Climate and pH predict the potential range of the invasive apple snail (Pomacea insularum) in the southeastern United States.
Predicting the potential range of invasive species is essential for risk assessment, monitoring, and management, and it can also inform us about a species' overall potential invasiveness. However, modeling the distribution of invasive species that have not reached their equilibrium distribution can be problematic for many predictive approaches. We apply the modeling approach of maximum entropy (MaxEnt) that is effective with incomplete, presence-only datasets to predict the distribution of the invasive island apple snail, Pomacea insularum. This freshwater snail is native to South America and has been spreading in the USA over the last decade from its initial introductions in Texas and Florida. It has now been documented throughout eight southeastern states. The snail's extensive consumption of aquatic vegetation and ability to accumulate and transmit algal toxins through the food web heighten concerns about its spread. Our model shows that under current climate conditions the snail should remain mostly confined to the coastal plain of the southeastern USA where it is limited by minimum temperature in the coldest month and precipitation in the warmest quarter. Furthermore, low pH waters (pH <5.5) are detrimental to the snail's survival and persistence. Of particular note are low-pH blackwater swamps, especially Okefenokee Swamp in southern Georgia (with a pH below 4 in many areas), which are predicted to preclude the snail's establishment even though many of these areas are well matched climatically. Our results elucidate the factors that affect the regional distribution of P. insularum, while simultaneously presenting a spatial basis for the prediction of its future spread. Furthermore, the model for this species exemplifies that combining climatic and habitat variables is a powerful way to model distributions of invasive species.


Child and adolescent conduct disorder substantially shares genetic influences with three socioemotional dispositions.
In a representative sample of twin children and adolescents, we tested the hypothesis that a substantial proportion of the genetic and environmental influences underlying conduct disorder (CD) are shared with three socioemotional dispositions: Prosociality, Negative Emotionality, and Daring. Caretaker ratings of each dispositional dimension were uniquely associated with a latent CD dimension that included both caretaker- and youth-reports of CD as indicators. Behavior genetic analyses indicated that moderate-to-high additive genetic and moderate nonshared environmental influences underlie all three dispositions and CD, with modest shared environmental influences on Prosociality. Forty percent of the additive genetic influences and all of the nonshared environmental influences on the latent CD dimension were shared in common with the three socioemotional dispositions. The finding that CD shares a substantial proportion of its genetic influences with three distinct socioemotional dispositions suggests new perspectives on the heterogeneous etiology of CD and new approaches to exploring its specific etiological mechanisms.


Reversibly acetylated lysine residues play important roles in the enzymatic activity of Escherichia coli N-hydroxyarylamine O-acetyltransferase.
CobB is a bacterial NAD(+)-dependent protein deacetylase. Although progress has been made in functional studies of this protein in recent years, its substrates and biological functions are still largely unclear. Using proteome microarray technology, potential substrates of Escherichia coli CobB were screened and nine proteins were identified, including N-hydroxyarylamine O-acetyltransferase (NhoA). In vitro acetylation/deacetylation of NhoA was verified by western blotting and mass spectrometry, and two acetylated lysine residues were identified. Site-specific mutagenesis experiments showed that mutation of each acetylated lysine decreased the acetylation level of NhoA in vitro. Further analysis showed that variant NhoA proteins carrying substitutions at the two acetylated lysine residues are involved in both the O-acetyltransferase and N-acetyltransferase activity of NhoA. Structural analyses were also performed to explore the effects of the acetylated lysine residues on the activity of NhoA. These results suggest that reversible acetylation may play a role in the activity of Escherichia coli NhoA.


Nutritional Assessment of Pre-School Children in Rural Villages of the Family Dynamics, Lifestyles and Nutrition Study (1997-2001) II. Prevalence of Undernutrition and Relationship to Household Socio-Economic Indicators.
This paper describes the nutritional status of pre-school children and analyzes its relationship to various household socio-economic indicators. Padi, rubber and fishing villages from the Functional Groups Study (1992-1996) were selected for having a high prevalence of child undernutrition, and all children between the ages of 12 and 72 months were measured for their weights and heights in April-May 1998. The NCHS reference values were used to calculate z-scores, which were categorised according to WHO (1983) recommendations. Children between minus 2SD and minus 1SD of reference median were classified as mildly malnourished. Prevalence of underweight was higher (30.5%) than stunting (22.3%), while wasting was only 9.7%. Padi villages had the highest prevalence of undernutrition, followed by fishing, and then rubber villages. Mean household incomes were found to be significantly lower for children with worse nutritional status, and undernutrition was higher in households below the poverty line income. The odds ratios for having stunted children were significantly higher for households whose heads were agricultural own-account workers (OR 3.66, 95% CI = 1.37-9.79), agricultural waged workers (OR 2.75, 95% CI = 1.06-7.10), and non-agricultural manual workers (OR 2.49, 95% CI = 1.04-6.00) compared to non-manual workers. Various household socio-economic indicators showed significantly higher odds ratios for underweight, stunting and wasting. After adjusting for confounding effects by logistic regression analysis, however, only mother's education was found to be a significant predictor for stunting, while poverty level and access to piped water supply were significant predictors for both underweight and stunting. Households without livestock were significant predictors for wasting. Thus, this study identified specific socio-economic factors that should be prioritized for policy and research towards the amelioration of childhood malnutrition in rural areas.


Correlation of the antiproliferative effect and the Mx-homologous protein induction by IFN in patients with malignant melanoma.
The human interferon-induced intracellular protein homologous to the murine Mx-protein has recently been identified by means of a specific monoclonal antibody. Three of six melanoma cell lines elicited this intracellular human Mx-homolog upon incubation with IFN-alpha or IFN-gamma, yet all six melanoma cell lines tested were susceptible to the antiproliferative effect of IFN-alpha and IFN-gamma. Compared per antiviral unit, IFN-gamma had weaker Mx-inducing but stronger antiproliferative activity than IFN-alpha. These data suggest that the IFN-induced Mx-homologous protein is not involved in the antiproliferative action of IFN on malignant melanoma cell lines. Furthermore, 51 patients with advanced malignant melanoma were treated thrice weekly with 10 x 10(6) IU rIFN-alpha-2b and 6 x 10(6) nIFN-alpha, respectively. Nine of the 51 patients experienced systemic objective tumor responses (3 complete response, 6 partial response), but had Mx concentrations in their mononuclear cells equal to the Mx levels of non-responders during IFN-alpha therapy. Therefore, the level of Mx-homologous protein induced during IFN therapy is not a predictive marker for an antitumor response in malignant melanoma.


Comparison of the Diagnostic Performance of Four Quantitative Myocardial Perfusion Estimation Methods Used in Cardiac MR Imaging: CE-MARC Substudy.
To compare the diagnostic performance of four tracer kinetic analysis methods to quantify myocardial perfusion from magnetic resonance (MR) imaging cardiac perfusion data sets in terms of their ability to lead to the diagnosis of myocardial ischemia. The study was approved by the regional ethics committee, and all patients gave written consent. A representative sample of 50 patients with suspected ischemic heart disease was retrospectively selected from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease trial data set. Quantitative myocardial blood flow (MBF) was estimated from rest and adenosine stress MR imaging perfusion data sets by using four established methods. A matching diagnosis of both an inducible defect as assessed with single photon emission computed tomography and a luminal stenosis of 70% or more as assessed with quantitative x-ray angiography was used as the reference standard for the presence of myocardial ischemia. Diagnostic performance was evaluated with receiver operating characteristic (ROC) curve analysis for each method, with stress MBF and myocardial perfusion reserve (MPR) serving as continuous measures. Area under the ROC curve with stress MBF and MPR as the outcome measures, respectively, was 0.86 and 0.92 for the Fermi model, 0.85 and 0.87 for the uptake model, 0.85 and 0.80 for the one-compartment model, and 0.87 and 0.87 for model-independent deconvolution. There was no significant difference between any of the models or between MBF and MPR, except that the Fermi model outperformed the one-compartment model if MPR was used as the outcome measure (P = .02). Diagnostic performance of quantitative myocardial perfusion estimates is not affected by the tracer kinetic analysis method used.


Fast specific field detection of RHDVb.
This work describes a simple and rapid test for field detection of the emerging rabbit pathogen RHDVb. The assay is specific for RHDVb, showing no cross-reactivity with other RHDV types giving a specific result in under 10 min using rabbit liquid exudates or liver homogenate samples taken at necropsy.


Psychosis and identity: Alteration or loss?
The onset of psychotic disorders often brings major changes to an individual, which, for some, are never fully reversed and remain a dominant force. Despite such changes, the individual still experiences themselves as a continuous person and must find some way to assimilate these shifts into their self-concept. From a philosophical perspective, the various models of continuing identity all depend upon some notion of fundamental stability, which seems a poor fit for the trajectory associated with psychotic disorders. This article will explore, in more depth, how the transitions that accompany psychotic disorders present a challenge to conventional and philosophical notions of selfhood. If we are not simply to judge psychotic disorders as bringing about a loss of selfhood, we will need an alternative model of identity to use in this context.


Discontinuous nonequilibrium phase transitions in a nonlinearly pulse-coupled excitable lattice model.
We study a modified version of the stochastic susceptible-infected-refractory-susceptible (SIRS) model by employing a nonlinear (exponential) reinforcement in the contagion rate and no diffusion. We run simulations for complete and random graphs as well as d-dimensional hypercubic lattices (for d=3,2,1). For weak nonlinearity, a continuous nonequilibrium phase transition between an absorbing and an active phase is obtained, such as in the usual stochastic SIRS model [Joo and Lebowitz, Phys. Rev. E 70, 036114 (2004)]. However, for strong nonlinearity, the nonequilibrium transition between the two phases can be discontinuous for d>or=2, which is confirmed by well-characterized hysteresis cycles and bistability. Analytical mean-field results correctly predict the overall structure of the phase diagram. Furthermore, contrary to what was observed in a model of phase-coupled stochastic oscillators with a similar nonlinearity in the coupling [Wood, Phys. Rev. Lett. 96, 145701 (2006)], we did not find a transition to a stable (partially) synchronized state in our nonlinearly pulse-coupled excitable elements. For long enough refractory times and high enough nonlinearity, however, the system can exhibit collective excitability and unstable stochastic oscillations.


