Intralymphatic histiocytosis in a patient with lung adenocarcinoma treated with pembrolizumab: a case report.
Pembrolizumab, an anti-programmed cell death-1 protein monoclonal antibody, is effective for patients with advanced non-small-cell lung cancer. However, immune checkpoint inhibitors such as pembrolizumab induce various immune-related adverse events, involving the lung, liver, gastrointestinal, endocrine system, and skin. Intralymphatic histiocytosis (ILH) is a rare, chronic cutaneous disorder with a reactive inflammatory component, which often occurs in patients with rheumatoid arthritis. We present a 67-year-old man with lung adenocarcinoma who developed ILH associated with pembrolizumab treatment. He was treated with palliative thoracic radiotherapy for superior vena cava syndrome. Subsequently, he received four cycles of pembrolizumab. Approximately 2.5 months after the initiation of pembrolizumab, he developed erythema on the trunk of his body. Based on findings of skin biopsies, he was diagnosed with pembrolizumab-induced ILH. Moreover, the upregulation of tumor necrosis factor-α was observed during pembrolizumab therapy. This is the first report of ILH induced by pembrolizumab in a patient with lung adenocarcinoma.


Inhaled proteins: challenges and perspectives.
Due to recent developments in biochemical engineering and in the understanding of the physiopathology of many diseases, therapeutic biologics are expected to become of increasing importance. Pulmonary delivery of these proteins could constitute an attractive, non-invasive alternative to parenteral delivery. It can be considered for either topical use for treating lung diseases or for systemic use for treating a variety of other diseases. However, administration of proteins to the lungs presents several challenges such as the need for appropriate formulation strategies to overcome high inter-particle interactions and physico-chemical degradation that can lead to loss of biological activity and/or safety issues. In addition, various lung clearance mechanisms have to be avoided to provide a sufficient level of intact protein in the lungs. If systemic action is desired, it is also necessary for the molecule to cross the alveolar epithelium, which is particularly challenging for large proteins with many hydrophilic domains. The purpose of this article is to review the main challenges in the formulation of proteins for inhalation and the possible strategies that can be applied. Because of the particular success of dry formulations in stabilising proteins, there is a special focus on their development, along with the drying techniques and stabilising excipients used. Finally, an overview is given of the existing commercial preparations and of the main clinical developments in inhaled proteins for either topical or systemic applications.


Personalized medicine: present and future of breast cancer management.
Breast cancer is the first cause of cancer in women worldwide. Recent molecular analyses have shown that it is not a single disease but a mixture of several diseases with different biological behaviors, which should lead to treatment customization for each patient. Personalized medicine is based on tumor and/or patient molecular profiles. This new way to think oncology is currently applied at different stages of breast cancer management, including prognosis, prediction of treatment efficacy, and development of new therapies via new kinds of clinical trials. These trials are not only based on tumor site but also on tumor genetic characterization using genomic tools such as gene expression profiling, array-CGH or next-generation sequencing technologies. The aim of personalized medicine is to tailor treatment according to the specificities of a single disease in a given patient. In this review, we present the advances in treatment personalization which are currently used in daily practice as well as the technologies and therapies under investigation in various clinical trials.


An experimental study on the physical properties of the cupula. Effect of cupular sectioning on the ampullary nerve action potential.
The frog posterior semicircular canal (PSC) was isolated and a part of the ampullary wall was cut to allow removal of the cupula from the crista. The cupula was replaced on the crista and the PSC ampullary action potential was recorded. The cupula was again removed and was sectioned in half, either in the plane vertical to the crista (vertical sectioning), or in the plane parallel to the crista (horizontal sectioning). The sectioned half of the cupula was then replaced on the crista. The action potentials after replacement of the vertical or horizontal segments of the cupula were compared to those achieved when the entire cupula was replaced. After vertical sectioning, the action potentials were significantly reduced; they were 50.3% of the completely replaced cupula when a small stimulus was used and 79.1% when a large stimulus was used. A reduced attachment surface between the cupular base and the crista is possibly responsible for the decreased action potential in the vertically sectioned specimen. After horizontal sectioning, the action potentials were 64.5% for the small stimulus and 108.2% for the large stimulus. These results indicate that elicited responses are related to the height of the cupula and the deflection angle. This further suggests that the movement of the cupula is represented by that of the elastic system.


