Lead decreases parasitemia and enhances survival of Plasmodium berghei-infected mice.
Malaria, a disease accounting for more than one million deaths per year, is caused by intraerythrocytic growth of Plasmodia. Parasitemia may be blunted by suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and phosphatidylserine exposure. Triggers of eryptosis include lead nitrate (Pb(NO3)2). As shown here, Pb(NO3)2 (> or = 10 microM) increased phosphatidylserine exposure of Plasmodium falciparum-infected human erythrocytes, an effect significantly more marked than in noninfected cells. Pb(NO3)2 treatment accelerated the clearance of erythrocytes from circulating blood. Parasitemia in Plasmodium berghei-infected mice was significantly decreased and mouse survival significantly enhanced by 100 microM Pb(NO3)2 (20 ppm) in drinking water. The treatment significantly increased reticulocyte number but did not significantly decrease erythrocyte number in noninfected mice and in infected animals mainly triggered the disappearance of P. berghei harbouring erythrocytes. In conclusion, Pb(NO3)2 accelerates eryptosis and subsequent clearance of infected erythrocytes and thus favourably influences the course of malaria.


Overall Survival Following Thoracoscopic vs Open Lobectomy for Early-stage Non-small Cell Lung Cancer: A Meta-analysis.
A majority of observational studies on overall survival following thoracoscopic vs open lobectomy for early-stage non-small cell lung cancer did not demonstrate a significant difference, whereas several meta-analyses on this topic showed a significant difference. The PubMed, Scopus, and Web of Science databases were queried for studies published in the English language. We searched for meta-analyses and original studies comparing overall survival between thoracoscopic and open lobectomy for early-stage non-small cell lung cancer. Our meta-analysis, using random effect models and with a hazard ratio as a measure of effect, was performed on original studies. Publication bias was evaluated with funnel plots of precision and the Egger test. Seven meta-analyses on this topic were found and all of them have shown that thoracoscopic lobectomy is associated with significantly more favorable overall survival than open lobectomy, using odds ratio, risk ratio, or risk difference as measures of effect. Our meta-analysis of 11 observational studies demonstrated no significant difference in overall survival between thoracoscopic (n = 2386) and open lobectomy (n = 3494) for early-stage non-small cell lung cancer (pooled hazard ratio: 0.91, 95% confidence interval: 0.76-1.09, P = 0.30). Neither funnel plots of precision nor the Egger test suggested a publication bias. Our meta-analysis, using a hazard ratio as a measure of effect for a time-to-event outcome, did not demonstrate a significant difference in overall survival between thoracoscopic and open lobectomy with the current dataset available in the literature, as opposed to previous meta-analyses.


[Diagnosis of human rotavirus infection by the dot hybridization method].
The use of the dot-hybridization assay for the diagnosis of human rotavirus infection was shown to be principally possible. 32P-labeled RNA segments of porcine rotavirus transcribed in an in vitro system by activation of endogenous RNA-dependent RNA-polymerase were used as hybridization probes. The transcripts were synthesized to all 11 segments of the parental virus genome. The method proved to be highly specific and very sensitive detecting 10 picograms of viral RNA in fecal filtrates of the patients.


Constraint-induced therapy approach to restoring function after neurological injury.
Traditional rehabilitation programs for persons with neurologic dysfunction emphasize a compensation, true recovery, or substitution approach to improve functional abilities. Constraint-induced (CI) movement therapy substantially increases more-affected extremity use in the life situation due to the influence of two different underlying mechanisms: overcoming learned nonuse and inducing use-dependent cortical reorganization. In this way, it bypasses the debate over whether a compensation, true recovery, or substitution approach should be used. The purposes of this article are to describe the CI therapy approach, discuss its proposed modes of action, and discuss other unique aspects of CI therapy as a rehabilitation technique.


Severe restrictive lung disease in systemic sclerosis.
We sought to identify risk factors for developing severe restrictive lung disease and to determine the time of onset and rate of progression in patients with systemic sclerosis (SSc). Using the University of Pittsburgh Scleroderma Databank, we grouped patients according to their lowest forced vital capacity (FVC) value: > 75% predicted, 50-75% predicted, and < 50% predicted. In patients with severe restrictive disease, we examined serial pulmonary function test (PFT) results to determine the rate of loss of lung volume over time. Of 890 SSc patients, 60% (n = 531) never had an FVC < or = 75% predicted; 27% (n = 243) had moderate restrictive disease, with an FVC value of 50-75% predicted; and only 13% (n = 116) of the patients had severe restrictive disease, with FVC < or = 50% predicted. Black race, male sex, early disease, and primary cardiac involvement due to SSc were the features most frequently associated with severe restrictive lung disease (by multiple logistic regression). Fifty-five patients with severe restrictive lung disease had their first of at least 2 PFTs during the first 5 years after onset of any SSc (not pulmonary) symptoms. In 30 patients, the FVC declined by 32% per year in the first 2 years of illness, in 16 patients the annual loss was 12% in years 2-4 after disease onset, and in 9 patients annual loss was 3% during years 4-6 of disease (P < 0.005 by 1-way analysis of variance). In SSc patients, black men with early disease who have cardiac involvement are the most likely to have factors associated with the development of severe restrictive lung disease (which is increasingly becoming a major cause of death). Disease subtype (diffuse versus limited cutaneous) and serum anti-topoisomerase I antibody do not differentiate between moderate and severe restrictive disease. Careful monitoring of pulmonary function early in the disease, when the greatest loss of lung function occurs, may help identify patients likely to respond to new therapy.


[Changing views on the place of loop and thiazide diuretics in the treatment of chronic heart failure. Part II. Influence on outcomes and clinical application].
Results of studies of effects of loop and thiazide diuretics on clinical outcomes in patients with chronic heart failure (CHF) are discussed. A number of prospective trials have shown that in patients with CHF not receiving angiotensin converting enzyme inhibitors (ACEI) diuretics lessen considerably probability of decompensation. At the same time retrospective analysis of some large randomized trials revealed elevated mortality among patients with CHF receiving high doses of loop diuretics without potassium sparing diuretics. Especially significant during treatment with high doses of loop diuretics is elevated risk of sudden (or arrhythmic) death which according to data from SOLVD and PRAISE trials increases 30-50%. Current recommendations on the use of loop and thiazide diuretics in complex therapy of patients with CHF are given. An attention is paid to that therapy of CHF should be started with prescription of ACEI and diuretic added in the presence of symptoms and signs of congestion. In moderate and severe CHF as basic therapy it is recommended to use combination of ACEI, b-adrenoblocker and spironolactone, which allow to confine to medium doses of loop diuretics (furosemide not more than 80 mg/day). Mechanisms of diuretic resistance in CHF and methods of its management are also reviewed in detail.


Oxidation of 5'-site guanine at GG and GGG sequences induced by a metabolite of carcinogenic heterocyclic amine PhIP in the presence of Cu(II) and NADH.
Adduct formation has been considered to be a major causal factor of DNA damage by carcinogenic heterocyclic amines. By means of experiments with an electrochemical detector coupled to a high-performance liquid chromatograph, we revealed that N-hydroxy metabolite of 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) induced the formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in the presence of Cu(II). Addition of an endogenous reductant NADH enhanced the 8-OH-dG formation. Experiments with (32)P-labeled DNA fragments showed that this metabolite [PhIP(NHOH)] caused 8-hydroxylation of guanines in the presence of Cu(II) and NADH, and subsequent treatment with formamidopyrimidine-DNA glycosylase led to chain cleavages at the 5'-site guanine of GG and GGG sequences. Interestingly, antioxidant enzyme SOD enhanced the intensity of DNA damage, and thymine residues were appended to its guanine-predominant cleavage sites. Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). A UV-visible spectroscopic study indicated that Cu(II) and SOD catalyze the autoxidation of PhIP(NHOH). These results suggest that Cu(II)-dependent autooxidation of PhIP(NHOH) coupled with NADH-mediated reduction of its oxidized product form redox cycle, resulting in oxidative DNA damage by low concentrations of PhIP(NHOH). We conclude that in addition to DNA adduct formation, oxidative DNA damage may be involved in the carcinogenic process of PhIP.


Creation of a local interface terminology to SNOMED CT.
This paper describes the steps followed in the creation of a local Interface Terminology to SNOMED CT (as reference terminology) with a strong focus on user acceptability. The resulting list of terms is used for clinical data input by physicians and nurses at the Hospital Italiano in Buenos Aires, Argentina. Description includes data model, mappings to SNOMED CT and classifications, subsets definitions and extensibility mechanisms. The Interface Terminology is currently used in the recording of diagnosis and procedures in inpatient discharge summaries and its coverage is improving from user feedback. Its current size is 24,800 concepts, 67% of them needed post-coordination for appropriate semantic representation, due to a very flexible policy that allows the use of any number of modifiers on concepts.


Biomechanical, histologic and macroscopic assessment of articular cartilage in a sheep model of osteoarthritis.
Our primary objective was to explore the full potential of the ovine medial meniscectomy (MMx) model of early osteoarthritis (OA) for studies to validate non-destructive articular cartilage (AC) assessments and therapeutic interventions. Our secondary objective was to re-evaluate the relationships between the different types of AC assessment after MMx in sheep. Macroscopic assessments, dynamic shear modulus (G*), phase lag and AC thickness measurements were performed at a total of 5437 reference points on all six articular surfaces in four normal joints and 16 MMx ovine stifle (knee) joints. Comparisons with histologic assessments of gross structural damage, collagen organisation (birefringence) and proteoglycan content were possible at 702 of these points. Histologic gross structural damage and proteoglycan loss were seen throughout the joint with greatest severity (fibrillation) in closest proximity to the MMx site. Increases in AC (30-50%) thickness, reductions in G* (30-40%) and collagen birefringence intensity (15-30%) occurred more evenly throughout the joint. Macroscopic softening was evident only when G* declined by 80%. G* correlated with AC thickness (rho=-0.47), collagen organisation rho=0.44), gross structural damage (rho=-0.44) and proteoglycan content (rho=0.42). Multivariate analysis showed that collagen organisation contributed twice as much to dynamic shear modulus (t=6.66 as proteoglycan content (t=3.21). Collagen organisation (rho=0.11) and proteoglycan content (rho=0.09) correlated only weakly to phase lag. Macroscopic assessments were insensitive to AC softening suggesting that arthroscopic assessments of AC status might also perform poorly. Collagen integrity was more important for the maintenance of AC stiffness (G*) than proteoglycan content. The development of major AC softening and thickening throughout the joint following MMx suggested involvement of non-mechanical (e.g., protein and biochemical) chemical and cytokine mediated processes in addition to the disturbance in biomechanical loading. The ovine MMx model provides a setting in which the spectrum of AC changes associated with the initiation and progression of OA may be evaluated.


