Outcomes of a conservative approach to management in amoebic liver abscess.
Unfortunately, there is confusion among the medical community regarding the management of amoebic liver abscess (ALA). Therapeutic options range from simple pharmacotherapy to use of interventions like a needle or catheter aspiration under ultrasound guidance to surgical intervention. There is a plethora of thresholds for parameters such as the maximum diameter of the abscess and volume on ultrasound examination suggested by various authors to serve as a criterion to help to decide when to use which modality in these cases. To assess the outcome of patients with uncomplicated ALA treated using a conservative approach. Moreover, to identify factors associated with its failure. A prospective, observational study was carried out at a large municipal urban health care center over a period of 3-year (2011-2014) in India. Patients with uncomplicated ALA were recruited. All patients were managed with pharmacotherapy initially for a period of 72 h. Response to treatment was assessed by resolution of symptoms within the given time frame. Failure to respond was considered an indication for intervention. Needle aspiration was offered to these patients and response assessed within 72 h. Failure to respond to aspiration was considered an indication for catheter drainage. Data recorded were entered in a Microsoft Office Excel Sheet and analyzed using the SPSS version 16.0 (IBM). Sixty patients with ALA were included in the study over its duration. Forty-nine (81.67%) patients were managed conservatively, while 11 (18.33%) patients needed an intervention for relief. Patients who required intervention had deranged liver function at presentation, a larger abscess diameter (10.09 ± 2.23 vs. 6.33 ± 1.69 cm P < 0.001) and volume (399.73 ± 244.46 vs. 138.34 ± 117.85 ml, P < 0.001) compared to those who did not need it. Patients that required intervention had a longer length of hospital stay (7.1 ± 2.4 vs. 4.8 ± 0.9 days, P < 0.001). On post hoc analysis, a maximum diameter of >7.7 cm was found to be the optimal criterion to predict the need of intervention in cases of ALA. A conservative approach is effective in the management of ALA for a majority of patients. Failure of conservative management was predicted by the size of the abscess (maximum diameter >7.7 cm). Even in the cases of failure, a gradual step-up with interventions was found to be safe and effective.


Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics.
The Escherichia coli microcin C (McC) and related compounds are potent Trojan horse peptide-nucleotide antibiotics. The peptide part facilitates transport into sensitive cells. Inside the cell, the peptide part is degraded by nonspecific peptidases releasing an aspartamide-adenylate containing a phosphoramide bond. This nonhydrolyzable compound inhibits aspartyl-tRNA synthetase. In addition to the efficient export of McC outside the producing cells, special mechanisms have evolved to avoid self-toxicity caused by the degradation of the peptide part inside the producers. Here, we report that histidine-triad (HIT) hydrolases encoded in biosynthetic clusters of some McC homologs or by standalone genes confer resistance to McC-like compounds by hydrolyzing the phosphoramide bond in toxic aspartamide-adenosine, rendering them inactive.IMPORTANCE Uncovering the mechanisms of resistance is a required step for countering the looming antibiotic resistance crisis. In this communication, we show how universally conserved histidine-triad hydrolases provide resistance to microcin C, a potent inhibitor of bacterial protein synthesis.


Primary amines enhance the antiviral activity of interferon against a membrane virus: role of intracellular pH.
Inhibition of vesicular stomatitis virus (VSV) replication in LB cells by interferon (IFN) resembles the action of IFN on some retroviruses, in that the incorporation of glycoprotein into virions is defective. Primary amines added between 1 and 2 h post-infection significantly enhanced (five- to 1000-fold) the antiviral activity of IFN against VSV, but no enhancement of the antiviral activity of IFN against encephalomyocarditis virus, a virus with no membrane component, by primary amines was seen. SDS-PAGE and immunofluorescence analysis of viral proteins, and Nycodenz gradient fractionation, suggested that both IFN and primary amines inhibited the transport of VSV glycoprotein (G) to the plasma membrane; instead, G accumulated in the trans-Golgi network (TGN). Using sensitive intracellular pH (pHi) indicators, we found that IFN treatment significantly raised the pHi. A further increase in pHi was seen with a combination of IFN and primary amines; the increase in pHi correlated with an enhancement of the antiviral activity of IFN by primary amines. Amiloride inhibited the IFN-induced increase in pHi and a concomitant increase in the concentration of Na+ ions; this observation suggested that IFN induced cytoplasmic alkalinization by activating an Na+/H+ antiporter system. These results indicated that the IFN-induced increase in pHi may be responsible for the accumulation of G in the TGN, thereby producing G-deficient virus particles with reduced infectivity.


Continuous Passive Motion Promotes and Maintains Chondrogenesis in Autologous Endothelial Progenitor Cell-Loaded Porous PLGA Scaffolds during Osteochondral Defect Repair in a Rabbit Model.
Continuous passive motion (CPM) is widely used after total knee replacement. In this study, we investigated the effect of CPM combined with cell-based construct-transplantation in osteochondral tissue engineering. We created osteochondral defects (3 mm in diameter and 3 mm in depth) in the medial femoral condyle of 36 knees and randomized them into three groups: ED (empty defect), EPC/PLGA (endothelial progenitor cells (EPCs) seeded in the poly lactic-co-glycolic acid (PLGA) scaffold), or EPC/PLGA/CPM (EPC/PLGA scaffold complemented with CPM starting one day after transplantation). We investigated the effects of CPM and the EPC/PLGA constructs on tissue restoration in weight-bearing sites by histological observation and micro-computed tomography (micro-CT) evaluation 4 and 12 weeks after implantation. After CPM, the EPC/PLGA construct exhibited early osteochondral regeneration and prevention of subchondral bone overgrowth and cartilage degeneration. CPM did not alter the microenvironment created by the construct; it up-regulated the expression of the extracellular matrix components (glycosaminoglycan and collagen), down-regulated bone formation, and induced the biosynthesis of lubricin, which appeared in the EPC/PLGA/CPM group after 12 weeks. CPM can provide promoting signals during osteochondral tissue engineering and achieve a synergistic effect when combined with EPC/PLGA transplantation, so it should be considered a non-invasive treatment to be adopted in clinical practices.


Following one's heart: cardiac rhythms gate central initiation of sympathetic reflexes.
Central nervous processing of environmental stimuli requires integration of sensory information with ongoing autonomic control of cardiovascular function. Rhythmic feedback of cardiac and baroreceptor activity contributes dynamically to homeostatic autonomic control. We examined how the processing of brief somatosensory stimuli is altered across the cardiac cycle to evoke differential changes in bodily state. Using functional magnetic resonance imaging of brain and noninvasive beat-to-beat cardiovascular monitoring, we show that stimuli presented before and during early cardiac systole elicited differential changes in neural activity within amygdala, anterior insula and pons, and engendered different effects on blood pressure. Stimulation delivered during early systole inhibited blood pressure increases. Individual differences in heart rate variability predicted magnitude of differential cardiac timing responses within periaqueductal gray, amygdala and insula. Our findings highlight integration of somatosensory and phasic baroreceptor information at cortical, limbic and brainstem levels, with relevance to mechanisms underlying pain control, hypertension and anxiety.


Season of birth and other perinatal risk factors for melanoma.
Ultraviolet radiation (UVR) exposure is the main risk factor for cutaneous malignant melanoma (CMM), but its specific effect in infancy is unknown. We examined whether season of birth, a proxy for solar UVR exposure in the first few months of life, is associated with CMM in childhood through young adulthood. National cohort study of 3,571,574 persons born in Sweden in 1973-2008, followed up for CMM incidence through 2009 (maximum age 37 years) to examine season of birth and other perinatal factors. There were 1595 CMM cases in 63.9 million person-years of follow-up. We found a sinusoidal pattern in CMM risk by season of birth (P=0.006), with peak risk corresponding to birthdates in spring (March-May). Adjusted odds ratios for CMM by season of birth were 1.21 [95% confidence interval (CI), 1.05-1.39; P=0.008] for spring, 1.07 (95% CI, 0.92-1.24; P=0.40) for summer and 1.12 (95% CI, 0.96-1.29; P=0.14) for winter, relative to fall. Spring birth was associated with superficial spreading subtype of CMM (P=0.02), whereas there was no seasonal association with nodular subtype (P=0.26). Other CMM risk factors included family history of CMM in a sibling (>6-fold) or parent (>3-fold), female gender, high fetal growth and high paternal education level. In this large cohort study, persons born in spring had increased risk of CMM in childhood through young adulthood, suggesting that the first few months of life may be a critical period of UVR susceptibility. Sun avoidance in early infancy may play an important role in the prevention of CMM in high-risk populations.


Tissue disposition of 3H-actinomycin D (NSC-3053) in the rat, monkey, and dog.
Tissue concentration of 3H-actinomycin D have been determined in the rat, monkey, and dog after an iv dose of 0.6 mg/m2 body surface area. The drug-tissue half-life was determined for various tissues of the rat, monkey, and dog. A mean drug-tissue half-life of 47 hours was calculated for the tissues of the dog. Exceptions were the testis and brain. Significant concentrations of 3H-actinomycin D failed to accumulate in the brain. Although testis drug concentrations were lower than most other tissues evaluated, the drug-tissue half-life was significantly greater than that of other tissues. In all species studied 3H-actinomycin D was rapidly depleted from serum after iv dosage, with concomitant accumulation of drug in the tissues. 3H-actinomycin D was excreted via the biliary and urinary routes in all species studied. No metabolites of 3H-actinomycin D were detected in the bile or urine of the rat, monkey, or dog with the methods employed. When expressed on a body weight basis, body surface area doses were more than threefold greater in the rat than in the dog. However, the average ratio of concentration X time values (rat C X T/dog C X T) for 11 different tissues of the rat and dog was only 1.3. The results strongly suggest that an equivalent dose of actinomycin D, with dosage based on a body surface area basis, results in nearly equal tissue-drug exposure for most tissues in various mammalian species.