Leptospirosis and Depression: A Nationwide Cohort Analysis.
We conducted a retrospective cohort study to investigate whether leptospirosis is a risk factor for depression. From the Taiwan National Health Insurance Research Database between 2000 and 2010, patients with leptospirosis (ICD-9 code 100) who did not have a history of depression (ICD-9-CM codes 296.2, 296.3, 300.4, and 311) before the index date were enrolled (leptospirosis cohort). For each patient with leptospirosis, 1 control without a history of leptospirosis and depression was randomly selected (nonleptospirosis cohort). Cox proportional hazards regression models were used to analyze the risk of depression according to sex, age, and comorbidities. In the leptospirosis and nonleptospirosis cohorts, we observed 34 patients with depression, with the incidence rate of 2.87 per 1,000 person-years, and 25 patients with depression, with the incidence rate of 1.93 per 1,000 person-years, respectively, yielding a crude hazard ratio (HR) of 1.49 (95% confidence interval [CI], 1.25-1.77) and an adjusted HR (aHR) of 1.58 (95% CI, 1.34-1.88). Compared with the nonleptospirosis cohort, the leptospirosis cohort had a risk of depression stratified by sex, age, and comorbidity that was higher in female patients (aHR = 2.08; 95% CI, 1.54-2.80), patients younger than 49 years old (aHR = 3.19; 95% CI, 2.39-4.27), and patients without comorbidity (aHR = 2.14; 95% CI, 1.68-2.71). The risk of depression was higher in women than in men (aHR = 1.90; 95% CI, 1.61-2.25) and in patients with comorbidities, namely hyperlipidemia (aHR = 1.80; 95% CI, 1.40-2.31), coronary artery disease (aHR = 2.47; 95% CI, 1.96-3.12), stroke (aHR = 1.77; 95% CI, 1.39-2.24), and septicemia (aHR = 2.06; 95% CI, 1.64-2.58). Patients with leptospirosis have a 1.58-fold higher risk of depression than that in the general population. Physicians should be alert to the emotional condition and depression symptoms of people who had been suffering from leptospirosis.


Rapid Detection of Ractopamine and Salbutamol in Swine Urine by Immunochromatography Based on Selenium Nanoparticles.
The purpose of this study was to establish a lateral flow immunoassay using selenium nanoparticles (Se-NPs) as a probe to detect ractopamine (RAC) and salbutamol (SAL) in swine urine. SDS and PEG were used as templates to prepare Se-NPs; anti-RAC monoclonal antibodies or anti-SAL monoclonal antibodies were labelled with Se-NPs; and rapid detection kits were prepared. The sensitivity, specificity, and stability were measured, and actual samples were analysed. The Se-NPs were spherical with a diameter of 40.63 ± 5.91 nm, and were conjugated successfully with an anti-RAC antibody to give a total diameter of 82.33 ± 17.91 nm. The detection limit of a RAC kit in swine urine was 1 ng/mL, and that of a SAL kit was 3 ng/mL. Both procedures could be completed within 5 minutes. No cross-reaction occurred with clenbuterol, bambuterol and phenylethanolamine A. Samples were tested consistently across different batches of kits for swine urine. The results of the kits were identical to those of actual clinical samples analysed by ELISA, and the coincidence rate was 100%. The assay kit does not require any special device for reading the results, and the readout is a simple colour change that can be evaluated with the naked eye. It is easy to operate, sensitive, specific, and stable This kit is suitable for the rapid and real-time detection of RAC and SAL residues in swine urine samples. Swine urines samples were used under approval from the Experimental Animal Ethics committee of the Joint National Laboratory for Antibody Drug Engineering, Henan University.


Skin of color images in pediatric dermatology textbooks.
Due to globalization, dermatologists routinely see patients of different ethnicities and skin tones. Surveys from the US have shown that dermatologists felt that their training was lacking in diagnosing dermatoses in skin-of-color patients. Underrepresentation of skin of color in dermatology textbooks has been reported. We evaluated clinical images in selected pediatric dermatology textbooks with regard to skin color.


Generation of multi-gene knockout rabbits using the Cas9/gRNA system.
The prokaryotic clustered regularly interspaced short palindromic repeat (CRISPR)-associated system (Cas) is a simple, robust and efficient technique for gene targeting in model organisms such as zebrafish, mice and rats. In this report, we applied CRISPR technology to rabbits by microinjection of Cas9 mRNA and guided RNA (gRNA) into the cytoplasm of pronuclear-stage embryos. We achieved biallelic gene knockout (KO) rabbits by injection of 1 gene (IL2rg) or 2 gene (IL2rg and RAG1) Cas9 mRNA and gRNA with an efficiency of 100%. We also tested the efficiency of multiple gene KOs in early rabbit embryos and found that the efficiency of simultaneous gene mutation on target sites is as high as 100% for 3 genes (IL2rg, RAG1 and RAG2) and 33.3% for 5 genes (IL2rg, RAG1, RAG2, TIKI1 and ALB). Our results demonstrate that the Cas9/gRNA system is a highly efficient and fast tool not only for single-gene editing but also for multi-gene editing in rabbits.


[Histological studies of normal and pathological furcations in the rat].
In order to study the histological structure of healthy and pathological furcations in the rat, two groups of animals were submitted to two different diets: one normal and one rich in sucrose. In the first group, certain particularities were demonstrated in the periodontal ligament in the interradicular region: the fibrous network was very loose in this zone and the fibrous insertions were essentially cemento-cemental and not cemento-osseous. In the rats submitted to the high sucrose diet, a disequilibrium was noted between the apposition zones and the zones in bone and cementum resorption.


Model-based inference from multiple dose, time course data reveals Wolbachia effects on infection profiles of type 1 dengue virus in Aedes aegypti.
Infection is a complex and dynamic process involving a population of invading microbes, the host and its responses, aimed at controlling the situation. Depending on the purpose and level of organization, infection at the organism level can be described by a process as simple as a coin toss, or as complex as a multi-factorial dynamic model; the former, for instance, may be adequate as a component of a population model, while the latter is necessary for a thorough description of the process beginning with a challenge with an infectious inoculum up to establishment or elimination of the pathogen. Experimental readouts in the laboratory are often static, snapshots of the process, assayed under some convenient experimental condition, and therefore cannot comprehensively describe the system. Different from the discrete treatment of infection in population models, or the descriptive summarized accounts of typical lab experiments, in this manuscript, infection is treated as a dynamic process dependent on the initial conditions of the infectious challenge, viral growth, and the host response along time. Here, experimental data is generated for multiple doses of type 1 dengue virus, and pathogen levels are recorded at different points in time for two populations of mosquitoes: either carrying endosymbiont bacteria Wolbachia or not. A dynamic microbe/host-response mathematical model is used to describe pathogen growth in the face of a host response like the immune system, and to infer model parameters for the two populations of insects, revealing a slight-but potentially important-protection conferred by the symbiont.


Simple assay and extraction of periplasmic penicillinase in Escherichia coli.
Benzylpenicillin was clearly separated from benzylpenicilloic acid by ascending chromatography on a diethylaminoethyl cellulose paper using 0.1 M ammonium acetate as a solvent. Using this chromatographic system, penicillinase was assayed by measuring the formation of [14C]benzylpenicilloic acid from [14C]benzylpenicillin. This assay remedies the lack of specificity of the commonly used iodometric assays. Periplasmic penicillinase was released from Escherichia coli by suspension in a mixture of 1% phenethyl alcohol and 5 mM ethylenediaminetetraacetate (pH 7.0). This simple extraction method not only facilitates the assay of penicillinase in an E. coli culture, but will also be useful for large-scale purification of periplasmic penicillinase.


Indirubin-3-monoxime and thymoquinone exhibit synergistic efficacy as therapeutic combination in in-vitro and in-vivo models of Lung cancer.
In this study, we report the combination of indirubin-3-monoxime (I3M) and thymoquinone (Tq) to have excellent therapeutic efficacy in models of Lung cancer (LC). Preliminary screening was done with A549 cells. Cell cycle, apoptosis and NFκB phosphorylation were determined by flow cytometry, while apoptotic proteins, Akt and mTOR were assessed by western blotting. Mouse xenograft model was used to assess the therapeutic efficacy in-vivo. Synergistic reduction in cell viability was observed with I3M + Tq combinations, which were non-toxic to normal HFL-1 cells. Cell cycle analysis indicated G1 phase reduction with subsequent accumulation of sub G0 contents. Annexin V assay revealed higher apoptotic cells with combinations compared to individual treatments with a decrease in Bcl-2/Bax ratio. The combinations exhibited anti-metastasis activity in cell migration in the scratch, scatter and tumour cell migration assays and effectively reduced the tumour growth in mouse xenograft model. Expression levels of p-AKT, p-mTOR, Caspase-3, p-53 and NFκB were significantly reduced in the combination treated mice compared to individual treatments. Results of current study demonstrate clear efficacy of I3M + Tq combinations in LC models mediated by suppressing Akt/mTOR/NFκB signalling. Further research is recommended to transform these findings into novel therapeutic combinations against LC.


Neural regulation of muscle acetylcholinesterase is exerted on the level of its mRNA.
In rat muscles, AChE activity drops rapidly after denervation, and the patterns of AChE molecular forms in slow and fast muscles differ considerably. Both observations imply that muscle AChE is regulated by the motor nerve. In order to obtain a better insight into the underlying mechanism, AChE regulation in rat muscles was examined on the level of its catalytic subunit mRNA using northern blot analysis. The level of two AChE transcripts (2.4 and 3.2 kb) was much higher in the fast sternomastoid (STM) than in the slow soleus muscle, which explains the difference in AChE activity between the two types of muscles. Expression of AChE mRNA in the extrajunctional region of STM muscle is fairly high so that little difference in the level of AChE mRNAs was observed in comparison to the region rich in the neuromuscular junctions. This indicates that very high AChE activity in the neuromuscular junctions is achieved by unique posttranslational modifications and cellular processing of AChE enhancing stability of the junctional in comparison to the extrajunctional AChE. Denervation as well as botulinum toxin evoked paralysis of STM muscle caused rapid decline of AChE transcripts to almost undetectable levels both in the junctional and extrajunctional regions. The low level of AChE mRNA is therefore largely responsible for low AChE activity in denervated rat muscles. It seems that either muscle activity and/or quantal ACh release enhance the level of AChE mRNA in the junctional as well as extrajunctional regions. In rat muscles, extrajunctional mRNA level of the catalytic subunit of AChE is neurally regulated in exact opposite fashion from that of acetylcholine receptor subunits.