Molecular genetic analysis of the melanoma regulatory locus in Xiphophorus interspecies hybrids.
Development of spontaneous melanoma in Xiphophorus interspecies backcross hybrid progeny, (X. hellerii × [X. maculatus Jp 163 A × X. hellerii]) is due to Mendelian segregation of a oncogene (xmrk) and a molecularly uncharacterized locus, called R(Diff), on LG5. R(Diff) is thought to suppresses the activity of xmrk in healthy X. maculatus Jp 163 A parental species that rarely develop melanoma. To better understand the molecular genetics of R(Diff), we utilized RNA-Seq to study allele-specific gene expression of spontaneous melanoma tumors and corresponding normal skin samples derived from 15 first generation backcross (BC1 ) hybrids and 13 fifth generation (BC5 ) hybrids. Allele-specific expression was determined for all genes and assigned to parental allele inheritance for each backcross hybrid individual. Results showed that genes residing in a 5.81 Mbp region on LG5 were exclusively expressed from the X. hellerii alleles in tumor-bearing BC1 hybrids. This observation indicates this region is consistently homozygous for X. hellerii alleles in tumor bearing animals, and therefore defines this region to be the R(Diff) locus. The R(Diff) locus harbors 164 gene models and includes the previously characterized R(Diff) candidate, cdkn2x. Twenty-one genes in the R(Diff) region show differential expression in the tumor samples compared to normal skin tissue. These results further characterize the R(Diff) locus and suggest tumor suppression may require a multigenic region rather than a single gene variant. Differences in gene expression between tumor and normal skin tissue in this region may indicate interactions among several genes are required for backcross hybrid melanoma development.


Comparison between air and carbon dioxide insufflation in the endoscopic submucosal excavation of gastrointestinal stromal tumors.
To evaluate the safety and efficacy of CO(2) insufflation compared with air insufflation in the endoscopic submucosal excavation (ESE) of gastrointestinal stromal tumors. Sixty patients were randomized to undergo endoscopic submucosal excavation, with the CO(2) group (n = 30) and the air group (n = 30) undergoing CO(2) insufflation and air insufflation in the ESE, respectively. The end-tidal CO(2) level (pETCO(2)) was observed at 4 time points: at the beginning of ESE, at total removal of the tumors, at completed wound management, and 10 min after ESE. Additionally, the patients' experience of pain at 1, 3, 6 and 24 h after the examination was registered using a visual analog scale (VAS). Both the CO(2) group and air group were similar in mean age, sex, body mass index (all P > 0.05). There were no significant differences in PetCO(2) values before and after the procedure (P > 0.05). However, the pain scores after the ESE at different time points in the CO(2) group decreased significantly compared with the air group (1 h: 21.2 ± 3.4 vs 61.5 ± 1.7; 3 h: 8.5 ± 0.7 vs 42.9 ± 1.3; 6 h: 4.4 ± 1.6 vs 27.6 ± 1.2; 24 h: 2.3 ± 0.4 vs 21.4 ± 0.7, P < 0.05). Meanwhile, the percentage of VAS scores of 0 in the CO(2) group after 1, 3, 6 and 24 h was significantly higher than that in the air group (60.7 ± 1.4 vs 18.9 ± 1.5, 81.5 ± 2.3 vs 20.6 ± 1.2, 89.2 ± 0.7 vs 36.8 ± 0.9, 91.3 ± 0.8 vs 63.8 ± 1.3, respectively, P < 0.05). Moreover, the condition of the CO(2) group was better than that of the air group with respect to anal exsufflation. Insufflation of CO(2) in the ESE of gastrointestinal stromal tumors will not cause CO(2) retention and it may significantly reduce the level of pain, thus it is safe and effective.


Porous double-layer polymer tubing for the potential use in heterogeneous continuous flow reactions.
Functional polymer tubing with an OD of 1/16 or 1/8 in. was fabricated by a simple polymer coextrusion process. The tubing was made of an outer impervious polypropylene layer and an inner layer, consisting of a blend of a functional polymer, polyethylene-co-methacrylic acid, and a sacrificial polymer, polystyrene. After a simple solvent leaching step using common organic solvents, the polystyrene was removed, leaving behind a porous inner layer that contains functional carboxylic acid groups, which could then be used for the immobilization of target molecules. Solution-phase reactions using amines or isocyanates have proven successful for the immobilization of a series of small molecules and polymers. This flexible multilayered functional tubing can be easily cut to the desired length and connected via standard microfluidic fittings.


Minor complications arising in alveolar distraction osteogenesis.
This study evaluates complications that arise during mandibular alveolar distraction osteogenesis and suggests treatments. We monitored complications that arose during alveolar distraction osteogenesis in 5 patients who underwent a total of 7 distractions, in all cases using an intraosseous distractor (Lead System, Leibinger, Germany). We report our responses to each type of complication. All 7 distractions were followed by the placement of 2 implants. The restoration was ideal in 4 of the 7 cases and functional but not ideal in the remaining 3. In all 7 distractions, we observed complications, although many were minor complications readily avoided by the use of appropriate technique. The complications were, first, intraoperative complications, namely 1) fracture of the transport segment (1 of 7 cases; appropriate preventative measures), 2) difficulties in finishing the osteotomy on the lingual side (7 of 7 cases; use of fine chisels made from cement spatulas), and 3) excessive length of the threaded rod (1 of 7 cases; cut the rod). Second, complications arose during distraction: 1) incorrect direction of distraction (2 of 7 cases; no corrective measures necessary in the present cases), 2) perforation of the mucosa by the transport segment (2 of 7 cases; response: smooth the crest of the segment with a bone rongeur), and 3) suture dehiscence (1 of 7 cases; no significant implications). Third, there were postdistraction complications, namely bone formation defects (4 of 7 cases; response: guided bone regeneration). A number of complications may arise during alveolar distraction osteogenesis. Most of these complications can be considered minor and are readily avoided or resolved by the use of appropriate procedures.


A new insertion sequence element, ISLdl1, in Lactobacillus delbrueckii subsp. lactis ATCC 15808.
A new insertion sequence element designated ISLdl1 has been isolated and characterized from Lactobacillus delbrueckii subsp. lactis ATCC 15808. It is the first IS element of L. delbrueckii subsp. lactis described. ISLdl1 is a 1508 bp element flanked by 26 bp imperfect inverted repeats, and generates an 8 bp AT-rich target duplication upon insertion. It contains one ORF encoding a protein of 455 amino acids. This protein shows significant homology to the transposases of the ISL3 family and to other bacterial transposases and putative transposases, and no homology to other proteins. Based on these structural features, ISLdl1 belongs to the ISL3 family. ISLdl1 is present in about 10-12 copies in the genome of ATCC 15808 based on Southern hybridization analysis. Location sites of eight ISLdl1 copies have been determined in more detail by cloning and sequencing one or both of the flanking regions of each ISLdl1 copy. ISLdl1 or ISLdl1-like IS elements were found exclusively in Lactobacillus delbrueckii species and in all strains of subsp. lactis tested. The nucleotide sequence of ISLdl1 is deposited under the accession number AJ302652.


Depot versus daily administration of gonadotrophin-releasing hormone agonist protocols for pituitary down regulation in assisted reproduction cycles.
Gonadotrophin-releasing hormone agonist (GnRHa) is commonly used to switch off (down regulate) the pituitary gland and thus suppress ovarian activity in women undergoing in vitro fertilisation (IVF). Other fertility drugs (gonadotrophins) are then used to stimulate ovulation in a controlled manner. Among the various types of pituitary down regulation protocols in use, the long protocol achieves the best clinical pregnancy rate. The long protocol requires GnRHa administration until suppression of ovarian activity occurs, within approximately 14 days. GnRHa can be used either as daily low-dose injections or through a single injection containing higher doses of the drug (depot). It is unclear which of these two forms of administration is best, and whether single depot administration may require higher doses of gonadotrophins. To compare the effectiveness and safety of a single depot dose of GHRHa versus daily GnRHa doses in women undergoing IVF. We searched the following databases: Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched July 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7), MEDLINE (1966 to July 2012), EMBASE (1980 to July 2012) and LILACS (1982 to July 2012). We also screened the reference lists of articles. We included RCTs comparing depot and daily administration of GnRHa for long protocols in IVF treatment cycles in couples with any cause of infertility, using various methods of ovarian stimulation. The primary review outcomes were live birth or ongoing pregnancy, clinical pregnancy and ovarian hyperstimulation syndrome (OHSS). Other outcomes included number of oocytes retrieved, miscarriage, multiple pregnancy, number of gonadotrophin (FSH) units used for ovarian stimulation, duration of gonadotrophin treatment, cost and patient convenience. Two review authors independently selected studies, extracted data and assessed study quality. For dichotomous outcomes, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) per woman randomised. Where appropriate, we pooled studies. Sixteen studies were eligible for inclusion (n = 1811 participants), 12 (n = 1366 participants) of which were suitable for meta-analysis. No significant heterogeneity was detected.There were no significant differences between depot GnRHa and daily GnRHa in live birth/ongoing pregnancy rates (OR 0.95, 95% CI 0.70 to 1.31, seven studies, 873 women), but substantial differences could not be ruled out. Thus for a woman with a 24% chance of achieving a live birth or ongoing pregnancy using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 18% and 29%.There was no significant difference between the groups in clinical pregnancy rate (OR 0.96, 95% CI 0.75 to 1.23, 11 studies, 1259 women). For a woman with a 30% chance of achieving clinical pregnancy using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 25% and 35%.There was no significant difference between the groups in the rate of severe OHSS (OR 0.84, 95% CI 0.29 to 2.42, five studies, 570 women), but substantial differences could not be ruled out. For a woman with a 3% chance of severe OHSS using daily GnRHa injections, the corresponding risk using GnRHa depot would be between 1% and 6%.Compared to women using daily GnRHa, those on depot administration required significantly more gonadotrophin units for ovarian stimulation (standardised mean difference (SMD) 0.26, 95% CI 0.08 to 0.43, 11 studies, 1143 women) and a significantly longer duration of gonadotrophin use (mean difference (MD) 0.65, 95% CI 0.46 to 0.84, 10 studies, 1033 women).Study quality was unclear due to poor reporting. Only four studies reported live births as an outcome and only five described adequate methods for concealment of allocation. We found no evidence of a significant difference between depot and daily GnRHa use for pituitary down regulation in IVF cycles using the long protocol, but substantial differences could not be ruled out. Since depot GnRHa requires more gonadotrophins and a longer duration of use, it may increase the overall costs of IVF treatment.