Role of snus (oral moist snuff ) in smoking cessation and smoking reduction in Sweden.
To assess to what extent snus has been used as an aid to stop smoking among Swedish smokers. A random telephone retrospective survey of Swedish smokers and ex-smokers. Survey conducted in November-December 2000. A national sample of 1000 former and 985 current daily smokers aged 25-55 years. Smoking status, date and method of quitting by self-report. Thirty-three per cent of former smokers and 27% of current smokers had ever used snus. The difference was larger among men (55% versus 45%, P = 0.003). Current smokers who made use of snus smoked on average fewer cigarettes per day than non-users of snus. The mean duration of abstinence among former smokers was not influenced by snus use. Conditionally on age, education and use of nicotine replacement therapy there was an increased probability of being a former rather than a current smoker with ever use (OR 1.72, 95% CI = 1.30-2.28) or current use (OR 1.81, 95% CI = 1.31-2.53) of snus. Having used snus at the latest quit attempt increased the probability of being abstinent by about 50% (OR 1.54, 95% CI = 1.09-2.20). Our study suggests that by using snus, Swedish male smokers may increase their overall chances of abstinence. However, 71% of the men in this sample who quit smoking did so without using snus and the duration of abstinence was not affected by snus use. This suggests that snus is not a necessary component of smoking cessation at the population level. Snus use was very rare among women.


MicroRNAs Associated with Epithelial-Mesenchymal Transition Can Be Targeted to Inhibit Peritoneal Dissemination of Human Scirrhous Gastric Cancers.
Scirrhous gastric cancers grow rapidly, and frequently invade the peritoneum. Such peritoneal dissemination properties markedly reduce patient survival. Thus, an effective means for inhibiting peritoneal dissemination is urgently required. We previously established a cell line, HSC-58, from a scirrhous gastric cancer patient, and further successfully isolated a metastatic line, 58As9, in nude mice upon orthotopic inoculation. Using the lines, we examined the mechanism underlying peritoneal dissemination from the viewpoint of microRNA (miRNA) expression. miRNA array and qRT-PCR analysis showed that the expressions of epithelial-mesenchymal transition (EMT)-associated miRNAs such as miR-200c and miR-141 were significantly low in 58As9. Using 58As9 with stably overexpressing miR-200c, miR-141, or both, together with a luciferase reporter assay, we found that miR-200c targeted zinc finger E-box-binding homeobox 1 (ZEB1) and miR-141 targeted ZEB2. The overexpressed lines reversed the EMT status from mesenchymal to epithelial in 58As9, and significantly reduced the invasion activity and peritoneal dissemination for a significant prolongation of survival in the orthotopic tumor models in nude mice. EMT-associated miRNAs such as miR-200c and miR-141 and their target genes ZEB1/ZEB2 have good potential for antiperitoneal dissemination therapy in patients with scirrhous gastric cancers.


Radiographic detection and characterization of palmar lesions in the equine fetlock joint.
Subchondral lesions were identified in the distal palmar region of the third metacarpus in 21 fetlock joints of 15 Thoroughbred horses. The lesions were more commonly identified on the lateromedial and flexed lateral projection, with the flexed lateral projection permitting optimal visualization of the lesion. Lesions appeared as poorly marginated, radiolucent defects and were located at the level of the base of the proximal sesamoid bones. The shape and distribution of the radiolucent defects were: crescent, 4; flattened, 4; shallow concavity, 5; deep concavity, 3; oval, 3; and circular, 2. Secondary joint disease was commonly identified in joints with these lesions and was more severe when the lesions increased in size and were irregular at the subchondral bony surface. Three horses with the palmar lesions were rested and re-examined after 16, 40, or 56 weeks. The lesions appeared smaller and less distinct on a subsequent examination for 2 horses, but the degree of secondary joint disease had increased in all 3 horses. Identification of palmar lesions when small seems important for the successful return of the Thoroughbred to racing soundness.


Bubbles, gating, and anesthetics in ion channels.
We suggest that bubbles are the bistable hydrophobic gates responsible for the on-off transitions of single channel currents. In this view, many types of channels gate by the same physical mechanism-dewetting by capillary evaporation-but different types of channels use different sensors to modulate hydrophobic properties of the channel wall and thereby trigger and control bubbles and gating. Spontaneous emptying of channels has been seen in many simulations. Because of the physics involved, such phase transitions are inherently sensitive, unstable threshold phenomena that are difficult to simulate reproducibly and thus convincingly. We present a thermodynamic analysis of a bubble gate using morphometric density functional theory of classical (not quantum) mechanics. Thermodynamic analysis of phase transitions is generally more reproducible and less sensitive to details than simulations. Anesthetic actions of inert gases-and their interactions with hydrostatic pressure (e.g., nitrogen narcosis)-can be easily understood by actions on bubbles. A general theory of gas anesthesia may involve bubbles in channels. Only experiments can show whether, or when, or which channels actually use bubbles as hydrophobic gates: direct observation of bubbles in channels is needed. Existing experiments show thin gas layers on hydrophobic surfaces in water and suggest that bubbles nearly exist in bulk water.


Bindarit: an anti-inflammatory small molecule that modulates the NFκB pathway.
The activation of nuclear factor (NF)κB pathway and its transducing signaling cascade has been associated with the pathogenesis of many inflammatory diseases. The central role that IκBα and p65 phosphorylation play in regulating NFκB signalling in response to inflammatory stimuli made these proteins attractive targets for therapeutic strategies. Although several chemical classes of NFκB inhibitors have been identified, it is only for a few of those that a safety assessment based on a comprehensive understanding of their pharmacologic mechanism of action has been reported. Here, we describe the specific anti-inflammatory effect of bindarit, an indazolic derivative that has been proven to have anti-inflammatory activity in a variety of models of inflammatory diseases (including lupus nephritis, arthritis and pancreatitis). The therapeutic effects of bindarit have been associated with its ability to selectively interfere with monocyte recruitment and the "early inflammatory response," although its specific molecular mechanisms have remained ill-defined. For this purpose, we investigated the effect of bindarit on the LPS-induced production of inflammatory cytokines (MCP-1 and MCPs, IL-12β/p40, IL-6 and IL-8/KC) in both a mouse leukaemic monocyte-macrophage cell line and bone marrow derived macrophages (BMDM). Bindarit inhibits the LPS-induced MCP-1 and IL-12β/p40 expression without affecting other analyzed cytokines. The effect of bindarit is mediated by the downregulation of the classical NFκB pathway, involving a reduction of IκBα and p65 phosphorylation, a reduced activation of NFκB dimers and a subsequently reduced nuclear translocation and DNA binding. Bindarit showed a specific inhibitory effect on the p65 and p65/p50 induced MCP-1 promoter activation, with no effect on other tested activated promoters. We conclude that bindarit acts on a specific subpopulation of NFκB isoforms and selects its targets wihtin the whole NFκB inflammatory pathway. These findings pave the way for future applications of bindarit as modulator of the inflammatory response.


Indicators of Quality of Care in Individuals With Traumatic Spinal Cord Injury: A Scoping Review.
Scoping review. To identify a practical and reproducible approach to organize Quality of Care Indicators (QoCI) in individuals with traumatic spinal cord injury (TSCI). A comprehensive literature review was conducted in the Cochrane Central Register of Controlled Trials (CENTRAL) (Date: May 2018), MEDLINE (1946 to May 2018), and EMBASE (1974 to May 2018). Two independent reviewers screened 6092 records and included 262 full texts, among which 60 studies were included for qualitative analysis. We included studies, with no language restriction, containing at least 1 quality of care indicator for individuals with traumatic spinal cord injury. Each potential indicator was evaluated in an online, focused group discussion to define its categorization (healthcare system structure, medical process, and individuals with Traumatic Spinal Cord Injury related outcomes), definition, survey options, and scale. A total of 87 indicators were identified from 60 studies screened using our eligibility criteria. We defined each indicator. Out of 87 indicators, 37 appraised the healthcare system structure, 30 evaluated medical processes, and 20 included individuals with TSCI related outcomes. The healthcare system structure included the impact of the cost of hospitalization and rehabilitation, as well as staff and patient perception of treatment. The medical processes included targeting physical activities for improvement of health-related outcomes and complications. Changes in motor score, functional independence, and readmission rates were reported as individuals with TSCI-related outcomes indicators. Indicators of quality of care in the management of individuals with TSCI are important for health policy strategists to standardize healthcare assessment, for clinicians to improve care, and for data collection efforts including registries.


Prenatal diagnosis of congenital adrenal hyperplasia caused by P450 oxidoreductase deficiency.
Mutations in the electron donor enzyme P450 oxidoreductase (POR) result in congenital adrenal hyperplasia with apparent combined 17α-hydroxylase/17,20 lyase and 21-hydroxylase deficiencies, also termed P450 oxidoreductase deficiency (PORD). Major clinical features present in PORD are disordered sex development in affected individuals of both sexes, glucocorticoid deficiency, and multiple skeletal malformations. The objective of the study was to establish a noninvasive approach to prenatal diagnosis of PORD including assessment of malformation severity to facilitate optimized prenatal diagnosis and timely treatment. We analyzed 20 pregnancies with children homozygous or compound heterozygous for disease-causing POR mutations and 1 pregnancy with a child carrying a heterozygous POR mutation by recording clinical and biochemical presentations and fetal ultrasound findings. In 4 of the pregnancies (3 homozygous and 1 heterozygous for disease-causing POR mutations), prenatal analysis of steroid metabolite excretion in maternal urine was carried out by gas chromatography/mass spectrometry during gestational weeks 11-23. Pregnancy complications in our cohort included maternal virilization (6 of 20) with onset in the second trimester. Seven pregnant women presented with low unconjugated estriol at prenatal screening (triple or quadruple antenatal screening test). Overt dysmorphic features were noted in 19 of the 20 babies at birth but observed in only 5 by prenatal ultrasound. These 5 had the most severe malformation phenotypes and poor outcome, whereas the other babies showed normal development. Steroid profiling of maternal urine revealed significantly increased steroids of fetal origin, namely the pregnenolone metabolite epiallopregnanediol and the androgen metabolite androsterone, with concomitant low values for estriol. Diagnostic steroid ratios conclusively indicated PORD as early as gestational week 12. In the heterozygous pregnancy, steroid ratios were only slightly elevated and estriol excretion was normal. Prenatal diagnosis in PORD is readily established via urinary steroid metabolite analysis of maternal urine. Visible malformations at prenatal ultrasound predict a severe malformation phenotype.


EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts.
The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored.


A case with insulinoma localized by combined use of various means.
A patient with insulinoma diagnosed by clinical features and localized preoperatively using a combination of contrast-enhanced ultrasonography (CEUS), dual phase contrast enhanced spiral computed tomography (DPSCT) and arterial stimulation and venous sampling (ASVS) was reported. A 37-year-old man was admitted to our hospital because of hypoglycemic attacks, palpitations, and muscular weakness. Fajans' ratio reported to be an index for insulinoma was positive. Transabdominal computed tomography and ultrasonography failed to detect any abnormalities. CEUS showed a small low echoic lesion in the pancreatic body with blood flow and the early arterial phase of DPSCT revealed a small strengthening focus, which mimicked a pancreatic tumor in the pancreatic body. ASVS showed that the insulin levels in the hepatic vein were extremely increased by calcium injection to the gastroduodenal artery. An open intra-abdominal operation was performed and an insulinoma was confirmed in the pancreatic body. Enucleation of tumor was undertaken and histopathological examination showed an adenoma, insulin expression was positive in immunofluorescence staining. Symptomatic hypoglycemia never happened even without glucose infusion since the operation. His blood glucose level improved to within the normal range.


A review of the inclusion of equity stratifiers for the measurement of health inequalities within health and social care data collections in Ireland.
Health equity differs from the concept of health inequality by taking into consideration the fairness of an inequality. Inequities may be culturally specific, based on social relations within a society. Measuring these inequities often requires grouping individuals. These groupings can be termed equity stratifiers. The most common groupings affected by health inequalities are summarised by the acronym PROGRESS (Place of residence, Race, Occupation, Gender, Religion, Education, Socioeconomic status, Social capital). The aim of this review was to examine the use of equity stratifiers in routinely collected health and social care data collections in Ireland. One hundred and twenty data collections were identified from the Health Information and Quality Authority (HIQA) document, "Catalogue of national health and social care data collections: Version 3.0". Managers of all the data collections included were contacted and a data dictionary was requested where one was not available via the HIQA website. Each of the data dictionaries available was reviewed to identify the equity stratifiers recorded. Eighty-three of the 120 data collections were considered eligible to be included for review. Twenty-nine data dictionaries were made available. There was neither a data dictionary available nor a response to our query from data collection managers for twenty-three (27.7%) of the data collections eligible for inclusion. Data dictionaries were from national data collections, regional data collections and national surveys. All data dictionaries contained at least one of the PROGRESS equity stratifiers. National surveys included more equity stratifiers compared with national and regional data collections. Definitions used for recording social groups for the stratifiers examined lacked consistency. While there has been much discussion on tackling health inequalities in Ireland in recent years, health and social care data collections do not always record the social groupings that are most commonly affected. In order to address this, it is necessary to consider which equity stratifiers should be used for the Irish population and, subsequently, for agreed stratifiers to be incorporated into routine health data collection. These are lessons that can be shared internationally as other countries begin to address deficits in their use of equity stratifiers.


Host and viral determinants of Mx2 antiretroviral activity.
Myxovirus resistance 2 (Mx2/MxB) has recently been uncovered as an effector of the anti-HIV-1 activity of type I interferons (IFNs) that inhibits HIV-1 at an early stage postinfection, after reverse transcription but prior to proviral integration into host DNA. The mechanistic details of Mx2 antiviral activity are not yet understood, but a few substitutions in the HIV-1 capsid have been shown to confer resistance to Mx2. Through a combination of in vitro evolution and unbiased mutagenesis, we further map the determinants of sensitivity to Mx2 and reveal that multiple capsid (CA) surfaces define sensitivity to Mx2. Intriguingly, we reveal an unanticipated sensitivity determinant within the C-terminal domain of capsid. We also report that Mx2s derived from multiple primate species share the capacity to potently inhibit HIV-1, whereas selected nonprimate orthologs have no such activity. Like TRIM5α, another CA targeting antiretroviral protein, primate Mx2s exhibit species-dependent variation in antiviral specificity against at least one extant virus and multiple HIV-1 capsid mutants. Using a combination of chimeric Mx2 proteins and evolution-guided approaches, we reveal that a single residue close to the N terminus that has evolved under positive selection can determine antiviral specificity. Thus, the variable N-terminal region can define the spectrum of viruses inhibited by Mx2. Importance: Type I interferons (IFNs) inhibit the replication of most mammalian viruses. IFN stimulation upregulates hundreds of different IFN-stimulated genes (ISGs), but it is often unclear which ISGs are responsible for inhibition of a given virus. Recently, Mx2 was identified as an ISG that contributes to the inhibition of HIV-1 replication by type I IFN. Thus, Mx2 might inhibit HIV-1 replication in patients, and this inhibitory action might have therapeutic potential. The mechanistic details of how Mx2 inhibits HIV-1 are currently unclear, but the HIV-1 capsid protein is the likely viral target. Here, we determine the regions of capsid that specify sensitivity to Mx2. We demonstrate that Mx2 from multiple primates can inhibit HIV-1, whereas Mx2 from other mammals (dogs and sheep) cannot. We also show that primate variants of Mx2 differ in the spectrum of lentiviruses they inhibit and that a single residue in Mx2 can determine this antiviral specificity.


Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid-induced differentiation.
The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.


Clinical roundtable monograph. The oncologist's role in management of venous thromboembolism.
Thromboembolism is the second leading cause of death in cancer patients. Patients with venous thromboembolism (VTE) and malignancy have a significantly higher probability of death. Pulmonary embolism can lead to a fatal outcome, and this condition often goes undiagnosed in cancer patients despite the presence of symptoms. Risk of VTE is increased by a number of clinical factors, which can be patient-derived, cancer-related, and treatment-related. Increasingly, clinicians are seeking predictable biomarkers to identify those patients at the greatest risk. To that end, a newly developed and validated predictive risk model may help identify patients who could benefit from prophylaxis. In addition, serum levels of coagulation cascade factors may predict the survival rate of cancer patients; elevated D-dimer levels are associated with decreased survival time. Anticoagulants, particularly low-molecular-weight heparin, can be useful in preventing the recurrence of clots in cancer patients with VTE. Current and future investigations are aimed at determining if prophylaxis with anticoagulants can improve patient survival. Future management strategies may involve the use of low-molecular-weight heparin or other novel anticoagulants as part of palliative care for high-risk patients. Although treatment with low-molecular-weight heparin can significantly reduce the risks of clots, the impact on cancer survival is unclear.


Vasopressin-induced bradycardia in barodenervated rats.
Experiments were performed on conscious chronically instrumented rats to determine the contribution of baroreceptor reflex (BRR)-independent mechanisms in the bradycardia associated with intravenous administration of arginine vasopressin (AVP). At least 2 wk prior to experimentation, the aortic and carotid baroreceptors were denervated in six rats. Following recovery, the maximum bradycardic responses to pressor doses of phenylephrine (PE) or AVP were determined on separate days in each animal. Pulse interval (PI) was calculated from heart rate (HR), and the slopes of PI vs. mean arterial blood pressure (MABP) and PI vs. dose were determined for each experiment by linear regression. There was no significant correlation of PI vs. MABP in response to bolus PE in these barodenervated rats. However, there was a significant correlation of PI vs. MABP and PI vs. dose in response to AVP in five of the six barodenervated rats. These data suggest that pressor levels of AVP may elicit bradycardia independent of the BRR. Another group of experiments was performed in the Langendorff-isolated rat heart preparation to assess the direct chronotropic effect of AVP. Hearts were not paced, and the coronary arteries were perfused at a constant flow. HR was determined at various concentrations of AVP (n = 4 at each dose). In addition, because unpaced hearts exhibited low intrinsic rates, the same protocol was performed in hearts receiving isoproterenol to elevate basal HR (n = 4 at each AVP dose). There was no chronotropic effect of AVP in isolated hearts with or without isoproterenol administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Mycotoxins in crude building materials from water-damaged buildings.
We analyzed 79 bulk samples of moldy interior finishes from Finnish buildings with moisture problems for 17 mycotoxins, as well as for fungi that could be isolated using one medium and one set of growth conditions. We found the aflatoxin precursor, sterigmatocystin, in 24% of the samples and trichothecenes in 19% of the samples. Trichothecenes found included satratoxin G or H in five samples; diacetoxyscirpenol in five samples; and 3-acetyl-deoxynivalenol, deoxynivalenol, verrucarol, or T-2-tetraol in an additional five samples. Citrinine was found in three samples. Aspergillus versicolor was present in most sterigmatocystin-containing samples, and Stachybotrys spp. were present in the samples where satratoxins were found. In many cases, however, the presence of fungi thought to produce the mycotoxins was not correlated with the presence of the expected compounds. However, when mycotoxins were found, some toxigenic fungi usually were present, even if the species originally responsible for producing the mycotoxin was not isolated. We conclude that the identification and enumeration of fungal species present in bulk materials are important to verify the severity of mold damage but that chemical analyses are necessary if the goal is to establish the presence of mycotoxins in moldy materials.


Quantification of AAV particle titers by infrared fluorescence scanning of coomassie-stained sodium dodecyl sulfate-polyacrylamide gels.
Adeno-associated virus (AAV)-based vectors have gained increasing attention as gene delivery vehicles in basic and preclinical studies as well as in human gene therapy trials. Especially for the latter two-for both safety and therapeutic efficacy reasons-a detailed characterization of all relevant parameters of the vector preparation is essential. Two important parameters that are routinely used to analyze recombinant AAV vectors are (1) the titer of viral particles containing a (recombinant) viral genome and (2) the purity of the vector preparation, most commonly assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by silver staining. An important, third parameter, the titer of total viral particles, that is, the combined titer of both genome-containing and empty viral capsids, is rarely determined. Here, we describe a simple and inexpensive method that allows the simultaneous assessment of both vector purity and the determination of the total viral particle titer. This method, which was validated by comparison with established methods to determine viral particle titers, is based on the fact that Coomassie Brilliant Blue, when bound to proteins, fluoresces in the infrared spectrum. Viral samples are separated by SDS-PAGE followed by Coomassie Brilliant Blue staining and gel analysis with an infrared laser-scanning device. In combination with a protein standard, our method allows the rapid and accurate determination of viral particle titers simultaneously with the assessment of vector purity.