Lymphopoiesis in the nude fetal thymus following sympathectomy.
This study was carried out to examine the innervation of the nude fetal thymus during ontogeny and to see if lymphopoietic activity would occur within these thymic lobes in the absence of sympathetic neuronal input. Fetal thymic rudiments from nu/nu mice were removed and examined for galoxylic acid-induced histofluorescence to detect the catecholaminergic nerves. Some of these lobes were organ cultured for 5 to 7 days in the presence of deoxyguanosine to eliminate any existing lymphoid cells within the rudiments. Such "nonlymphoid" thymic rudiments were implanted into the anterior eye chambers of syngenic BALB/c mice (heterozygous) from which cervical sympathetic ganglia and part of the sympathetic chain had been surgically removed (right side) one week earlier. The left side was only sham operated. The thymic implants were allowed to grow for up to 21 days on both sides; they were then removed and examined by histofluorescence, immunofluorescence, and light microscopy. The results indicate for the first time that the nude fetal thymus is innervated by sympathetic nerves and that following sympathectomy the nude thymus is able to sustain lymphopoietic activity and generate lymphoid cells which have characteristics present on thymocytes during in vivo development in normal mice, such as binding to peanut agglutinin and expression of Thy-1 antigen. The relationship between the presence of sympathetic inhibitory influence and the thymic atrophy seen in the nude mice during ontogeny, is being investigated.


Insect stings: clinical features and management.
In human beings, local and systemic reactions can be caused both by blood-sucking insects and by venomous insect stings. In Central Europe, the insects that most commonly cause such reactions are honeybees, certain social wasps, mosquitoes, and flies. This article is based on a selective literature review, including guidelines from Germany and abroad. Insect venom induces a toxic reaction at the site of the sting. Large local reactions are due to allergy and occur in up to 25% of the population; as many as 3.5% develop IgE-mediated, potentially life-threatening anaphylaxis, of which about 20 people die in Germany each year. Mastocytosis is found in 3% to 5% of patients with sting anaphylaxis, rendering these patients prone to very severe reactions. Blood-sucking by hematophagous insects can elicit a local allergic reaction, presenting as a wheal or papule, in at least 75% of the population. Large local reactions may ensue, but other diseases are rare. The acute symptoms of an insect sting are treated symptomatically. Patients who have had a systemic reaction or a large local reaction due to insect allergy must take permanent measures to avoid further allergen contact, and to make sure they can treat themselves adequately if stung again. Most patients with systemic anaphylactic reactions to bee or wasp stings need specific immunotherapy. Insect stings can cause severe disease. Anaphylaxis due to bee or wasp stings is not a rare event; specific immunotherapy protects susceptible persons from further, potentially life-threatening reactions.


Mortality and morbidity due to exposure to ambient particulate matter.
The aim of this study was to investigate spatial variation and health risk of the exposure to PM2.5 (particulate matter with a diameter of 2.5 µm or less) and PM10 (particulate matter with a diameter of 10 µm or less) in Sabzevar, Iran. PM2.5 and PM10 were measured during three campaigns from April to November 2017, in 26 sampling points. Spatial analysis was performed using kriging and autocorrelations (Moran's index) model in Arc GIS software. Relationship between exposure to the PM2.5 and PM10 and their health impacts were investigated by AirQ 2.2.3 software. The mean concentrations (and standard deviation) of PM 2.5 and PM10 over the entire study period were 32.54 (37.28) and 42.61 (47.76) μg/m3, respectively, which were higher than the guideline of World Health Organization. According to the spatial analysis, the maximum concentrations of PM2.5 and PM10 were around the main highway (beltway) which placed all over the south of Sabzevar. According to the Moran's index, the emission patterns for PM2.5 (Z-score = 2.53; P-value = 0.011) and PM10 (Z-score = 2.82; P-value = 0.004) were clustered. The attributable percentage (AP) of total mortality related to PM2.5 and PM10 were 3.544% (95% confidence interval (CI): 2.623-4.447%) and 2.055% (95% CI: 1.379-2.721%) per increasing each 10 μg/m3 of these pollutants, respectively. According to observed results, it is suggested that the beltway and other pollution sources, such as industries, should be placed at a greater distance from the city, to reduce PM amounts in residential areas.