Effect of Shielding Gas Arc Welding Process on Cavitation Resistance of Welded Joints of AlMg4.5Mn Alloy.
The effect of the shielding gas arc welding process on the cavitation resistance of the three-component aluminum alloy AlMg4.5Mn and its welded joints was investigated. Welding was performed using the GTAW and GMAW processes in a shielded atmosphere of pure argon. After the welding, metallographic tests were performed, and the hardness distribution in the welded joints was determined. The ultrasonic vibration method was used to evaluate the base metal's and weld metal's resistance to cavitation. The change in mass was monitored to determine the cavitation rates. The morphology of the surface damage of the base metal and weld metal due to cavitation was monitored using scanning electron microscopy to explain the effect of the shielding gas arc welding process on their resistance to cavitation.


Stable expression of human endothelin receptors ETA and ETB by transfected baby hamster kidney cells.
The cDNAs for human endothelin receptors ETA and ETB were subcloned into the eukaryotic expression vector pMPSV/CMV and transfected, in parallel with plasmids carrying resistances for hygromycin B and puromycin, into baby hamster kidney (BHK) cells. Cell clones constitutively expressing high levels of either receptor were obtained through the combined selective pressure of both antibiotics. This was further confirmed by Northern blot analysis using ETA- or ETB-specific oligonucleotide probes. The calculated KD for endothelin (ET)-1 binding to ETA and ETB were 2.2 x 10(-10) M and 5.3 x 10(-10) M, respectively. Competitive binding experiments using the different ET forms showed the expected isopeptide-selective and non-isopeptide-selective profiles for ETA and ETB, respectively. BQ 123, a specific ETA antagonist, competed with ET-1 for binding to ETA but not to ETB.


A model for mercuric ion reduction in recombinant Escherichia coli.
Plasmid-encoded mercuric reduction involves transfer of Hg(2+) across the cellular envelope and reduction to Hg(0) by the cytoplasmic mercuric reductase using NADPH. A mathematical model was developed for the binding and transfer of Hg(2+) by transport proteins and the subsequent reduction of Hg(2+). The values of the model parameters were determined using experimental data. The derived rate expressions were similar to the previously experimentally determined ones. The model predicted that a differential amplification of the transport protein relative to mercuric reductase expression levels may enhance the Hg(2+) reduction rate in whole cells.


Iron metabolism in the Belgrade rat.
Iron metabolism in the Belgrade rat was examined in the intact animal and in the reticulocyte suspensions. The plasma iron turnover was increased. However, when allowance was made for the effect of the elevated plasma iron concentration, erythroid marrow capacity for iron uptake was at basal levels. Numbers of erythroid cells in marrow and spleen measured by the radioiron dilution technique were increased. Thus iron uptake was not proportionate to the erythroid hyperplasia in the b/b rat, despite a more than adequate plasma iron supply. This relative deficiency in iron uptake was reflected in a severe microcytosis and elevated red cell protoporphyrin. Reticulocyte incubation studies demonstrated an unimpaired uptake of the transferrin-iron-receptor complex but a marked reduction in iron accumulation. The diferric transferrin molecule, when it did give up iron within the cell, released both of its iron atoms so that only apotransferrin was returned to the media. In contrast to the nearly complete release of iron within the normal reticulocyte, the major portion of iron taken up by the Belgrade reticulocyte was returned to the plasma. The release mechanism that can be impaired in iron-deficient reticulocytes by EDTA or cadmium was shown to be affected by lower concentrations of these substances in the Belgrade reticulocyte. It is concluded that the Belgrade rat has an abnormality of iron release within the absorptive vacuole that is responsible for a state of intracellular iron deficiency, involving the erythron and other body tissues.


Identification of the tetraspanin CD82 as a new barrier to xenotransplantation.
Significant immunological obstacles are to be negotiated before xenotransplantation becomes a clinical reality. An initial rejection of transplanted vascularized xenograft is attributed to Galα1,3Galβ1,4GlcNAc-R (Galα1,3-Gal)-dependent and -independent mechanisms. Hitherto, no receptor molecule has been identified that could account for Galα1,3-Gal-independent rejection. In this study, we identify the tetraspanin CD82 as a receptor molecule for the Galα1,3-Gal-independent mechanism. We demonstrate that, in contrast to human undifferentiated myeloid cell lines, differentiated cell lines are capable of recognizing xenogeneic porcine aortic endothelial cells in a calcium-dependent manner. Transcriptome-wide analysis to identify the differentially expressed transcripts in these cells revealed that the most likely candidate of the Galα1,3-Gal-independent recognition moiety is the tetraspanin CD82. Abs to CD82 inhibited the calcium response and the subsequent activation invoked by xenogeneic encounter. Our data identify CD82 on innate immune cells as a major "xenogenicity sensor" and open new avenues of intervention to making xenotransplantation a clinical reality.


Changes in phenamine effects after repeated treatment and subsequent withdrawal of phenobarbital, carbamazepine and a combination of both.
The present study sought to establish participation of the dopaminergic and noradrenergic mediator systems in the mechanism of induction of tolerance and physical dependence by carbamazepine and phenobarbital through influencing the phenamine-caused group toxicity and group stereotypy. In an acute experiment, treatment with a combination of phenobarbital and carbamazepine reduced the phenamine toxicity in confined animals. Phenobarbital and the combination of phenobarbital and carbamazepine prolonged the latent period of phenamine-induced stereotypy. Duration of stereotypy was lengthened by phenobarbital and carbamazepine and significantly shortened by their combination. A 14-day treatment with phenobarbital, carbamazepine and a combination of both significantly curtailed the latent period of stereotypy. After discontinuation of the treatment stereotypy duration was significantly reduced. The latent period until stereotypy occurred also shortened with varying statistical significance for the different intervals of withdrawal.


Dynamic bacterial genome organization.
Recently completed projects of sequencing chromosomal fragments and entire chromosomes, as well as physical mapping of genomes, have opened novel inroads to the understanding of the biology of bacterial genomes. From these studies one may draw some conclusions. (i) The organization of orthologous genes on the bacterial chromosome is not conserved during evolution. (ii) The bacterial genome is more complex and also more flexible than hitherto thought. Genetic elements are sometimes part of the chromosome, while at other times they are independent elements or parts of alternative replicons (e.g. large plasmids). Such replicons, carrying essential genes, now seem to deserve the designation 'secondary chromosomes'. A study of the regulation of replication and segregation of these essential genetic elements will be of great interest.


Exploring the economic impact of inappropriate antibiotic use: the case of upper respiratory tract infections in Ghana.
Antibiotic consumption is increasing worldwide, particularly in low and middle-income countries (LMICs). Access to lifesaving antibiotics in LMICs is crucial while minimising inappropriate use. Studies assessing the economic impact of inappropriate antibiotic use in LMICs are lacking. We explored the economic impact of inappropriate antibiotic use using the example of upper respiratory tract infections (URIs) in Ghana, as part of the ABACUS (AntiBiotic ACcess and USe) project. A top-down, retrospective economic impact analysis of inappropriate antibiotic use for URIs was conducted. Two inappropriate antibiotic use situations were considered: (1) URIs treated with antibiotics, against recommendations from clinical guidelines; and (2) URIs that should have been treated with antibiotics according to clinical guidelines, but were not. The analysis included data collected in Ghana during the ABACUS project (household surveys and exit-interviews among consumers buying antibiotics), scientific literature and stakeholder consultations. Included cost types related to health care seeking behaviour for URIs. Additionally, cost saving projections were computed based on potential effects of future interventions that improve antibiotic use. Health care costs related to inappropriate antibiotic use for URIs were estimated to be around 20 million (M) USD annually, including 18 M USD for situation 1 and 2 M USD for situation 2. Travel costs and lost income due to travel, together, were estimated to be around 44 M USD for situation 1 and 18 M USD for situation 2. Possible health care cost savings range from 2 to 12 M USD for situation 1 and from 0.2 to 1 M USD for situation 2. This study indicates that inappropriate antibiotic use leads to substantial economic costs in a LMIC setting that could have been prevented. We recommend investment in novel strategies to counter these unnecessary expenditures. As the projections indicate, this may result in considerable cost reductions. By tackling inappropriate use, progress can be made in combatting antibiotic resistance.


Clients' and genetic counselors' perceptions of empathy in Japan: A pilot study of simulated consultations of genetic counseling.
The rapidly increasing availability of genetic testing is driving the acceleration of genetic counseling implementation. Empathy is important in medical encounters in general and forms a core component of a successful genetic counseling session; however, empirical evidence on empathy in genetic counseling is minimal. This study aimed to explore the perceptions of empathy in simulated genetic counseling consultations from the perspectives of clients and genetic counselors. Semi-structured interviews and interpersonal process recall were used with participants of simulated genetic counseling consultations to elicit their experiences of empathy. A constructivist grounded theory was used for data analysis. A total of 15 participants, including 10 clients and 5 genetic counselors, participated in 10 simulated counseling sessions. The genetic counselors attempted to demonstrate empathy and were sensitive toward detecting changes in clients. Meanwhile, the clients' perceptions represented their feelings and thoughts elicited through the counselors' empathic approaches. This was the first process study to examine empathy in simulated genetic counseling sessions. Our model of communication of empathy is a process in which counselors try to address implicit aspects of clients, and clients are provided with time and a safe place for introspection, which contributes to discussions on building good relationships with patients. There is also a suggestion of the utility of simulated consultations for healthcare providers to learn empathic communication.


The toxicity of substituted phenolic compounds to a detoxifying and an acetic acid bacterium.
In the detoxifying bacterium Acinetobacter calcoaceticus 69-V and in the acetic acid bacterium Acetobacter methanolicus MB 58, glucose and xylose are oxidized, respectively, via PQQ-dependent membrane-bound dehydrogenases, which are linked to the respiratory chain in a manner enabling energy conservation via electron transport phosphorylation (ETP) in the cytoplasmic membrane. Neither the glucose and gluconic acid nor the xylose and xylonic acid are metabolized. Therefore, measurements of sugar oxidation-driven ATP syntheses ought not to be disturbed by ATP drainage caused by anabolic processes. Studying the effect of substituted phenolic compounds on these energization processes reveals that their toxicity increases with an increasing degree of chlorination and that A. calcoaceticus 69-V is more stable than A. methanolicus MB 58 against chlorinated phenols. On the other hand, A. methanolicus MB 58 is more stable against 2,4-dinitrophenol (2,4-DNP) and 2,4-dichlorophenoxyacetic acid (2,4-D), especially in the acidic pH range, in which the sensitivity of ATP synthesis to the uncouplers is higher than that of respiration. The toxicity caused by protonophoric activities ought to be barely detectable by respiratory and dehydrogenase tests. The luminescence system of Photobacterium phosphoreum tested in the luminescent bacteria test was much more sensitive. This test system should be used as a screening tool and the effects measured must be confirmed by toxicity tests evaluating the stability of bacteria themselves involved in processes of detoxification as well as the production of toxic metabolites, monitored with respect to their velocity and efficiency.


