; paranasal sinus, 14%; and nose, 11.6%. They were most prevalent during the seventh decade of life (34.9%), and twice as prevalent in men as in women. The immunohistochemical technique allowed conclusive diagnosis for 60.5% of the tumors and was suggestive for 20.9% of the biopsies. The most prevalent cell pattern was round cells (51.2%), followed by epithelioid cells (20.9%), spindle cells (16.3%), myxoid pattern (9.3%) and pleomorphic cells (2.3%). Our results demonstrate the fundamental role of the immunohistochemical technique for conclusive diagnosis of undifferentiated tumors.


Ventilatory support of the critically ill foal.
Critically ill foals often have respiratory failure and benefit from respiratory support. Conventional mechanical ventilation using modem mechanical ventilators is easily adapted to foals. Establish-ing ventilator settings is a dynamic process aided by constant monitoring of blood gas values, end-tidal carbon dioxide, airway pressures, respiratory volumes, airway resistance, and respiratory compliance. Early weaning is as important as timely initiation of ventilation.


Hypoglycemia complicating dehydration in children with acute gastroenteritis.
A study was done to estimate the prevalence of hypoglycemia among children with dehydration due to acute gastroenteritis, and to identify clinical variables associated with hypoglycemia in these children. A retrospective case series of children older than 1 month of age and younger than 5 years of age who presented to an urban children's hospital Emergency Department with acute gastroenteritis and dehydration was performed. Medical records were reviewed; demographic and clinical data, including pretreatment serum glucose concentrations, were recorded. There were 196 children comprising the study population. Eighteen children (9.2%) were hypoglycemic. The duration of vomiting was longer for the children with hypoglycemia (2.6 days, SD +/- 1.5) than for those without hypoglycemia (1.6, SD +/- 1.8), 95% CI 0.13 to 1.88. Hypoglycemia may complicate dehydration due to acute gastroenteritis in young children. Clinicians should examine the serum glucose concentration in these children.


Involvement of PKA and Sp1 in the induction of p27(Kip1) by tamoxifen.
We have previously shown that tamoxifen (Tam) inhibits proliferation of estrogen receptor-negative human non-small cell lung cancer cells and this inhibition is associated with induction of p27(Kip1). In this study, we investigated the mechanism by which Tam increases p27(Kip1) expression. Because intracellular p27(Kip1) protein level is mainly controlled via posttranslational regulation, we first tested whether Tam might affect protein stability of p27(Kip1). Metabolic labeling and pulse chase assays showed that Tam did not affect the half-life of this protein. We next examined whether Tam enhanced p27(Kip1) expression through transcriptional activation. Our results demonstrated that Tam directly stimulated the p27(Kip1) promoter in lung cancer cells. Deletion and mutation analysis revealed that two Sp1 consensus sites located between -545 and -532bp from the transcription start site were crucial for the induction of p27(Kip1) by Tam. Conversely, mutation in a CTF site (-525/-520) nearby these two Sp1 sites had little effect. Electromobility shift assays showed that Sp1 transcription factor bound to these consensus sites and the DNA binding activity of Sp1 was enhanced by Tam. Our data also demonstrated that induction of p27(Kip1) by Tam was inhibited by protein kinase A inhibitor H89, but not by protein kinase C inhibitor calphostin C and mitogen-activated kinase kinase inhibitor PD98059. Taken together, our results suggest that Tam transcriptionally activates p27(Kip1) expression via the Sp1 consensus sites in the p27(Kip1) promoter and PKA is involved in this process.


Recognition of post-learning alteration of hippocampal ripples by convolutional neural network differs in the wild-type and AD mice.
Evidence indicates that sharp-wave ripples (SWRs) are primary network events supporting memory processes. However, some studies demonstrate that even after disruption of awake SWRs the animal can still learn spatial task or that SWRs may be not necessary to establish a cognitive map of the environment. Moreover, we have found recently that despite a deficit of sleep SWRs the APP/PS1 mice, a model of Alzheimer's disease, show undisturbed spatial reference memory. Searching for a learning-related alteration of SWRs that could account for the efficiency of memory in these mice we use convolutional neural networks (CNN) to discriminate pre- and post-learning 256 ms samples of LFP signals, containing individual SWRs. We found that the fraction of samples that were correctly recognized by CNN in majority of discrimination sessions was equal to ~ 50% in the wild-type (WT) and only 14% in APP/PS1 mice. Moreover, removing signals generated in a close vicinity of SWRs significantly diminished the number of such highly recognizable samples in the WT but not in APP/PS1 group. These results indicate that in WT animals a large subset of SWRs and signals generated in their proximity may contain learning-related information whereas such information seem to be limited in the AD mice.


A Convenient Synthesis of γ-Amino-Ynamides via Additions of Lithiated Ynamides to Aryl Imines. Observation of an Aza-Meyer-Schuster Rearrangement.
Efforts in developing an expeditious and convenient method for synthesizing γ-amino-ynamides via nucleophilic addition of lithiated ynamides to aryl imines are described. This work also features an aza-variant of a Meyer-Schuster rearrangement of γ-amino-ynamides and the synthetic utility of γ-amino-ynamides in an intramolecular ketenimine-[2 + 2] cycloaddition.


Higher serum lipocalin 2 is associated with post-stroke depression at discharge.
Post-stroke depression (PSD), as one of the common complications after stroke, seriously affects the physical and mental health and functional prognosis of patients. Previous studies have shown that the increase of inflammatory mediators is associated with the occurrence of PSD. Lipocalin 2 (LCN2), as an acute phase protein, is involved in the development of acute ischemic stroke (AIS), and its expression is up-regulated in patients with depression, suggesting that there is a potential correlation between serum LCN2 and depression. The aim of this study was to explore the relationship between serum LCN2 at admission and PSD at discharge. A total of 358 AIS patients were retrospectively included. All patients had fasting venous blood taken within 24 h of admission to detect serum LCN2. The patients were evaluated by 17-item Hamilton Depression Scale (HAMD) before discharge. Patients with HAMD score > 7 were diagnosed with PSD. The correlation between serum LCN2 and PSD was tested using binary logistic regression analysis. In our study, 92 (25.7%) patients were diagnosed with PSD at discharge. According to the serum LCN2 value, the patients were divided into three layers (Tertile1 ≤ 105.24ng/ml; Tertile2: 105.24-140.12ng/ml; Tertile3 ≥ 140.12ng/ml), with T1 layer (the lowest levels) as a reference, after adjusting for multiple potential confounding factors, T3 layer (the highest levels) was independently associated with the occurrence of PSD (odds ratio [OR] = 2.639, 95% confidence interval [CI]: 1.317-5.287, P = 0.006). Similar results were found when the serum LCN2 was analyzed as a continuous variable. The optimal cut-off value of serum LCN2 at admission to predict PSD at discharge was 117.60ng/ml, at this threshold, the sensitivity was 77.2%, and the specificity was 53.4%. High serum LCN2 levels at admission are an independent risk factor for PSD in patients with AIS at discharge.


A Randomized Controlled Study of the Use of ProRoot Mineral Trioxide Aggregate and Endocem as Direct Pulp Capping Materials: 3-month versus 1-year Outcomes.
The purpose of this study was to assess the long-term clinical outcomes of direct pulp capping (DPC) with ProRoot MTA (Dentsply, Tulsa, OK) and Endocem (Maruchi, Wonju, Korea) as pulp capping materials. To this end, the 1-year cumulative successes of both materials were evaluated and compared with those of the 3-month outcomes in a prospective, randomized controlled trial. Patients were recruited from the Department of Conservative Dentistry of the Yonsei University Dental Hospital, Seoul, South Korea, from January to May 2013. Of the 48 teeth that met the inclusion criteria, 46 teeth were randomly allocated to either ProRoot MTA or Endocem groups (n = 23). Direct pulp capping was performed, and clinical and radiographic examinations were conducted over 1 year after the treatment. Survival analyses were conducted to compare the cumulative successes between ProRoot MTA and Endocem and to evaluate other clinical variables. Forty-one teeth were recalled 1 year after the treatments (recall rate = 89.13%). There were no significant differences between the cumulative successes of ProRoot MTA and Endocem in either log-rank or Cox proportional hazard regression analyses (P > .05). Among the other clinical variables, cavity type (class I, II, III vs class V) was determined to be significant in both the log-rank test (P = .001) and Cox regression analysis (P = .006). Both ProRoot MTA and Endocem exhibited similar cumulative successes as direct pulp capping materials up to 1 year. The teeth restored with class V cavities exhibited significantly lower cumulative success rates after direct pulp capping compared with the teeth restored with other types of cavities.


Rigid and remodelled: cerebrovascular structure and function after experimental high-thoracic spinal cord transection.
High-thoracic or cervical spinal cord injury (SCI) is associated with several critical clinical conditions related to impaired cerebrovascular health, including: 300-400% increased risk of stroke, cognitive decline and diminished cerebral blood flow regulation. The purpose of this study was to examine the influence of high-thoracic (T3 spinal segment) SCI on cerebrovascular structure and function, as well as molecular markers of profibrosis. Seven weeks after complete T3 spinal cord transection (T3-SCI, n = 15) or sham injury (Sham, n = 10), rats were sacrificed for either middle cerebral artery (MCA) structure and function assessments via ex vivo pressure myography, or immunohistochemical analyses. Myogenic tone was unchanged, but over a range of transmural pressures, inward remodelling occurred after T3-SCI with a 40% reduction in distensibility (both P < 0.05), and a 33% reduction in vasoconstrictive reactivity to 5-HT trending toward significance (P = 0.09). After T3-SCI, the MCA had more collagen I (42%), collagen III (24%), transforming growth factor β (47%) and angiotensin II receptor type 2 (132%), 27% less elastin as well as concurrent increased wall thickness and reduced lumen diameter (all P < 0.05). Sympathetic innervation (tyrosine hydroxylase-positive axon density) and endothelium-dependent dilatation (carbachol) of the MCA were not different between groups. This study demonstrates profibrosis and hypertrophic inward remodelling within the largest cerebral artery after high-thoracic SCI, leading to increased stiffness and possibly impaired reactivity. These deleterious adaptations would substantially undermine the capacity for regulation of cerebral blood flow and probably underlie several cerebrovascular clinical conditions in the SCI population.