Use of an Android application "clinometer" for measurement of head down tilt given during subarachnoid block.
Head down tilt is given to patients after sub arachnoid block for adjustment of height of block. However, the amount of tilt given is subjective and cannot be documented. We used an android application named "clinometer" to measure exact degree of tilt given by anesthesiologists as their routine practice. This observational study, at a medical college hospital, was done in 130 patients given sub arachnoid block for lower abdominal surgeries. We observed and documented vital data of patients and measured tilt given by application "clinometer." We observed that the application was easy to use and measured tilt each time. The result obtained can be documented, digitally saved and transferred. In 130 patients studied, we observed incidence of degree of tilt as follows: 6-8° tilt in 38 patients (29.23%), 8-10 in 36 patients (27.69%), 10-12 in 30 patients (23.08%), 12-14 in 12 patients (9.23%) and 14-16° tilt in 14 patients (10.77%). Use of application was received with enthusiasm by practicing anesthesiologists. Various possible uses of this application are discussed.


Direct evidence for rifampicin-promoted readthrough of the partial terminator tL7 in the rpoBC operon of Escherichia coli.
The RNA polymerase subunits beta and beta' of Escherichia coli, encoded by the genes rpoB and rpoC, are co-transcribed with four 50 S ribosomal protein genes, rplKAJL. After treatment with the antibiotic rifampicin a partial uncoupling of rpoBC from rplKAJL transcription occurs. We have been investigating the role played in uncoupling by tL7, an 80% efficient terminator of transcription present in the 319 bp intercistronic space between rplL and rpoB, using S1 nuclease mapping of transcripts produced in vivo in normal (rpoBC haploid) strains. Our results show directly that rifampicin stimulates readthrough of tL7 on the chromosome by approximately twofold, an effect sufficient to explain the observed increase in beta beta' protein synthesis. We also provide preliminary evidence for the map position of PL7, and show that both this and P beta, two very weak promoters which might in principle be activated by rifampicin, are not in fact stimulated by the drug.


Effects of morphine on place conditioning and ERK1/2 phosphorylation in the nucleus accumbens of psychogenetically selected Roman low- and high-avoidance rats.
Extracellular signal-regulated kinase (ERK1/2) phosphorylation is critical for neuronal and behavioural functions; in particular, phosphorylated ERK1/2 (pERK1/2) expression in the nucleus accumbens (Acb) of the rat is stimulated by addictive drugs with the exception of morphine, which decreases accumbal ERK1/2 phosphorylation in the Sprague-Dawley and Wistar rats. The psychogenetically selected Roman low- (RLA) and high-avoidance (RHA) rats differ behaviourally and neurochemically in many responses to addictive drugs. In particular, morphine elicits a greater increment in locomotor activity and in dopamine transmission in the Acb of RHA vs RLA rats. However, the effects of morphine on place conditioning (conditioned place preference (CPP)) and ERK1/2 phosphorylation in the Roman lines remain unknown. To characterize in the Roman lines the reinforcing properties of morphine (i.e. morphine-elicited CPP acquisition) and the relationship between these properties and its effects on ERK1/2 phosphorylation in the Acb, the behavioural effects of morphine were evaluated in a place-conditioning apparatus and ERK1/2 phosphorylation was assessed by immunohistochemistry in the shell and core subregions of the Acb of rats both acutely administered with morphine or undergoing conditioning. Morphine elicited CPP in both Roman lines and decreased pERK1/2 expression in the Acb of RLA but not RHA rats. Such decrease was prevented by conditioning. These findings indicate that the selective breeding of the Roman lines has generated a divergence, in terms of morphine-elicited pERK1/2 expression but not of morphine-elicited CPP, between RLA and RHA rats and sustain the observation that changes in pERK1/2 expression in the Acb are not a requisite for the reinforcing effects of morphine.


[Non-intensive care of COVID-19 patients: treatment plan and therapeutic orientations.]
Despite the recent emergence of COVID-19 and the absence of a specific cure, the hospital treatment of patients affected by this virus is well established. It is based on symptomatic treatments including oxygen therapy, physiotherapy and anticoagulation therapy. The treatment plan and potential therapeutic limitations must be well defined and adapted to the severity, predisposition and wishes of the patient.