Resveratrol Confers Vascular Protection by Suppressing TLR4/Syk/NLRP3 Signaling in Oxidized Low-Density Lipoprotein-Activated Platelets.
This study investigated the effect of resveratrol on Toll-like receptor 4- (TLR4-) mediated matrix metalloproteinase 3 (MMP3) and MMP9 expression in oxidized low-density lipoprotein- (ox-LDL-) activated platelets and the potential molecule mechanism. Human platelets were used in the present study. The results showed that resveratrol suppressed TLR4, MMP3, and MMP9 expression in ox-LDL-activated platelets. The TLR4 inhibitor CLI-095 also inhibited MMP3 and MMP9 expression and secretion in ox-LDL- and lipopolysaccharide- (LPS-) activated platelets. The combination of resveratrol and CLI-095 synergistically suppressed MMP3 and MMP9 expression in ox-LDL- and LPS-activated platelets. These findings suggest that the resveratrol-induced inhibition of MMP3 and MMP9 expression is linked to the suppression of TLR4 activation. Resveratrol also suppressed spleen tyrosine kinase (Syk) phosphorylation and nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) expression and IL-1β secretion in ox-LDL- and LPS-treated platelets. The coimmunoprecipitation results showed that resveratrol inhibited the binding of Syk and NLRP3. Finally, resveratrol reduced vascular senescence cells and the expression of TLR4, MMP3, and MMP9 and prevented alterations of vascular structure in 52-week-old mice. Our findings demonstrated that resveratrol decreased inflammatory protein expression and improved vascular structure in aged mice. Resveratrol inhibited the expression of TLR4 and secretion of MMP3, MMP9, and IL-1β. The mechanism of action of resveratrol appears to be associated with the inhibition of TLR4/Syk/NLRP3 activation in ox-LDL-activated platelets.


Parental anxiety and response to symptoms of minor illness in infants.
Examined the relationship between parental anxiety and parental contact with the clinic following a child's initial DPT immunization. The subjects were 80 volunteer mothers who brought their 8-week-old infants to an outpatient clinic for a well-child visit. At the time of the visit, maternal anxiety, anxiety proneness, perception of the infant as fussy or difficult, and demographic information were assessed. Seventy-two hours after the immunization, subjects reported DPT side effects and physician contacts. Discriminant function analysis found that mothers who were anxious prior to DPT administration and who had infant girls were more likely to contact the clinic by telephone. This relationship was independent of prior maternal experience with DPT immunization, maternal perception of the infant's general fussiness, and maternal Trait anxiety.


Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade.
Impaired skin wound healing is a major medical problem in diabetic subjects. Kinins exert a number of vascular and other actions limiting organ damage in ischaemia or diabetes, but their role in skin injury is unknown. We investigated, through pharmacological manipulation of bradykinin B1 and B2 receptors (B1R and B2R respectively), the role of kinins in wound healing in non-diabetic and diabetic mice. Using two mouse models of diabetes (streptozotocin-induced and db/db mice) and non-diabetic mice, we assessed the effect of kinin receptor activation or inhibition by subtype-selective pharmacological agonists (B1R and B2R) and antagonist (B2R) on healing of experimental skin wounds. We also studied effects of agonists and antagonist on keratinocytes and fibroblasts in vitro. Levels of Bdkrb1 (encoding B1R) and Bdkrb2 (encoding B2R) mRNAs increased 1-2-fold in healthy and wounded diabetic skin compared with in non-diabetic skin. Diabetes delayed wound healing. The B1R agonist had no effect on wound healing. In contrast, the B2R agonist impaired wound repair in both non-diabetic and diabetic mice, inducing skin disorganization and epidermis thickening. In vitro, B2R activation unbalanced fibroblast/keratinocyte proliferation and increased keratinocyte migration. These effects were abolished by co-administration of B2R antagonist. Interestingly, in the two mouse models of diabetes, the B2R antagonist administered alone normalized wound healing. This effect was associated with the induction of Ccl2 (encoding monocyte chemoattractant protein 1)/Tnf (encoding tumour necrosis factor α) mRNAs. Thus stimulation of kinin B2 receptor impairs skin wound healing in mice. B2R activation occurs in the diabetic skin and delays wound healing. B2R blockade improves skin wound healing in diabetic mice and is a potential therapeutic approach to diabetic ulcers.


The empirical status of empirically supported psychotherapies: assumptions, findings, and reporting in controlled clinical trials.
This article provides a critical review of the assumptions and findings of studies used to establish psychotherapies as empirically supported. The attempt to identify empirically supported therapies (ESTs) imposes particular assumptions on the use of randomized controlled trial (RCT) methodology that appear to be valid for some disorders and treatments (notably exposure-based treatments of specific anxiety symptoms) but substantially violated for others. Meta-analytic studies support a more nuanced view of treatment efficacy than implied by a dichotomous judgment of supported versus unsupported. The authors recommend changes in reporting practices to maximize the clinical utility of RCTs, describe alternative methodologies that may be useful when the assumptions underlying EST methodology are violated, and suggest a shift from validating treatment packages to testing intervention strategies and theories of change that clinicians can integrate into empirically informed therapies.


Clinical Value of Squamous Cell Carcinoma Antigen (SCCAg) in Anal Cancer - A Single-Center Retrospective Analysis.
To assess the clinical value of squamous cell carcinoma antigen (SCCAg) in anal cancer for chemoradiotherapy (CRT) patients. In 24 patients with SCC of the anus, SCCAg was determined before CRT and at every follow-up visit. 16/24 (66.7%) had normal SCCAg and 11/16 (68.8%) achieved complete remission (CR), while 7/8 (87.5%) with elevated SCCAg achieved CR. In two patients, elevated SCCAg was observed after radiotherapy. One was false-positive and one was true-positive leading to diagnosis of metachronous recurrent and metastatic disease after interim CR. SCCAg was inappropriate to predict the clinical outcome but can provide additional information on the regular follow-up examinations to detect a relapse.


Biobased 2,5-Bis(hydroxymethyl)furan as a Versatile Building Block for Sustainable Polymeric Materials.
Furanic polymers, currently mainly represented by polyethylene 2,5-furandicarboxylate (PEF), also known as polyethylene furanoate, have a fantastic potential to replace fossil-based polymers: for example, polyethylene terephthalate (PET). While 2,5-furandicarboxylic acid (FDCA), a precursor of PEF, and its derived polymers have been studied extensively, 2,5-bis(hydroxymethyl)furan (BHMF) has received relatively little attention so far. Similarly to FDCA, BHMF is a biobased platform chemical derived from renewable sources such as sugars. This review highlights different polymerization techniques for BHMF-based polyesters and addresses BHMF's relative instability during the synthesis of BHMF-derived polymers, including polycarbonates and polyurethanes. Furthermore, the degradability of furanic polyesters is discussed and BHMF's toxicity is briefly elaborated.


Chemical composition of the volatile extract and antioxidant activities of the volatile and nonvolatile extracts of Egyptian corn silk (Zea mays L.).
A total of 36 compounds, which comprised 99.4% of the extract, were identified by gas chromatography and mass spectrometry (GC-MS) in the volatile dichloromethane extract obtained from Egyptian corn silk. The main constituents of the volatile extract were cis-alpha-terpineol (24.22%), 6,11-oxidoacor-4-ene (18.06%), citronellol (16.18%), trans-pinocamphone (5.86%), eugenol (4.37%), neo-iso-3-thujanol (2.59%), and cis-sabinene hydrate (2.28%). Dried Egyptian corn silk was also directly extracted with petroleum ether, ethanol, and water. All extracts from solvent extraction and the volatile extract described above exhibited clear antioxidant activities at levels of 50-400 microg/mL in the 2,2-diphenyl-1-picrylhydrazyl (DPPH)/linoleic acid assay. The ethanol extract inhibited DPPH activity by 84% at a level of 400 microg/mL. All samples tested via the beta-carotene bleaching assay also exhibited satisfactory antioxidant activity with clear dose responses. This study indicates that corn silk could be used to produce novel natural antioxidants as well as a flavoring agent in various food products.


Crystal structure of the aspartic proteinase from Rhizomucor miehei at 2.15 A resolution.
The crystal structure of the aspartic proteinase from Rhizomucor miehei (RMP, EC 3. 4. 23. 23) has been refined to 2.15 A resolution to a crystallographic R-value of 0.215 and an Rfree of 0.281. The root-mean-square (r.m.s.) error for the atomic coordinates estimated from a Luzzati plot is 0.2 A. The r.m.s. deviations for the bond distances and bond angles from ideality are 0.01 A and 1.7 degrees, respectively. RMP contains two domains that consist predominantly of beta-sheets. A large substrate-binding cleft is clearly visible between the two domains, and the two catalytic residues Asp38 and Asp237 are located in the middle of the cleft with a water molecule bridging the carboxyl groups of Asp38 and Asp237. Due to crystal packing, the C-terminal domain is more mobile than the N-terminal domain. Most of the aspartic proteinases (except renin) reach their maximum activity at acidic pH. We propose that the optimum pH of each aspartic proteinase is determined by the electrostatic potential at the active site, which, in turn, is determined by the positions and orientations of all the residues near the active site. RMP is the most glycosylated among the aspartic proteinases. The carbohydrate moieties are linked to Asn79 and Asn188. Asn79 is in the middle of a beta-strand and Asn188 is on a surface loop in contrast to the previous hypothesis proposed by Brown and Yada that they are both on surface beta-turns. RMP has a very high thermal stability. The high thermal stability is probably due to the high level of glycosylation. We propose that the highly flexible carbohydrates act as heat reservoirs to stabilize the conformation of RMP and therefore give the enzyme a high level of thermal stability. Three-dimensional structural and sequence alignments of RMP with other aspartic proteinases show that RMP is most structurally homologous to that of Mucor pusillus (MPP), and differs from other fungal enzymes as much as it does from the mammalian enzymes. This suggests that RMP and MPP diverged from the main stream of aspartic proteinases at an early stage of evolution. The present study adds a second member to this subfamily of aspartic proteinases.