Cyclic Compression Testing of Three Elastomer Types-A Thermoplastic Vulcanizate Elastomer, a Liquid Silicone Rubber and Two Ethylene-Propylene-Diene Rubbers.
Thermoplastic elastomer vulcanizate (TPV) and liquid silicone rubber (LSR) are replacement candidates for ethylene-propylene-diene rubbers (EPDM), as they offer the possibility for two-component injection moulding. In this study, these material types were compared side by side in cyclic compression tests. The materials were also characterized to provide details on the formulations. Compared to the rubbers, the TPV had higher compression set (after a given cycle) and hysteresis loss, and a stronger Mullins effect. This is due to the thermoplastic matrix in the TPV. The LSR had lower compression set (after a given cycle) than the EPDM, but stronger Mullins effect and higher relative hysteresis loss. These differences between the LSR and the EPDM are likely due to differences in polymer network structure and type of filler. Methods for quantifying the Mullins effect are proposed, and correlations between a Mullins index and parameters such as compression set are discussed. The EPDMs showed a distinct trend in compression set, relative hysteresis loss and relaxed stress fraction vs. strain amplitude; these entities were almost independent of strain amplitude in the range 15-35%, while they increased in this range for the TPV and the LSR. The difference between the compression set values of the LSR and the EPDM decreased with increasing strain amplitude and increasing strain recovery time.


The Effect of Moringa Isothiocyanate-1 on Renal Damage in Diabetic Nephropathy.
Diabetic nephropathy (DN) is the most common clinical complication of diabetes mellitus. Moringa isothiocyanate-1 (MIC-1) is effective in the treatment of diabetes mellitus, but its mechanism of action in DN remains obscure. This research specifically probed the role of MIC-1 in modulating renal injury in DN. Six db/m mice were assigned to control group and twelve db/db mice were randomly allocated to the db/db and db/db + MIC-1 groups. The body and kidney weights of the mice were monitored. Renal function indicators and oxidative stress-related markers were assessed by automatic biochemical analyzer and ELISA method. The pathological changes, apoptosis of renal tissues, extracellular regulated protein kinases (ERK) 1/2/ Nuclear factor erythroid2-related factor 2 (Nrf2) pathway-related markers, and the positive expressions of podocalyxin (Pod) and synaptopodin (Syn) were measured by H&E, PAS, and TUNEL staining, Western blot, and IHC assay. MIC-1 reduced the body and kidney weights, and increased the kidney organ index (calculated as 100*kidney weight/ body weight) in db/db mice. In addition, MIC-1 improved renal function, kidney tissue injury, and apoptosis of db/db mice. MIC1 noticeably repressed the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) and enhanced the contents of (glutathione) GSH, superoxide dismutase (SOD), and catalase (CAT) in db/db mice. At molecular level, db/db mice showed a decrease in p-ERK/ERK, Nrf2, SOD-1, heme oxygenase 1 (HO-1), and CAT and an increase in p- inhibitor kappa B alpha (IKBα) and p-Nuclear factor-kappa B (P65/P65), which were reversed when MIC-1 was administered. Furthermore, MIC-1 facilitated the positive expressions of Pod and Syn of the kidney tissues in db/db mice. MIC-1 reduces oxidative stress and renal injury by activating the ERK/Nrf2/HO-1 signaling and repressing the NFκB signaling in db/db mice. DOI: 10.52547/ijkd.7515.


Current production and metal oxide reduction by Shewanella oneidensis MR-1 wild type and mutants.
Shewanella oneidensis MR-1 is a gram-negative facultative anaerobe capable of utilizing a broad range of electron acceptors, including several solid substrates. S. oneidensis MR-1 can reduce Mn(IV) and Fe(III) oxides and can produce current in microbial fuel cells. The mechanisms that are employed by S. oneidensis MR-1 to execute these processes have not yet been fully elucidated. Several different S. oneidensis MR-1 deletion mutants were generated and tested for current production and metal oxide reduction. The results showed that a few key cytochromes play a role in all of the processes but that their degrees of participation in each process are very different. Overall, these data suggest a very complex picture of electron transfer to solid and soluble substrates by S. oneidensis MR-1.


Study of serum fucose and serum sialic acid levels in oral squamous cell carcinomia.
Serum fucose and sialic acid levels were determined in 50 oral cancer patients and 25 healthy controls. A statistically significant increase was noted in the study group. The increase in serum fucose level correlated well with the clinical staging in the study group whereas sialic acid did not. These values were independent of age, sex and histopathological grading. The result suggest that the serum fucose level is a better biochemical tumor marker than sialic acid level. However its usefulness may be limited if used judiciously to assess the prognosis of the disease.


Involvement of the Oct-1 regulatory element of the gadd45 promoter in the p53-independent response to ultraviolet irradiation.
The gadd45 gene, a growth arrest and DNA damage (gadd)-induced gene, is transcriptionally activated by UV irradiation through two distinct pathways. One requires the sequence-specific binding of the p53 tumor suppressor protein to a responsive element within the third intron of the gadd45 gene, and the other is p53-independent activation of the gadd45 promoter region, although the UV-response element that mediates this has yet to be defined. To investigate the sequences involved in induction of gadd45 by UV irradiation in a p53-independent pathway, we performed mutation analyses of the human gadd45 promoter fused to the luciferase reporter gene in cell lines in which p53 was inactivated. We found that the UV-responsive element was involved in the Oct-1 binding site at -99 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that Oct-1, a transcription factor, bound this element on the gadd45 gene, although the intensity and mobility pattern of the retarded bands were not altered by UV irradiation. These results suggest that the Oct-1 regulatory element might be one of the essential elements involved in the activation of the gadd45 promoter by UV irradiation in a p53-independent pathway.


The benefits of using clickers in small-enrollment seminar-style biology courses.
Although the use of clickers and peer discussion is becoming common in large-lecture undergraduate biology courses, their use is limited in small-enrollment seminar-style courses. To investigate whether facilitating peer discussion with clickers would add value to a small-enrollment seminar-style course, we evaluated their usefulness in an 11-student Embryology course at the University of Colorado, Boulder. Student performance data, observations of peer discussion, and interviews with students revealed that adding clickers to a small-enrollment course 1) increases the chance students will do the required reading before class, 2) helps the instructor engage all students in the class, and 3) gives students a focused opportunity to share thinking and to learn from their peers.


Cyclic compressive loading facilitates recovery after eccentric exercise.
To assess the biologic basis of massage therapies, we developed an experimental approach to mimic Swedish massage and evaluate this approach on recovery from eccentric exercise-induced muscle damage using a well-controlled animal model. Tibialis anterior muscles of six New Zealand White rabbits were subjected to one bout of damaging, eccentric contractions. One muscle was immediately subjected to cyclic compressive loads, and the contralateral served as the exercised control. We found that commencing 30 min of cyclic compressive loading to the muscle, immediately after a bout of eccentric exercise, facilitated recovery of function and attenuated leukocyte infiltration. In addition, fiber necrosis and wet weight of the tissue were also reduced by compressive loading. We conclude that subjecting muscle to compressive loads immediately after exercise leads to an enhanced recovery of muscle function and attenuation of the damaging effects of inflammation in the rabbit model. Although these observations suggest that skeletal muscle responds to cyclic compressive forces similar to those generated by clinical approaches, such as therapeutic massage, further research is needed to assess the translational efficacy of these findings.


Curcumin and its Multi-target Function Against Pain and Inflammation: An Update of Pre-clinical Data.
Pain is an unpleasant sensation that has complex and varying causative etiology. Modern drug discovery focuses on identifying potential molecules that target multiple pathways with a safer profile compared to those with a single target. The current treatment of pain and inflammation with the available therapeutics has a number of major side effects. Pain is one of the major clinical problems that need functional therapeutics which act on multiple targets and with low toxicity. Curcumin, a naturally occurring polyphenolic compound from Curcuma longa, has been used for years in Ayurvedic, Chinese, and in many other systems of traditional medicine. Pre-clinical data published thus far demonstrated that curcumin possesses multi-target biological functions, suggesting its potential use to cure different diseases. However, there is no or very brief systematic review of its potential use in pain and inflammation with underlying mechanisms for such activities. Accordingly, the aim of the current review was to update the pre-clinical data of curcumin and its multiple targeting pathways for analgesic and anti-inflammatory effects, and to further propose a molecular mechanism(s). A literature study was conducted using different known databases, including Pubmed, SciFinder, Google Scholar, and Science Direct. Available pre-clinical data suggest the ameliorating effect of curcumin in pain and inflammation is rendered through the modulation of pain pathways, including inhibition of a number of pro-inflammatory mediators, inhibition of oxidative stress and cyclooxygenase-2 (COX-2), down-regulation of Ca2+/calmodulin-depend protein kinase II (CaMKIIα) and calcium channels like transient receptor potential (TRP), modulation of metabotropic glutamate receptor-2 (mGlu2), modulation of monoamine system, inhibition of JAK2/STAT3 signaling pathway, remodeling of extracellular matrix proteins, inhibition of apoptosis, inhibition of JNK/MAPK and ERK/CREB signaling pathway, and activation of the opioid system. Taken all together, it is evident that curcumin is one of the promising, safe, and natural polyphenolic molecules that target multiple molecular pathways in pain and can be beneficial in the treatment and management of pain and inflammation.