A novel mortality risk score predicting intensive care mortality in cardiogenic shock patients treated with veno-arterial extracorporeal membrane oxygenation.
Mortality after veno-arterial extracorporeal membrane oxygenation (VA-ECMO) implantation remains a major problem in patients with cardiogenic shock. Our objective was to assess the utility of the SOFA score in combination with markers of right ventricular (RV) dysfunction in predicting mortality in the ICU. Data were retrospectively obtained from all adult patients (n=103) who were treated with VA-ECMO between November 2004 and January 2016. The primary outcome of this study was ICU mortality after VA-ECMO implantation. Using the clinical, demographic and echocardiographic data, we developed a novel mortality risk score, the SOFA-RV score, which combine RV-function to the SOFA score at the time of VA-ECMO implantation. Out of 103 patients, 37 (36%) died in the ICU. The median duration of VA-ECMO support was 7 days [IQR 4-11], mean age 49 ± 16 years, and 54% were male. SOFA-RV score has an AUC of 0.70, and was significantly better than SOFA alone (AUC of 0.57) in predicting ICU mortality. In addition, SAVE and MELD scores were not able to predict ICU mortality. Adding RV-function to the existing SOFA score improves significantly the prediction of ICU mortality in patients on VA-ECMO. Dedicated evaluation of RV function in patients with VA-ECMO is therefore recommended.


Loop-mediated isothermal amplification (LAMP) assays for the detection of Theileria annulata infection in China targeting the 18S rRNA and ITS sequences.
We have developed two loop-mediated isothermal amplification (LAMP) assays for the detection of Theileria annulata, an economically important cattle disease in China that occurs in subtropical and tropical areas. These assays target the ribosomal RNA (18S rRNA) and ITS LAMP sequences. The primer set for each gene target consists of four primers, and each set recognizes six distinct regions on the target gene to allow for the highly specific detection of T. annulata. The specific ladder bands were amplified from the autologous genomic DNA of four Chinese-laboratory-preserved standard T. annulata stocks, and there were no cross-reactions with the genomic DNA of normal bovine blood and other protozoan species. The LAMP assays were sufficiently sensitive to detect 0.1 pg/μl of genomic DNA. Furthermore, DNA extracted from blood collected from cattle experimentally infected with T. annulata (18-105 days post-infection) was amplified, demonstrating the high sensitivity of these primers. Of the 351 field samples collected from China, 24.5% were positively detected by two LAMP primers, and 18.2% were found to be positive for T. annulata infection by PCR. These results indicate that the LAMP assay could be a potential diagnostic tool for epidemiological studies of T. annulata infection in China.


Mechanisms of gradient detection: a comparison of axon pathfinding with eukaryotic cell migration.
The detection of gradients of chemotactic cues is a common task for migrating cells and outgrowing axons. Eukaryotic gradient detection employs a spatial mechanism, meaning that the external gradient has to be translated into an intracellular signaling gradient, which affects cell polarization and directional movement. The sensitivity of gradient detection is governed by signal amplification and adaptation mechanisms. Comparison of the major signal transduction pathways underlying gradient detection in three exemplary chemotaxing cell types, Dictyostelium, neutrophils, and fibroblasts and in neuronal growth cones, reveals conserved mechanisms such as localized PI3 kinase/PIP3 signaling and a common output, the regulation of the cytoskeleton by Rho GTPases. Local protein translation plays a role in directional movement of both fibroblasts and neuronal growth cones. Ca(2+) signaling is prominently involved in growth cone gradient detection. The diversity of signaling between different cell types and its functional implications make sense in the biological context.


Disseminated Cryptococcus neoformans infection associated to COVID-19.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus associated with immune dysregulation. The use of immunosuppressant drugs as part of COVID-19 treatment (such as Tocilizumab or high -dose corticosteroids) increases the risk of opportunistic infections. Here we present a case of a patient without prior immunosuppression that developed a serious fungal infection after the use of high dose corticosteroids in the setting of severe COVID-19 and cryptogenic organizing pneumonia.