Using time-to-onset for detecting safety signals in spontaneous reports of adverse events following immunization: a proof of concept study.
Disproportionality analyses (DPA) are widely used in pharmacovigilance for detecting safety signals from spontaneous reports of adverse events. In these analyses, time-to-onset (TTO; the time between vaccination and the onset of the adverse event) is rarely considered. Our objective is to assess the potential use of TTO to improve signal detection (SD). Adverse events were defined as signals for a vaccine if the TTO distribution was significantly different from the distribution of other events for the same vaccine and from the distribution obtained with the same event for other vaccines. Distributions were compared within a time window of 30 days by using the two-sample Kolmogorov-Smirnov statistic. With the use of the product label as a proxy of true positive safety signals, TTO SD was compared with a standard DPA method (based on stratified empirical Bayesian geometric mean) for an oral live pediatric vaccine (Rotarix™) and an inactivated adult vaccine (Fluarix™). With the use of the GlaxoSmithKline spontaneous reports database for Rotarix™, 10 Medical Dictionary for Regulatory Activities preferred terms were identified as signals, and among them, five were listed in the product label. The DPA method identified only three preferred terms from the label, that is, TTO SD showed higher sensitivity and specificity. For Fluarix™, TTO SD also showed higher sensitivity but lower specificity. This TTO SD method is complementary, conceptually and practically, to more traditional DPA and does not share the major drawback of DPA known as the masking effect. Higher sensitivity and/or specificity can be achieved using TTO SD.


Generalization after intradimensional discrimination training in 2-year-old children.
Two-year-old children received intradimensional discrimination training at initially distant points on a circle-ellipse continuum. This training often did not produce stimulus control by circle-ellipse differences smaller than the original training values. The lack of control did not reflect capacity limitations, however. Good control was established when the children were given further training at nearer points on the continuum. The data confirm results of earlier research on stimulus generalization, extending them to a developing human subject population.


MetRec: A dataset for meter classification of arabic poetry.
In this data article, we report a dataset related to the research titled "Meter Classification of Arabic Poems Using Deep Bidirectional Recurrent Neural Networks"[2]. The dataset was collected from a large repository of Arabic poems, Aldiwan website [1]. The data collection was done using a Python script that scrapes the website to find the poems and their associated meters. The dataset contains the verses and their corresponding meter classes. Meter classes are represented as numbers from 0 to 13. The dataset can be highly useful for further research in order to improve the field of Arabic poems' meter classification.


Beyond sports-doping headlines: the science of laboratory tests for performance-enhancing drugs.
This primer on urine analysis in sports-doping control is an overview with an emphasis on the main analytical chemistry technologies in use: gas chromatography-mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC-MS-MS), isotope ratio mass spectrometry detection of exogenous testosterone use, and isoelectric focusing detection of recombinant erythropoietin (EPO) use. Included are graphic examples of GC-MS selected ion monitoring and full scan, LC-MS-MS, and EPO test electropherogram data; a list of common acronyms; and answers to questions frequently asked about tampering and test accuracy.


Niacin increases adiponectin and decreases adipose tissue inflammation in high fat diet-fed mice.
To determine the effects of niacin on adiponectin and markers of adipose tissue inflammation in a mouse model of obesity. Male C57BL/6 mice were placed on a control or high-fat diet (HFD) and were maintained on such diets for the duration of the study. After 6 weeks on the control or high fat diets, vehicle or niacin treatments were initiated and maintained for 5 weeks. Identical studies were conducted concurrently in HCA2 (-/-) (niacin receptor(-/-)) mice. Niacin increased serum concentrations of the anti-inflammatory adipokine, adiponectin by 21% in HFD-fed wild-type mice, but had no effect on lean wild-type or lean or HFD-fed HCA2 (-/-) mice. Niacin increased adiponectin gene and protein expression in the HFD-fed wild-type mice only. The increases in adiponectin serum concentrations, gene and protein expression occurred independently of changes in expression of PPARγ C/EBPα or SREBP-1c (key transcription factors known to positively regulate adiponectin gene transcription) in the adipose tissue. Further, niacin had no effect on adipose tissue expression of ERp44, Ero1-Lα, or DsbA-L (key ER chaperones involved in adiponectin production and secretion). However, niacin treatment attenuated HFD-induced increases in adipose tissue gene expression of MCP-1 and IL-1β in the wild-type HFD-fed mice. Niacin also reduced the expression of the pro-inflammatory M1 macrophage marker CD11c in HFD-fed wild-type mice. Niacin treatment attenuates obesity-induced adipose tissue inflammation through increased adiponectin and anti-inflammatory cytokine expression and reduced pro-inflammatory cytokine expression in a niacin receptor-dependent manner.


Three dimensional scapular prints for evaluating glenoid morphology: An exploratory study.
Computerised Tomography (CT) scans are conventionally employed to assess the glenoid morphology prior to total shoulder arthroplasty (TSA). This study explores the role of three-dimensional (3D) models for assessing glenoid morphology. CT scans of 32 patients scheduled for TSA were reconstructed to scapular models using customised software and a desktop 3D printer. The size and aspect ratios were maintained. Glenoid version, glenoid maximum height and width, and the maximum acromion antero-posterior (AP) length were compared between the models and CT scans. The models were an accurate qualitative reflection of scapular anatomy. The average retroversion in 3D models was 8.19°±30.8° compared to 10.26°±42.5° in scan images. The mean difference was 2.07°±24.6° (p=0.408). However, the mean absolute error was 5.02°±12.3°. The mean difference of the glenoid maximum width and the acromion maximum AP length was 0.22±3.33mm (p=0.862) and 0.32±14.12mm (p=0.213) respectively. However, the mean difference was significant for the glenoid maximum height measuring 3.67±12.04mm with p=0.004. The correlation between the examiners was high for all parameters, with intraclass correlation ranging between 0.94 and 0.99. 3D printing technology promises to be a useful tool for preoperative planning with accurate reproduction of transverse plane anatomy. 3D prints represent superior definition of reconstructed anatomical measures such as glenoid height as compared to conventional CT Scans.


The effectiveness of theory-based smoking cessation interventions in patients with chronic obstructive pulmonary disease: a meta-analysis.
Smoking cessation can effectively reduce the risk of death, alleviate respiratory symptoms, and decrease the frequency of acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). Effective smoking cessation strategies are crucial for the prevention and treatment of COPD. Currently, clinical interventions based on theoretical frameworks are being increasingly used to help patients quit smoking and have shown promising results. However, theory-guided smoking cessation interventions have not been systematically evaluated or meta-analyzed for their effectiveness in COPD patients. To improve smoking cessation rates, this study sought to examine the effects of theory-based smoking cessation interventions on COPD patients. We adhered to the PRISMA guidelines for our systematic review and meta-analysis. The Cochrane Library, Web of Science, PubMed, Embase, Wanfang, CNKI, VIP Information Services Platform, and China Biomedical Literature Service System were searched from the establishment of the database to April 20, 2023. The study quality was assessed using the Cochrane Collaboration's risk assessment tool for bias. The revman5.4 software was used for meta-analysis. The I2 test was used for the heterogeneity test, the random effect model and fixed effect model were used for meta-analysis, and sensitivity analysis was performed by excluding individual studies. A total of 11 RCTs involving 3,830 patients were included in the meta-analysis. Results showed that theory-based smoking cessation interventions improved smoking cessation rates, quality of life, and lung function in COPD patients compared to conventional nursing. However, these interventions did not significantly affect the level of nicotine dependence in patients. Theory-based smoking cessation intervention as a non-pharmacologically assisted smoking cessation strategy has a positive impact on motivating COPD patients to quit smoking and improving their lung function and quality of life. PROSPERO registration Number: CRD42023434357.


Characterization of a MAVS ortholog from the Chinese tree shrew (Tupaia belangeri chinensis).
Human mitochondrial antiviral signaling protein (hMAVS, also known as IPS-1, VISA, or Cardif) is essential for antiviral innate immunity. The Chinese tree shrew (Tupaia belangeri chinenses), a close relative of primates, is emerging as a potential animal model for investigating viral infection. However, there is a lack of biological knowledge about the antiviral innate immunity of the tree shrew. In this study, we identified and characterized the function of the Chinese tree shrew MAVS gene (tMAVS). The cDNA of tMAVS was 2771 bp in length and encoded a polypeptide of 501 amino acids. Phylogenetic analyses based on the amino acid sequences revealed a closer affinity of tMAVS with those of primates. Quantitative real-time PCR analysis indicated that tMAVS mRNA was constitutively expressed in all seven tissues analyzed in this study. The tMAVS mRNA expression was rapidly and significantly increased after RNA virus infections. Ectopic-expression of tMAVS significantly potentiated the virus-triggered activation of IRF3, NF-κB and interferon-β (IFN-β), whereas knockdown of tMAVS displayed the opposite effect. Furthermore, tMAVS mutants lacking the caspase activation and recruitment (CARD) domains or the transmembrane (TM) domain were unable to induce IFN-β. Similar with hMAVS, mitochondrial localization of tMAVS was dependent on its domain. Collectively, this study revealed evolutionary conservation of the MAVS antiviral signaling pathway in the Chinese tree shrew.


Cerebral preparation of spontaneous movements: An EEG study.
The current study sought to determine whether there is a Bereitschaftspotential (BP) before uninstructed, spontaneous movements. 14 participants were seated on a comfortable armchair for one hour without any instruction except not to fall asleep and to keep their eyes open. Electroencephalography (EEG) and electromyography (EMG) activity were recorded during the whole session. EEG activity was analyzed before spontaneous movements and compared with EEG activity before repetitive, instructed movements in a separate session. BPs were identified in most participants with the spontaneous movements. The BPs with spontaneous movements were mostly localized in the medial frontocentral regions. The BPs with the instructed movements were localized primarily in the central regions and had larger amplitude. Presence of a BP before movement does not depend on instruction and may be independent of conscious volition. The amplitude of the BP may depend on the amount of attention. This study shows that the presence of a BP before movement is not an "artifact" of the experimental instructions.


Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma.
The relationship between loss of intercellular adhesion and the biologic properties of human squamous cell carcinoma is not well understood. We investigated how abrogation of E-cadherin-mediated adhesion influenced the behavior and phenotype of squamous cell carcinoma in 3D human tissues. Cell-cell adhesion was disrupted in early-stage epithelial tumor cells (HaCaT-II-4) through expression of a dominant-negative form of E-cadherin (H-2Kd-Ecad). Three-dimensional human tissue constructs harboring either H-2Kd-Ecad-expressing or control II-4 cells (pBabe, H-2Kd-EcadDeltaC25) were cultured at an air-liquid interface for 8 days and transplanted to nude mice; tumor phenotype was analyzed 2 days and 2 and 4 weeks later. H-2Kd-Ecad-expressing tumors demonstrated a switch to a high-grade aggressive tumor phenotype characterized by poorly differentiated tumor cells that infiltrated throughout the stroma. This high-grade carcinoma revealed elevated cell proliferation in a random pattern, loss of keratin 1 and diffuse deposition of laminin 5 gamma2 chain. When II-4 cell variants were seeded into type I collagen gels as an in vitro assay for cell migration, we found that only E-cadherin-deficient cells detached, migrated as single cells and expressed N-cadherin. Function-blocking studies demonstrated that this migration was matrix metalloproteinase-dependent, as GM-6001 and TIMP-2, but not TIMP-1, could block migration. Gene expression profiles revealed that E-cadherin-deficient II-4 cells demonstrated increased expression of proteases and cell-cell and cell-matrix proteins. These findings showed that loss of E-cadherin-mediated adhesion plays a causal role in the transition from low- to high-grade squamous cell carcinomas and that the absence of E-cadherin is an important prognostic marker in the progression of this disease.


Inulin-type oligosaccharides of Morinda officinalis exerted antidepressant effects by reducing hippocampal inflammation.
Neuroinflammation contributes to the pathogenesis of depression. Inulin-type oligosaccharides of Morinda officinalis (IOMO) exert antidepressant-like effects in rodents and patients with depression, while the underlying mechanisms remain unclear. This study used chronic restraint stress (CRS) and lipopolysaccharide (LPS) to induce depression-like behaviors in mice. Western blotting and ELISA analysis were used to investigate the effects of IOMO on inflammatory cytokine levels. Immunofluorescence analysis was used to investigate the effects of IOMO on hippocampal NLRP3 inflammasome and microglial cells. The results suggested that 6 weeks of CRS induced significant depression-like behaviors based on the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST), which were accompanied by increases in the expression of IL-6 and the activation of hippocampal microglial cells. Chronic treatment with IOMO (25 mg/kg, i.g.) for 28 days significantly reversed these depression-like behaviors and inhibited the activation of microglial cells. Furthermore, LPS (0.5 mg/kg, i.p.) also significantly induced depression-like behaviors in the TST, FST, and novelty-suppressed feeding test (NSFT), as well as increased the expression of IL-1β and caspase-1, and activated the microglial cells and the NLRP3 inflammasome in the hippocampus. Treatment with IOMO for 9 days significantly reversed these depression-like behaviors and normalized the LPS-induced activation of the microglial cells and NLRP3 inflammasome. Taken together, these results suggested that IOMO exerted antidepressant-like effects via hippocampal microglial NLRP3 inflammasome mediation followed by caspase-1 inhibition and the production of IL-1β. These findings provide a basis for developing new antidepressants targeting the microglial NLRP3 inflammasome.


Bimatoprost, latanoprost, and tafluprost induce differential expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases.
Differences in the increase in matrix metalloproteinase (MMP) and decrease in tissue inhibitor of metalloproteinase (TIMP) activity may contribute to the different characteristics observed clinically on decreased intraocular pressure in patients with glaucoma or ocular hypertension. The purpose of this study was to investigate differences in the expression profiles of MMPs and TIMPs induced by the prostaglandin analogs bimatoprost, latanoprost, and tafluprost in human non-pigmented ciliary epithelial cells (HNPCECs). HNPCECs were cultured for 24 h with 0, 10, 100, or 1000 μM of the free acid forms of bimatoprost, latanoprost, and tafluprost. We measured the expression levels of MMPs and TIMPs using real-time polymerase chain reaction, and compared the results. Enzyme activities of MMP-2 and -9 in conditioned media were measured by gelatin zymography. All prostaglandin analogs we examined dose-dependently increased expression levels of MMP-1, -2, -3, -9, and -17, whereas expression levels of TIMP-1 and -2 decreased with increasing concentrations of each analog. Each prostaglandin analog induced different levels of increases in MMPs and decreases in TIMPs. Unique expression profiles of MMPs and TIMPs induced by bimatoprost, latanoprost, and tafluprost, as shown in HNPCECs, may contribute to clinically different effects on intraocular pressure decreases in patients with glaucoma or ocular hypertension.


Exploiting death: apoptotic immunity in microbial pathogenesis.
Innate immunity typically is responsible for initial host responses against infections. Independently, nucleated cells that die normally as part of the physiological process of homeostasis in mammals (including humans) suppress immunity. Specifically, the physiological process of cell death (apoptosis) generates cells that are recognized specifically by viable cells of all types and elicit a profound transient suppression of host immunity (termed 'innate apoptotic immunity' (IAI)). IAI appears to be important normally for the maintenance of self-tolerance and for the resolution of inflammation. In addition, pathogens are able to take advantage of IAI through a variety of distinct mechanisms, to enable their proliferation within the host and enhance pathogenicity. For example, the protist pathogen Leishmania amazonensis, at its infective stage, mimics apoptotic cells by expressing apoptotic-like protein determinants on the cell surface, triggering immunosuppression directly. In contrast, the pathogenic bacterium Listeria monocytogenes triggers cell death in host lymphocytes, relying on those apoptotic cells to suppress host immune control and facilitate bacterial expansion. Finally, although the inhibition of apoptotic cell death is a common attribute of many viruses which facilitates their extended replication, it is clear that adenoviruses also reprogram the non-apoptotic dead cells that arise subsequently to manifest apoptotic-like immunosuppressive properties. These three instances represent diverse strategies used by microbial pathogens to exploit IAI, focusing attention on the potency of this facet of host immune control. Further examination of these cases will be revealing both of varied mechanisms of pathogenesis and the processes involved in IAI control.


Quality of life and factors affecting it in patients with Alzheimer's disease: a cross-sectional study.
Quality of life (QoL) is a growing area of interest in dementia research. However, it remains a controversial topic. This study aimed to determine the QoL of people with Alzheimer's disease (PwAD) and investigate the factors affecting patients' and caregivers' QoL scores. A cross-sectional study design was used. A total of 98 home-dwelling PwADs and their primary caregivers were recruited in the study. Sociodemographic characteristics and QoL scores, activities of daily living (ADL) and instrumental ADL (IADL), Mini-mental State Examination (MMSE) scores, neuropsychiatric inventory (NPI), and NPI-distress were determined to assess the relevant outcomes. All statistical analyses were performed using SPSS version 22.0. Descriptive statistics, t-test, Pearson correlation, and multinomial regression were used for analysis. The patients' ratings of their QoL were higher than those of the caregivers. Caregiver education, patients' ADL, and IADL were associated with the patients' score on the Quality of Life in Alzheimer's Disease (QoL-AD) scale. In addition to these variables, MMSE, NPI, and NPI-distress were associated with the caregiver scores on QoL-AD. From a clinical point of view, the proxy-rated scores of QoL cannot replace the self-ratings of the patients. This study suggests that both self- and proxy-rated QoL scores should be applied whenever possible. Focusing on the management of behavioral problems and supporting functionality and cognitive functions may be modifiable factors that may represent targets for intervention to improve the QoL. The findings of this study should also be used to design caregiver educational programs about the determinants of QoL.


Influence of height, weight and obesity on risk of breast cancer in an unselected Swedish population.
A number of recent studies have shown an association between breast-cancer risk and height, weight and dietary habits, especially fat consumption. In the present study, height and weight were determined for 179 consecutive, unselected, breast-cancer patients and age-matched controls selected from a computerized population register. Height and weight for these two groups were compared, including two different indices for overweight (Quetelet's index and Broca's index). Comparisons were repeated after subdivision into pre- and postmenopausal women. In all calculations, the mean values of patients and controls were very similar and without significant difference. It therefore seems improbable that increased height and weight or obesity constitute risk factors for breast cancer. Earlier studies may have shown differences as the result of selection mechanisms not present in this study.


Rapid and persistent adaptability of human oculomotor control in response to simulated central vision loss.
The central region of the human retina, the fovea, provides high-acuity vision. The oculomotor system continually brings targets of interest into the fovea via ballistic eye movements (saccades). Thus, the fovea serves both as the locus for fixations and as the oculomotor reference for saccades. This highly automated process of foveation is functionally critical to vision and is observed from infancy. How would the oculomotor system adjust to a loss of foveal vision (central scotoma)? Clinical observations of patients with central vision loss suggest a lengthy adjustment period, but the nature and dynamics of this adjustment remain unclear. Here, we demonstrate that the oculomotor system can spontaneously and rapidly adopt a peripheral locus for fixation and can rereference saccades to this locus in normally sighted individuals whose central vision is blocked by an artificial scotoma. Once developed, the fixation locus is retained over weeks in the absence of the simulated scotoma. Our data reveal a basic guiding principle of the oculomotor system that prefers control simplicity over optimality. We demonstrate the importance of a visible scotoma on the speed of the adjustment and suggest a possible rehabilitation regimen for patients with central vision loss.