Complementary and Integrative Healthcare in a Long-term Care Facility: A Pilot Project.
The world's population is aging quickly, leading to increased challenges of how to care for individuals who can no longer independently care for themselves. With global social and economic pressures leading to declines in family support, increased reliance is being placed on community- and government-based facilities to provide long-term care (LTC) for many of society's older citizens. Complementary and integrative healthcare (CIH) is commonly used by older adults and may offer an opportunity to enhance LTC residents' wellbeing. Little work has been done, however, rigorously examining the safety and effectiveness of CIH for LTC residents. The goal of this work is to describe a pilot project to develop and evaluate one model of CIH in an LTC facility in the Midwestern United States. A prospective, mixed-methods pilot project was conducted in two main phases: (1) preparation and (2) implementation and evaluation. The preparation phase entailed assessment, CIH model design and development, and training. A CIH model including acupuncture, chiropractic, and massage therapy, guided by principles of collaborative integration, evidence informed practice, and sustainability, was applied in the implementation and evaluation phase. CIH services were provided for 16 months in the LTC facility. Quantitative data collection included pain, quality of life, and adverse events. Qualitative interviews of LTC residents, their family members, and LTC staff members queried perceptions of CIH services. A total of 46 LTC residents received CIH care, most commonly for musculoskeletal pain (61%). Participants were predominantly female (85%) and over the age of 80 years (67%). The median number of CIH treatments was 13, with a range of 1 to 92. Residents who were able to provide self-report data demonstrated, on average, a 15% decline in pain and a 4% improvement in quality of life. No serious adverse events related to treatment were documented; the most common mild and expected side effect was increased pain (63 reports over 859 treatments). Qualitative interviews revealed most residents, family members and LTC staff members felt CIH services were worthwhile due to perceived benefits including pain relief and enhanced psychological and social wellbeing. This project demonstrated that with extensive attention to preparation, one patient-centered model of CIH in LTC was feasible on several levels. Quantitative and qualitative data suggest that CIH can be safely implemented and might provide relief and enhanced wellbeing for residents. However, some aspects of model delivery and data collection were challenging, resulting in limitations, and should be addressed in future efforts.


[Our experience with duodenal tumors].
The authors report 3 cases of benign duodenal tumors and one case of duodenal cancer. In two cases the benign tumors were adenomatous polyps, in one case with signs of dysplasia. One case of benign tumor was a lipoma. All the three benign tumors were removed through a duodenotomy, in one case associated with a sphincteroplasty. The case of duodenal cancer, arisen in a patient operated since 24 years with a gastric resection, was treated with a Whipple technique but for the very old age and the bad health conditions, the patient died in 11th post-operative day for myocardium infarct.


The Drawbacks of Project Funding for Epistemic Innovation: Comparing Institutional Affordances and Constraints of Different Types of Research Funding.
Over the past decades, science funding shows a shift from recurrent block funding towards project funding mechanisms. However, our knowledge of how project funding arrangements influence the organizational and epistemic properties of research is limited. To study this relation, a bridge between science policy studies and science studies is necessary. Recent studies have analyzed the relation between the affordances and constraints of project grants and the epistemic properties of research. However, the potentially very different affordances and constraints of funding arrangements such as awards, prizes and fellowships, have not yet been taken into account. Drawing on eight case studies of funding arrangements in high performing Dutch research groups, this study compares the institutional affordances and constraints of prizes with those of project grants and their effects on organizational and epistemic properties of research. We argue that the prize case studies diverge from project-funded research in three ways: 1) a more flexible use, and adaptation of use, of funds during the research process compared to project grants; 2) investments in the larger organization which have effects beyond the research project itself; and 3), closely related, greater deviation from epistemic and organizational standards. The increasing dominance of project funding arrangements in Western science systems is therefore argued to be problematic in light of epistemic and organizational innovation. Funding arrangements that offer funding without scholars having to submit a project-proposal remain crucial to support researchers and research groups to deviate from epistemic and organizational standards.


Trichoscopy - a valuable tool for identifying conditions mimicking androgenetic alopecia.
Androgenetic alopecia (AGA) is the most prevalent type of hair loss in women and men. Recently, a European consensus group published guidelines for the diagnostic evaluation of AGA in men, women, and adolescents. This S1 guideline presents expert opinion-based recommendations for gender-dependent steps in the diagnostic procedure, which can easily be implemented in the daily clinical routine. For diagnosing AGA, detailed anamnesis and objective learning are not enough because there are several conditions mimicking this disease. Trichoscopy can be considered an important, non-invasive tool for diagnosing hair and scalp disorders that may have similar clinical signs to AGA.


IGF-I gene transfer in thermally injured rats.
Exogenous insulin-like growth factor-I (IGF-I) is known to improve the pathophysiology of a thermal injury, however, deleterious side-effects have limited its utility. Cholesterol-containing cationic liposomes that encapsulate complementary DNA (cDNA) are nonviral carriers used for in vivo gene transfection. We propose that liposome IGF-I gene transfer will accelerate wound healing in burned rats and attenuate deleterious side-effects associated with high levels of IGF-I. To test this hypothesis IGF-I gene constructs, encapsulated in liposomes, were studied for their efficacy in modulating the thermal injury response. Thirty adult male Sprague-Dawley rats were given a 60% TBSA scald burn and randomly divided into three groups to receive weekly subcutaneous injections of liposomes plus the lacZ gene coding for beta-galactosidase, liposomes plus cDNA for IGF-I and beta-galactosidase or liposomes plus the rhIGF-I protein. Body weights and wound healing were measured. Muscle and liver dry/wet weights and IGF-I concentrations in serum, skin and liver were measured by radioimmunoassay. Transfection was confirmed by histochemical staining for beta-galactosidase. Rats receiving the IGF-I cDNA constructs exhibited the most rapid wound re-epithelialization and greatest increase in body weight and gastrocnemius muscle protein content (P < 0.05). Local IGF-I protein concentrations in the skin were higher when compared to liposomes containing only the lacZ gene (P < 0.05) Transfection was apparent in the cytoplasm of myofibroblasts, endothelial cells and macrophages of the granulation tissue. Liposomes containing the IGF-I gene constructs proved effective in preventing muscle protein wasting and preserving total body weight after a severe thermal injury.


Effect of increased consumption of whole-grain foods on blood pressure and other cardiovascular risk markers in healthy middle-aged persons: a randomized controlled trial.
Three daily portions of whole-grain foods could lower cardiovascular disease risk, but a comprehensive intervention trial was needed to confirm this recommendation. We aimed to assess the effects of consumption of 3 daily portions of whole-grain foods (provided as only wheat or a mixture of wheat and oats) on markers of cardiovascular disease risk in relatively high-risk individuals. This was a randomized controlled dietary trial in middle-aged healthy individuals. After a 4-wk run-in period with a refined diet, we randomly allocated volunteers to a control (refined diet), wheat, or wheat + oats group for 12 wk. The primary outcome was a reduction of cardiovascular disease risk factors by dietary intervention with whole grains, which included lipid and inflammatory marker concentrations, insulin sensitivity, and blood pressure. We recruited a total of 233 volunteers; 24 volunteers withdrew, and 3 volunteers were excluded. Systolic blood pressure and pulse pressure were significantly reduced by 6 and 3 mm Hg, respectively, in the whole-grain foods groups compared with the control group. Systemic markers of cardiovascular disease risk remained unchanged apart from cholesterol concentrations, which decreased slightly but significantly in the refined group. Daily consumption of 3 portions of whole-grain foods can significantly reduce cardiovascular disease risk in middle-aged people mainly through blood pressure-lowering mechanisms. The observed decrease in systolic blood pressure could decrease the incidence of coronary artery disease and stroke by ≥15% and 25%, respectively. This trial was registered at clinicaltrials.gov as ISRCTN27657880.


ReMap 2020: a database of regulatory regions from an integrative analysis of Human and Arabidopsis DNA-binding sequencing experiments.
ReMap (http://remap.univ-amu.fr) aims to provide the largest catalogs of high-quality regulatory regions resulting from a large-scale integrative analysis of hundreds of transcription factors and regulators from DNA-binding experiments in Human and Arabidopsis (Arabidopsis thaliana). In this 2020 update of ReMap we have collected, analyzed and retained after quality control 2764 new human ChIP-seq and 208 ChIP-exo datasets available from public sources. The updated human atlas totalize 5798 datasets covering a total of 1135 transcriptional regulators (TRs) with a catalog of 165 million (M) peaks. This ReMap update comes with two unique Arabidopsis regulatory catalogs. First, a catalog of 372 Arabidopsis TRs across 2.6M peaks as a result of the integration of 509 ChIP-seq and DAP-seq datasets. Second, a catalog of 33 histone modifications and variants across 4.5M peaks from the integration of 286 ChIP-seq datasets. All catalogs are made available through track hubs at Ensembl and UCSC Genome Browsers. Additionally, this update comes with a new web framework providing an interactive user-interface, including improved search features. Finally, full programmatically access to the underlying data is available using a RESTful API together with a new R Shiny interface for a TRs binding enrichment analysis tool.


Erythromycin for Gastric Emptying in Patients Undergoing General Anesthesia for Emergency Surgery: A Randomized Clinical Trial.
Patients undergoing emergency procedures under general anesthesia have impaired gastric emptying and are at high risk for aspiration of gastric contents. Erythromycin has strong gastric prokinetic properties. To evaluate the efficacy of erythromycin lactobionate in gastric emptying in patients undergoing emergency surgery. The Erythro-Emerge trial was a single-center, randomized, double-blinded, placebo-controlled clinical trial in patients undergoing emergency surgery under general anesthesia at Geneva University Hospitals. We included 132 patients from March 25, 2009, through April 10, 2013, and all patients completed the study. Randomization was stratified for trauma and nontrauma procedures. The randomization code was opened on April 23, 2013, and analyses were performed through July 26, 2013. We performed an intention-to-treat analysis. Patients were randomized to intravenous erythromycin lactobionate, 3 mg/kg, or placebo 15 minutes before tracheal intubation. Patients were followed up for 24 hours. The primary outcome was a clear stomach, defined as less than 40 mL of liquids and no solids and identified through endoscopy immediately after intubation. The secondary outcome was the pH level of residual gastric content. A clear stomach was diagnosed in 42 of 66 patients (64%) receiving placebo compared with 53 of 66 patients (80%) receiving erythromycin (risk ratio, 1.26 [95% CI, 1.01-1.57]). In the population undergoing surgery for nontrauma, the association between receipt of erythromycin and having a clear stomach (adjusted odds ratio [95% CI]) was statistically significant (13.4 [1.49-120]; P = .02); in the population undergoing surgery for trauma, it was not (1.81 [0.64-5.16]; P = .26). Median (interquartile range) pH of the residual gastric liquid was 2 (1-4) in 36 patients receiving placebo and 6 (3-7) in 16 receiving erythromycin (P = .002). Patients receiving erythromycin had nausea (20 [30%] vs 4 [6%]) and stomach cramps (15 [23%] vs 2 [3%]) more often than those receiving placebo. One patient receiving erythromycin vomited before induction of anesthesia. In patients undergoing general anesthesia for emergency procedures, erythromycin administration increased the proportion with a clear stomach and decreased the acidity of residual gastric liquid. Erythromycin was particularly efficacious in the nontrauma population. Adverse effects were minor. Further large-scale studies are warranted to confirm the potential of erythromycin to reduce the incidence of bronchoaspiration in patients undergoing emergency surgery. ClinicalTrials.gov identifier: NCT00827216.