Imidazoline receptors in the heart: characterization, distribution, and regulation.
Imidazoline receptors were identified in cardiac tissues of various species. Imidazoline receptors were immunolocalized in the rat heart. Membrane binding and autoradiography on frozen heart sections using 0.5 nM para-iodoclonidine (125I-PIC) revealed that binding was equally and concentration-dependently inhibited by epinephrine and imidazole-4-acetic acid (IAA), implying 125I-PIC binding to cardiac alpha2-adrenergic and I1-receptors, respectively. After irreversible blockade of alpha2-adrenergic receptors, binding was inhibited by the selective I1-agonist, moxonidine, and the I1-antagonist, efaroxan, in a concentration-dependent (10-12 to 10-5 M) manner. Calculation of kinetic parameters revealed that in canine left and right atria, I1-receptor Bmax was 13.4 +/- 1.7 and 20.1 +/- 3.0 fmol/mg protein, respectively. Compared to age-matched normotensive Wistar Kyoto rats, I1-receptors were increased in 12-week-old hypertensive rat (SHR) right (22.6 +/- 0.3 to 43.7 +/- 4.4 fmol/unit area, p < 0.01) and left atria (13.3 +/- 0.6 to 30.2 +/- 4.1 fmol/unit area, p < 0.01). Also, compared to corresponding normal controls, Bmax was increased in hearts of hamsters with advanced cardiomyopathy (13.9 +/- 0.4 to. 26.0 +/- 2.3 fmol/unit area, p < 0.01) and in human ventricles with heart failure (12.6 +/- 1.3 to 35.5 +/- 2.9 fmol/mg protein, p < 0.003). These studies demonstrate that the heart possesses imidazoline I1-receptors that are up-regulated in the presence of hypertension or heart failure, which would suggest their involvement in cardiovascular regulation.


Nickel-catalyzed decarbonylative addition of anhydrides to alkynes.
An intermolecular nickel-catalyzed addition reaction has been developed where phthalic anhydrides react with alkynes to afford substituted isocoumarins. A mechanistic rationale is proposed, implying reductive elimination of Ni(0) promoted by ZnCl(2) cocatalyst as the key step of the catalytic cycle.


The role of antibiotic tolerance in the response to treatment of pyelonephritis due to Staphylococcus aureus in rats.
The effect of tolerance to methicillin on the response to treatment of hematogenous pyelonephritis due to Staphylococcus aureus was evaluated in rats. Tolerance was defined as a ratio of minimal bactericidal concentration to minimal inhibitory concentration of greater than or equal to 32. Rats that were infected with tolerant or nontolerant stains of S. aureus were treated with methicillin with equal success as judged by the number of bacteria in the kidneys and the proportion of rats with infected kidneys. In this animal model, tolerance does not play a role in the outcome of treatment.


Epistaxis: are temperature and seasonal variations true factors in incidence?
To investigate the previously documented inverse association between ambient temperature and presentation rates for patients with epistaxis and seasonal variation of emergency presentation rates for patients with epistaxis. A retrospective analysis of all consecutive emergency patients with epistaxis presenting to hospital from the community over a five-year period, 1997-2002 (1830 days), including those who required admission to hospital with epistaxis over the same period. Patients in whom there was a clear aetiology for the epistaxis (traumatic, recurrent, iatrogenic, coagulopathic and hypertensive) were excluded. A tertiary referral centre in south-west London serving a population in excess of 2.8 million. A retrospective analysis of all patients presenting or admitted to St George's Hospital with epistaxis over a five-year period. Daily ambient temperature readings from London Heathrow airport were recorded for the same period. Presentations were correlated with monthly temperature variations and the month itself. Statistical analysis with Pearson's correlation coefficient was performed. 1373 patients with epistaxis presented to our department, of whom 386 (28.1 per cent) were admitted to hospital. No correlation is seen between ambient temperature and presentation rate for patients with epistaxis. No seasonal preponderance is noted for presentation rate (Pearson r = 0.160, p = 0.221) in this series. To our knowledge, this is the largest study to date examining ambient temperature association and epistaxis, and the first to investigate presentation rate in place of admission rate. We feel that the exclusion of all patients with epistaxis not admitted to hospital introduces a bias. In this series, there is no correlation between ambient temperature, seasonal preponderance, presentation rate or admission rate for patients with epistaxis. This is contrary to previously reported findings. We do not support the view that there is a relationship between epistaxis and temperature or seasonal variation. This contradicts the current belief that incidence of epistaxis displays seasonality, and has implications for the allocation of resources for healthcare provision within ENT departments.


The genetics of overwintering performance in two-year old common carp and its relation to performance until market size.
Using farmed common carp, we investigated the genetic background of the second year overwintering performance and its relation to the performance during the third growing season and at market size. The experimental stock was established by partial factorial design with a series of 4 factorial matings of 5 dams and 10 sires each. The families were reared communally and pedigree was re-constructed with 93.6% success using 12 microsatellites on 2008 offspring. Three successive recordings (second autumn, third spring, and third autumn-market size) covering two periods (second overwintering, third growing season) were included. Body weight, Fulton's condition factor and percent muscle fat content were recorded at all times and headless carcass yield and fillet yield were recorded at market size. Specific growth rate, absolute and relative fat change and overall survival were calculated for each period. Heritability estimates were significantly different from zero and almost all traits were moderately to highly heritable (h2 = 0.36-1.00), except survival in both periods and fat change (both patterns) during overwintering (h2 = 0.12-0.15). Genetic and phenotypic correlations imply that selection against weight loss and fat loss during overwintering is expected to lead to a better winter survival, together with a positive effect on growth in the third growing season. Interestingly, higher muscle fat content was genetically correlated to lower survival in the following period (rg = -0.59; -0.53, respectively for winter and the third summer). On the other hand, higher muscle fat was also genetically linked to better slaughter yields. Moreover, selection for higher condition factor would lead to better performance during winter, growing season and at market size.


Preparation of Micro-Nano Material Composed of Oyster Shell/Fe3O4 Nanoparticles/Humic Acid and Its Application in Selective Removal of Hg(II).
Micro-nano composite material was prepared to adsorb Hg(II) ions via the co-precipitation method. Oyster shell (OS), Fe3O4 nanoparticles, and humic acid (HA) were used as the raw materials. The adhesion of nanoparticles to OS displayed by scanning electron microscopy (SEM), the appearance of the (311) plane of standard Fe3O4 derived from X-ray diffraction (XRD), and the transformation of pore sizes to 50 nm and 20 μm by mercury intrusion porosimetry (MIP) jointly revealed the successful grafting of HA-functionalized Fe3O4 onto the oyster shell surface. The vibrating sample magnetometer (VSM) results showed superparamagnetic properties of the novel adsorbent. The adsorption mechanism was investigated based on X-ray photoelectron spectroscopy (XPS) techniques, which showed the process of physicochemical adsorption while mercury was adsorbed as Hg(II). The effects of pH (3-7), initial solution concentration (2.5-30 mg·L-1), and contact time (0-5 h) on the adsorption of Hg(II) ions were studied in detail. The experimental data were well fitted to the Langmuir isotherm equation (R2 = 0.991) and were shown to follow a pseudo-second-order reaction model (R2 = 0.998). The maximum adsorption capacity of Hg(II) was shown to be 141.57 mg·g-1. In addition, this new adsorbent exhibited excellent selectivity.


Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency.
Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule in the cytosol of myeloid cells, required for induction of T-helper cells producing interleukin-17 (Th17 cells) and important in antifungal immunity. In a patient suffering from Candida dubliniensis meningoencephalitis, mutations in the CARD9 gene were found to result in the loss of protein expression. Apart from the reduced numbers of CD4(+) Th17 lymphocytes, we identified a lack of monocyte-derived cytokines in response to Candida strains. Importantly, CARD9-deficient neutrophils showed a selective Candida albicans killing defect with abnormal ultrastructural phagolysosomes and outgrowth of hyphae. The neutrophil killing defect was independent of the generation of reactive oxygen species by the reduced NAD phosphate oxidase system. Taken together, this demonstrates that human CARD9 deficiency results in selective defect in the host defense against invasive fungal infection, caused by an impaired phagocyte killing.


Antimicrobial and anti-inflammatory properties of Funtumia elastica.
Funtumia elastica (Preuss) Stapf. (Apocynaceae) has a long ethnopharmacological history for uses such as treatment of whooping cough, asthma, blennorhea, painful menstruation, fungal infections, and wounds. To investigate the antimicrobial and anti-inflammatory properties of ethanol extracts from the leaves and stem bark of Funtumia elastica based on its ethnopharmacological uses and also determine the secondary metabolites present in the extracts. The antimicrobial activities of ethanol leaf and bark extracts of F. elastica were determined using the microdilution technique (MIC determination) and agar diffusion method using 10, 25, and 50 mg/mL concentrations against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Candida albicans, Aspergillus flavus and Aspergillus niger as test organisms. Anti-inflammatory activities of the doses of extracts at 30, 100, and 300 mg/kg per body weight were determined by carrageenan-induced edema in the footpad of 7-day-old chicks and the foot volumes measured at hourly interval post-treatment for 5 h. The MIC ranges of both ethanol leaf and bark extracts against the test organisms were 125 (lowest MIC) to 1550 µg/mL (highest MIC) and 125 (lowest MIC) to 1750 µg/mL (highest MIC), respectively. The ethanol leaf and bark extract of F. elastica showed significant anti-inflammatory activity (p ≤ 0.001) at 30, 100 and 300 mg/kg. Preliminary phytochemical screening revealed that F. elastica bark contains hydrolysable tannins, sapogenetic glycosides, steroids and saponins while the leaves contain hydrolysable tannins, flavonoids, starch and alkaloids. Tannin contents of the leaf and stem bark were 2.4 and 1.3% w/w (related to the dried material), respectively. Both ethanol leaf and bark extracts of F. elastica showed antimicrobial and anti-inflammatory activities and these pharmacological properties may be responsible for the ethnomedicinal uses of the leaves and stem bark of the plant.


Hippocampal circuitry complicates analysis of long-term potentiation in mossy fiber synapses.
Much of the current interest in the hippocampus concerns a rapid and persistent form of synaptic plasticity, called long-term potentiation (LTP), that is a candidate substrate for some of the mnemonic functions of this structure. There are at least two kinds of LTP in the hippocampus. One form is found at the synapse between the mossy fibers of the granule cells and the pyramidal neurons of the CA3 region. Attempts to examine the mechanism underlying this form of LTP have yielded contradictory conclusions. The authors show how the complex circuitry of the dentate gyrus and adjacent hippocampus may have caused the contradictions. To overcome problems introduced by the circuitry, a specific set of procedures and criteria for evoking and identifying mossy fiber responses is proposed. Use of these or similar procedures and criteria will improve the design and interpretation of experiments on mossy fiber LTP and allow more informative comparisons among species and brain regions and across laboratories.