Decreasing Central Line Associated Bloodstream Infection Through Limiting the Use of Central Venous Catheters for Routine Blood Draws.
The majority of patients admitted to intensive care units (ICU) require central venous catheters (CVC) for medication delivery, monitoring and blood draws. Repeated access of CVCs for collection of blood can cause central line associated bloodstream infection (CLABSI). If the number of times CVCs accessed for routine blood draws can be limited, the incidence of CLABSI in ICUs could be decreased. The focus of this quality improvement (QI) project was to decrease the CLABSI rate through limiting the use of and standardizing the process for routine blood draws through CVCs. All nursing staff were educated on the process change. Pre and post education CLABSI rates were compared to measure the outcome. The number of times CVCs accessed for routine blood work and CLABSI rate decreased after the intervention. The data collected supported that decreasing the use of CVCs for routine blood draws can decrease the number of times CVCs are accessed per shift and decrease the CLABSI rate. Nurses are at the front line in preventing, reducing, and sustaining zero CLABSI rate through implementing evidence based practices.


Determination of paracetamol and its metabolites in urine by high-performance liquid chromatography using ion-pair systems.
Paracetamol (P) and its four main metabolites, the sulphate (S), glucuronide (G), cysteine (C) and mercapturic acid (M) conjugates, are separated on ODS/TMS silica using a standard eluent, water-methanol-formic acid (86:14:0.1, v/v/v), in the order S, G, P, C, M. On addition of the ion-paring cations dioctylammonium (DOA) and tetrabutylammonium (TBA), the retention of S is vastly increased while those of G and M are substantially increased and that is C is reduced. The excessive retention of S and to a lesser extent that of M and G can be controlled by the addition of a suitable concentration of a co-ion such as nitrate. The order of elution is then G, C, P, M, S, although this can be varied by adjusting the amount of nitrate present. Loading of DOA is slow as it is very strongly adsorbed and typical concentrations in the eluent are below 7 mg/l. Loading by TBA is rapid with typical concentrations being around 200 mg/l. The effects of added co-ions such as nitrate can be explained in terms of simple ion-pair equilibria. Equilibration with respect to added salts is rapid. Application of the technique to analysis of therapeutic and overdose urines shows the presence of at least three additional metabolites, one of which is identified by mass spectrometry as most probably 3-methoxyparacetamol. Another appears to be a methoxymercapturic acid derivative. There is further evidence for a group of metabolites that elute unresolved from overdose urines as a broad band after the main metabolites.


Quantification of circulating endothelial progenitor cells in systemic sclerosis: a direct comparison of protocols.
It has been proposed that dysfunctional endothelial progenitor cells (EPCs) play a role in pathogenic vasculopathy in systemic sclerosis (SSc). However, there is some debate as to whether the EPC count is reduced in SSc. The European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group recently proposed recommendations for evaluating EPCs. To validate the proposed EUSTAR recommendations by a side-by-side comparison of methods for quantifying EPCs. Peripheral blood samples were obtained from 11 patients with SSc and 11 age-matched healthy controls. EPCs were simultaneously quantified by two methods: flow cytometry combined with immunomagnetic CD34+ cell enrichment or rosette-based lineage-negative (Lin-) cell enrichment. EPCs, defined as CD34+CD133+VEGFR2+ cells, were counted with and without fluorosphere calibration. EPC counts measured with fluorosphere calibration correlated well with each other, regardless of the enrichment procedure used. In contrast, EPC counts from protocols that did not use fluorospheres correlated poorly with results from other protocols. The EUSTAR recommendations are valid when they are combined with fluorosphere calibration.


Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting.
Chemical inhibition and genetic knockdown of enzymes are not equivalent in cells, but network-level mechanisms that cause discrepancies between knockdown and inhibitor perturbations are not understood. Here we report that enzymes regulated by negative feedback are robust to knockdown but susceptible to inhibition. Using the Raf-MEK-ERK kinase cascade as a model system, we find that ERK activation is resistant to genetic knockdown of MEK but susceptible to a comparable degree of chemical MEK inhibition. We demonstrate that negative feedback from ERK to Raf causes this knockdown-versus-inhibitor discrepancy in vivo. Exhaustive mathematical modeling of three-tiered enzyme cascades suggests that this result is general: negative autoregulation or feedback favors inhibitor potency, whereas positive autoregulation or feedback favors knockdown potency. Our findings provide a rationale for selecting pharmacologic versus genetic perturbations in vivo and point out the dangers of using knockdown approaches in search of drug targets.


Stromal circuits involving tumor-associated macrophages and cancer-associated fibroblasts.
The tumor associated macrophages (TAM) represent one of most abundant subpopulations across several solid cancers and their number/frequency is associated with a poor clinical outcome. It has been clearly demonstrated that stromal cells, such as the cancer associated fibroblasts (CAFs), may orchestrate TAM recruitment, survival and reprogramming. Today, single cell-RNA sequencing (sc-RNA seq) technologies allowed a more granular knowledge about TAMs and CAFs phenotypical and functional programs. In this mini-review we discuss the recent discoveries in the sc-RNA seq field focusing on TAM and CAF identity and their crosstalk in the tumor microenvironment (TME) of solid cancers.


"Keeping it on your radar"-assessing the barriers and facilitators to a timely diagnosis of type 1 diabetes in childhood: A qualitative study from the early detection of type 1 diabetes in youth study.
The aim of this study was to explore from the perspectives of key stakeholders involved in the pathway to diagnosis, the barriers and facilitators to a timely diagnosis of type 1 diabetes in childhood. Qualitative interviews and free-text analyses were undertaken in 21 parents with a child diagnosed with type 1 diabetes, 60 parents without a child diagnosed with type 1 diabetes, 9 primary healthcare professionals, 9 teachers and 3 community diabetes liaison nurses. Data were analysed thematically and 30% double coded. Two key themes were identified, namely the importance of widespread awareness and knowledge and seeking healthcare professional help. Parents with a child diagnosed with type 1 diabetes described seeking opinions from a number of individuals prior to seeking health professional help. Healthcare professionals recognized the rarity of the condition and the need for it to be kept on their "radar", to ensure they considered it when examining an unwell child. The process of obtaining a primary healthcare appointment was identified as potentially playing a crucial role in the diagnostic process. However, most parents with a child diagnosed with type 1 diabetes described receiving an appointment on the day they sought it. Knowledge and awareness of type 1 diabetes in childhood remain limited in the general population and misconceptions persist relating to how children present with this serious condition. An effective community-based intervention to raise awareness amongst key stakeholders is required to ensure children receive a timely diagnosis once symptomatic.


The impact of plain packaging and health warnings on consumer appeal of cannabis products.
Canada implemented 'plain packaging' regulations and rotating health warnings for cannabis products upon legalizing non-medical cannabis in October 2018. Plain packaging and health warnings are effective policy measures for reducing appeal of tobacco products; however, there is little evidence in the cannabis domain. An experimental task was conducted as part of the online International Cannabis Policy Study. Participants aged 16-65 from Canada (n = 9987) and US states with 'legal' (n = 7376) and 'illegal' (n = 9682) recreational cannabis were randomly assigned to see one of 18 cannabis product images. Outcomes were product appeal (0 = Not at all appealing, 10 = Very appealing) and perceived youth orientation (4 age groups). A 3 (branding: full branding, brand logo only, or plain black packaging) x 2 (health warning labels: present or absent) x 3 (product type: edible gummies, cannabis oil, or pre-rolled joints) factorial design was used. Compared to plain packaging or a brand logo, packages with full branding were considered more appealing and more likely to be youth-oriented (p < 0.001). Products with health warnings were considered less appealing than packages without warnings (p < 0.001). Edible gummies were perceived as more appealing and more likely to be youth-oriented than pre-rolled joints and cannabis oil (p < 0.001). Additionally, edible gummies were rated as significantly more appealing by 16-18 and 19-35-year-olds than by older adults (p < 0.02 for all). Comprehensive health warnings and 'plain packaging' regulations may reduce the appeal of cannabis products in a legal market. The results also provide empirical evidence that edible gummies are perceived to appeal to youth.


Tributyl phosphate biodegradation to butanol and phosphate and utilization by a novel bacterial isolate, Sphingobium sp. strain RSMS.
A Sphingobium sp. strain isolated from radioactive solid waste management site (RSMS) completely degraded 7.98 g/L of tributyl phosphate (TBP) from TBP containing suspensions in 3 days. It also completely degraded 20 mM dibutyl phosphate (DBP) within 2 days. The strain tolerated high levels of TBP and showed excellent stability with respect to TBP degradation over several repeated subcultures. On solid minimal media or Luria Bertani media supplemented with TBP, the RSMS strain showed a clear zone of TBP degradation around the colony. Gas chromatography and spectrophotometry analyses identified DBP as the intermediate and butanol and phosphate as the products of TBP biodegradation. The RSMS strain utilized both TBP and DBP as the sole source of carbon and phosphorous for its growth. The butanol released was completely utilized by the strain as a carbon source thereby leaving no toxic residue in the medium. Degradation of TBP or DBP was found to be suppressed by high concentration of glucose which also inhibited TBP or DBP dependent growth. The results highlight the potential of Sphingobium sp. strain RSMS for bioremediation of TBP and for further molecular investigation.


Diagnosis in a patient with fundus albipunctatus and atypical fundus changes.
We report a case of an 11-year old Caucasian female with nyctalopia since early childhood with an atypical clinical presentation of fundus albipunctatus (FA), and a novel mutation in the RDH5 gene. In addition to white spots in the fundus, patchy areas of hypopigmentation were noted, which were reminiscent for an early stage of retinitis punctata albescens (RPA). Electroretinographic testing (ERG) showed a non-detectable, dark adapted, isolated rod response and a markedly decreased combined rod and cone response to an achromatic stimulus. After patching one eye overnight, both the isolated rod response and combined rod and cone scotopic white flash response were normal. A Goldmann-Weekers dark adapted final threshold response was also within the normal range. The patient showed a previously reported heterozygous mutation for Gly238Trp, and a novel Arg157Gln mutation. Genetic testing and extended ERG and psychophysical testing may be necessary to diagnose FA from early stages of progressive RPA.


Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease.
The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide, morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were determined by sensitive and specific RIA procedures. Pharmacodynamics were assessed by pupillometry and vital sign determinations. Codeine elimination half-life and mean residence time were increased significantly in the hemodialysis group (18.69 +/- 9.03 hours and 12.77 +/- 7.09 hours, mean +/- SD, respectively) compared with the healthy volunteer group (4.04 +/- 0.60 hours and 3.90 +/- 0.52 hours, respectively). The total body clearance and volume of distribution of codeine were not significantly different between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites were also not significantly different between the groups, in part as a result of significant interpatient variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen may be required in some patients with uremia receiving multiple-dose codeine therapy.


Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese Adverse Drug Event Report database and literature.
Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated effectiveness in treating ovarian, breast, and other cancers, particularly those with specific molecular subtypes including, but not limited to, BRCA1/2 mutations. Consequently, its utilization is expected to increase in the future. For this reason, it is important to acknowledge the potential for adverse events associated with olaparib, including the relatively rare but significant risk of drug-induced interstitial lung disease (DIILD). Since DIILD can lead to fatal outcomes, its early detection is crucial. The dissemination of knowledge regarding DIILD can be facilitated through case reports; however, specific reports of DIILD caused by olaparib have only been published in Japanese. To the best of our knowledge, this is the first report in English of our experience with three cases of DIILD caused by olaparib. Cases 1, 2, and 3 involved Japanese women with ovarian cancer who had been receiving olaparib at a dose of 600 mg/day. Case 1, a 72-year-old woman who had been on olaparib for 4 months, and case 2, a 51-year-old woman who had been on olaparib for 8 months, reported fever and general malaise. Chest computed tomography (CT) revealed pale ground glass opacity (GGO) similar to hypersensitivity pneumonitis. The severity grade was 2 in both cases. Case 3, a 78-year-old woman who had been on olaparib for 3 weeks, presented with cough and reported dyspnea on exertion. Chest CT revealed non-specific interstitial pneumonia and organizing pneumonia-like shadows. The severity grade was 4. Olaparib was discontinued in all cases. Case 1 received 0.6 mg/kg of prednisolone due to mild hypoxia, while prednisolone was not administered in case 2 due to the absence of hypoxia. Case 3 received steroid pulse therapy due to severe hypoxia. Olaparib administration was not resumed in any patient. DIILD caused by olaparib in Japan, including the present three cases, commonly presents with GGO, similar to hypersensitivity pneumonitis on chest CT. The prognosis for the majority of patients is favorable; however, there have been instances of severe cases. Early recognition of drug-induced lung injury and further accumulation of cases is important.


Killing of Mycobacterium tuberculosis in tissue by microwaves with simultaneous tissue fixation.
Guinea-pig liver heavily infected with M. tuberculosis has been sterilised by exposure to microwaves in a standard commercially available domestic oven. Subsequent histology showed good tissue preservation and organisms of normal morphology were identified by Ziehl Neelsen staining. The findings allow the safe use of frozen sections for diagnosis in tissue containing M. tuberculosis.


Influence of Anatomical and Clinical Characteristics on Long-Term Prognosis of FFR-Guided Deferred Coronary Lesions.
The aim of this study was to evaluate the clinical and anatomical features to predict the long-term outcomes in patients with fractional flow reserve (FFR)-guided deferred lesions, verified by intravascular ultrasound (IVUS). Deferral of nonsignificant lesion by FFR is associated with a low risk of clinical events. However, the impact of combined information on clinical and anatomical factors is not well known. The study included 459 patients with 552 intermediate lesions who had deferred revascularization on the basis of a nonischemic FFR (>0.80). Grayscale IVUS was examined simultaneously. The primary endpoint was patient-oriented composite outcome (POCO) (a composite of all-cause death, myocardial infarction, and any revascularization) during 5-year follow-up. The rate of 5-year POCO was 9.8%. Diabetes mellitus (hazard ratio: 3.50; 95% confidence interval [CI]: 1.86 to 6.57; p < 0.001), left ventricular ejection fraction ≤40% (hazard ratio: 4.80; 95% CI: 1.57 to 14.63; p = 0.006), and positive remodeling (hazard ratio: 2.04; 95% CI: 1.03 to 4.03; p = 0.041) were independent predictors for POCO. When the lesions were classified according to the presence of the adverse clinical characteristics (diabetes, left ventricular ejection fraction ≤40%) or adverse plaque characteristics (positive remodeling, plaque burden ≥70%), the risk of POCO was incrementally increased (4.3%, 13.6%, and 21.3%, respectively; p < 0.001). In patients with FFR-guided deferred lesions, 5-year clinical outcomes were excellent. Lesion-related anatomical factors from intravascular imaging as well as patient-related clinical factors could provide incremental information about future clinical risks.


Exercise-induced pulmonary blood volume changes and diastolic dysfunction of the aged heart.
Impaired diastolic function has been described in healthy elderly subjects. Pulmonary blood volume (PBV) changes with exercise have been associated with left ventricular dysfunction, but not directly related to diastolic abnormalities. Exercise-induced relative changes in PBV were measured using gated blood pool imaging with count density comparisons over the lung in 20 healthy volunteers: 13 elderly, age 76 +/- 5 years and seven young, age 27 +/- 4 years. Serial (first exercise stage, peak exercise, and post exercise) PBV ratios were measured and correlated to peak early filling rate, peak late filling rate, and percent atrial filling obtained from the resting left ventricular time-activity curve analysis. PBV ratios tended to be higher in elderly subjects, but reached significance only at the first stage of exercise (1.04 +/- 0.07 vs. 0.93 +/- 0.10, p less than 0.01). Significant correlations were found between PBV ratios at first exercise stage and peak early filling rate (r = -0.64), peak late filling rate (r = 0.47), and percent atrial filling (r = 0.48). A significant correlation was found between PBV changes at peak exercise and resting diastolic parameters. Exercise-induced PBV changes are associated with left ventricular diastolic dysfunction at rest. Diastolic abnormalities of the aged heart may explain the differential PBV response early into exercise between young and elderly healthy subjects.


Simultaneous lung resection for cancer and myocardial revascularization without cardiopulmonary bypass (off-pump coronary artery bypass grafting).
Patients with resectable lung cancer and unstable coronary heart disease are at high risk of postoperative death or severe cardiovascular complications. The aim of this study was to present the early results of radical lung resection for cancer with simultaneous myocardial revascularization on the beating heart (off-pump coronary artery bypass [OPCAB]). From 1999 to 2002, thirteen patients (9 men and 4 women, aged 54 to 71 years, mean age 64 yrs) with resectable lung cancer and unstable angina or a recent history of myocardial infarction, were operated on. All of them underwent coronary angiography and neither coronary angioplasty nor stenting were feasible. Eight lobectomies, three pneumonectomies, and two wedge resections were carried out together with aortocoronary graft implantation (mean number of grafts: 1.7 per patient). Myocardial revascularization without cardiopulmonary bypass (OPCAB) preceded the lung resections. The preferred approach to the heart and lung was by sternotomy. There were no postoperative deaths in this group of patients. The most frequent postoperative complication was prolonged air leakage and one patient required respiratory support for two days. In one patient, significant blood loss was observed with a need for rethoracotomy. Transient supraventricular cardiac arrhythmias occurred in three patients. None of the patients showed evidence of myocardial ischemia after surgery. Patients were followed up for 7 to 36 months. None had acute myocardial infarction. In one patient, who underwent lobectomy, local recurrence was found. In another patient, who underwent pneumonectomy, distant metastases occurred in the third year of observation. Lung resection carried out simultaneously with OPCAB is a safe and effective method for the treatment of lung cancer and myocardial ischemia.


Selection of Higher Risk Pregnancies into Veterans Health Administration Programs: Discoveries from Linked Department of Veterans Affairs and California Birth Data.
To describe variation in payer and outcomes in Veterans' births. Secondary data analyses of deliveries in California, 2000-2012. We performed a retrospective, population-based study of all live births to Veterans (confirmed via U.S. Department of Veterans Affairs (VA) enrollment records), to identify payer and variations in outcomes among: (1) Veterans using VA coverage and (2) Veteran vs. all other births. We calculated odds ratios (aOR) adjusted for age, race, ethnicity, education, and obstetric demographics. We anonymously linked VA administrative data for all female VA enrollees with California birth records. From 2000 to 2012, we identified 17,495 births to Veterans. VA covered 8.6 percent (1,508), Medicaid 17.3 percent, and Private insurance 47.6 percent. Veterans who relied on VA health coverage had more preeclampsia (aOR 1.4, CI 1.0-1.8) and more cesarean births (aOR 1.2, CI 1.0-1.3), and, despite similar prematurity, trended toward more neonatal intensive care (NICU) admissions (aOR 1.2, CI 1.0-1.4) compared to Veterans using other (non-Medicaid) coverage. Overall, Veterans' birth outcomes (all-payer) mirrored California's birth outcomes, with the exception of excess NICU care (aOR 1.15, CI 1.1-1.2). VA covers a higher risk fraction of Veterans' births, justifying maternal care coordination and attention to the maternal-fetal impacts of Veterans' comorbidities.