Controlling inventory in a small specialty hospital.
Controlling inventory in a small specialty hospital has many parallels to controlling inventory in a large, acute care hospital. However, in a specialty hospital, there seems to be a plethora of specialty items that must always be on hand in ample supply. To achieve a significant inventory reduction, a strategic plan was developed that revolved around training sessions with the materiel management team, meetings with key hospital staff, and the establishment of two prime vendor contracts. In 1991, the annual inventory value in the general storeroom was approximately $2.3 million; in 1992, the inventory value was $1.6 million, and the projected inventory value for 1993 is $1.2 million. Implementing a just-in-time program to control inventory is best achieved through a collaborative effort with all of the materiel management team feeling a sense of contribution as well as receiving recognition from hospital administration.


Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation.
The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation (AF). In this 12-week, parallel-group, multicentre, multinational study, 1,146 patients with AF and risk of stroke were randomised to edoxaban 30 mg qd, 30 mg bid, 60 mg qd, or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0-3.0. The study was double-blind to edoxaban dose, but open-label to warfarin. Primary outcomes were occurrence of major and/or clinically relevant non-major bleeding and elevated hepatic enzymes and/or bilirubin. Mean age was 65 +/- 8.7 years and 64.4% were warfarin-naïve. Whereas major plus clinically relevant non-major bleeding occurred in 3.2% of patients randomised to warfarin, the incidence of bleeding was significantly higher with the edoxaban 60 mg bid (10.6%; p=0.002) and 30 mg bid regimens (7.8%; p=0.029), but not with the edoxaban 60 mg qd (3.8%) or 30 mg qd regimens (3.0%). For the same total daily dose of 60 mg, both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group. There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups. The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin. In contrast, the edoxaban bid regimens were associated with more bleeding than warfarin. These results suggest that in this three-month study, edoxaban 30 or 60 mg qd are safe and well-tolerated.


Ultrastructure of spontaneous and urethan-induced thymomas in buffalo rats.
Normal thymuses from Buffalo and Long-Evans rats of various ages, and spontaneous and urethan-induced thymomas in Buffalo rats, were examined by electron microscopy. Histological variabilities among thymomas of the lymphoid, mixed, and epithelial cell types were a reflection of the number of lymphoid cells within the network composed of neoplastic epithelial reticular cells. In the cytoplasm of these cells, development of tonofilaments and membrane-bound bodies and inverse development of the rough-surfaced endoplasmic reticulum were recognized in the sequential process from the lymphoid cell type to the epithelial cell type. An important role of the development of the rough-surfaced endoplasmic reticulum for thymic function was suggested. Phagocytic activity of the neoplastic epithelial reticular cells was revealed, and some of the membrane-bound bodies in these cells, especially those with moniliform structures, were regarded as remnants of damaged lymphocytes. Evidence for neoplastic epithelial reticular cell-lymphoid cell transformation could not be established from study of the thymoma tissue. No virus-like structures were observed in these thymomas.


Group A streptococcal pharyngitis and immune-mediated complications: from diagnosis to management.
Group A streptococcal pharyngitis remains the most important bacterial pharyngitis because of its frequency and potential complications. Group A streptococcal pharyngitis is most common in children 5-11 years of age in winter-spring, and a rapid test or culture is necessary for accurate diagnosis. We propose a management strategy for those geographic areas with very low acute rheumatic fever rates, emphasizing selective testing that avoids testing those patients with viral-like features (e.g., rhinorrhea and cough). Acute rheumatic fever is the most important immune-mediated sequela and has become rare in most areas of the USA and Western Europe, most probably due to decreased circulation of highly rheumatogenic group A streptococcal strains.


Comparison of frictional resistance between self-ligating and conventional brackets tied with elastomeric and metal ligature in orthodontic archwires.
To compare the frictional resistance between self-ligating and conventional brackets tied to different types of wire. Abzil Kirium Capelozza (Pattern I) and Easy Clip (Roth prescription) incisor brackets were used. An elastomeric ligature or a 0.10-in ligating wire was used to ligate the wire to the Abzil bracket. Three types of orthodontic archwire alloys were assessed: 0.016-in NiTi wire, 0.016 x 0.021-in NiTi wire and 0.019 x 0.025-in steel wire. Ten observations were carried out for each bracket-archwire angulation combination. Brackets were mounted in a special appliance, positioned at 90 degrees in relation to the wire and tested in two angulations. Frictional test was performed in a Universal Testing Machine at 5 mm/min and 10 mm of displacement. The means (MPa) were submitted to ANOVA and Tukey's test set at 5% of significance. The surfaces of wires and brackets were observed at SEM. Steel-tied brackets (16.48 ± 8.31) showed higher means of frictional resistance than elastomeric-tied brackets (4.29 ± 2.16 ) and self-ligating brackets (1.66 ± 1.57) (P < 0.05), which also differed from each other (P < 0.05). As for the type of wire, 0.019 x 0.025-in steel wire (5.67 ± 3.97) showed lower means (P < 0.05) than 0.16-in NiTi wire (8.26 ± 10.92) and 0.016 x 0.021-in NiTi wire (8.51 ± 7.95), which did not differ from each other (P > 0.05). No statistical differences (P > 0.05) were found between zero (7.76 ± 8.46) and five-degree (7.19 ± 7.93) angulations. Friction was influenced not only by the type of bracket, but also by the ligating systems. Different morphological aspects were observed for the brackets and wires studied.


Three members of the LC8/DYNLL family are required for outer arm dynein motor function.
The highly conserved LC8/DYNLL family proteins were originally identified in axonemal dyneins and subsequently found to function in multiple enzyme systems. Genomic analysis uncovered a third member (LC10) of this protein class in Chlamydomonas. The LC10 protein is extracted from flagellar axonemes with 0.6 M NaCl and cofractionates with the outer dynein arm in sucrose density gradients. Furthermore, LC10 is specifically missing only from axonemes of those strains that fail to assemble outer dynein arms. Previously, the oda12-1 insertional allele was shown to lack the Tctex2-related dynein light chain LC2. The LC10 gene is located approximately 2 kb from that of LC2 and is also completely missing from this mutant but not from oda12-2, which lacks only the 3' end of the LC2 gene. Although oda12-1 cells assemble outer arms that lack only LC2 and LC10, this strain exhibits a flagellar beat frequency that is consistently less than that observed for strains that fail to assemble the entire outer arm and docking complex (e.g., oda1). These results support a key regulatory role for the intermediate chain/light chain complex that is an integral and highly conserved feature of all oligomeric dynein motors.


Associations Between Hypothyroidism and Subclinical Atherosclerosis Among Male and Female Patients Without Clinical Disease Referred to Computed Tomography.
Hypothyroidism is recognized as a risk factor for coronary artery disease (CAD). However, reports are conflicting when the results are stratified by sex and the underlying risk of CAD. We examine the sex-specific associations of hypothyroidism with coronary calcification and plaques. Retrospective cross-sectional study was conducted among adult patients referred to (64 multidetector spiral) computed tomography. Those with pre-existing CAD were excluded. Hypothyroidism was defined as thyroid-stimulating hormone ≥ 4.5 mU/L. Plaques were determined based on quantification of coronary calcium and coronary computed tomography angiography. A total of 2499 patients (1544 male and 955 female) were included. The prevalence of hypothyroidism was significantly higher in female than in male patients (18.0% vs 12.9%, P < .001), in all patients and those <65 years. Hypothyroidism in male patients was significantly associated with higher coronary calcium score > 0, higher coronary calcium score groups, and both soft and calcified plaques (P = .027, P = .032, P = .005, and P = .017, respectively). After adjusting for traditional coronary risk factors, the higher risk in male patients remained significant for coronary plaque but not for coronary calcium score >0 (odds ratios and CIs were 1.77, 1.08-2.90, P = .023 and .98, 0.63-1.52, P = .925, respectively). On the other hand, hypothyroidism in female patients was not significantly associated with coronary calcification nor plaques in both univariate and multivariate analyses. There are sex-specific differences in the association of hypothyroidism with subclinical atherosclerosis. The higher risk of coronary plaques but not calcification in male patients was independent of traditional coronary risk factors. The lack of associations in female patients may be related to lower underlying risk of CAD.


An unusual cause of a sellar mass.
A 57-year-old man presented with features suggestive of a non-functioning pituitary tumour. He underwent trans-sphenoidal resection of the tumour which was found to be a chordoma and not a pituitary adenoma. This case demonstrates that a chordoma may directly involve the sellar region and mimic a pituitary adenoma. We also discuss the aetiology, areas of involvement, management and prognosis of this unusual tumour.