Generation of a radially polarized light beam using space-variant subwavelength gratings at 1064 nm.
The generation of radially polarized beams at a wavelength of 1064 nm by the use of a polarization transformer device consisting of space-variant subwavelength gratings (SGs) is demonstrated experimentally. The SG generates a pi phase retardation between the TE and TM polarizations, acting as a half-wave plate, reflecting the polarization vector with respect to the axes of the plate. The polarization transformer is characterized by polarization analysis and by far-field measurements. The characterization results show good agreement with theory. The device is suitable for operation with Nd:YAG lasers; thus it is attractive for biological, optical tweezers, and material processing applications.


Baseline Performance Predicts tDCS-Mediated Improvements in Language Symptoms in Primary Progressive Aphasia.
Primary Progressive Aphasia (PPA) is a neurodegenerative condition characterized by insidious irreversible loss of language abilities. Prior studies suggest that transcranial direct current stimulation (tDCS) directed toward language areas of the brain may help to ameliorate symptoms of PPA. In the present sham-controlled study, we examined whether tDCS could be used to enhance language abilities (e.g., picture naming) in individuals with PPA variants primarily characterized by difficulties with speech production (non-fluent and logopenic). Participants were recruited from the Penn Frontotemporal Dementia Center to receive 10 days of both real and sham tDCS (counter-balanced, full-crossover design; participants were naïve to stimulation condition). A battery of language tests was administered at baseline, immediately post-tDCS (real and sham), and 6 weeks and 12 weeks following stimulation. When we accounted for individuals' baseline performance, our analyses demonstrated a stratification of tDCS effects. Individuals who performed worse at baseline showed tDCS-related improvements in global language performance, grammatical comprehension and semantic processing. Individuals who performed better at baseline showed a slight tDCS-related benefit on our speech repetition metric. Real tDCS may improve language performance in some individuals with PPA. Severity of deficits at baseline may be an important factor in predicting which patients will respond positively to language-targeted tDCS therapies. Clinicaltrials.gov ID: NCT02928848.


Ambroxol for the treatment of COVID-19 among hospitalized patients: A multicenter retrospective cohort study.
Ambroxol is a commonly used mucolytic agent principally used to treat respiratory diseases, which may have a role as adjunctive therapy for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, but there is lack of evidence about its effectiveness on coronavirus disease-2019 (COVID-19) patients. To study the association between ambroxol use and clinical outcomes among hospitalized patients of COVID-19 infection. We conducted a multicenter retrospective cohort study involving 3,111 patients with confirmed SARS-CoV-2 infection from three hospitals in Wuhan from 19 December 2019 to 15 April 2020, and the primary outcome was in-hospital mortality. COVID-19 patients were classified into ambroxol and non-ambroxol groups based on the administration of ambroxol during hospitalization. Two analyses including propensity score matching (PSM) to obtain a 1:1 balanced cohort and logistic regression were used to control for confounding factors. The average age of 3,111 patients was 57.55 ± 14.93 years old, 127 of them died during hospitalization, and 924 of them used ambroxol. Treatment with ambroxol did not have a significant effect on in-hospital mortality of COVID-19 patients when compared with non-ambroxol in PSM model after adjusting for confounders (8.0% vs. 3.5%, adjusted OR, 1.03 [95% CI, 0.54-1.97], p = 0.936). Adverse events such as nausea/vomiting, headache, and rash were comparable between the two groups. Our results suggest that the use of ambroxol is not significantly associated with in-hospital mortality in COVID-19 patients, which provides evidence for evaluating the effects of ambroxol on COVID-19 patient outcomes and may be helpful for physicians considering medication alternatives for COVID-19 patients.


Acute appendicitis secondary to Entamoeba histolytica infestation.
Acute appendicitis secondary to amoebic infestation is a rare possibility, especially in endemic areas. If left untreated, significant postoperative morbidity and mortality can result from the spread of amoebic trophozoites and subsequent tissue reaction. Histopathological examination of the resected appendix with demonstration of invasion by the parasite is mandatory for establishing a diagnosis. Careful examination of the specimen is thus of paramount importance.


Interaction in vitro of type III intermediate filament proteins with triplex DNA.
As previously shown, type III intermediate filaments (IFs) select from a mixture of linear mouse genomic DNA fragments mobile and repetitive, recombinogenic sequences that have also been identified in SDS-stable crosslinkage products of vimentin and DNA isolated from intact fibroblasts. Because these sequences also included homopurine.homopyrimidine (Pu.Py) tracts known to adopt triple-helical conformation under superhelical tension, and because IF proteins are single-stranded (ss) and supercoiled DNA-binding proteins, it was of interest whether they have a particular affinity for triplex DNA. To substantiate this, IF-selected DNA fragments harboring a (Pu.Py) segment and synthetic d(GA)(n) microsatellites were inserted into a vector plasmid and the constructs analyzed for their capacity to interact with IF proteins. Band shift assays revealed a substantially higher affinity of the IF proteins for the insert-containing plasmids than for the empty vector, with an activity decreasing in the order of vimentin > glial fibrillary acidic protein > desmin. In addition, footprint analyses performed with S1 nuclease, KMnO(4), and OsO(4)/bipyridine showed that the (Pu.Py) inserts had adopted triplex conformation under the superhelical strain of the plasmids, and that the IF proteins protected the triple-helical insert sequences from nucleolytic cleavage and chemical modification. All these activities were largely reduced in extent when analyzed on linearized plasmid DNAs. Because intramolecular triplexes (H-DNA) expose single-stranded loops, and the prokaryotic ssDNA-binding proteins g5p and g32p also protected at least the Pu-strand of the (Pu.Py) inserts from nucleolytic degradation, it seemed likely that the IF proteins take advantage of their ssDNA-binding activity in interacting with H-DNA. However, in contrast to g5p and E. coli SSB, they produced no clear band shifts with single-stranded d(GA)(20) and d(TC)(20), so that the interactions rather appear to occur via the duplex-triplex and triplex-loop junctions of H-DNA. On the other hand, the IF proteins, and also g32p, promoted the formation of intermolecular triplexes from the duplex d[A(GA)(20).(TC)(20)T] and d(GA)(20) and d(TC)(20) single strands, with preference of the Py (Pu.Py) triplex motif, substantiating an affinity of the proteins for the triplex structure as such. This triplex-stabilizing effect of IF proteins also applies to the H-DNA of (Pu.Py) insert-containing plasmids, as demonstrated by the preservation of intramolecular triplex-vimentin complexes upon linearization of their constituent supercoiled DNAs, in contrast to poor complex formation from free, linearized plasmid DNA and vimentin. Considering that (Pu.Py) sequences are found near MAR/replication origins, in upstream enhancer and promoter regions of genes, and in recombination hot spots, these results might point to roles of IF proteins in DNA replication, transcription, recombination, and repair.


Assessment of cry1 gene contents of Bacillus thuringiensis strains by use of DNA microarrays.
A single Bacillus thuringiensis strain can harbor numerous different insecticidal crystal protein (cry) genes from 46 known classes or primary ranks. The cry1 primary rank is the best known and contains the highest number of cry genes which currently totals over 130. We have designed an oligonucleotide-based DNA microarray (cryArray) to test the feasibility of using microarrays to identify the cry gene content of B. thuringiensis strains. Specific 50-mer oligonucleotide probes representing the cry1 primary and tertiary ranks were designed based on multiple cry gene sequence alignments. To minimize false-positive results, a consentaneous approach was adopted in which multiple probes against a specific gene must unanimously produce positive hybridization signals to confirm the presence of a particular gene. In order to validate the cryArray, several well-characterized B. thuringiensis strains including isolates from a Mexican strain collection were tested. With few exceptions, our probes performed in agreement with known or PCR-validated results. In one case, hybridization of primary- but not tertiary-ranked cry1I probes indicated the presence of a novel cry1I gene. Amplification and partial sequencing of the cry1I gene in strains IB360 and IB429 revealed the presence of a cry1Ia gene variant. Since a single microarray hybridization can replace hundreds of individual PCRs, DNA microarrays should become an excellent tool for the fast screening of new B. thuringiensis isolates presenting interesting insecticidal activity.


Dispersal Flights of the Formosan Subterranean Termite (Isoptera: Rhinotermitidae).
The Formosan subterranean termite, Coptotermes formosanus Shiraki, is a pest of major economic concern. This termite is particularly known for its tendency to establish populations in nonendemic areas via maritime vessels as well as human-aided transport of infested materials. The natural spread of this species after new introductions occurs in part by dispersal flights originating from mature colonies. Dispersal flight activity is also the primary variable for the evaluation of area-wide management programs. Few studies exist describing the dynamics and distribution of a typical dispersal flight for this species. The present study used data collected by mark-recapture of C. formosanus alates over 12 individual evenings of dispersal flights in the New Orleans French Quarter. In this study, we found that for one selected flight dispersal location, which was not affected by a high density of trap locations nearby, alates flew on average 621 m from their parent colony. A new record of a 1,300-m dispersal flight was recorded. Spatial analysis showed that neither wind nor light affected the direction of flight, which may, however, be attributed to scarce light and wind measurements in the study region.


Providing family support through community guides.
The Family Support Opportunities program in the state of Washington has a unique component. People with extensive knowledge of local communities, referred to as community guides, were made available to all families enrolled in the program. Community guides assisted families by seeking information about community resources that families needed and helping families connect to those resources. Responses from a survey of 312 families were analyzed to determine the impact of the community guides' services. Results suggest that when families indicated satisfaction with their community guides, they reported better outcomes in terms of their needs being met, satisfaction with Family Support Opportunities, and connections to their local communities.