Rhinovirus Infections and Associated Respiratory Morbidity in Infants: A Prospective Cohort Study.
Risk factors promoting rhinovirus (RV) infections are inadequately described in healthy populations, especially infants. To determine the frequency of symptomatic and asymptomatic RV infections and identify possible risk factors from host and environment among otherwise healthy infants. In a prospective birth cohort, respiratory health was assessed in 41 term-born infants by weekly telephonic interviews during the first year of life, and weekly nasal swabs were collected to determine RV prevalence. In a multilevel logistic regression model, associations between prevalence and respiratory symptoms during RV infections and host/environmental factors were determined. Twenty-seven percent of nasal swabs in 41 infants tested positive for RVs. Risk factors for RV prevalence were autumn months [odds ratio (OR) = 1.71, P = 0.01, 95% confidence interval (CI): 1.13-2.61], outdoor temperatures between 5 and 10°C (OR = 2.33, P = 0.001, 95% CI: 1.41-3.86), older siblings (OR = 2.60, P = 0.001, 95% CI: 1.50-4.51) and childcare attendance (OR = 1.53, P = 0.07, 95% CI: 0.96-2.44). Fifty-one percent of RV-positive samples were asymptomatic. Respiratory symptoms during RV infections were less likely during the first 3 months of life (OR = 0.34, P = 0.003, 95% CI: 0.17-0.69) and in infants with atopic mothers (OR = 0.44, P = 0.008, 95% CI: 0.24-0.80). Increased tidal volume (OR = 1.67, P = 0.03, 95% CI: 1.04-2.68) and outdoor temperatures between 2 and 5°C (OR = 2.79, P = 0.02, 95% CI: 1.17-6.61) were associated with more symptoms. RVs are highly prevalent during the first year of life, and most infections are asymptomatic. Frequency of RV infections is associated with environmental factors, while respiratory symptoms during RV infections are linked to host determinants like infant age, maternal atopy or premorbid lung function.


Tunable arrangement of hydrogel and cyclodextrin-based metal organic frameworks suitable for drug encapsulation and release.
The present study focused on the integration of beta-cyclodextrin based metal-organic frameworks (β-CDMOF) with polymer to obtain hybrid materials with advantageous properties compared to traditional single-component polymers or metal-organic frameworks (MOF) matrixes. We fabricated two complexes with different morphology and structure. During the in situ growth of β-CDMOF around the hydrogel, potassium ions on polysaccharides gradually dissociated to participate in the growth of crystals, while other potassium ions on the carboxylic acid groups provided bridges between crystals and hydrogel, forming a necklace-shaped complex (SHPs@β-CDMOF). Hydrogen bonding and coordination interactions between β-CDMOF and hydrogel are present in a dendritic sandwich-shaped complex (β-CDMOF@SHPs). Furthermore, using the hydrophobic molecule curcumin as a model drug, we have demonstrated that SHPs@β-CDMOF and β-CDMOF@SHPs hybrid materials stabilize the included drug and have potential for controlled drug release. Collectively, the integration of MOF with polymer holds a great promise for drug delivery applications.


The necessity-concerns framework predicts adherence to medication in multiple illness conditions: A meta-analysis.
This meta-analysis investigated whether beliefs in the necessity and concerns of medicine and the necessity-concerns differential are correlated with medication adherence on a population level and in different conditions. An electronic search of Web of Science, EMBASE, PubMed and CINAHL was conducted for manuscripts utilising the Beliefs about Medicines Questionnaire and comparing it to any measure of medication adherence. Studies were pooled using the random-effects model to produce a mean overall effect size correlation. Studies were stratified for condition, adherence measure, power and study design. Ninety-four papers were included in the meta-analysis. The overall effect size(r) for necessity, concerns, and necessity-concerns differential was 0.17, -0.18 and 0.24 respectively and these were all significant (p<0.0001). Effect size for necessity was stronger in asthma and weaker in the cardiovascular group compared to the overall effect size. Necessity and concerns beliefs and the necessity-concerns differential were correlated with medication adherence on a population level and across the majority of included conditions. The effect sizes were mostly small with a magnitude comparable to other predictors of adherence. This meta-analysis suggests that necessity and concern beliefs about medicines are one important factor to consider when understanding reasons for non-adherence.