Immunoaffinity chromatographic purification of cellobiohydrolase II mutants from recombinant trichoderma reesei strains devoid of major endoglucanase genes.
Efficient purification of Trichoderma reesei cellobiohydrolase II (CBHII) requires the use of affinity chromatography based on a substrate analogue. Due to altered substrate binding, the purification of many active-site mutants of CBHII from the complex fungal culture media represents a considerable challenge. Here we describe a combination of two approaches to facilitate the purification: the first is based on the construction of novel engineered T. reesei strains devoid of the major contaminating endoglucanases, and the second uses immunoaffinity chromatography as the final purification step. Two different procedures for the preparation of the antibody matrix were tested. Crosslinking of the monoclonal antibody to Protein G matrix instead of the conventional immobilization via cyanogen bromide increased the binding efficiency. Three different active-site mutants of CBHII bound to the immunoaffinity column in neutral pH and were eluted in pH 2.7. The purity of the CBHII mutant preparations was tested using small chromophoric substrates and hydroxyethyl cellulose, which are hydrolyzed by many other cellulases but not by CBHII. The immunoaffinity column purified the CBHII mutants over 800-fold in a single step and resulted in homogeneous protein preparations free of proteolytically cleaved forms of CBHII. The use of the double replacement T. reesei production strains, especially the one lacking the genes coding for both the endogeneous CBHII and the endoglucanase II (EGII), helped to reduce the total endoglucanase activity in the preparations.


Botulinum toxin type A and B for the reduction of hypersalivation in children with neurological disorders: a focus on effectiveness and therapy adherence.
Botulinum toxin (BoNT) is an established treatment option to reduce hypersalivation in children with chronic neurological disorders. Objective of this study was (1) to discriminate differences in efficacy and safety of repeated interventions using BoNT with a focus on different preparations used and (2) to look for effectiveness and treatment adherence from a qualitative research perspective in this single-center cohort study. We prospectively assessed goal attainment scaling, drooling severity and frequency score and the number of towels/day before, and 4 to 8 weeks after intervention. A parent questionnaire assessed therapy-related effects on quality of life retrospectively. A total of 19 out of 34 patients received repeated injections of BoNT (106 total). Mean dose: 95 units onabotulinumtoxinA (Botox®), 2383 units rimabotulinumtoxinB (Neuro-/Myobloc®). Outcome parameters showed a distinct reduction in all treatment groups with a higher efficacy of riB. The child's need for care was reduced in 79% and social interaction improved in 84%. Main reason for discontinuation was "not enough effect" and "formation of antibodies." riB showed to be more effective in reducing hypersalivation, but antibody-formation seems to be clinically relevant. Despite clinical efficacy treatment adherence is influenced by personal and environmental factors of parents and caretakers balancing the short-term clinical benefit versus the burden of intervention.


Acute intermittent porphyria--diagnostic and treatment traps.
Acute intermittent porphyria (AIP) is a rare metabolic disease defined by mutations coding the deaminaze enzyme of porphobilinogen (PBGD). Porphyrias are somewhat misdiagnosed as a consequence of light symptoms in patients. Acute forms of porphyria can be life-threatening, so a correct diagnosis and an accurate treatment are highly important. The authors presented the case of a 38-years-old patient admitted for persistent abdominal pain that previously presented two generalized convulsive seizures. The diagnosis of AIP was established by the raised concentration of urinary porphyrins. Despite treatment with carbohydrates and hemines, the clinical picture of the patient worsened, with tetraplegia and severe respiratory failure. The patient died seven weeks after the initial presentation of the disease.


DNA microarrays for virus detection in cases of central nervous system infection.
A low-density, high-resolution diagnostic DNA microarray comprising 38 gene targets for 13 viral causes of meningitis and encephalitis was constructed. The array has been used for the detection of multiplex PCR-amplified viruses in cerebrospinal fluid (CSF) and non-CSF specimens. A total of 41 clinical specimens were positive for echoviruses (23 samples), herpes simplex virus type 2 (4 samples), varicella-zoster virus (4 samples), human herpesvirus 7 (1 sample), human herpesvirus 6A (1 sample) and 6B (2 samples), Epstein-Barr virus (three samples), polyomavirus JC (1 sample), and cytomegalovirus (2 samples). Probes for herpes simplex virus type 1, polyomavirus BK, and mumps and measles viruses were also included on the array. Three samples were false negative by the microarray assay due to discordant results between the multiplex PCR for all 13 viruses simultaneously and the virus-specific PCR alone. Fifteen CSF specimens were true negative. The clinical sensitivity, specificity, and negative and positive predictive values of the assay were 93, 100, 100, and 83%, respectively, when the results were compared to those of the single-virus PCR, which was used as the "gold standard." The microarray-based virus detection assay is qualitative and provides a single-format diagnostic tool for the detection of panviral CNS infections.


Coping with child sexual abuse among college students and post-traumatic stress disorder: the role of continuity of abuse and relationship with the perpetrator.
The purpose of this study was to examine the effects of child sexual abuse (CSA) on the use of coping strategies and post-traumatic stress disorder (PTSD) scores in young adults, as well as the role of avoidance and approach coping strategies in those PTSD scores in CSA victims. The role of coping strategies was studied by considering their possible interactive effect with the continuity of abuse and the relationship with the perpetrator; the effect of coping strategies on PTSD was also compared between CSA victim and non-CSA victim participants. The sample was comprised of 138 victims of CSA and another 138 participants selected as a comparison group. Data about child sexual abuse were obtained from a questionnaire developed for this purpose. Coping strategies were assessed with the How I Deal with Things Scale (Burt & Katz, 1987), while PTSD scores were assessed with the "Escala de Gravedad de Síntomas del Trastorno de Estrés Postraumático" (Severity of Symptoms of PTSD Scale; Echeburúa et al., 1997). Participants who had been victims of CSA showed significantly higher PTSD scores and lower approach coping strategies scores. However, differences in avoidance coping strategies between groups were not consistent and did not always follow the expected direction. Only the use of avoidance coping strategies was related to PTSD, participants who used these showing higher scores. The effects of avoidance strategies were stronger in continued than in isolated abuse, in intrafamilial than in extrafamilial abuse and in CSA victims than in non-victims. These results confirm the idea of CSA as a high-risk experience that can affect the victim's coping strategies and lead to PTSD to a lesser or greater extent depending on the coping strategy used. Moreover, the role of these strategies varies depending on whether or not the participant is a victim of CSA and on the characteristics of abuse (continuity and relationship with the perpetrator). In terms of intervention, a reduction of avoidance-type strategies appears to have a beneficial effect, especially in the case of intrafamilial and/or continued CSA victims. The encouragement of "spontaneous" approach strategies (devised by the victim herself, without counseling) would probably not lead to more positive outcomes in terms of PTSD symptomatology. However, encouraging CSA survivors to engage in therapy aimed at developing effective approach strategies, as other studies have suggested, may help reduce PTSD symptoms.


Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents.
Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations. To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents. Investigators at seven North American sites in the Genetic Disorders of Mucociliary Clearance Consortium prospectively and systematically assessed individuals (aged 0-18 yr) referred due to high suspicion for PCD. The investigators defined specific clinical questions for the clinical report form based on expert opinion. Diagnostic testing was performed using standardized protocols and included nasal nitric oxide measurement, ciliary biopsy for ultrastructural analysis of cilia, and molecular genetic testing for PCD-associated genes. Final diagnoses were assigned as "definite PCD" (hallmark ultrastructural defects and/or two mutations in a PCD-associated gene), "probable/possible PCD" (no ultrastructural defect or genetic diagnosis, but compatible clinical features and nasal nitric oxide level in PCD range), and "other diagnosis or undefined." Criteria were developed to define early childhood clinical features on the basis of responses to multiple specific queries. Each defined feature was tested by logistic regression. Sensitivity and specificity analyses were conducted to define the most robust set of clinical features associated with PCD. From 534 participants 18 years of age and younger, 205 were identified as having "definite PCD" (including 164 with two mutations in a PCD-associated gene), 187 were categorized as "other diagnosis or undefined," and 142 were defined as having "probable/possible PCD." Participants with "definite PCD" were compared with the "other diagnosis or undefined" group. Four criteria-defined clinical features were statistically predictive of PCD: laterality defect; unexplained neonatal respiratory distress; early-onset, year-round nasal congestion; and early-onset, year-round wet cough (adjusted odds ratios of 7.7, 6.6, 3.4, and 3.1, respectively). The sensitivity and specificity based on the number of criteria-defined clinical features were four features, 0.21 and 0.99, respectively; three features, 0.50 and 0.96, respectively; and two features, 0.80 and 0.72, respectively. Systematically defined early clinical features could help identify children, including infants, likely to have PCD. Clinical trial registered with ClinicalTrials.gov (NCT00323167).


Delivering reproductive health services through non-state providers in Pakistan: understanding the value for money of different approaches.
Delivering Reproductive Health Results(DRHR) programme used social franchising (SF) and social marketing (SM) approaches to increase the supply of high quality family planning services in underserved areas of Pakistan. We assessed the costs, cost-efficiency and cost-effectiveness of DRHR to understand the value for money of these approaches. Financial and economic programme costs were calculated. Costs to individual users were captured in a pre-post survey. The cost per couple years of protection (CYP) and cost per new user were estimated as indicators of cost efficiency. For the cost-effectiveness analysis we estimated the cost per clinical outcome averted and the cost per disability-adjusted life year (DALY) averted. Approximately £20 million were spent through the DRHR programme between July 2012 and September 2015 on commodities and services representing nearly four million CYPs. Based on programme data, the cumulative cost-efficiency of the entire DRHR programme was £4.8 per CYP. DRHR activities would avert one DALY at the cost of £20. Financial access indicators generally improved in programme areas, but the magnitude of progress varies across indicators. The SF and SM approaches adopted in DRHR appear to be cost effective relative to comparable reproductive health programmes. This paper adds to the limited evidence on the cost-effectiveness of different models of reproductive health care provision in low- and middle-income settings. Further studies are needed to nuance the understanding of the determinants of impact and value for money of SF and SM.


Directed Self-Assembly of Ge Quantum Dots Using Focused Si2+ Ion Beam Patterning.
We show that templating a Si surface with a focused beam of Si2+ or Si+ ions can create suitable nucleation sites for the subsequent growth of self-assembled Ge quantum dots by chemical vapor deposition. To determine the mechanism of patterning we use atomic force microscopy to show that, similar to Ga+ patterning, the formation of a surface pit is required to enable control over Ge quantum dot locations. We find that relatively high implantation doses are required to achieve patterning, and these doses lead to amorphization of the substrate. We assess the degree to which the substrate crystallinity can be recovered by subsequent processing. Using in situ transmission electron microscopy heating experiments we find that recrystallization is possible at the growth temperature of the Ge quantum dots, but defects remain that follow the pattern of the initial implantation. We discuss the formation mechanism of the defects and the benefits of using Si ions for patterning both defects and quantum dots on Si substrates.