Gamma Glutamyl Transferase Activity Has Limited Utility in Assessment of Alkaline Phosphatase Elevations.
As part of an ongoing effort to improve healthcare value for patients, laboratories increasingly implement test utilization review. Alkaline phosphatase (ALP) isoenzymes (hereafter: isoenzymes) testing distinguishes the various ALP isoforms to explain elevations in total serum ALP. Gamma glutamyl transferase activity (GGT) has served as a proxy for total ALP elevations attributable to the hepatic isoform given that both are membrane-bound proteins with a shared mechanism of release. We assessed the utility of GGT in evaluating isoenzymes requests. We obtained 8 years of isoenzymes results and identified same-patient GGT measurements obtained within 7 days. We assessed the ability of GGT to predict elevations in hepatic, bone, intestinal, and nonhepatic ALP isoforms overall. We generated ROC curves and calculated sensitivity and specificity using our in-house reference limits for GGT. GGT as a predictor of hepatic isoform elevation had an area under the ROC curve (AUC) of 0.68, and GGT activity above the upper reference limit was 46.6% sensitive and 85.0% specific for hepatic ALP elevation. GGT activity as a predictor of nonhepatic isoform elevation had an AUC of 0.52, and GGT within reference limits was 59.8% sensitive and 46.4% specific for elevation in a nonhepatic ALP isoform. In 133 individuals with hepatic isoform elevations, 93 had a concurrent elevation in a nonhepatic ALP isoform. GGT was reasonably specific but insensitive for hepatic ALP isoform elevation and was a poor predictor of ALP isoform elevation overall, suggesting that its usefulness in evaluating isoenzymes orders is limited.


Glucocorticoids are involved in the long-term effects of a single immobilization stress on the hypothalamic-pituitary-adrenal axis.
We have previously observed that a single exposure to a severe stressor such as immobilization (IMO) induces long-lasting desensitization of the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to the same stressor that enhances rather than dissipates with time (days). As this desensitization of the HPA axis was not observed in response to a novel stressor, we suggested this might be a particular type of learning linked to severe stressful situations. Taking into account the evidence that glucocorticoids are involved in learning and memory, the present study addresses the role of glucocorticoids in the induction of long-term effects of an acute exposure to IMO. Three different experimental approaches were used: (i) blockade of stress-induced corticosterone release by using adrenalectomized rats supplemented with a low dose of corticosterone in the drinking saline (ADX+B); (ii) blockade of corticosterone synthesis during the first exposure to IMO with the 11-beta-hydroxylase inhibitor metyrapone (200 mg/kg); and (iii) administration of the glucocorticoid receptor antagonist RU486 (100 mg/kg). Previous exposure to IMO resulted in an enhanced post-stress recovery of the HPA response to the same stressor 1 week later. These long-term effects of IMO were blocked in ADX+B rats, were partially reduced in metyrapone-treated rats and only modestly affected by RU486 administration. These data suggest that glucocorticoids play a partial role in the induction of long-term effects of IMO on the HPA responsiveness to the same stressor, although the weak effect of RU486 suggests that non-classical corticosteroid receptors may be involved. The role of glucocorticoids in the expression of the phenomenon is suggested by the full blockade of the phenomenon in ADX+B rats, but further studies are needed. As blockade of corticosterone synthesis only partially blunted the long-term effect of IMO, it appears that full induction of the long-term effects of acute exposure to IMO on the HPA axis is only achieved by the concerted action of several endocrine (or neurochemical) factors.


Interictal EEG and ECG for SUDEP Risk Assessment: A Retrospective Multicenter Cohort Study.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although lots of effort has been made in identifying clinical risk factors for SUDEP in the literature, there are few validated methods to predict individual SUDEP risk. Prolonged postictal EEG suppression (PGES) is a potential SUDEP biomarker, but its occurrence is infrequent and requires epilepsy monitoring unit admission. We use machine learning methods to examine SUDEP risk using interictal EEG and ECG recordings from SUDEP cases and matched living epilepsy controls. This multicenter, retrospective, cohort study examined interictal EEG and ECG recordings from 30 SUDEP cases and 58 age-matched living epilepsy patient controls. We trained machine learning models with interictal EEG and ECG features to predict the retrospective SUDEP risk for each patient. We assessed cross-validated classification accuracy and the area under the receiver operating characteristic (AUC) curve. The logistic regression (LR) classifier produced the overall best performance, outperforming the support vector machine (SVM), random forest (RF), and convolutional neural network (CNN). Among the 30 patients with SUDEP [14 females; mean age (SD), 31 (8.47) years] and 58 living epilepsy controls [26 females (43%); mean age (SD) 31 (8.5) years], the LR model achieved the median AUC of 0.77 [interquartile range (IQR), 0.73-0.80] in five-fold cross-validation using interictal alpha and low gamma power ratio of the EEG and heart rate variability (HRV) features extracted from the ECG. The LR model achieved the mean AUC of 0.79 in leave-one-center-out prediction. Our results support that machine learning-driven models may quantify SUDEP risk for epilepsy patients, future refinements in our model may help predict individualized SUDEP risk and help clinicians correlate predictive scores with the clinical data. Low-cost and noninvasive interictal biomarkers of SUDEP risk may help clinicians to identify high-risk patients and initiate preventive strategies.


Topiramate: effects on serum lipids and lipoproteins levels in children.
The present controlled study aims to evaluate topiramate (TPM) effect on total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein, very low-density lipoprotein, apolipoproteins A1, B and lipoprotein (a). Seventy patients in evolving age suffering from various types of epilepsy, treated with TPM, (age range: 6 months-22 years) were evaluated before and after 12 months of treatment and compared with 110 sex- and age-matched subjects. At baseline, no significant difference was present between controls and children treated with TPM. After a year, the BMI did not show significant change in adults and remained into respective growth curve. No significant difference in lipids and lipoproteins neither between first and second evaluation nor between patients and controls was found. Some intra-group variation has been noticed: whilst controls maintained similar levels, the 70 patients on TPM monotherapy showed a slight decrease in TC, triglycerides and HDL. These fluctuations, however, occurred in the normal range so neither dietary nor pharmacological treatment of hyperlipidaemia after a year of TPM was necessary.


The hazards of surgical smoke. Not to be sniffed at!
This article is based on a presentation given at Congress 2001 in Harrogate. It focuses on the risks to perioperative team members arising from the production of smoke during electrosurgical and laser procedures. It identifies the sources and nature of the risks, the failure of masks to provide adequate protection and suggests the standards that need to be set to reduce the risks.


Histogenesis of spontaneous regression of cervical intraepithelial neoplasias.
It is justifiable to assume that a spontaneous regression of cervical intraepithelial neoplasia is in progress when pathologic epithelium is replaced by normal epithelium. Very rare histologic pictures of this process are shown. Dysplastic squamous epithelium or intraepithelial carcinomas become detached from their bases and are pushed up by replacement tissue in the form of normal squamous or columnar epithelium.


Amorphous Indium Selenide Thin Films Prepared by RF Sputtering: Thickness-Induced Characteristics.
The influence of indium composition, controlled by changing the film thickness, on the optical and electrical properties of amorphous indium selenide thin films was studied for the application of these materials as Cd-free buffer layers in CI(G)S solar cells. Indium selenide thin films were prepared using RF magnetron sputtering method. The indium composition of the amorphous indium selenide thin films was varied from 94.56 to 49.72 at% by increasing the film thickness from 30 to 70 nm. With a decrease in film thickness, the optical transmittance increased from 87.63% to 96.03% and Eg decreased from 3.048 to 2.875 eV. Carrier concentration and resistivity showed excellent values of ≥1015 cm(-3) and ≤ 10(4) Ω x cm, respectively. The conductivity type of the amorphous indium selenide thin films could be controlled by changing the film-thickness-induced amount of In. These results indicate the possibility of tuning the properties of amorphous indium selenide thin films by changing their composition for use as an alternate buffer layer material in CI(G)S solar cells.


A phenomenological look at giving an injection.
Phenomenology attempts to get beyond the surface structure of experience to examine the underlying meaning of the realities of everyday life. In this paper, the writer attempts to answer the question, what is it live to give an injection? The paper is based on essays and interviews with ten experienced nurses, ten undergraduate nursing students and four diabetic patients who administered their own insulin. The author explores the meaning of the language used relating to an injection, the meaning that giving an injection has for the nurse, the feelings involved in preparing and giving the injection, and the meaning of the patient's response to the nurse. Two particular client groups create additional feelings for the nurse; the child and the unconscious patient. The phenomenologist never reaches a conclusion. The essay should challenge the reader to respond by saying, 'Yes, it is like this,' or 'No, I don't believe it is like that.' In responding, further understanding is developed. The aim of the author is to stimulate readers so they better understand the anxiety nursing students feel about giving an injection.


Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients.
Tenofovir (TDF) is one of the most widely used antiretroviral drug. Despite the high degree of tolerability a small percentage of patients experienced alteration in tubular function during TDF use. Intracellular TDF disposition is regulated by ATP-binding cassette (ABC) drug efflux transporters and, a reduced transport activity may be implicated in accumulation of TDF into the cells. The aim of our study was to assess the major determinants of TDF associated tubular dysfunction (KTD) in a real-life setting including the usefulness of single-nucleotide polymorphisms (SNPs) mapping into ABCC2, ABCC4 and ABCC10 genes. We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from April 2013 to June 2016. All patients treated with TDF who underwent a genotypization for the functional variants mapping in ABCC2 rs717620 (-24 C > T), ABCC4 rs1751034 (3463 A > G) and ABCC10 rs2125739 (T > C) were evaluated. KTD was defined as the presence of urine phosphate wasting and/or proteinuria at 24 h urine analysis. One hundred fifty-eight patients were genotyped, of which 42 (26.6%) experienced signs of KTD. No statistical significant differences were observed among patients with or without KTD regarding age, gender, ethnicity and comorbidities (hypertension and diabetes). The percentage of patients with KTD was higher among those with "GG" genotype at rs1751034 of ABCC4 compared to patients without KTD [6 (14.3%) vs 4 (3.5%), p = 0.01]. No statistical significant differences were observed regarding the distribution of ABCC2 and ABCC10 SNPs. Carriers of "G" allele in homozygous status at rs1751034 of ABCC4 showed a significant association with KTD (Odds Ratio 4.67, 95% CI 1.25-17.46, p = 0.02) in bivariate analysis, but this association was lost in multivariable analysis. A significant association between bone diseases and KTD was observed (Odds Ratio 3.178, 95%CI 1.529-6.603, p = 0.002). According to our results ABCC4 rs1751034 could be a genetic determinant of KTD; however validation studies are needed for therapy personalization. Noteworthy, a strong association between bone disease and KTD was also observed.