Germline Testing for Individuals with Pancreatic Adenocarcinoma and Novel Genetic Risk Factors.
Germline genetic variants implicated in increasing lifetime risk of pancreatic cancer (PDAC) have been identified in ∼4% to 10% of cases. Clinical features such as family history have poor sensitivity in identifying carriers of these risk variants. Genetic testing for these germline variants has potential to guide risk assessment and surveillance recommendations in high-risk individuals to promote prevention and early detection measures. Furthermore, identification of novel germline variants can offer important insights into pathogenesis that may inform precision medicine approaches. This article reviews current understanding of germline mutations associated with PDAC risk and implications of genetic testing.


Modeling evaluation of the fluid-dynamic microenvironment in tissue-engineered constructs: a micro-CT based model.
Natural cartilage remodels both in vivo and in vitro in response to mechanical stresses, hence mechanical stimulation is believed to be a potential tool to modulate extra-cellular matrix synthesis in tissue-engineered cartilage. Fluid-induced shear is known to enhance chondrogenesis in engineered cartilage constructs. The quantification of the hydrodynamic environment is a condition required to study the biochemical response to shear of 3D engineered cell systems. We developed a computational model of culture medium flow through the microstructure of a porous scaffold, during direct- perfused culture. The 3D solid model of the scaffold micro-geometry was reconstructed from 250 micro-computed tomography (micro-CT) images. The results of the fluid dynamic simulations were analyzed at the central portions of the fluid domain, to avoid boundary effects. The average, median and mode shear stress values calculated at the scaffold walls were 3.48, 2.90, and 2.45 mPa respectively, at a flow rate of 0.5 cm(3)/min, perfused through a 15 mm diameter scaffold, at an inlet fluid velocity of 53 microm/s. These results were compared to results estimated using a simplified micro-scale model and to results estimated using an analytical macro-scale porous model. The predictions given by the CT-based model are being used in conjunction with an experimental bioreactor model, in order to quantify the effects of fluid-dynamic shear on the growth modulation of tissue-engineered cartilage constructs, to potentially enhance tissue growth in vitro.


Effects of Rosmarinus officinalis L. on memory performance, anxiety, depression, and sleep quality in university students: A randomized clinical trial.
To evaluate the effects of oral rosemary on memory performance, anxiety, depression, and sleep quality in university students. In this double-blinded randomized controlled trial, the 68 participating students randomly received 500 mg rosemary and placebo twice daily for one month. Prospective and retrospective memory performance, depression, anxiety and sleep quality of the students were measured using Prospective and Retrospective Memory Questionnaire, Hospital Anxiety and Depression Scale, and Pittsburgh Sleep Quality Inventory at baseline and after one month. The scores of all the scales and subscales except the sleep latency and sleep duration components of Pittsburgh Sleep Quality Inventory were significantly decreased in the rosemary group in comparison with the control group after one month. Rosemary as a traditional herb could be used to boost prospective and retrospective memory, reduce anxiety and depression, and improve sleep quality in university students.


Microsomal activation of 1- and 3-nitrobenzo[a]pyrene to mutagens in Chinese hamster ovary cells.
1- and 3-nitrobenzo[a]pyrene (1- and 3-nitro-BaP) are environmental pollutants and are S9-mediated mutagens in the Chinese hamster ovary (CHO) cell/hypoxanthine-guanine phosphoribosyl transferase assay. In this study, we examined the pathways leading to the mutagenic activation of these compounds in CHO cells. The microsomal metabolites of 1- and 3-nitro-BaP, the 1- and 3-nitro-BaP trans-7,8-dihydroxy-7,8-dihydrodiols (trans-7,8-dihydrodiols) and the 1- and 3-nitro-BaP trans-9,10-dihydrodiols, were isolated and tested for mutagenicity. At the concentrations assayed, both trans-9,10-dihydrodiols were non-mutagenic with and without S9 activation. In contrast, the trans-7,8-dihydrodiols of 1- and 3-nitro-BaP were direct-acting mutagens and these responses were similar in magnitude to the S9-mediated mutagenicities of the parent nitro-BaPs. S9 increased the mutagenic responses of the trans-7,8-dihydrodiols approximately 20-fold. Inhibition of epoxide hydrolase decreased the S9-mediated mutagenicity of 1-nitro-BaP by half, but doubled the S9-mediated mutagenicity of 3-nitro-BaP. These results suggest that in CHO cells: (i) the major route of mutagenic activation of 1- and 3-nitro-BaP involves S9-generated derivatives of the trans-7,8-dihydrodiols, e.g. bay-region diol epoxides; (ii) reactive nitroarene oxides may contribute to mutation induction by 3-nitro-BaP; and (iii) metabolic routes involving trans-9,10-dihydrodiol formation result in detoxification.


[Significance of functional and nutritive pulmonary circulation for vital reactions in the form of embolisms].
The functional and nutritive circulation in the lungs is connected by anastomoses between the pulmonary and bronchial arteries. The anastomoses have the structure of blocked arteries from which arteriovenous anastomoses proceed to the peribronchial plexus. The pulmonary artery is provided with a flow impulse by the anastomoses, and oxygen-containing blood is admixed with the venous blood, thus forming an "aortalization" in the lungs. By diverting the bloodstream, venous blood can reach the bronchial artery. The peculiarities of the lung circulation are important for vital reactions in the form of macro- and microembolisms. Macroembolisms prove the functionality of the system if branches of the pulmonary artery are closed before the arteries are blocked. A hemorrhagic infarction either arises or does not arise, and the hemorrhagic infarction cannot exceed a certain limit. A microembolism is over and above the anastomoses. If the microembolism is greater, pressure in the arteria pulmonaris can cause blood from the pulmonary artery to overflow into the bronchial artery. Because arteriovenous anastomoses arise from the blocked arteries, microemboli can now reach the systemic circulation. Thus, the system described can explain the passage of microemboli into the systemic circulation, avoiding the capillaries of the lungs; on the other hand, larger microembolisms can prove the functionality of the system.


Implementing RFID technology in a novel triage system during a simulated mass casualty situation.
The purpose of this study is to determine the applicability of Radio Frequency Identification (RFID) technology and commercial cellular networks to provide an online triage system for handling mass casualty situations. This was tested by a using a pilot system for a simulated mass casualty situation during a military field exercise. The system proved to be usable. Compared to the currently used system, it also dramatically improves the general view of mass casualty situations and enhances medical emergency readiness in a military medical setting. The system can also be adapted without any difficulties by the civilian sector for the management of mass casualty disasters.


Judicial Commission of the International Committee on Systematics of Prokaryotes: Minutes of the Meeting on 27 July 2022.
The minutes of the online meeting of the Judicial Commission of the International Committee on Systematics of Prokaryotes that was held on 27 July 2022 per video conference are presented.


Pulsatile tinnitus cured by angioplasty and stenting of petrous carotid artery stenosis.
Pulsatile tinnitus may result from turbulent flow within the ipsilateral internal carotid artery. Surgical endarterectomy and carotid artery ligation have been used to treat atherosclerotic stenosis with or without associated pulsatile tinnitus. To our knowledge, this is the first reported case of pulsatile tinnitus, attributable to internal carotid artery stenosis, successfully treated by angioplasty and stenting.


A new ground and reference technique for invasive EEG recordings.
To demonstrate a subdermal wire electrode technique for establishing a ground (GND) and reference (REF) during long-term EEG monitoring (LTM) with intracranial electrodes. Usually, a separate GND and REF are required and this GND&REF pair can be selected contacts in the invasive electrode arrays themselves, special invasive electrodes, or standard surface disc electrodes which require frequent maintenance. We investigated the use of a pair of chronic Subdermal Wire Electrodes (SWE) for use as GND&REF. A pair of SWEs as GND&REF was tested in nine patients undergoing invasive EEG monitoring. SWE impedances were monitored in two patients and compared to disc electrode impedances. Without maintenance, SWE impedances remained low and stable during the entire recording period (up to 20 days), whereas disc electrodes showed rapid impedance increase after the first day. In all nine patients, the consistent and durable integrity of the GND&REF pair of SWE allowed for a good quality EEG recording. No local skin complications were observed. A pair of SWE electrodes provides a GND&REF system that is easy to place, maintain, and provides a high quality recording with long-term stability when coupled with referential based EEG recording system from invasive electrodes. A more efficient means of establishing a GND&REF pair during the monitoring of patients with invasive electrodes is described.


The treatment of venous thromboembolism.
Venous thromboembolism is usually treated with heparin followed by oral anticoagulants for approximately 3 months. The optimal length of heparin therapy is uncertain. There is now good evidence that treatment failures are associated with inadequate heparin effects. Heparin can be administered with similar safety and effectiveness by either intravenous infusion or 2 hourly subcutaneous injection. Oral anticoagulant therapy is effective and safe if given in a dose which prolongs the prothrombin time to an international normalized ratio of 2.0 to 2.5. Thrombolytic therapy is indicated in patients with major pulmonary embolism and in selected patients with recent acute venous thrombosis. Vena caval interruption is usually confined to patients who have contraindications to anticoagulant therapy. Surgical removal of thromboembolic obstruction should be considered in selected patients with thromboembolic pulmonary hypertension.


Toward Return to Duty Decision-Making After Military Mild Traumatic Brain Injury: Preliminary Validation of the Charge of Quarters Duty Test.
Determining duty-readiness after mild traumatic brain injury (mTBI) remains a priority of the United States Department of Defense as warfighters in both deployed and non-deployed settings continue to sustain these injuries in relatively large numbers. Warfighters with mTBI may experience unresolved sensorimotor, emotional, cognitive sequelae including problems with executive functions, a category of higher order cognitive processes that enable people to regulate goal-directed behavior. Persistent mTBI sequelae interfere with warfighters' proficiency in performing military duties and signal the need for graded return to activity and possibly rehabilitative services. Although significant strides have been carried out in recent years to enhance the identification and management of mTBI in garrison (EXORD 165-13) and deployed settings (EXORD 242-11; DoDI 6,490.11), the Department of Defense still lacks reliable, valid, and clinically feasible functional assessments to help inform duty-readiness decisions. Traditional functional assessments lack face validity for warfighters and may have ceiling effects, especially as related to executive functions. Performance-based multitasking assessments have been shown to be sensitive to executive dysfunction after acquired brain injury but no multitasking assessments have been validated in adults with mTBI. Existing multitasking assessments are not ecologically valid relative to military contexts. A multidisciplinary military-civilian team of researchers developed and evaluated a performance-based assessment called the Assessment of Military Multitasking Performance. One of the Assessment of Military Multitasking Performance multitasks, the Charge of Quarters Duty Test (CQDT), was designed to challenge the divided attention, foresight, and planning dimensions of executive functions. Here, we report on the preliminary validation results of the CQDT. The team conducted a measurement development study at Fort Bragg, NC, enrolling 83 service members (33 with mTBI and 50 healthy controls). Discriminant validity was evaluated by comparing differences in CQDT sub-scores of warfighters with mTBI and healthy controls. Associations between CQDT sub-scores and neurocognitive measures known to be sensitive to mTBI were examined to explore convergent validity. The study was approved by the Womack Army Medical Center Institutional Review Board (Fort Bragg). There were significant between-group differences in two of the four CQDT sub-scores (number of visits, p = 0.012; and performance accuracy, p = 0.020). Correlations between the CQDT sub-scores and some neurocognitive measures were statistically significant but weak, ranging from 0.287 (CQDT performance accuracy and NAB Numbers and Letters, Part D) to -0.421 (CQDT total number of visits and Automated Neuropsychological Assessment Metrics Tower Task). There were group differences in terms of participants' reading level, education, years in military, and stress symptoms; some of these characteristics may have influenced CQDT performance. The CQDT demonstrated initial evidence of discriminant validity. Further study is warranted to more formally evaluate convergent/divergent validity and ultimately how and whether this performance-based multitasking measure can inform readiness to return to duty after mTBI.