Terpenoids, flavonoids and caffeic acid derivatives from Salvia viridis L. cvar. Blue Jeans.
Three diterpenoids, 1-oxomicrostegiol (1), viroxocin (2), viridoquinone (3), were isolated from the roots of Salvia viridis L. cvar. Blue Jeans. Five known diterpenoids, microstegiol (4), 7α-acetoxy-14-hydroxy-8,13-abietadiene-11,12-dione (5; 7-O-acetylhorminone tautomer), 7α,14-dihydroxy-8,13-abietadiene-11,12-dione (6; horminone tautomer), ferruginol and salvinolonyl 12-methyl ether (7) were also found in the roots together with 1-docosyl ferulate (8), and a mixture of 2-(4'-alkoxyphenyl) ethyl alkanoates (9). Two lupane triterpenoids, 2α-acetoxy-lup-20(29)-en-3β-ol (10), and 3β-acetoxy-lup-20(29)-en-2α-ol (11) were found in the aerial parts together with known compounds, lup-20(29)-ene-2α,3β-diol (12), ursolic acid, oleanolic acid, β-sitosterol and β-sitosterol glucoside. A known phenylpropanoid, trans-verbascoside (or acteoside; 13), was the main constituent in the polar fraction of the aerial part, and it is now reported in the genus Salvia for the first time. Other polyphenolic compounds were cis-verbascoside (14), leucosceptoside A (15), martynoside (16), caffeic acid, 6-O-caffeoyl-glucose (18), rosmarinic acid, salidroside, luteolin-7-O-α-rhamnopyranosyl-(1→6)-β-galactopyranoside, luteolin-7-O-β-galactopyranoside, luteolin-7-O-α-rhamnopyranosyl-(1→6)-β-glucopyranoside, luteolin-7-O-β-glucopyranoside, and apigenin-7-O-β-glucopyranoside. The structures were determined by 1D-, 2D-NMR and HR-ESI-MS techniques. Compounds 6, 10, ferruginol, ursolic acid and oleanolic acid exhibited antibacterial activity against Enterococcus faecalis (ATCC 775) with MIC 50 μM, 25 μM, 50 μM, 12.5 μM, 12.5 μM respectively. Ferruginol, ursolic acid and oleanolic acid were also active against Staphylococcus aureus (ATCC 6571), and Bacillus cereus (ATCC 2599) with MIC 12.5-50 μM. 4 was also active against S.aureus (ATCC 6571) with MIC 50 μM. These values are consistent with previous studies on the antimicrobial activity of Salvia diterpenoids.


Management of chronic pulmonary disease in the time of coronavirus disease 2019.
The purpose of this review is to discuss the most recent data describing the impact of coronavirus disease 2019 (COVID-19) on the pediatric population with chronic pulmonary disease. We specifically focus on children with asthma, cystic fibrosis (CF), and lung transplant recipients. Children with asthma, CF, and lung transplant recipients do not appear to have an increased risk of morbidity or mortality with COVID-19 infection compared to the general pediatric population. Data does not support the change or withdrawal of any asthma or CF maintenance medications; however, does advocate for the cessation of aerosolized medications whenever possible to minimize transmission risk. It may not be necessary to adjust immunosuppressive therapy when managing COVID-19 in pediatric lung transplant patients. Mechanisms of infection in airway epithelial cells in children may differ from adults, resulting in a milder phenotype. Current data about pediatric patients with chronic lung disease infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is promising but remains scarce. Additional study is needed to definitively understand the complex interplay of the SARS-CoV-2 virus in the airway of children with chronic lung disease, how it differs from adults, and how best to manage the symptoms of acute infection.


Neuroprotective Effects of Red Ginseng Saponins in Scopolamine-Treated Rats and Activity Screening Based on Pharmacokinetics.
Ginseng has been used to alleviate age-related dementia and memory deterioration for thousands of years. This study investigated the protective effect of red ginseng saponins against scopolamine-induced cerebral injury. Meanwhile, pharmacokinetics of ginsenosides in normal and scopolamine-treated rats were compared. After scopolamine injection, glutathione, catalase and superoxide dismutase levels were significantly decreased when compared with control group. Compared with SA group, pretreatment of rats with red ginseng saponins could increase glutathione, catalase and superoxide dismutase level. Treatment with red ginseng saponins significantly decreased malondialdehyde level. In the pharmacokinetic analysis, a pattern recognition analysis method was used to investigate the pharmacokinetics of the absorbed compounds in blood. The pharmacokinetic parameters of Rg1, Rg2, Rh3, Rg5 and Rk1 in model group had higher area under the curve (AUC), mean residence time (MRT) and peak plasma concentration (Cmax) values; area under the curve (AUC) values and peak plasma concentration (Cmax) of model group was significantly different from that of normal group (p < 0.05). The Cmax value of Rk3, Rh1, Rh2 and Rh4 in model group was higher than normal group, but their AUC values were not significantly different. There was no significantly difference in time at Cmax (Tmax), AUC and Cmax values of Rb1, Rb2 Re, Rc, Rd and Rf between the model and normal group. 16 ginsenosides were grouped into three separate clusters according to principal component analysis (PCA) score plot based on pharmacokinetic data. The results suggested red ginseng saponins have significant protective effect against scopolamine-induced memory deficit and scopolamine-induced rats could lead to the changes of pharmacokinetic behaviors of ginsenosides.


Design and implementation of a portable long-term physiological signal recorder.
This paper describes a design and implementation of a portable physiological signal recorder. The device is designed for measuring electrocardiography, bioimpedance, and user's activity. The bioimpedance measures the dynamic changes in the impedance, and its main application is monitoring user's respiration. Activity is measured with three-axis acceleration sensor. During the design, a special attention is paid on the device's power consumption and the target has been set to a 24-h operating time. Functionality of the implemented measurement device is proven with test measurements, which include, e.g., comparison of measurement signals against reference signals, testing the device operation under vigorous upper body movements, and during a light exercise. In order to verify the device operation during real-life activities, one full day, 24-h long, measurement is carried out. The measurement system is tested with both commercial Ag/AgCl gel-paste electrodes and custom-made textile electrodes. Device is proven to be operational with both electrodes, but textile electrodes are found to be more sensitive for movement artifacts. This paper also gives a small review of other existing portable and wearable physiological measurement devices and discusses some general requirements of these devices.


Variant forms of alpha-fetoprotein transcripts expressed in human hematopoietic progenitors. Implications for their developmental potential towards endoderm.
Hematopoietic stem cells have been identified as multipotent cells that give rise to all adult hematopoietic lineages. Although the hematopoietic lineage is derived from the mesodermal germ layer in the embryo, recent data suggest that bone marrow cells with an antigenic profile consistent with that of hematopoietic stem cells can also differentiate to cell types of the endodermal lineages, such as hepatocytes. However, the molecular mechanisms associated with these events are entirely unknown. For decades, alpha-fetoprotein (AFP) has been used as a differentiation marker for endodermal cells, because it was thought that the transcription of AFP mRNA is tightly regulated in a developmental and tissue-specific process. In this report we describe two new variant forms of AFP transcripts in human hematopoietic progenitors that are not expressed in mature cells. The variant AFP (vAFP) cDNA sequences isolated from a multipotent hematopoietic cell line, K562, revealed that the vAFP differed from the authentic transcript, consisting of 15 exons, by replacing exon 1 of AFP with one or two exons located in the 5'-untranslated region of the AFP gene. In addition to the K562 cell line, vAFP transcripts were detected in normal bone marrow, thymus, and brain but were not detected in normal spleen, intestine, liver, or the hepatocellular carcinoma cell line, HepG2. This suggests expression in normal hematopoietic progenitors. This hypothesis was confirmed by the finding that CD34(+)Lin(-) hematopoietic progenitor cells purified from cord blood by flow cytometric sorting also expressed the variant transcripts. These results suggest that some hematopoietic progenitors are in a state that permits them to express certain types of transcripts that have been considered unique to endoderm.


COVID-19 pandemic: Its impact on liver disease and liver transplantation.
Severe pulmonary disease caused by the novel coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], has devastated many countries around the world. It has overwhelmed the medical system. The priorities of many institutions have changed to manage critically ill corona virus infectious disease-2019 (COVID-19) patients, which affected the working style of many departments. Hepatologists and transplant surgeons look after a very sensitive patient group. Patients with liver disease need special attention and continuous follow-up. Similarly, transplant candidates also need special care. Healthcare professionals in the field of hepatology face the overwhelming task of taking care of COVID-19 patients with hepatic complications, liver disease or transplant patients who are SARS-CoV-2 positive, and the patients on routine surveillance who do not have COVID-19. This review will evaluate COVID-19 from the perspective of its effect on the liver and its possible effects on patients with liver disease. Furthermore, the level of care for liver transplant recipients during the pandemic will be discussed.


History of cancer in Iran.
The history of human and animal cancers date back to antiquity. The earliest written document on cancer appeared on Egyptian papyrus. For centuries, the theory of "four humors" was the primary hypothesis that explained the cause for cancer. Finally, in the 19th century a new era began with the detection of the cellular origin of cancer; in due course, the nature of this lethal disease was better recognized and led to further achievements in cancer treatment. During the 20th century researchers investigated several risk factors for cancer such as tobacco smoking and environmental chemicals, in addition to the carcinogenic role of certain viruses, occupational association of cancer, its relationship with certain hormones and dietary habits, and the genetic basis of cancer. These investigations resulted in more efficient cancer management. After the advent of radiotherapy and chemotherapy as two complementary therapeutic modalities to surgery, the campaign against cancer has improved. However, cancer remains a major health challenge that accounts for substantial morbidity and mortality worldwide. The present paper briefly reviews the history of cancer in Iran, particularly during the last decades of the 20th century.