Serum lipids in 8- to 35-day-old Zucker rats.
The serum concentrations of triacylglycerols, cholesterol, and phospholipids were measured in 8- to 35-day-old Zucker rats. The animals were killed at 35 days of age. and their phenotype is determined on the basis of the weight of their inguinal subcutaneous fat pads. The serum lipid concentrations in all the rats increased from the 8th day of life, reaching a maximum at day 17 to 21. Weaning produced a large decrease in the concentrations of all three types of lipids. In the obese rats, the serum concentration of triacylglycerols was significantly raised from day 35 of life, that of cholesterol from day 21, and that of phospholipids from as early as day 8. At this age this latter concentration nevertheless cannot be used as a factor for detecting the obese phenotype.


Escherichia coli 4.5S RNA gene function can be complemented by heterologous bacterial RNA genes.
The essential 4.5S RNA gene of Escherichia coli can be complemented by 4.5S RNA-like genes from three other eubacteria, including both gram-positive and gram-negative organisms. Two of the genes encode RNAs similar in size to the E. coli species; the third, from Bacillus subtilis, specifies an RNA more than twice as large. The heterologous genes are expressed efficiently in E. coli, and the product RNAs resemble those produced by cognate cells. We conclude that the heterologous RNAs can replace E. coli 4.5S RNA and that the essential function of 4.5S RNA is evolutionarily conserved. A consensus structure is presented for the functionally related 4.5S RNA homologs.


An assessment of health risk from radiation exposures.
A methodology has been developed to assess potential hazards from low-level exposures to radioactive pollutants. Estimates of dose rates to reference organs from internal and external exposure pathways (inhalation of contaminated air, ingestion of contaminated food or water, immersion in contaminated air, and exposure to contaminated ground surfaces) are computed with contemporary dosimetric models. These dose rates are used in a life-table analysis to estimate the radiation-induced cancer deaths and resultant years of life lost in an exposed cohort of 100,000 persons, all simultaneously liveborn and subject to the same risks of dying from competing causes (including natural background radiation). Estimates of the potential health risk are tabulated for approx. 150 radionuclides for each of the exposure pathways; results are summarized in terms of the probability of premature radiation-induced death for a member of the cohort due to incremental radiation exposure, and the average number of years of life lost per incremental fatality. The estimates of radiation-induced mortality generated by these methods provide a useful means of quantifying radiation risk; however, these estimates may be subject to large uncertainties, and can be best interpreted as a measure of the relative degree of hazard associated with exposures to various radionuclides through several exposure pathways.


[Roles of Toll-like receptor 2 (TLR2) and TLR4 in immune responses to Chlamydia trachomatis genital tract infection in mice].
To evaluate the roles of Toll-like receptor 2 (TLR2) and TLR4 in immune responses to Chlamydia trachomatis (Ct) genital tract infection in mice. The wild type (WT, n=11), TLR2(-/-) (n=14) and TLR4(-/-) (n=11) mice were inoculated intravaginally with 1×10(4) inclusion forming units (IFUs) of live C.muridarum (strain MoPn/Nigg) to establish the models of Ct genital tract infection. The vaginal swabs were taken at the 3rd, 7th, 10th, 17th, 24th, 31st, 38th, 45th day after the infection. Immunofluorescence assay was used to quantify live organisms from each swab. The inflammatory cytokines interleukin-1α (IL-1α), IL-6 and macrophage inflammatory protein 2 (MIP-2) were measured using ELISA. The 70th day post infection, the titers of mouse serum Ct-specific antibody isotypes were determined using an immunofluorescence technique; after the macrophages harvested from peritoneal cavity were infected with MoPn strain for 24 hours, the culture supernatants were examined for the contents of cytokines IL-1α, IL-6 and MIP-2 using ELISA. The harvested splenocytes were stimulated with UV-inactivated chlamydial antigens for 72 hours, and the culture supernatants were measured for the levels of cytokines interferon γ (IFN-γ), IL-17, IL-4 and IL-5 using ELISA. No significant difference was observed in the number of IFUs from the vaginal swabs at any time points post infection among WT, TLR2(-/-) and TLR4(-/-) mice. All mice displayed similar time course of live organism shedding. Until the 38th day, all mice cleared live organism. Macrophages lacking TLR2 produced significantly decreased amounts of IL-1α, IL-6 and MIP-2 compared with those in WT mice; however, there was no significant difference between WT and TLR4(-/-) mice. The vaginal swab samples from TLR2(-/-) mice also had lower levels of inflammatory cytokines. Splenocytes from the three groups of mice all produced high levels of both IFN-γ and IL-17, and low levels of both IL-4 and IL-5, and no significant difference was found among the three groups. The ratio of serum IgG2a/IgG1 in the three groups of mice was greater than 1, and no significant difference was found among the three groups. TLR2, rather than TLR4 mediates early immune response following Ct genital tract infection in mice. However, neither TLR4 nor TLR2 is required for adaptive immune responses induced by Ct genital tract infection.


Mechanistic and structural determinants of NMDA receptor voltage-dependent gating and slow Mg2+ unblock.
NMDA receptor (NMDAR)-mediated currents depend on membrane depolarization to relieve powerful voltage-dependent NMDAR channel block by external magnesium (Mg(o)(2+)). Mg(o)(2+) unblock from native NMDARs exhibits a fast component that is consistent with rapid Mg(o)(2+) -unbinding kinetics and also a slower, millisecond time scale component (slow Mg(o)(2+) unblock). In recombinant NMDARs, slow Mg(o)(2+) unblock is prominent in GluN1/2A (an NMDAR subtype composed of GluN1 and GluN2A subunits) and GluN1/2B receptors, with slower kinetics observed for GluN1/2B receptors, but absent from GluN1/2C and GluN1/2D receptors. Slow Mg(o)(2+) unblock from GluN1/2B receptors results from inherent voltage-dependent gating, which increases channel open probability with depolarization. Here we examine the mechanisms responsible for NMDAR subtype dependence of slow Mg(o)(2+) unblock. We demonstrate that slow Mg(o)(2+) unblock from GluN1/2A receptors, like GluN1/2B receptors, results from inherent voltage-dependent gating. Surprisingly, GluN1/2A and GluN1/2B receptors exhibited equal inherent voltage dependence; faster Mg(o)(2+) unblock from GluN1/2A receptors can be explained by voltage-independent differences in gating kinetics. To investigate the absence of slow Mg(o)(2+) unblock in GluN1/2C and GluN1/2D receptors, we examined the GluN2 S/L site, a site responsible for several NMDAR subtype-dependent channel properties. Mutating the GluN2 S/L site of GluN2A subunits from serine (found in GluN2A and GluN2B subunits) to leucine (found in GluN2C and GluN2D) greatly diminished both voltage-dependent gating and slow Mg(o)(2+) unblock. Therefore, the residue at the GluN2 S/L site governs the expression of both slow Mg(o)(2+) unblock and inherent voltage dependence.


A Team-based Assignment to Integrate Basic Science and Pharmacotherapeutic Principles for Anticancer Agents.
Objective. To implement and evaluate an active-learning, team-based assignment centered on anticancer agents for the integration of basic science and pharmacotherapeutic principles. Methods. Student teams were assigned a specific anticancer agent and were expected to answer a series of questions on the written section of the assignment, followed by a presentation to the class. Each assignment was assessed using a grading rubric that was mapped to the 2013 CAPE educational outcomes. Student perceptions of the assignment were assessed using a short survey. Results. Student cohort performance on the assignment was in the B range (83%) with a mean of 33.2 out of 40. Using the grading rubric, the 12 student cohorts performed particularly well under professionalism (Domain 4.4) that focuses on personal and professional development from CAPE 2013 with means >4 on a 1-5 scale. Student impressions of the assignment suggested that students believed the assignment had a positive effect on their learning and should be continued. Conclusion. The assignment provided a focused review of basic science and pharmacotherapeutic principles and enabled integration of concepts relating to the therapeutic application of anticancer agents, and management of anticancer agent mediated adverse effects. The assignment could contribute toward preparing students for the evolving role of the pharmacist in the management of cancer.


Calculation of protein-ligand binding affinities.
Accurate methods of computing the affinity of a small molecule with a protein are needed to speed the discovery of new medications and biological probes. This paper reviews physics-based models of binding, beginning with a summary of the changes in potential energy, solvation energy, and configurational entropy that influence affinity, and a theoretical overview to frame the discussion of specific computational approaches. Important advances are reported in modeling protein-ligand energetics, such as the incorporation of electronic polarization and the use of quantum mechanical methods. Recent calculations suggest that changes in configurational entropy strongly oppose binding and must be included if accurate affinities are to be obtained. The linear interaction energy (LIE) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods are analyzed, as are free energy pathway methods, which show promise and may be ready for more extensive testing. Ultimately, major improvements in modeling accuracy will likely require advances on multiple fronts, as well as continued validation against experiment.


Neuropeptide Y: potential role in recurrent developmental seizures.
Seizures induce profound plastic changes in the brain, including altered expression of neuropeptide Y (NPY) and its receptors. Here, I discuss a potential role of NPY plasticity in the developmental brain: in a rat model of febrile seizures (FS), the most common type of seizures in infants and young children, NPY expression was up-regulated in hippocampus after experimentally induced FS. Interestingly, NPY up-regulation was associated with an increased seizure threshold for additional (recurrent) FS, and this effect was abolished when an antagonist against NPY receptor type 2 was applied. These findings suggest that inhibitory actions of NPY, released after seizures, exert a protective effect that reduces the risk of seizure recurrence in the developing brain.


Acral lentiginous melanoma: Clinicopathologic and survival differences according to tumour location.
Acral lentiginous melanoma (ALM) is a melanoma subtype associated with atypical locations on the hands and feet and advanced disease at diagnosis. There is a limited understanding of whether the survival is similar for nail, non-nail, lower limb and upper limb ALM patients. We therefore explored clinicopathologic characteristics and melanoma-specific survival of ALM patients according to tumour location. A prospectively collected cohort study was performed of all primary invasive cutaneous acral lentiginous melanomas with known thickness and tumour location reviewed at a tertiary referral centre over 21 years. A total of 101 ALM patients were reviewed from 1994 until 2016. The majority of cases (82/101) occurred on the feet. Hand ALMs were thicker and more likely to be ulcerated than feet ALMs (P = 0.05 and 0.02, respectively); however, survival was not statistically different between these two groups (univariate HR 0.48 P = 0.11, 95% CI, 0.20-1.17; multivariate HR 0.67 P = 0.40, 95% CI, 0.27-1.69, respectively). Non-nail ALM patients had longer survival when compared to nail ALM on univariate analysis (HR 0.40, 95% CI, 0.17 to 0.90) which was accounted for by Breslow thickness and ulceration (multivariate HR 0.56, 95% CI, 0.24 to 1.34). The reduced melanoma-specific survival in nail ALM patients was likely due to their greater thickness and ulceration. Although hand ALMs are thicker and more frequently ulcerated, this is likely due to the higher proportion of nail ALMs present in this location.