Effect of vanadate on water transport by the toad bladder.
Vanadate increases renal Na and water excretion. The mechanism whereby vanadate impairs water transport was examined in the toad bladder. Vanadate did not alter baseline water transport but caused a significant inhibition of water transport elicited by high doses of AVP. The inhibition of AVP stimulated water flow by vanadate was dose dependent with inhibition present with concentration as low as 10(-7) and maximal inhibition occurring at 10(-5) M. Vanadate also inhibited water transport stimulated by cyclic AMP or by phosphodiesterase inhibition indicating that vanadate has an effect beyond cyclic AMP step, in addition to whatever effect it might have on adenylate cyclase. The inhibitory effect of vanadate on AVP stimulated water flow was not altered by prior Na-K-ATPase or prostaglandin inhibition. Since vanadate has been shown to stimulate adenylate cyclase in other tissues we examined whether addition of vanadate 10 minutes after addition of AVP would enhance water transport. Vanadate caused a transient enhancement of AVP stimulated water flow. These data demonstrate that vanadate can inhibit or stimulate water flow in the toad bladder.


Re-irradiating spinal column metastases using IMRT and VMAT with and without flattening filter - a treatment planning study.
The aim of this study was to investigate the potential of the flattening filter free (FFF) mode of a linear accelerator for intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) for patients with in-field recurrence of vertebral metastases. An Elekta Synergy Linac with Agility™ head is used to simulate the treatment of ten patients with locally recurrent spinal column metastases. Four plans were generated for each patient treating the vertebrae sparing the spinal cord: Dual arc VMAT and nine field step and shoot IMRT each with and without flattening filter. Plan quality was assessed considering target coverage and sparing of the spinal cord and normal tissue. All plans were verified by a 2D-ionisation-chamber-array, peripheral doses were measured and compared to calculations. Delivery times were measured and compared. The Wilcoxon test was used for statistical analysis with a significance level of 0.05. Target coverage, homogeneity index and conformity index were comparable for both flat and flattening filter free beams. The volume of the spinal cord receiving the allowed maximum dose to keep the risk of radiation myelopathy at 0 % was at the same time significantly reduced to below the clinically relevant 1 ccm using FFF mode. In addition the mean dose deposited in the surrounding healthy tissue was significantly reduced in the FFF mode. All four techniques showed equally good gamma scores for plan verification. FFF plans required considerably more MU per fraction dose. Regardless of the large number of MU, out-of-field point dose was significantly lower for FFF plans, with an average reduction of 33 % and mean delivery time was significantly reduced by 22 % using FFF beams. When compared to IMRT FF, VMAT FFF offered even a reduction of 71 % in delivery time and 45 % in peripheral dose. FFF plans showed a significant improvement in sparing of normal tissue and the spinal cord, keeping target coverage and homogeneity comparable. In addition, delivery times were significantly reduced for FFF treatments, minimizing intrafractional motion as well as strain for the patient. Shortest delivery times were achieved using VMAT FFF. For radiotherapy of spinal column metastases VMAT FFF may therefore be considered the preferable treatment option for the combination of Elekta Synergy Linacs and Oncentra® External Beam v4.5 treatment planning system.


Synthesis of guanidino analogues of PMPDAP and their immunobiological activity.
A series of novel 9-, 7- and 3-substituted 2- or 6-guanidinopurines as analogues of potent antiviral and immunobiologically active compound enantiomers of PMPDAP was synthesized and evaluated for their biological activity. Compounds containing the combination of guanidino and amino group at the purine moiety enhanced the interferon-gamma-triggered NO production in murine macrophages and stimulated the secretion of cytokines and chemokines in both murine macrophages and human peripheral blood mononuclear cells. The most active compounds are 27 and 54. None of the compounds tested exhibited any significant cytostatic effect or antiviral effect.


Effect of anti-epileptic drugs on first trimester screening test results.
To evaluate first trimester screening test parameters in epileptic patients using anti-epileptic drugs. We retrospectively evaluated first trimester screening test results of 23 epileptic pregnant women using anti-epileptic drugs with a control group consisting of 92 healthy pregnancies. The anti-epileptic drugs used in this study were carbamazepine, levatiracetam, valproic acid and lamotrigine. Single drug or multi-drug regimens were used according to the clinical conditions. Patients with any known chronic or acute disease and drug usage were excluded from the study. Comparisons were performed via Mann-Whitney U test. First trimester screening test biochemical markers were compared and maternal serum PAPP-A MoM values were found to be similar in study and control groups while β-hCG MoM values were significantly higher in pregnancies using epileptic drugs (p: 0,737 and p < 0.001, respectively). Biochemical first trimester screening test results may be affected by anti-epileptic drug usage, which may lead to misinterpretation of the risk level. Thus, validation of MoM values should be necessary in order to obtain optimal results.


Toxic effects of hydrogen sulfide donor NaHS induced liver apoptosis is regulated by complex IV subunits and reactive oxygen species generation in rats.
In recent years, the protective effect of hydrogensulfide donor sodium hydrosulfide(NaHS) on multiple organs has been widely reported. The study aimed to explorethe effect of commonly used concentration of NaHS on theliver and its potential damage mechanism. Rats divided into 4 groups: control, NaHS I (1 mg/kg), II (3 mg/kg) and III(5 mg/kg) groups, and each group is divided into four-timepoints (2, 6, 12, and 24 hours). Results showed that H2S concentration increased, mitochondrial complex IV activity inhibited, the COX I and IV subunits and mitochondrial apoptosis pathway-related proteins expression increased in atime- and dose-dependent manner. We confirmed that 1 mg/kg NaHS had no injuryeffect on the liver, 3 and 5 mg/kg NaHS inhibitsthe activity of mitochondrial complex IV by promoting COX I and IV subunits expression, leading to the increase in ROS and ultimately inducing apoptosis and liver injury.


Ugt1a is required for the protective effect of selenium against irinotecan-induced toxicity.
Irinotecan (CPT-11) is widely used for the treatment of patients with colorectal cancer. However, the adverse effects associated with the treatment have hindered the efficacies of irinotecan. We have shown that organic selenium compounds could significantly attenuate irinotecan-associated toxicity and enhance antitumor activity in xenograft tumor models. The objective of this study is to determine the role of a specific group of uridine diphosphate glucuronosyltransferases, which is coded by UGT1A, in detoxification process of irinotecan as well as selenium-associated protective effect against irinotecan-induced toxicity. In this study, the toxicities of irinotecan, docetaxel and cisplatin in the Ugta1 mutant rats and their wild-type controls were compared. The plasma concentrations of irinotecan and SN-38 were measured. The modulatory effect of a selenium compound on irinotecan-induced toxicity was analyzed in these rats. We demonstrated that the maximum tolerated doses of irinotecan in the homozygous mutant rats were significantly lower than those in wild-type rats, 25 mg/kg × 1 versus 200 mg/kg × 1 and 3 mg/kg/day × 3 versus 100 mg/kg/day × 3, respectively. The enhanced sensitivity was specific to irinotecan and was not observed with other chemotherapeutic agents, such as docetaxel and cisplatin, where Ugt1a is not required for their metabolism. Our results also showed that selective protection against irinotecan-induced toxicity by 5-methylselenocysteine was achieved in the wild-type rats but not in the Ugt1a null rats. These data support the hypothesis that expression of UGT1A is critical for 5-methylselenocysteine to exert its protective effect against irinotecan-induced toxicity.


Treatment failure in pneumonia: impact of antibiotic treatment and cost analysis.
The aim of this study was to investigate treatment failure (TF) in hospitalised community-acquired pneumonia (CAP) patients with regard to initial antibiotic treatment and economic impact. CAP patients were included in two open, prospective multicentre studies assessing the direct costs for in-patient treatment. Patients received treatment either with moxifloxacin (MFX) or a nonstandardised antibiotic therapy. Any change in antibiotic therapy after >72 h of treatment to a broadened antibiotic spectrum was considered as TF. Overall, 1,236 patients (mean ± SD age 69.6 ± 16.8 yrs, 691 (55.9%) male) were included. TF occurred in 197 (15.9%) subjects and led to longer hospital stay (15.4 ± 7.3 days versus 9.8 ± 4.2 days; p < 0.001) and increased median treatment costs (€2,206 versus €1,284; p<0.001). 596 (48.2%) patients received MFX and witnessed less TF (10.9% versus 20.6%; p < 0.001). After controlling for confounders in multivariate analysis, adjusted risk of TF was clearly reduced in MFX as compared with β-lactam monotherapy (adjusted OR for MFX 0.43, 95% CI 0.27-0.68) and was more comparable with a β-lactam plus macrolide combination (BLM) (OR 0.68, 95% CI 0.38-1.21). In hospitalised CAP, TF is frequent and leads to prolonged hospital stay and increased treatment costs. Initial treatment with MFX or BLM is a possible strategy to prevent TF, and may thus reduce treatment costs.


Screening for in vitro anti-tumor promoting activities of edible plants from Thailand.
A total of 112 species of edible plants (122 samples) from Thailand were randomly collected, and their methanol extracts were screened for in vitro anti-tumor promoting activity using the inhibition test of Epstein-Barr virus (EBV) activation in Raji cells induced by 12-O-hexadecanoylphorbol-13-acetate (HPA, 40 ng/ml). It was found that 60% of these extracts inhibited EBV activation by 30% or more at a concentration of 200 mg/ml. Significantly, the ratio is markedly higher than that (26%) previously observed in common edible plants in Japan. Thus, physiological potentiality of edible Thai plants has been implied in terms of cancer chemoprevention.


Alkaline phosphatase and tartrate resistant acid phosphatase activity in cells of prolymphocytic leukemia.
In a typical case of prolymphocytic leukemia, blood smears and lymph node imprints have been investigated cytologically and cytochemically. It could be shown that many leukemic cells in both blood smears and lymph node imprints contained tartrate resistant acid phosphatase activity. Furthermore, the lymph node imprints disclosed many cells with a positive alkaline phosphatase reaction. Such a reaction hitherto has not been described in malignant cells of lymphoproliferative diseases. The cytochemical results underline that prolymphocytic leukemia indeed is a separate entity which can be differentiated from hairy cell leukemia and chronic lymphatic leukemia not only morphologically but also cytochemically. In addition, the case shows that leukemic blood cells are not inevitably identical with those occurring in organ infiltrates.