Comparing patient-centered outcomes and efficiency of space closure between nickel-titanium closed-coil springs and elastomeric power chains during orthodontic treatment.
To compare patient-reported pain, discomfort, and difficulty in maintaining proper brushing between nickel-titanium closed-coil springs (CS) and elastomeric power chains (PC) when used for space closure. The secondary aims were to compare plaque control and efficiency of space closure between these two force delivery systems. A total of 48 patients who required extractions of upper first premolars and distal movement of upper canines had the CS randomly allocated to either the right or left side. Blinding was applied at data collection and analysis. Primary outcomes were pain intensity measured on visual analog scale, pain onset and duration, discomfort, and difficulty in maintaining proper brushing from the start of canine retraction at baseline and at 6 and 12 weeks thereafter. Secondary outcomes were plaque scores and the rate of space closure. No significant differences in mean pain scores, pain onset, and duration at different time intervals between CS and PC were observed. The CS side was significantly less comfortable than the PC (P < .0001) and more difficult to keep clean (P = .008). No significant differences in plaque scores were observed between CS and PC groups at any time interval. CS produced a faster rate of space closure than did PC (P = .008). CS were less tolerated than PC by patients but produced an average of 0.5 mm more movement than did the PC during the 12-week study period.


Modulating ICT emission: a new strategy to manipulate the CPL sign in chiral emitters.
A new strategy to manipulate the circularly polarized luminescence (CPL) handedness in chiral emitters, based on modulating the population of an emissive ICT state, is proposed. Such a strategy is particularly interesting for conformationally rigid and non-aggregating chiral organic emitters, opening up new perspectives for the development of CPL applications based on organic molecules.


[Biomarkers of Metabolism and Iron Nutrition].
Iron deficiency anemia is the most common nutritional deficiency worldwide, and the most susceptible groups are infants, preschoolers, women of childbearing age, and pregnant women. It is therefore essential to understand the mechanisms of regulation of iron uptake, transport, and absorption at the cellular level, particularly in enterocytes, and to identify blood biomarkers that allow the evaluation of iron status. This review describes how iron absorption is regulated by intestinal epithelial cells, the main proteins involved (iron transporters, oxidoreductases, storage proteins), and the main blood biomarkers of iron metabolism.


Revision of the Neotropical water scavenger beetle genus Globulosis García, 2001 (Coleoptera: Hydrophilidae: Acidocerinae).
The Neotropical water scavenger beetle genus Globulosis García, 2001 is revised. Originally described from a single male specimen from southeastern Venezuela, the genus has since been found in localities across the Guiana Shield region and beyond, including Colombia, Suriname, Guyana, and Brazil. The genus is redescribed. Morphological characters and genetic data from the mitochondrial gene COI from ten populations across its range provide support for two distinct species, corresponding loosely to geography. The type species, G. hemisphericus García, is redescribed and newly recorded from Guyana, Suriname, and Brazil (Amazonas, Para). One new species is described, Globulosis flavus sp. n. from southwestern Venezuela (Amazonas, Bolivar). The genus is associated with lotic habitats, and typically found along the margins of small to medium sized streams. High-resolution habitus and aedeagal images and distribution maps for all species are provided.


Endocrine aspects of early pregnancy in pony mares: a comparison of uterine luminal and peripheral plasma levels of steroids during the estrous cycle and early pregnancy.
Comparisons of estrone, 17 beta-estradiol, and plasma progestin concentrations were made in uterine fluid and peripheral blood of nonpregnant and pregnant pony mares. Concentrations of these steroids were also measured within yolk sac fluid from blastocysts on days 12, 14, 16, and 18 of pregnancy to obtain more complete analyses of the uterine environment (uterine fluid plus yolk sac fluid) of early pregnancy. Thirty mares were randomly assigned to six treatment groups (n = 5/group), and uterine fluid and peripheral blood samples were obtained on days 8, 12, 14, 16, 18, and 20 postovulation. After a recovery period of one estrous cycle, mares were bred at their next estrus. Animals were hysterectomized on the same treatment day to which they had previously been assigned in the nonpregnant phase of this study. Using this design, uterine fluid and peripheral blood samples were collected from each mare on equivalent days of the estrous cycle and pregnancy. Significant differences in day trends were found between nonpregnant and pregnant animals for estrogens and progestins in both uterine fluid and peripheral plasma. Furthermore, these data demonstrate that large increases in estrogens occur after day 12 of pregnancy in uterine and yolk sac fluids, with estrone becoming the predominant estrogen by days 18 and 20 in yolk sac and uterine fluids, respectively. These changes were not detected in peripheral plasma, which indicates that changes occurring within the uterine environment are not discernible in the systemic circulation during early pregnancy. These results indicate that the large amounts of estrogens appearing in uterine fluids during early pregnancy are of conceptus origin and may be an important factor in regulating the environment in which the conceptus develops.


Pulmonary cryptococcosis: CT and pathologic findings.
The purpose of this work was to describe the CT and pathologic findings of pulmonary cryptococcosis. CT scans of 11 patients (7 immunocompromised, 4 immunocompetent) with proven pulmonary cryptococcosis were analyzed for number, morphologic characteristics, and distribution of parenchymal abnormalities as well for presence of lymphadenopathy and pleural effusion. Pathology of lung specimens obtained by open biopsy or resection (n = 5) and transbronchial biopsy (n = 1) was reviewed by one dedicated pulmonary pathologist. Pulmonary nodules, either solitary or multiple, were the most common CT finding, present in 10 of 11 patients (91%); associated findings included masses (n = 4), CT halo sign (n = 3), and consolidation (n = 2). On histologic examination, focal areas of ground-glass attenuation surrounding or adjacent to nodules were found to represent airspace collections of macrophages and proteinaceous fluid. Pulmonary cryptococcosis should be considered in the differential diagnosis of solitary or multiple pulmonary nodules (with or without associated CT halo sign), particularly in immunocompromised patients.


Effect of group means on the probability of consensus.
In this study, groups who could not reach a consensus were investigated using the group polarization paradigm. The purpose was to explore the conditions leading to intragroup disagreement and attitude change following disagreement among 269 participants. Analysis indicated that the probability of consensus was low when the group means differed from the grand mean of the entire sample. When small differences among group members were found, depolarization (reverse direction of polarization) followed disagreement. These results suggested the groups which deviated most from the population tendency were the most likely to cause within-group disagreement, while within-group variances determined the direction of attitude change following disagreement within the group.


GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy.
Obesity is recognized as a major healthcare challenge. Following years of slow progress in discovery of safe, effective therapies for weight management, recent approval of the glucagon-like peptide 1 receptor (GLP-1R) mimetics, liraglutide and semaglutide, for obesity has generated considerable excitement. It is anticipated these agents will pave the way for application of tirzepatide, a highly effective glucose-dependent insulinotropic polypeptide receptor (GIPR), GLP-1R co-agonist, recently approved for management of type 2 diabetes mellitus. Following promising weight loss in obese individuals in Phase III clinical trials, liraglutide and semaglutide were approved for weight management without diabetes. Tirzepatide has attained Fast Track designation for obesity management by the US Food and Drug Association. This narrative review summarizes experimental, preclinical, and clinical data for these agents and related GLP-1R/GIPR co-agonists, prioritizing clinical research published within the last 10 years where possible. GLP-1R mimetics are often discontinued within 24 months meaning long-term application of these agents in obesity is questioned. Combined GIPR/GLP-1R agonism appears to induce fewer side effects, indicating GLP-1R/GIPR co-agonists may be more suitable for enduring obesity management. After years of debate, this GIPR-biased GLP-1R/GIPR co-agonist highlights the therapeutic promise of including GIPR modulation for diabetes and obesity therapy.


[Research progress of self-assembled beads drug delivery system prepared from cyclodextrins and oils].
Recently, increasing attention has been paid to beads, an innovative self-assembled drug delivery system prepared from cyclodextrins and oils. Beads are new core-shell minispheres containing poorly water-soluble drugs or lipophilic drugs dissolved in the lipid core without the use of organic solvents and surfactants. Therefore, beads with high drug loading and improved oral bioavailability have great potential for oral delivery of poorly water-soluble drugs and lipophilic drugs. The preparation mechanisms, formulations and methods, the in vitro and in vivo properties of beads were reviewed in order to provide the theoretical basis for further application of beads.


Association of ferritin with prostate cancer.
Prostate specific antigen (PSA) has been widely used as the unique serum biomarker for the diagnosis and/ or pre-diagnosis of prostate cancer (PCa). However, the diagnostic value of PSA is a subject of ongoing debate owing to its lack of specificity, especially when the PSA level is moderately increased (e.g., 4-10 ng/ml). Thus, we suggest the need for identification of a new biomarker to discriminate PCa cases from benign prostatic hyperplasia (BPH) and normal controls (N). Urine or tissue samples of PCa patients, BPH patients, and normal controls were systematically collected. The expression of ferritin light chain (FTL) and ferritin heavy chain (FTH) was verified by immunohistochemistry in the tissue. The concentration of urinary ferritin was measured by Access Immunoassay. The level of creatinine in the urine was detected on a HITACHI 7080 system to calculate the ferritin-creatinine ratio (FCR). The data were statistically analyzed using the rank sum test. Immunohistochemical characterization of tissues in patients with PCa and BPH was conducted. We found representative immunohistochemical expression of FTL and FTH, with strong staining intensity in PCa and weak staining intensity in BPH. Furthermore, there were differences in urinary FCR among the three groups, with significant differences in the PCa group (134.46±47.01) compared to both the BPH (24.18±3.17, p = 0.009) and control (6.42±0.82, p = 0.003) groups. In contrast, there was no significant difference between the BPH and N groups (p = 0.649). Ferritin is a potential urinary biomarker to discriminate between PCa and BPH patients.