Dental problems associated with hypophosphataemic vitamin D resistant rickets.
To review a series of cases of hypophosphataemic vitamin D resistant rickets. SUBJECTS INCLUDED: Seventeen cases, aged between 2 years 1 month and 15 years 9 months at first referral, and with an established diagnosis of vitamin D resistant rickets from twelve families were included in the review. Information was drawn from patient records for follow-up periods between 9 months and 20 years 4 months. All subjects had been referred to the Eastman Dental Hospital between 1973 and 1997. Abscessed non-carious primary and/or permanent teeth were a presenting feature in eleven of the seventeen cases. Although attrition and exposure of the abnormally formed dentine accounted for the route of infection in primary teeth, the route for microbial invasion of pulpal tissues in permanent teeth remained unexplained in a number of patients. The possible part played by infractures of the enamel as a portal of entry for infection is discussed. Enamel defects were observed in only six patients, in three of whom these changes were limited to the primary dentition. Taurodontism of permanent molar teeth was confirmed as a feature of the condition in the more severely affected male subjects.


Secreted phospholipase A2 revisited.
Phospholipase A(2) (PLA(2)) catalyses the hydrolysis of the sn-2 position of glycerophospholipids to yield fatty acids and lysophospholipids. So far, more than 30 enzymes that possess PLA(2) or related activity have been identified in mammals. About one third of these enzymes belong to the secreted PLA(2) (sPLA(2)) family, which comprises low molecular weight, Ca(2+) requiring, secreted enzymes with a His/Asp catalytic dyad. Individual sPLA(2)s display distinct localizations and enzymatic properties, suggesting their specialized biological roles. However, in contrast to intracellular PLA(2)s, whose roles in signal transduction and membrane homoeostasis have been well documented, the biological roles of sPLA(2)s in vivo have remained obscure until recently. Over the past decade, information fuelled by studies employing knockout and transgenic mice as well as specific inhibitors, in combination with lipidomics, has clarified when and where the different sPLA(2) isoforms are expressed, which isoforms are involved in what types of pathophysiology, and how they exhibit their specific functions. In this review, we highlight recent advances in PLA(2) research, focusing mainly on the physiological functions of sPLA(2)s and their modes of action on 'extracellular' phospholipid targets versus lipid mediator production.


[Fast separation and analysis of water-soluble vitamins in spinach by capillary electrophoresis with high voltage].
In capillary electrophoresis, 0-40 kV (even higher) voltage can be reached by a connecting double-model high voltage power supply. In the article, water-soluble vitamins, VB1, VB2, VB6, VC, calcium D-pantothenate, D-biotin, nicotinic acid and folic acid in vegetable, were separated by using the high voltage power supply under the condition of electrolyte water solution as running buffer. The separation conditions, such as voltage, the concentration of buffer and pH value etc. , were optimized during the experiments. The results showed that eight water-soluble vitamins could be baseline separated in 2.2 min at 40 kV applied voltage, 25 mmol/L sodium tetraborate buffer solution (pH 8.8). The water-soluble vitamins in spinach were quantified and the results were satisfied. The linear correlation coefficients of the water-soluble vitamins ranged from 0.9981 to 0.9999. The detection limits ranged from 0.2 to 0.3 mg/L. The average recoveries ranged from 88.0% to 100.6% with the relative standard deviations (RSD) range of 1.15%-4.13% for the spinach samples.


Solitary Large Keratoacanthomas of the Head and Neck: An Observational Study.
Solitary large keratoacanthomas (KAs) of the head and neck present a management dilemma, as no reliable means to predict the clinical course is available. Although typically considered a low-grade tumor, KAs are reported to invade/metastasize, prompting more aggressive treatment. There is little published regarding factors that predict when a KA behaves more like an aggressive squamous cell carcinoma (SCC). To study the clinical and pathologic features of large solitary head and neck KAs and assess response to intralesional methotrexate (IL-MTX) as well as predictors of clinical course. An observation study of 14 patients with large solitary head and neck KAs were treated with IL-MTX and then excised by Mohs micrographic surgery (MMS) at a later time point. Clinical presentation, treatment, response, and pathology were recorded. Features of classic KAs were compared with those with an aggressive SCC course. Ten of fourteen lesions responded with necrosis, a decrease in size and/or pain, and histological clearance on MMS. However, 4/14 lesions continued to have progression despite IL-MTX therapy. These showed persistent pain, perineural invasion, moderate/poor differentiation, and an infiltrative growth. Small sample size. Significant pain, or continued growth may suggest an underlying aggressive SCC in clinically classic large KAs. In these cases, surgical management with assessment for high-risk tumor features is recommended.


Telomere length predicts neutrophil recovery in the absence of G-CSF after autologous peripheral blood stem cell transplantation.
Haemopoietic regeneration after autologous peripheral blood progenitor cell (PBPC) transplantation can be delayed in some patients despite adequate infusion of CD34(+) cells. This suggests variability in the proliferation potential of the implanted cells, a capacity that may be predicted by their telomere length. To test this theory, telomere length was measured on stored apheresis samples from 36 patients aged 46.6+/-11.1 years, who had undergone successful autologous PBPC transplantation with a median of 5.6 x 10(6)/kg (1.3 x 10(6)-36.1 x 10(6)/kg) CD34(+) cells. The mean PBPC telomere length for the cohort was 9.4+/-2.3 kbp. For patients who did not receive G-CSF post transplantation (n=7), days to absolute neutrophil recovery (ANC), >/=0.1, 0.5 and 1.0 x 10(9) cells/l, were significantly inversely correlated with telomere length of the infused PBPC (r=-0.88, -0.81, -0.77, respectively; P<0.05,). However, no correlation was found for patients who received G-CSF from day 1 post transplantation (n=20). These data suggest that for transplantation with sufficient CD34(+) cells, neutrophil recovery is less efficient in patients receiving infusions of cells with short telomeres, but this deficiency can be corrected with adequate post transplantation administration of G-CSF. Bone Marrow Transplantation (2004) 34, 439-445. doi:10.1038/sj.bmt.1704607 Published online 19 July 2004


Preparation of new nitrogen-bridged heterocycles. 59. Syntheses and intramolecular interactions of 3-(acylmethylthio)- and 3-[(3-ethoxycarbonyl-2-propenyl)thio]thieno[3,4-b]indolizine derivatives.
Various thieno[3,4-b]indolizine derivatives having an acylmethylthio or (3-ethoxycarbonyl-2-propenyl)thio group at the 3-position which could not be obtained by a conventional method were prepared by a new procedure using cyanoethyl group as a protecting group and their intramolecular arene-pi interactions were investigated. In the (1)H-NMR spectra of these thieno[3,4-b]indolizines, the low-field shifts (delta 0.10-0.33 ppm) for the 5-protons were observed in comparison with those of 3-(methylthio)thieno[3,4-b]indolizines as a standard. The UV spectra also exhibited a characteristic absorption band at 425-445 nm attributable to the arene-pi interaction but their intensities were generally lower than those of 3-(arylmethylthio)thieno[3,4-b]indolizines. In their X-ray analyses, the anti conformation for 3-(acylmethylthio)thieno[3,4-b]indolizines and the gauche one for the 3-(3-ethoxycarbonyl-2-propenyl)thio derivatives were exhibited.


Prenatal Ethanol-induced Effect on Cell Count of Pars Distalis of Pituitary Gland in the Rat Pups.
To determine the effects of prenatal administration of ethanol on cell count in pars distalis of pituitary gland in the rat pups. Experimental study. Department of Anatomy, College of Physicians and Surgeons Pakistan, Regional Centre, Islamabad, Pakistan, from April 2014 to April 2015. Sixteen female rats (Sprague Dawley) were selected by random sampling method. Rats were mated and divided into control group A and experimental group B. From gestational day 10 to 18, mother rats received intraperitoneal injection of ethanol (Group B) and normal saline (Group A). Mother rats were allowed to complete their gestation and deliver spontaneously. When pups were born, only male pups were selected for the study. They were reared till day five. At 5ᵗʰ; day, pituitary glands were taken out and histological study was done in PAS-OG stain. Cell count was made in unit area (10,000 μ2) of pars distalis of pituitary gland. Student t-test was applied for analysing the data of cell counts in unit area. Mean acidophil count was reduced in experimental group (70.19 ± 11.4) as compared to control group (92.65 ± 8.52, p<0.001). Mean basophil count was reduced in experimental group (27.05 ± 3.9) in comparison to control group (34.03 ± 7.9, p<0.001). Mean chromophobe count was increased (131.95 ± 10.7) in experimental group against the control group (104.62 ± 7.62, p < 0.001). Pups exposed to ethanol during gestation, showed significant reduction in acidophil and basophil count while increase in chromophobe cell count in pars distalis of pituitary gland.


Biosynthesis of streptomycin. Enzymatic formation of dihydrostreptomycin 6-phosphate from dihydrostreptosyl streptidine 6-phosphate.
Incubation of O-alpha-L-dihydrostreptose (1 leads to 4) streptidine 6-phosphate (I) with a protein-free extract from Streptomyces griseus as endogenous donor and a cell-free extract from this organism led to formation of dihydrostreptomycin 6-phosphate (II). The product was identified by paper chromatography and by its degradation to dihydrostreptobiosamine (III). II was not formed when either the donor solution or the dialysed cell-free extract was omitted. The results corroborate the role of I as intermediate in streptomycin biosynthesis. The synthesis of I from dTDP-L-dihydrostreptose, streptidine 6-phosphate and a dihydrostreptosyltransferase from S. griseus has been shown previously.


High mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling promotes progression of gastric cancer.
High mobility group box 1 and toll-like receptor 4/myeloid differentiation factor 88 signaling pathway have been indicated to have oncogenic effects in many cancers. However, the role of high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling pathway in the development of gastric cancer remains unclear. In this study, we demonstrated that high mobility group box 1, toll-like receptor 4, and myeloid differentiation factor 88 were overexpressed in gastric cancer tumors compared with the adjacent non-tumor tissues. The overexpression of high mobility group box 1, toll-like receptor 4, and myeloid differentiation factor 88 were correlated with tumor-node-metastasis stage (p = 0.0068, p = 0.0063, p = 0.0173) and lymph node metastasis (p = 0.0272, p = 0.0382, and p = 0.0495). Furthermore, we observed that knockdown of high mobility group box 1 by high mobility group box 1-small interfering RNA suppressed the expression of toll-like receptor 4 and myeloid differentiation factor 88. Blockage of high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling by high mobility group box 1-small interfering RNA resulted in elevation of apoptotic ratio and inhibition of cell growth, migration, and invasion by upregulating Bax expression and downregulating Bcl-2, matrix metalloproteinase-2, nuclear factor kappa B/p65 expression, and the nuclear translocation of nuclear factor kappa B/p65 in gastric cancer cells. Our findings suggest that high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling pathway may contribute to the development and progression of gastric cancer via the nuclear factor kappa B pathway and it also represents a novel potential therapeutic target for gastric cancer.


Oxidative DNA damage & repair: An introduction.
This introductory article should be viewed as a prologue to the Free Radical Biology & Medicine Special Issue devoted to the important topic of Oxidatively Damaged DNA and its Repair. This special issue is dedicated to Professor Tomas Lindahl, co-winner of the 2015 Nobel Prize in Chemistry for his seminal discoveries in the area repair of oxidatively damaged DNA. In the past several years it has become abundantly clear that DNA oxidation is a major consequence of life in an oxygen-rich environment. Concomitantly, survival in the presence of oxygen, with the constant threat of deleterious DNA mutations and deletions, has largely been made possible through the evolution of a vast array of DNA repair enzymes. The articles in this Oxidatively Damaged DNA & Repair special issue detail the reactions by which intracellular DNA is oxidatively damaged, and the enzymatic reactions and pathways by which living organisms survive such assaults by repair processes.


To mix or not to mix? A rapid systematic review of heterologous prime-boost covid-19 vaccination.
Coronavirus disease 2019 (COVID-19) has had an enormous impact worldwide, and vaccination is believed to be the method that will control the pandemic. Several types of vaccines developed using different platforms have been authorized, but the immunogenicity and reactogenicity of heterologous prime-boost vaccination with different vaccines remain largely unclear. Electronic databases including PubMed, Embase, medRxiv, Research Square, and SSRN were searched to investigate the immunogenicity and reactogenicity associated with heterologous vaccination.As of 30 June 2021, four trials including 1,862 participants were identified. Heterologous administration of BNT162b2 (BNT) in ChAdOx1 (ChAd)-primed participants (ChAd/BNT) showed noninferior immunogenicity to homologous BNT administration (both prime and booster were BNT vaccines, BNT/BNT) with tolerable reactogenicity and higher T cell responses. Compared with homologous ChAdOX1 vaccination (ChAd/ChAd), heterologous ChAd/BNT was found to elicit higher immunogenicity (ChAd/BNT vs. ChAd/ChAd, antibody titer ratio: 9.2). Our systematic review found robust immunogenicity and tolerable reactogenicity of heterologous administration of a BNT162b2 boost in ChAdOx1-primed participants. An additional benefit of stronger T cellular immunity was also observed. Heterologous vaccination is a reasonable and feasible strategy to combat COVID-19. Further studies are warranted to confirm the benefits and identify the optimal combinations, doses, and intervals.


Immunogold staining of intermediate-sized filaments of the vimentin type in human skin: a postembedding immunoelectron microscopic study.
We have studied the localization of vimentin in normal human skin at the ultrastructural level using a monoclonal mouse anti-vimentin antibody and a postembedding immunogold-staining technique on thin sections of Lowicryl K4M embedded biopsies. Selective immunogold labeling of intermediate-sized filaments (IF) of epidermal Langerhans cells and melanocytes and of dermal fibroblasts was demonstrated. The IF of fibroblasts were more intensely stained than those of the epidermal dendritic cells; cell processes and dendrites of all three cell populations exhibited a greater number of IF and more pronounced immunogold-labeling than the perinuclear cytoplasm, relating IF of the vimentin type to dendrite formation and/or function. The method described is an appropriate tool for immunoelectron microscopic studies of IF of the vimentin type in situ.


Medical management of claudication.
Peripheral artery disease (PAD) is common and associated with significant morbidity and mortality. Optimal medical management of PAD is required for each patient, irrespective of the decision regarding lower extremity revascularization. The goals include reducing cardiovascular morbidity and mortality and improving quality of life. The approach should consist of aggressive and individualized risk factor modification including smoking cessation, antiplatelet therapy, a statin, and an angiotensin-converting enzyme inhibitor. Exercise is critical for cardiovascular health and highly effective for improving claudication symptoms. Cilostazol may be considered for symptomatic treatment in certain patients.


Morphological and microbiological signs of endogenous C-virus in human oocytes.
Human oocytes in different stages of maturation were obtained by follicular aspiration from women given Clomovid and Gonadex. Particles similar to type-C virus were observed in three out of 16 oocytes. The particles were irregularly distributed along the oocyte membrane. They were seen both in a state of budding and lying free in the perivitelline space. Reverse transcriptase activity was detected in three out of nine samples of follicular fluid obtained from women other than those donating the oocytes. The supernatants from bat lung cells and dog thymus cells cultivated with oocytes or follicular fluids were tested for reverse transcriptase. An increased activity was observed only transiently in one case. It is assumed that these findings indicate the expression of endogenous retroviruses in human oocytes.


Weyl law for open systems with sharply divided mixed phase space.
A generalization of the Weyl law to systems with a sharply divided mixed phase space is proposed. The ansatz is composed of the usual Weyl term which counts the number of states in regular islands and a term associated with sticky regions in phase space. For a piecewise linear map, we numerically check the validity of our hypothesis, and find good agreement not only for the case with a sharply divided phase space but also for the case where tiny island chains surround the main regular island. For the latter case, a nontrivial power law exponent appears in the survival probability of classical escaping orbits, which may provide a clue to develop the Weyl law for more generic mixed systems.


Compressive stress inhibits proliferation in tumor spheroids through a volume limitation.
In most instances, the growth of solid tumors occurs in constrained environments and requires a competition for space. A mechanical crosstalk can arise from this competition. In this article, we dissect the biomechanical sequence caused by a controlled compressive stress on multicellular spheroids (MCSs) used as a tumor model system. On timescales of minutes, we show that a compressive stress causes a reduction of the MCS volume, linked to a reduction of the cell volume in the core of the MCS. On timescales of hours, we observe a reversible induction of the proliferation inhibitor, p27Kip1, from the center to the periphery of the spheroid. On timescales of days, we observe that cells are blocked in the cell cycle at the late G1 checkpoint, the restriction point. We show that the effect of pressure on the proliferation can be antagonized by silencing p27Kip1. Finally, we quantify a clear correlation between the pressure-induced volume change and the growth rate of the spheroid. The compression-induced proliferation arrest that we studied is conserved for five cell lines, and is completely reversible. It demonstrates a generic crosstalk between mechanical stresses and the key players of cell cycle regulation. Our results suggest a role of volume change in the sensitivity to pressure, and that p27Kip1 is strongly influenced by this change.


A three-year aeropalynological study in Estepona (southern Spain).
An aeropalynological study was carried out in the atmosphere of Estepona, a very popular tourist resort situated in the "Costa del Sol", (southern Spain) based on the data obtained during a three year air-monitoring programme (March 1995 to March 1998) using a volumetric pollen trap. The 34 taxa that reached a 10-day mean air pollen concentration equal to or greater than 1 grain of pollen/m(3) of air are reflected in the calendar. The first 10 taxa, in order of abundance, were: Cupressaceae, Olea europaea, Quercus, Poaceae, Urticaceae, Plantago, Pinus, Chenopodiaceae-Amaranthaceae, Ericaceae and Castanea, the first 3 of which accounted for approximately 56 % of the annual total pollen count. The greatest diversity of pollen type occurred during spring, while the highest pollen concentrations were reached from February-June, when approximately more than 80 % of the annual total pollen was registered. The lowest concentrations were obtaining during January, August and September. The annual quantity of pollen collected, the intensity and the dates on which the maximum peaks were recorded differed for the 3 years studied, which can be explained by reference to various meteorological parameters, especially rainfall and temperature. The pollen calendar spectrum is typically Mediterranean and similar to those of nearby localities, in which many pollen types are represented and the long tails indicating long flowering periods.


On the hydration state of amino acids and their derivatives at different ionization States: a comparative multinuclear NMR and crystallographic investigation.
(2)D, (13)C, (14)N, and (17)O NMR and crystallographic data from the literature were critically evaluated in order to provide a coherent hydration model of amino acids and selected derivatives at different ionization states. (17)O shielding variations, longitudinal relaxation times (T(1)) of (2)D and (13)C and line widths (Δν(1/2)) of (14)N and (17)O, may be interpreted with the hypothesis that the cationic form of amino acids is more hydrated by 1 to 3 molecules of water than the zwitterionic form. Similar behaviour was also observed for N-acetylated derivatives of amino acids. An exhaustive search in crystal structure databases demonstrates the importance of six-membered hydrogen-bonded conjugated rings of both oxygens of the α-carboxylate group with a molecule of water in the vicinity. This type of hydrogen bond mode is absent in the case of the carboxylic groups. Moreover, a considerable number of structures was identified with the propensity to form intramolecular hydrogen bond both in the carboxylic acid (NH⋯O=C) and in the carboxylate (NH ⋯ O(-)) ionization state. In the presence of bound molecules of water this interaction is significantly reduced in the case of the carboxylate group whereas it is statistically negligible in the carboxylic group.


Concentration of adenine nucleotides and glycolytic intermediates in erythrocytes, liver and muscle tissue in rats after thermal injury.
A 40% total body scald burn was produced in mature rats. An immediate decrease of the metabolic rate was followed by a hypermetabolic response similar to that described in human beings following thermal injury. The amounts of adenine nucleotides and hexosemonophosphates were monitored in three types of cells: erythrocytes (which lack mitochondria), skeletal muscle cells (which to a certain extent can rely on an increased glycolysis for their increased energy supply) and liver cells (which are sensitive to hypoxia and have a great need of energy in the post-traumatic period). Only in the liver did the energy charge derived from the individual concentrations of adenine nucleotides change significantly, but remained virtually constant in muscle cells and erythrocytes despite a change in total oxygen consumption, from minus 85% (in the early phase) to plus 30% (in the later phase) of the expected value. Altered energy metabolism in liver and muscle tissues is related to wound healing, whereas the biochemical changes in erythrocytes is related to the degree of haemolysis of younger cells induced by the thermal injury.