UK maternity care experiences of ethnic minority and migrant women: Systematic review.
The increasing population of immigrant and migrant women in the United Kingdom has implications to the provision of healthcare and for healthcare experiences. Eliciting women's experiences and perceptions of maternity care received is an important way of monitoring and evaluating the quality of maternity services. This study was designed to explore the maternity care experiences of ethnic minority and migrant women in the United Kingdom. A literature search for relevant studies was carried across seven databases. We included nine studies carried out between 2015 and February 2022 that met the inclusion criteria. Data were analyzed using a thematic analysis approach. Findings showed that ethnic minority women and migrant women have had mixed experiences while utilizing maternity services in the United Kingdom. However, most of the experiences were negative and included issues related to communication, discrimination, culture, access to care, physical comfort, and continuity of care. Only one of the studies reported that the respondents had a wholly positive communication experience, one found that a few women felt the staff were respectful and one reported that the midwives gave the women treatment options that would respect their cultural and religious beliefs. This study has highlighted some important gaps in the maternity care experiences specific to ethnic minority and migrant women in the United Kingdom which provides useful insights to future policy and clinical practice.


Endoscopic management of Ewing's sarcoma of ethmoid sinus within the AMORE framework: a new paradigm.
The Ablative surgery, MOulage brachytherapy and REconstruction) (AMORE) protocol developed in the Academic Medical Center of Amsterdam has been used successfully to treat sarcomas. The use of endoscopic surgery fits well within this framework. A 6-year-old boy presented with Ewing Sarcoma of left ethmoid sinus closest to orbit. The patient underwent neoadjuvant chemotherapy followed by complete endoscopic resection, brachytherapy and reconstruction. Brachytherapy was administered by iridium catheters through limited Lynch-Howarth incision. Skull base defect was reconstructed with a galea flap. The use of endoscopic surgery complemented by neoadjuvant chemotherapy and brachytherapy might maximize tumor control while reducing morbidity.


A non-competitive enzyme immunoassay of human alpha-lactalbumin in biological fluids and tissue extracts.
A sandwich non-competitive enzyme immunoassay for the measurement of human alpha-lactalbumin in serum, milk, and tumour tissue cytosol was developed using affinity-purified polyclonal antibody adsorbed to solid phase. The detection limits of this procedure in tubes (macromethod) and in wells of microtitre plates (micromethod) are 50 pg and 25 pg/sample, respectively, which means 2.5 micrograms/l of serum at appropriate dilution. The micromethod enables a reduction of the volumes used in the reaction with equal sensitivity, accuracy and reproducibility. A comparison of alpha-lactalbumin concentrations in serum of healthy, pregnant, and lactating women determined by our method with those measured formerly by radioimmunoassays proved the specificity of our procedure.


The effect of hydroxyl groups and surface area of hematite derived from annealing goethite for phosphate removal.
Synthetic goethite and thermally treated goethite at different temperatures were used to remove phosphate from sewage. The effect of annealing temperature on phosphate removal over time was investigated. X-ray diffraction (XRD), transmission electron microscopy (TEM), N2 adsorption and desorption (BET), and infrared emission spectrum (FT-IES) were utilized to characterize the phase, morphology, specific surface area, pore distribution, and the surface groups of samples. The results show that annealed products of goethite at temperatures over 250°C are hematite with the similar morphology as the original goethite with different hydroxyl groups and surface area. Increasing temperature causes the decrease in hydroxyl groups, consequential increase in surface area at first and then experiences a decrease (14.8-110.4-12.6 m(2)/g) and the subsequent formation of nanoscale pores. The variation rate of hydroxyl groups and surface area based on FT-IES and BET, respectively, are used to evaluate the effect of annealing temperature on phosphate removal. By using all of the characterization techniques, it is concluded that the changes of phosphate removal basically result from the total variation rate between hydroxyl groups and surface area.


In-silico identification of lysine residue for lysozyme immobilization on dialdehyde cellulose.
In the realm of enzymes, the Enzyme Immobilization technique can be extremely beneficial. More research into computational approaches could lead to a better understanding as well as lead us in the direction of a more environmentally friendly and greener path. In this study, molecular modelling techniques were used to collect information regarding the immobilization of Lysozyme (EC 22.214.171.124) on Dialdehyde Cellulose (CDA). Lysine, being the most nucleophilic, is most likely to interact with dialdehyde cellulose. Enzyme substrate interactions have been studied with and without the refinement of modified lysozyme molecules. A total of six CDA-modified lysine residues were selected for the study. The docking process for all modified lysozymes was carried out using four distinct docking programs: Autodock Vina, GOLD, Swissdock, and iGemdock. The binding affinity (-7.8 & -8.0 kcal mol-1 in case of non-refinement and -4.7 & -5.0 kcal mol-1 in case of refinement), calculated from Autodock vina, as well as the interaction similarity of Lys116 immobilized lysozyme with its substrate, were found to be 75 % (W/o simulation) & 66.7 % (With simulation) identical with the reference case (unmodified lysozyme) if Lys116 is bound to Dialdehyde Cellulose. The approach described here is utilized to identify amino acid residues that are used in the immobilization of lysozyme.