Alcohol consumption and sickness absence: evidence from microdata.
Aggregate time-series evidence has shown that overall per capita alcohol consumption is associated with sickness absence. This study re-examines the relationship between alcohol consumption and sickness absence by using individual-level microdata and methods that yield results which are less likely to be due to spurious correlations. Data on sickness absence and alcohol consumption for 18 Finnish regions over the period 1993-2005 was used. Sickness absence was measured as the number of sickness absence days during 1 year. Alcohol consumption was measured as the number of alcohol drinks consumed per week. The individual-level relationship between alcohol consumption and sickness absence was estimated by using Poisson regression models. Unobserved determinants of lifestyle behaviours associated with the region and survey year were controlled for. Personal characteristics as well as the clustering of observations by regions were also taken into account. The estimates show that alcohol consumption is associated with sickness absence. The positive relationship between alcohol consumption and sickness absence is particularly pronounced for low-educated males. Aggregate time-series evidence for the relationship between alcohol consumption and sickness absence is confirmed by using individual-level microdata. The policy lesson is that it is important to take into account the effects of alcohol consumption on the prevalence of sickness absence (i.e. labour supply on an intensive margin) when one is considering the level of taxation of alcoholic beverages.


Sunlight Exposure, Work Hours, Caffeine Consumption, and Sleep Duration in the Naval Environment.
Sailors in the U.S. Navy are habitual shiftworkers, often experiencing circadian misalignment due to their irregular work/rest schedules. This study assessed the effect of sunlight exposure, work hours, and caffeinated beverage consumption on the daily sleep duration of crewmembers of a U.S. Navy ship during a 2-wk underway period. Working in an artificially lit area with no access to sunlight during work hours, U.S. Navy crew members (N = 91) used daily logs to report their daily activity, caffeinated beverage consumption, and exposure to sunlight while off-duty; sleep was assessed by wrist-worn actigraphy. Hours of sunlight exposure, work duration, and the amount of coffee/tea/soft drinks were statistically significant predictors of sleep duration. On average, crewmembers who reported more than one half-hour of sunlight each day slept on average ∼40 min (10%) less than their peers working the same shifts who received less than one half-hour of sunlight (on average 6.05 ± 0.90 h vs. 6.71 ± 0.91 h, respectively). Exposure to sunlight, work hours, and consumption of caffeinated beverages are important factors when planning watchstanding schedules at sea. Even though further research is needed, our results suggest that even brief exposure to sunlight may contribute to circadian misalignment that negatively affects sleep in the operational environment. Educating crewmembers about sleep hygiene, especially the important roles played by sunlight and caffeine, could potentially improve the sleep and fatigue levels of this population of maritime shiftworkers.Shattuck NL, Matsangas P. Sunlight exposure, work hours, caffeine consumption, and sleep duration in the naval environment. Aerosp Med Hum Perform. 2017; 88(6):579-585.


Using Machine Learning to Aid the Interpretation of Urine Steroid Profiles.
Urine steroid profiles are used in clinical practice for the diagnosis and monitoring of disorders of steroidogenesis and adrenal pathologies. Machine learning (ML) algorithms are powerful computational tools used extensively for the recognition of patterns in large data sets. Here, we investigated the utility of various ML algorithms for the automated biochemical interpretation of urine steroid profiles to support current clinical practices. Data from 4619 urine steroid profiles processed between June 2012 and October 2016 were retrospectively collected. Of these, 1314 profiles were used to train and test various ML classifiers' abilities to differentiate between "No significant abnormality" and "?Abnormal" profiles. Further classifiers were trained and tested for their ability to predict the specific biochemical interpretation of the profiles. The best performing binary classifier could predict the interpretation of No significant abnormality and ?Abnormal profiles with a mean area under the ROC curve of 0.955 (95% CI, 0.949-0.961). In addition, the best performing multiclass classifier could predict the individual abnormal profile interpretation with a mean balanced accuracy of 0.873 (0.865-0.880). Here we have described the application of ML algorithms to the automated interpretation of urine steroid profiles. This provides a proof-of-concept application of ML algorithms to complex clinical laboratory data that has the potential to improve laboratory efficiency in a setting of limited staff resources.


Synthesis and some first-row transition-metal complexes of the 1,2,4-triazole-based Bis(terdentate) ligands TsPMAT and PMAT.
The employment of a strategy based on nucleophilic substitution, rather than Schiff base condensation, for the preparation of 1,2,4-triazole-based ligands has been investigated and has led to the synthesis of two new ligands, 4-amino-3,5-bis{[N-(2-pyridylmethyl)-N-(4-toluenesulfonyl)amino]methyl}-4H-1,2,4-triazole (TsPMAT, 14) and 4-amino-3,5-bis{[(2-pyridylmethyl)amino]methyl}-4H-1,2,4-triazole (PMAT, 15). These are the first examples of bis(terdentate) ligands incorporating the 1,2,4-triazole unit. TsPMAT (14) forms a dinuclear 2:2 complex with Co(BF4)2.6 H2O even when reacted in a metal-to-ligand molar ratio of 2:1. Similarly, the reaction of PMAT (15) with Mn(ClO4)2.6H2O or M(BF4)2.6 H2O (M=Fe, Co, Ni, Zn) in a ligand-to-metal molar ratio of 1:1 has afforded a series of complexes with the general formula [M(II) (2)(PMAT)2]X4. The metal centres in these complexes of TsPMAT (14) and PMAT (15) are encapsulated by two ligand molecules and doubly bridged by the N2 units of the 1,2,4-triazole moieties, which gives rise to N6 coordination spheres that are strongly distorted from octahedral, as evidenced by the X-ray crystal structure analyses of [Co(II) (2)(TsPMAT)(2)](BF(4))(4)6 MeCN (246 MeCN) and [Fe(II) 2(PMAT)2](BF4)4DMF (27DMF). Studies of the magnetic properties of [Co(II) 2(TsPMAT)2](BF4)4.4 H2O (244 H2O), [Mn(II) 2(PMAT)2](ClO4)4 (26), and [Co(II) 2(PMAT)2](BF4)4 (28) have revealed weak antiferromagnetic coupling (J=-3.3, -0.16, and -2.4 cm(-1), respectively) between the two metal centres in these complexes.


Ectoparasites of small ruminants in three selected agro-ecological sites of Tigray Region, Ethiopia.
A study on ectoparasites of small ruminants in three selected agro-ecological sites of Tigray Region, Ethiopia disclosed an overall prevalence of 55.5% and 58% in each examined 750 sheep and goats, respectively. In the sheep population, Melophagus ovinus (19.1%), tick infestations (16%), Damalinia ovis (15.3%), Linognathus africanus (11.5%), and Ctenocephalides felis (9%) were the major ectoparasites. The major ectoparasites identified in goats were tick infestations (29.7%), L. africanus (27.9%), Sarcoptes scabiei var. caprae (12.5%), C. felis (11.1%), and Demodex caprae (6.8%). In sheep, there was a statistically significant difference (P < 0.001) in the prevalence of Damalinia ovis, M. ovinus, L. africanus, and ticks between midland and highland. In goats, the risk of Sarcoptes scabiei var. caprae infestation in midland (odds ratio (OR) = 17.2, P < 0.001) and lowland (OR = 5.2, P < 0.001) was 17.2 times and 5.2 times, respectively, higher than the highland. Favorable climatic conditions, backward level of management, poor level of consciousness and awareness of farmers, and weak animal health extension services are believed to have contributed for widespread distribution and occurrences of ectoparasites. The growing threat of ectoparasites to small ruminant production and the tanning industry needs well-coordinated and urgent control intervention.


Importance of Process Parameters Influencing the Mean Diameters of siRNA-Containing Lipid Nanoparticles (LNPs) on the in Vitro Activity of Prepared LNPs.
Genetic drugs have the potential to treat a variety of diseases. Recently, lipid nanoparticles (LNPs) have attracted much attention among drug delivery systems for genetic drugs. LNPs have been practically used in small interfering RNA (siRNA) drugs and mRNA vaccines. Although LNPs are generally prepared by mixing nucleic acids in acidic aqueous buffer and lipid excipients in alcohol (i.e., ethanol), it is not well understood which process parameters in the LNPs formation affect the physicochemical properties and the functionality of LNPs. In this study, we used siRNA-containing LNPs as a model, and evaluated the effect that aqueous solution parameters (buffering agent type, salt concentration, and pH) and mixing parameters (ratio, speed, and temperature) exert on the physicochemical properties and in vitro gene-knockdown activity of LNPs. Among such parameters, the type of buffering agent, salt concentration (ionic strength), pH in acidic aqueous buffer, as well as the mixing ratio and speed significantly affected the mean particle diameter and in vitro gene-knockdown activity of LNPs. A strong correlation between the mean particle diameters and their in vitro gene-knockdown activities was observed. These observations suggest that the process parameters influencing the mean LNPs diameter are likely to be important in the formation of LNPs and also that these correlate with in vitro gene-knockdown activity. Because LNP systems are being further developed for future clinical applications of genetic drugs, information regarding the LNPs manufacturing process is of utmost importance. The results observed in this study will be useful for the manufacturing of optimal LNPs.


A critical analysis of walking policy in Ireland and its contribution to both national and international development goals.
Increasing population levels of walking holds benefits for public and planetary health. While individual level interventions to promote walking have been shown to be efficacious, upstream interventions such as policies harness the greatest potential for impact at the population level. However, little is known about the nature and presence of walking policy in Ireland and the extent to which it aligns to national and global goals. This paper aims to provide an overview of local and national walking policy in Ireland and to understand the potential of Irish walking policy to contribute to national and global targets. This study used multiple methods to provide a critical overview of walking policy. Firstly, a six-phase process was employed to conduct a content analysis of local and national walking policy in Ireland. Secondly, conceptual linkage exercises were conducted to assess the contribution of walking, and national walking policy in Ireland, to Ireland's National Strategic Outcomes and the United Nations Sustainable Development Goals. Overall, half (n = 13) of the counties in the Republic of Ireland were found to have no local level walking policies. Results from the content analysis suggest that counties which had walking specific local level policies (n = 2) were outdated by almost two decades. Walking was identified to hold the potential to contribute to over half (n = 6) of Ireland's National Strategic Outcomes, and over half (n = 7) of the United Nations Sustainable Development Goals. Ireland's only national level walking specific policy, the Get Ireland Walking Strategy and Action Plan 2017-2020, was identified to potentially contribute to four of Ireland's National Strategic Outcomes and three United Nations Sustainable Development Goals. Multidisciplinary action is required to update walking-related policy with embedded evaluation and governance mechanisms in all local walking systems. Furthermore, given sufficient collaboration across sectors, walking policy in Ireland has the potential to contribute to a wider breadth of national and global targets beyond the health, sport, tourism, and transport sectors.