Apparent species restriction in the isolation of proliferating embryonal carcinoma cell hybrids.
Proliferating somatic cell hybrids are readily obtained from the fusion of a metabolic co-operation-defective mouse embryonal carcinoma cell variant (R5/3) to LMTK- (1 fibroblastic mouse line derived from L-M) and to derivatives of the R5/3 parental cell line PC13. However it has not yet proved possible to produce growing hybrids from fusions between R5/3 and any non-mouse cell line. It appears, from both this work and that of others that although polyethylene glycol-induced fusion occurs between embryonal carcinoma cells and other cell types viable hybrids cannot always be isolated.


The efficacy of human papillomavirus prophylactic vaccination after conization in preventing cervical intraepithelial neoplasia recurrence: A prospective observational study in China.
High-risk human papillomavirus (hrHPV) infection is the cause of most cervical cancers. Since therapeutic vaccines are not yet available for clinical practice, the administration of HPV prophylactic vaccines in patients with cervical intraepithelial neoplasia (CIN) arouses great interest and its value after excisional treatment of CIN remains unclear. We conducted this prospective cohort study to evaluate the impact of HPV prophylactic vaccination on preventing women from subsequent infection and cervical lesions after excision treatment. 148 patients after loop electrosurgical excision procedure (LEEP) for CIN2+ disease received HPV prophylactic vaccination (6/11/16/18 vaccine, Gardasil®, Merck) after surgery (V-group) and 273 didn't get vaccination (NV-group). The HPV infection rates at the first and second year after LEEP were significantly lower in the V-group than that in NV-group (P = 0.049 and P = 0.026). CIN2+ recurrence was observed in 29 cases (10.62 %) in the NV-group and 2 cases (2.03 %) in the V-group. Logistic regression analysis showed that the HPV16/18 infection, the CIN3 pathology after LEEP and no vaccination after LEEP were significant risk factors of recurrence. Patients without HPV vaccination had a higher CIN2+ recurrence rate (OR = 12.35, 95 % CI 1.919-79.492, P = 0.008). Our study showed the quadrivalent prophylactic HPV vaccination after LEEP had a significantly protective role in the prevention of high-grade squamous intraepithelial lesion recurrence. Further randomized, controlled trials are required in elucidating the efficacy of the prophylactic HPV vaccines using shortly after LEEP in patients with CIN disease.


Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia.
Young adult patients with acute lymphoblastic leukaemia (ALL) represent a unique epidemiologic subgroup in that therapy may be provided by either adult or paediatric oncologists. There seem to be no differences in presenting clinical features, immunophenotypic characteristics, or cytogenetic abnormalities for young adult ALL patients treated on paediatric or adult protocols with the exception of median age (16-paediatric trials versus 19-adult trials). There is no evidence to suggest that age within the 16-21 year old subgroup has any prognostic significance. Compared with patients 1-9 years, young adult ALL patients have a lower incidence of favourable cytogenetics t(12; 21) hyperdiploidy, a slightly increased incidence of the t(9;22), and an increased frequency of T cell immunophenotype. Compared with patients >30 years, young adult ALL patients have a significantly lower incidence of the t(9; 22). In multiple studies, there is a consistent, large event-free survival and survival advantage for young adult patients treated on paediatric versus adult protocols.


Intraoperative transmission of blood-borne disease in haemophilia.
Because HIV and hepatitis B and C infection can be transmitted by exposure to infected blood or blood components, orthopaedists are at risk for HIV and hepatitis infection during surgical procedures. Thus, care must be taken to protect themselves from transmission of HIV and the hepatitis virus. The following precautions are recommended: double latex gloves, changed hourly, or a combination of cloth and latex gloves, enclosed hood and face-masks and operative isolator with umbilical-cord aspirator; knee-length impermeable gowns of high-count polyester weave or plastic-lined nonwoven spun-lace polyester; a combination of shoe-covers that provide waterproof coverage as high as the knee; and disposable drapes. If a member of the operating team is inadvertently pricked or cut, the wound should be washed immediately with iodine, soap and water. If the injured person has been immunized for the hepatitis B (and has adequate titres), or is positive for hepatitis B surface antigen or antibody, no further treatment is necessary. Otherwise, two doses of hepatitis B immune globulin should be given, 5 mL immediately and 5 mL after 1 month. Because HIV infection can be transmitted by exposure to infected blood, orthopaedic surgeons are also at risk for HIV infection. Prospective studies suggest that this risk is very low; nevertheless, healthcare workers need to adhere rigorously to the aforementioned infection-control precautions to minimize the risk of exposure to blood.


Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity.
Lipstatin, a new and very potent inhibitor of pancreatic lipase (the key enzyme of intestinal fat digestion) was isolated from Streptomyces toxytricini. Lipstatin contains a beta-lactone structure that probably accounts for the irreversible lipase inhibition. The IC50 of lipstatin for pancreatic lipase is 0.14 microM. In mice triolein absorption was dose-dependently inhibited by lipstatin, whereas oleic acid was absorbed normally. Other pancreatic enzymes, such as phospholipase A2 and trypsin, were not inhibited even at an inhibitor concentration of 200 microM.


Complete genome sequences of two Bacillus thuringiensis serovar kurstaki strains isolated from Lebanon and Tunisia, highly toxic against lepidopteran larvae.
Bacillus thuringiensis-based products are key in the biopesticides market. Bacillus thuringiensis kurstaki strains Lip and BLB1 were isolated from Lebanese and Tunisian soils, respectively. These strains are highly toxic against lepidopteran larvae, Ephestia kuehniella. Here, we report Lip and BLB1 complete genomes, including their plasmid and toxin contents.


Management of malignant melanoma: a retrospective analysis of 182 patients.
The records of 182 patients, referred to the Regional Radiotherapy Centre, Newcastle upon Tyne between January 1975 and December 1980, have been reviewed to evaluate the results of different modes of treatment. Fifty-two patients were managed for Stage 1, 83 for Stage 2 and 47 for Stage 3 disease. Fifty-seven patients with 95 sites of disease were given chemotherapy. The overall response rate was 35% (complete response (CR) 14%, partial response (PR) 21%) (median duration of remission = 4 months). Sixty-three patients with 74 sites of disease were treated by radiotherapy. The overall response rate was 73% (CR 47%, PR 26%) (median duration of remission = 7 months). In Stage 2 disease, no significant difference in the disease-free or overall survival was found between four different treatment groups. In disseminated disease, chemotherapy had little impact on the survival of patients with visceral metastases, while those with skin and lymph node metastases had significantly better survival. Radiotherapy was tolerated better and had lower morbidity than chemotherapy. The role of both modes in the management of advanced disease is discussed.


A novel plant lectin, NTL-125, interferes with SARS-CoV-2 interaction with hACE2.
COVID-19 caused by SARS-CoV-2 virus has had profound impact on the world in the past two years. Intense research is going on to find effective drugs to combat the disease. Over the past year several vaccines were approved for immunization. But SARS-CoV-2 being an RNA virus is continuously mutating to generate new variants, some of which develop features of immune escape. This raised serious doubts over the long-term efficacy of the vaccines. We have identified a unique mannose binding plant lectin from Narcissus tazetta bulb, NTL-125, which effectively inhibits SARS-CoV-2 replication in Vero-E6 cell line. In silico docking studies revealed that NTL-125 has strong affinity to viral Spike RBD protein, preventing it from attaching to hACE2 receptor, the gateway to cellular entry. Binding analyses revealed that all the mutant variants of Spike protein also have stronger affinity for NTL-125 than hACE2. The unique α-helical tail of NTL-125 plays most important role in binding to RBD of Spike. NTL-125 also interacts effectively with some glycan moieties of S-protein in addition to amino acid residues adding to the binding strength. Thus, NTL-125 is a highly potential antiviral compound of natural origin against SARS-CoV-2 and may serve as an important therapeutic for management of COVID-19.


Kakadumycins, novel antibiotics from Streptomyces sp NRRL 30566, an endophyte of Grevillea pteridifolia.
An endophytic streptomycete (NRRL 30566) is described and partially characterized from a fern-leaved grevillea (Grevillea pteridifolia) tree growing in the Northern Territory of Australia. This endophytic streptomycete produces, in culture, novel antibiotics - the kakadumycins. Methods are outlined for the production and chemical characterization of kakadumycin A and related compounds. This antibiotic is structurally related to a quinoxaline antibiotic, echinomycin. Each contains, by virtue of their amino acid compositions, alanine, serine and an unknown amino acid. Other biological, spectral and chromatographic differences between these two compounds occur and are given. Kakadumycin A has wide spectrum antibiotic activity, especially against Gram-positive bacteria, and it generally displays better bioactivity than echinomycin. For instance, against Bacillus anthracis strains, kakadumycin A has minimum inhibitory concentrations of 0.2-0.3 microg x ml(-1) in contrast to echinomycin at 1.0-1.2 microg x ml(-1). Both echinomycin and kakadumycin A have impressive activity against the malarial parasite Plasmodium falciparum with LD(50)s in the range of 7-10 ng x ml(-1). In macromolecular synthesis assays both kakadumycin A and echinomycin have similar effects on the inhibition of RNA synthesis. It appears that the endophytic Streptomyces sp. offer some promise for the discovery of novel antibiotics with pharmacological potential.


Introduction to hemodynamic forces by echocardiography.
Hemodynamic force (HDF) analysis represents a novel approach to quantify intraventricular pressure gradients, responsible for blood flow. A new mathematical model allows the derivation of HDF parameters from routine transthoracic echocardiography, making this tool more accessible for clinical use. HDF analysis is considered the fluid dynamics correlate of deformation imaging and may be even more sensitive to detect mechanical abnormalities. This has the potential to add incremental clinical value, allowing earlier detection of pathology or immediate evaluation of response to treatment. In this article, the theoretical background and physiological patterns of HDF in the left ventricle are provided. In pathological situations, the HDF pattern might alter, which is illustrated with a case of ST segment elevation myocardial infarction and non-ischemic cardiomyopathy with typical left bundle branch block.


Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice.
We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice. We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24 h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5 h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined. IND (10 mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine. These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.


Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.
Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. URL: https://www. gov; Unique identifier: NCT04461041.


Microbial dysbiosis and the host airway epithelial response: insights into HIV-associated COPD using multi'omics profiling.
People living with HIV (PLWH) are at increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) independent of cigarette smoking. We hypothesized that dysbiosis in PLWH is associated with epigenetic and transcriptomic disruptions in the airway epithelium. Airway epithelial brushings were collected from 18 COPD + HIV + , 16 COPD - HIV + , 22 COPD + HIV - and 20 COPD - HIV - subjects. The microbiome, methylome, and transcriptome were profiled using 16S sequencing, Illumina Infinium Methylation EPIC chip, and RNA sequencing, respectively. Multi 'omic integration was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents. A correlation > 0.7 was used to identify key interactions between the 'omes. The COPD + HIV -, COPD -HIV + , and COPD + HIV + groups had reduced Shannon Diversity (p = 0.004, p = 0.023, and p = 5.5e-06, respectively) compared to individuals with neither COPD nor HIV, with the COPD + HIV + group demonstrating the most reduced diversity. Microbial communities were significantly different between the four groups (p = 0.001). Multi 'omic integration identified correlations between Bacteroidetes Prevotella, genes FUZ, FASTKD3, and ACVR1B, and epigenetic features CpG-FUZ and CpG-PHLDB3. PLWH with COPD manifest decreased diversity and altered microbial communities in their airway epithelial microbiome. The reduction in Prevotella in this group was linked with epigenetic and transcriptomic disruptions in host genes including FUZ, FASTKD3, and ACVR1B.


Influence of PMSG on Superstimulation and Embryo Development Following Somatic Cell Nuclear Transfer in Holstein Cows in the United Arab Emirates.
The present study investigated the effect of superstimulation to improve in vitro embryo production in the Gulf area, where the temperature is high. Holstein cows were classified into the control and superstimulation groups. Superstimulation was induced with a single intramuscular injection of pregnant mare serum gonadotropin (PMSG; 2500 IU) on day 14 of the estrus cycle (day 0; estrus). The development of follicles was evaluated by ultrasonography of the ovaries daily. At 40 h after the PMSG injection, oocytes were collected by the ovum pick-up (OPU) technique. OPU was performed at the same stage of the estrus cycle in the control group as in the superstimulation group. The number of follicles with a diameter of more than 6 mm and the number of retrieved cumulus-oocyte complexes were significantly higher in the superstimulation group than in the control group. Furthermore, the maturation rate was higher in the superstimulation group than in the control group. Cloned embryos were produced by somatic cell nuclear transfer using matured oocytes. The cleavage and blastocyst formation rates were significantly higher in the superstimulation group than in the control group. In conclusion, a single injection of PMSG can facilitate the efficient production of cloned cow embryos.


Regional amplitude abnormities in the major depressive disorder: A resting-state fMRI study and support vector machine analysis.
Major depressive disorder (MDD) is a common mood disorder. However, it still remains challenging to select sensitive biomarkers and establish reliable diagnosis methods currently. This study aimed to investigate the abnormalities of the spontaneous brain activity in the MDD and explore the clinical diagnostic value of three amplitude metrics in altered regions by applying the support vector machine (SVM) method. A total of fifty-two HCs and forty-eight MDD patients were recruited in the study. The amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuation (fALFF) and percent amplitude of fluctuation (PerAF) metrics were calculated to assess local spontaneous brain activity. Then we performed correlation analysis to examine the association between cerebral abnormalities and clinical characteristics. Finally, SVM analysis was applied to conduct the classification model for evaluating the diagnostic value. Two-sample t-test exhibited that MDD patients had increased ALFF value in the right caudate and corpus callosum, increased fALFF value in the same regions and increased PerAF value in the inferior parietal lobule and right caudate compared to HCs. Moreover, PerAF value in the inferior parietal lobule was negatively correlated with the slow factor scores. The SVM results showed that a combination of mean ALFF and fALFF in the right caudate and corpus callosum selected as features achieved a highest area under curve (AUC) value (0.89), accuracy (79.79%), sensitivity (65.12%) and specificity (92.16%). Collectively, we found increased mean ALFF and fALFF may serve as a potential neuroimaging marker to discriminate MDD and HCs.


Changing environmental conditions have altered the feeding ecology of two keystone Arctic marine predators.
Environmental change in the Arctic has impacted the composition and structure of marine food webs. Tracking feeding ecology changes of culturally-valued Arctic char (Salvelinus alpinus) and ringed seals (Pusa hispida) can provide an indication of the ecological significance of climate change in a vulnerable region. We characterized how changes in sea ice conditions, sea surface temperature (SST), and primary productivity affected the feeding ecology of these two keystone species over a 13- and 18-year period, respectively, in northern Labrador, Canada. Arctic char fed consistently on pelagic resources (δ13C) but shifted over time to feeding at a higher trophic level (δ15N) and on more marine/offshore resources (δ34S), which correlated with decreases in chlorophyll a concentration. A reduction in Arctic char condition factor and lipid content was associated with higher trophic position. Ringed seals also shifted to feeding at a higher trophic level, but on more pelagic resources, which was associated with lower SST and higher chlorophyll a concentrations. Years with abnormally high SSTs and reduced sea ice concentrations resulted in large isotopic niche sizes for both species, suggesting abrupt change can result in more variable feeding. Changes in abundance and distribution of species long valued by the Inuit of Labrador could diminish food security.


Deciphering the Odorant Binding, Activation, and Discrimination Mechanism of Dhelobp21 from Dastarus Helophoroides.
Odorant-binding proteins (OBPs) play a pivotal role in transporting odorants through the sensillar lymph of insect chemosensory sensilla and increasing the sensitivity of the olfactory system. To address the ligand binding, activation, and release mechanisms of OBPs, we performed a set of conventional molecular dynamics simulations for binding of the odorant-binding protein DhelOBP21 from Dastarcus helophoroides with 18 ligands (1-NPN and 17 volatiles), as well as four constant-pH molecular dynamics simulations. We found that the open pocket DhelOBP21 at pH 5.0 could bind volatiles and form a closed pocket complex via transformation of its N-terminus into regular Helix at pH 7.0 and vice versa. Moreover, the discrimination of volatiles (selectivity and promiscuity) was determined by the characteristics of both the volatiles and the 'essential' and 'selective' amino acid residues in OBP binding pockets, rather than the binding affinity of the volatiles. This study put forward a new hypothesis that during the binding of volatiles there are two transitions for the DhelOBP21 amino-terminus: pH- and odorant binding-dependent random-coil-to-helix. Another important finding is providing a framework for the exploration of the complete coil-to-helix transition process and theoretically analyzing its underlying causes at molecular level.


Synthetic virus seeds for improved vaccine safety: Genetic reconstruction of poliovirus seeds for a PER.C6 cell based inactivated poliovirus vaccine.
Safety of vaccines can be compromised by contamination with adventitious agents. One potential source of adventitious agents is a vaccine seed, typically derived from historic clinical isolates with poorly defined origins. Here we generated synthetic poliovirus seeds derived from chemically synthesized DNA plasmids encoding the sequence of wild-type poliovirus strains used in marketed inactivated poliovirus vaccines. The synthetic strains were phenotypically identical to wild-type polioviruses as shown by equivalent infectious titers in culture supernatant and antigenic content, even when infection cultures are scaled up to 10-25L bioreactors. Moreover, the synthetic seeds were genetically stable upon extended passaging on the PER.C6 cell culture platform. Use of synthetic seeds produced on the serum-free PER.C6 cell platform ensures a perfectly documented seed history and maximum control over starting materials. It provides an opportunity to maximize vaccine safety which increases the prospect of a vaccine end product that is free from adventitious agents.


Cardiac and Kidney Adverse Effects of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Patients With CKD Not Receiving Dialysis: A Systematic Review and Meta-analysis.
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel, orally administered agents for anemia management in chronic kidney disease (CKD). We evaluated the cardiac and kidney-related adverse effects of HIF-PHIs among patients with CKD and anemia. Systematic review and meta-analysis of randomized controlled trials (RCTs). Patients with anemia and CKD not receiving maintenance dialysis. RCTs comparing HIF-PHIs to placebo or an erythropoiesis-stimulating agent (ESA) with primary outcomes of cardiac and kidney-related adverse events (AEs). Two independent reviewers evaluated RCTs for eligibility and extracted relevant data. Dichotomous variables were pooled using the Mantel-Haenszel method and presented as risk ratios (RRs). Subgroup analyses evaluated different intervention times and HIF-PHIs, as well as phase 2 versus phase 3 trials. The certainty of findings was rated according to GRADE criteria. Twenty-three studies with 15,144 participants were included. No significant difference in the risk of cardiac AEs was observed between the HIF-PHIs group and the placebo (RR, 1.02 [95% CI, 0.89-1.16]; moderate certainty) or ESA (RR, 1.06 [95% CI, 0.98-1.14]; low certainty) groups. No significant difference in the risk of kidney-related AEs was observed between the HIF-PHIs group and the placebo (RR, 1.09 [95% CI, 0.98-1.20]; moderate certainty) or ESA (RR, 1.00 [95% CI, 0.94-1.06]; low certainty) groups. The occurrence of hypertension and hyperkalemia was higher in the HIF-PHIs group than in the placebo group (RRs of 1.35 [95% CI, 1.14-1.60] and 1.25 [95% CI, 1.03-1.51], respectively; both findings had high certainty). The occurrence of hypertension was lower in the HIF-PHIs group than in the ESA group (RR, 0.89 [95% CI, 0.81-0.98]; moderate certainty). The reporting criteria of cardiac and kidney-related AEs and dosage of HIF-PHIs were inconsistent across trials. The occurrence of cardiac or kidney-related AEs in the HIF-PHI groups were not different compared with placebo or ESA groups. Registered at PROSPERO with registration number CRD42021228243.