Identification of UDP-glycosyltransferases involved in the biosynthesis of astringent taste compounds in tea (Camellia sinensis).
Galloylated catechins and flavonol 3-O-glycosides are characteristic astringent taste compounds in tea (Camellia sinensis). The mechanism involved in the formation of these metabolites remains unknown in tea plants. In this paper, 178 UGT genes (CsUGTs) were identified inC. sinensis based on an analysis of tea transcriptome data. Phylogenetic analysis revealed that 132 of these genes were clustered into 15 previously established phylogenetic groups (A to M, O and P) and a newly identified group R. Three of the 11 recombinant UGT proteins tested were found to be involved in the in vitro biosynthesis of β-glucogallin and glycosylated flavonols. CsUGT84A22 exhibited catalytic activity toward phenolic acids, in particular gallic acid, to produce β-glucogallin, which is the immediate precursor of galloylated catechin biosynthesis in tea plants. CsUGT78A14 and CsUGT78A15 were found to be responsible for the biosynthesis of flavonol 3-O-glucosides and flavonol 3-O-galactosides, respectively. Site-directed mutagenesis of the Q373H substitution for CsUGT78A14 indicated that the Q (Gln) residue played a catalytically crucial role for flavonoid 3-O-glucosyltransferase activity. The expression profiles of the CsUGT84A22, CsUGT78A14, and CsUGT78A15 genes were correlated with the accumulation patterns of β-glucogallin and the glycosylated flavonols which indicated that these three CsUGT genes were involved in the biosynthesis of astringent compounds inC. sinensis.


Planar Chiral [2.2]Paracyclophane-Based Bisoxazoline Ligands and Their Applications in Cu-Mediated N-H Insertion Reaction.
New catalysts for important C-N bond formation are highly sought after. In this work, we demonstrate the synthesis and viability of a new class of planar chiral [2.2]paracyclophane-based bisoxazoline (BOX) ligands for the copper-catalyzed N-H insertion of α-diazocarbonyls into anilines. The reaction features a wide substrate scope and moderate to excellent yields, and delivers the valuable products at ambient conditions.


Metformin raises hydrogen sulfide tissue concentrations in various mouse organs.
The epidemic of diabetes mellitus type 2 forces to intensive work on the disease medication. Metformin, the most widely prescribed insulin sensitizer, exerts pleiotropic actions on different tissues by not fully recognized mechanisms. Hydrogen sulfide (H2S) is involved in physiology and pathophysiology of various systems in mammals and is perceived as a potential agent in the treatment of different disorders. The interaction between biguanides and H2S is unknown. The aim of the study is to assess the influence of metformin on the H2S tissue concentrations in different mouse organs. Adult SJL female mice were administered intraperitoneally 100 mg/kg b.w. per day of metformin (group D1, n = 6) or 200 mg/kg b.w. per day of metformin (group D2, n = 7). The control group (n = 6) received physiological saline. The measurements of the free and acid-labile H2S tissue concentrations were performed with Siegel spectrophotometric modified method. There was a significant progressive increase in the H2S concentration along with the rising metformin doses as compared to the control group in the brain (D1 by 103.6%, D2 by 113.5%), in the heart (D1 by 11.7%, D2 by 27.5%) and in the kidney (D1 by 7.1%, D2 by 9.6%). In the liver, massive H2S accumulation was observed in the group D1 (increase by 420.4%), while in the D2 group only slight H2S level enhancement was noted (by 12.5%). Our experiment has shown that metformin administration is followed by H2S tissue concentrations increase in mouse brain, heart, kidney and liver.