Characterization of Maize miRNAs in Response to Synergistic Infection of Maize Chlorotic Mottle Virus and Sugarcane Mosaic Virus.
The synergistic infection of maize chlorotic mottle virus (MCMV) and sugarcane mosaic virus (SCMV) causes maize lethal necrosis, with considerable losses to global maize production. microRNAs (miRNAs) are conserved non-coding small RNAs that play essential regulatory roles in plant development and environmental stress responses, including virus infection. However, the characterization of maize miRNAs in response to synergistic infection of MCMV and SCMV remains largely unknown. In this study, the profiles of small RNAs from MCMV and SCMV single- and co-infected (S + M) maize plants were obtained by high-throughput sequencing. A total of 173 known miRNAs, belonging to 26 miRNA families, and 49 novel miRNAs were profiled. The expression patterns of most miRNAs in S + M-infected maize plants were similar to that in SCMV-infected maize plants, probably due to the existence of RNA silencing suppressor HC-Pro. Northern blotting and quantitative real-time PCR were performed to validate the accumulation of miRNAs and their targets in different experimental treatments, respectively. The down-regulation of miR159, miR393, and miR394 might be involved in antiviral defense to synergistic infection. These results provide novel insights into the regulatory networks of miRNAs in maize plants in response to the synergistic infection of MCMV and SCMV.


Predicting toxicities of reactive metabolite-positive drug candidates.
Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) are thought to be responsible for the pathogenesis of some IADRs, the potential for RM formation within new chemical entities is routinely examined with the ultimate goal of eliminating or reducing the liability through iterative design. Likewise, avoidance of structural alerts is almost a standard practice in drug design. However, the perceived safety concerns associated with the use of structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be overexaggerated. Numerous marketed drugs form RMs but do not cause idiosyncratic toxicity. In this review article, we present a critique of the structural alert/RM concept as applied in drug discovery and evaluate the evidence linking structural alerts and RMs to observed toxic effects. Pragmatic risk mitigation strategies to aid the advancement of drug candidates that carry a RM liability are also discussed.


Design and activity of novel lactoferrampin analogues against O157:H7 enterohemorrhagic Escherichia coli.
Lactoferrampin 265-284 (LFampin 265-284) is a peptide consisting of residues 265-284 of N1-domain of bovine Lactoferrin (LF). This peptide has several cationic groups in the C-terminal lobe, exhibiting an antibacterial activity against a wide range of microorganisms. However, LFampin 265-284 exhibits low antimicrobial activity against the O157:H7 enterohaemorrhagic Escherichia coli (EHEC O157:H7) when compared with Lactoferrin chimera and Lactoferricin. Here, we have designed three analogues of LFampin 265-284 based on the distribution of cationic groups, hydrophobicity, size, and sequence. Analogues were synthesized by solid phase chemistry using Fmoc methodology obtaining peptides with 95% purity. All peptides maintain the ability to adopt helical conformations (checked by circular dichroism spectra and molecular simulations). Some of these analogues exhibited a significant increase in antimicrobial activity by counting colony forming units against EHEC O157:H7 compared to native LFampin 265-284, with MIC of 10 and 40 µM for 264G-D265K and 264G-D265K/S272R, respectively. The incorporation of a GKLI sequence in the N-terminal lobe increased dramatically its antibacterial activity, an effect which has been attributed to the addition of cationic groups in the N-terminal side that may stabilize the helical conformation of the new designed peptides.


Clinical and metabolic response to flaxseed oil omega-3 fatty acids supplementation in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial.
Data on the effects of flaxseed oil omega-3 fatty acids supplementation on wound healing and metabolic status in subjects with diabetic foot ulcer (DFU) are scarce. This study was conducted to evaluate the effects of flaxseed oil omega-3 fatty acids supplementation on wound healing and metabolic status in subjects with DFU. The current randomized, double-blind, placebo-controlled trial was conducted among 60 subjects (aged 40-85years old) with grade 3 DFU. Subjects were randomly allocated into two groups (30 subjects each group) to receive either 1000mg omega-3 fatty acids from flaxseed oil supplements or placebo twice a day for 12weeks. After the 12-week intervention, compared with the placebo, omega-3 fatty acids supplementation resulted in significant decreases in ulcer length (-2.0±2.3 vs. -1.0±1.1cm, P=0.03), width (-1.8±1.7 vs. -1.0±1.0cm, P=0.02) and depth (-0.8±0.6 vs. -0.5±0.5cm, P=0.01). Additionally, significant reductions in serum insulin concentrations (-4.4±5.5 vs. +1.4±8.3 μIU/mL, P=0.002), homeostasis model of assessment-estimated insulin resistance (-2.1±3.0 vs. +1.0±5.0, P=0.005) and HbA1c (-0.9±1.5 vs. -0.1±0.4%, P=0.01), and a significant rise in the quantitative insulin sensitivity check index (+0.01±0.01 vs. -0.005±0.02, P=0.002) were seen following supplementation with omega-3 fatty acids compared with the placebo. In addition, omega-3 fatty acids supplementation significantly decreased serum high sensitivity C-reactive protein (hs-CRP) (-25.5±31.5 vs. -8.2±18.9μg/mL, P=0.01), and significantly increased plasma total antioxidant capacity (TAC) (+83.5±111.7 vs. -73.4±195.5mmol/L, P<0.001) and glutathione (GSH) concentrations (+60.7±140.2 vs. -15.5±129.7μmol/L, P=0.03) compared with the placebo. Overall, omega-3 fatty acids supplementation for 12weeks among subjects with DFU had beneficial effects on parameters of ulcer size, markers of insulin metabolism, serum hs-CRP, plasma TAC and GSH levels. In addition, flaxseed oil omega-3 fatty acids may have played an indirect role in wound healing due to its effects on improved metabolic profiles.


Noncholesteatomatous Cyst of the Tympanic Membrane: A Nonpublished Entity?
Introduction. The presence of a serous cyst in the tympanic membrane implies the description of a new or unpublished entity based on our knowledge whose origin may be very unlikely explained on actual embryologic and anatomic background. Clinical Case. We present a case of a 45-year-old woman with progressing right hearing loss. Physical examination revealed a whitish, round-shaped malformation in the posterior-inferior quadrant of the right tympanic membrane. The cyst was removed with a transcanal tympanoplasty. Discussion. A thorough PubMed search that involved the terms tympanic membrane gland, epithelial inclusion cysts, mucous-secreting cyst, and tympanic cyst has shown no positive results. The first description of an unknown entity, such as a tympanic membrane serous cyst, may be the key for clinicians to start paying attention to patients who suffer from similar pathologies and may pass unnoticed because of their rarity or peculiarity.


Does Diversity of Authorship Matter? An Analysis of Plastic Surgery's Top 100 Articles.
Diversity, whether related to age, gender, ethnicity, race, geography, or experience, is increasing in all realms of medicine, including plastic surgery. Research has also become more diverse in those who conduct studies and those who participate in them. Fittingly, surgeons who produce prominent research are likely to come from diverse backgrounds. This study was designed to analyze the diversity of authorship in peer-reviewed plastic surgery journals. Using the Web of Science database, the authors identified the 100 most-cited articles from the highest-impact plastic surgery journals from January 2010 to December 2020. Author, institutional, and topic information was collected. There was an average of 5.6 authors on the top 100 articles, of which 96.1% involved collaboration and 75.7% mixed-gender authorship. The average number of affiliations was 2.1, of which 51.5% involved cross-institutional collaboration, 12.6% came from both domestic and international institutions, 30.1% involved multiple specialties, and 10.7% came from both academia and private practice. Having both domestic and international authors was found to be most predictive of more citations on multiple regression, with year as a nonconfounding variable (P < 0.05), followed by mixed-gender authorship (P < 0.10). Impactful publications in plastic surgery come from diverse sets of authors and institutions.


Solvent effects on optical properties of molecules: a combined time-dependent density functional theory/effective fragment potential approach.
A quantum mechanics/molecular mechanics (QM/MM) type of scheme is employed to calculate the solvent-induced shifts of molecular electronic excitations. The effective fragment potential (EFP) method was used for the classical potential. Since EFP has a density dependent functional form, in contrast with most other MM potentials, time-dependent density functional theory (TDDFT) has been modified to combine TDDFT with EFP. This new method is then used to perform a hybrid QM/MM molecular dynamics simulation to generate a simulated spectrum of the n-->pi(*) vertical excitation energy of acetone in vacuum and with 100 water molecules. The calculated water solvent effect on the vertical excitation energy exhibits a blueshift of the n-->pi(*) vertical excitation energy in acetone (Delta omega(1)=0.211 eV), which is in good agreement with the experimental blueshift.


Predictive value of National Early Warning Score 2 (NEWS2) for intensive care unit admission in patients with SARS-CoV-2 infection.
Background: From January 2020, Coronavirus disease 19 (COVID-19) has rapidly spread all over the world. An early assessment of illness severity is important for the stratification of patients. We analysed the predictive value of National Early Warning Score 2 (NEWS2) for intensive care unit admission (ICU) in patients with Severe Acute Respiratory Syndrome- Coronavirus-2 (SARS-CoV-2) infection.Methods: Data of 71 patients with SARS-CoV-2 admitted from 1 March to 20 April 2020, to the Clinic of Infectious Diseases of Perugia Hospital, Italy, were retrospectively reviewed. NEWS2 at hospital admission, demographic, comorbidity and clinical data were collected. Univariate and multivariate analyses were performed to establish the correlation between each variable and ICU admission.Results: Among 68 patients included in the analysis, 27 were admitted to ICU. NEWS2 at hospital admission was a good predictor of ICU admission as shown by an area under the receiver-operating characteristic curve analysis of 0.90 (standard error 0.04; 95% confidence interval 0.82-0.97). In multivariate logistic regression analysis, NEWS2 was significantly related to ICU admission using thresholds of 5 and 7. No other clinical variables included in the model were significantly correlated with ICU admission.A NEWS2 threshold of 5 had higher sensitivity than a threshold of 7 (89% and 63%). Higher specificity, positive likelihood ratio and positive predictive value were found using a threshold of 7 than a threshold of 5.Conclusions: NEWS2 at hospital admission was a good predictor for ICU admission. Patients with severe COVID-19 were correctly and rapidly stratified.