Modulation of DNA supercoiling activity of Escherichia coli DNA gyrase by F plasmid proteins. Antagonistic actions of LetA (CcdA) and LetD (CcdB) proteins.
The letA (ccdA) and letD (ccdB) genes of F plasmid contribute to stable maintenance of the plasmid in Escherichia coli cells; a product of the latter has a lethal effect on the host cell and that of the former neutralizes functions of the letD. In cells that overproduce the LetD (CcdB) protein, the plasmid DNA is extensively relaxed. Correspondingly, DNA supercoiling activity in a cell-free extract of the overproducing strain decreases to a level of less than 1% of that seen in normal cells. However, the extract does not inhibit DNA gyrase reconstituted from purified subunits, thereby indicating that the intrinsic DNA gyrase is inactivated in the overproducing strain. Upon addition of purified LetA (CcdA) protein to the extract of LetD overproducing cells, the DNA supercoiling activity was fully restored. Using this rejuvenation as an assay, we purified the "inactivated gyrase" and obtained evidence that the LetD protein formed an isolable complex with the A subunit of DNA gyrase. Thus, the LetD and the LetA proteins constitute an opposing pair in modulating the DNA supercoiling activity of gyrase, probably by direct interaction.


The α2,8-sialyltransferase 6 (St8sia6) localizes in the ER and enhances the anchorage-independent cell growth in cancer.
Sialylation, the final stage of post-translational modification of proteins, is achieved in the Golgi apparatus and is related to the malignant phenotype of cancer. Disialylation of ganglioside (GD3) by St8sia1 and polysialylation by St8sia2 and 4 have been shown to be related to malignant phenotypes; however, di/oligosialylation by St8sia6 is still unknown. In this study, we analyzed the malignant phenotype of St8sia6 and found that upregulation of St8sia6 in melanoma B16 cells increased anchorage-independent cell growth, which was not due to sialic acid cleavage by a sialidase. Moreover, unlike other sialyltransferases, St8sia6 localized to the endoplasmic reticulum (ER). We found that the localization to the Golgi apparatus could be regulated by swapping experiments using St8sia2; however, the malignant phenotype did not change. These data demonstrate that the enhancement of anchorage-independent cell growth by St8sia6 is not due to its localization of ER, but is due to the expression of the protein itself.


Identification of QTL for kernel weight and size and analysis of the pentatricopeptide repeat (PPR) gene family in cultivated peanut (Arachis hypogaea L.).
Peanut (Arachis hypogaea L.) is an important oilseed crop worldwide. Improving its yield is crucial for sustainable peanut production to meet increasing food and industrial requirements. Deciphering the genetic control underlying peanut kernel weight and size, which are essential components of peanut yield, would facilitate high-yield breeding. A high-density single nucleotide polymorphism (SNP)-based linkage map was constructed using a recombinant inbred lines (RIL) population derived from a cross between the variety Yuanza9102 and a germplasm accession wt09-0023. Kernel weight and size quantitative trait loci (QTLs) were co-localized to a 0.16 Mb interval on Arahy07 using inclusive composite interval mapping (ICIM). Analysis of SNP, and Insertion or Deletion (INDEL) markers in the QTL interval revealed a gene encoding a pentatricopeptide repeat (PPR) superfamily protein as a candidate closely linked with kernel weight and size in cultivated peanut. Examination of the PPR gene family indicated a high degree of collinearity of PPR genes between A. hypogaea and its diploid progenitors, Arachis duranensis and Arachis ipaensis. The candidate PPR gene, Arahy.JX1V6X, displayed a constitutive expression pattern in developing seeds. These findings lay a foundation for further fine mapping of QTLs related to kernel weight and size, as well as validation of candidate genes in cultivated peanut.


Gene Delivery to Nonhuman Primate Preimplantation Embryos Using Recombinant Adeno-Associated Virus.
Delivery of genome editing tools to mammalian zygotes has revolutionized animal modeling. However, the mechanical delivery method to introduce genes and proteins to zygotes remains a challenge for some animal species that are important in biomedical research. Here, an approach to achieve gene delivery and genome editing in nonhuman primate embryos is presented by infecting zygotes with recombinant adeno-associated viruses (rAAVs). Together with previous reports from the authors of this paper and others, this approach is potentially applicable to a broad range of mammals. In addition to genome editing and animal modeling, this rAAV-based method can facilitate gene function studies in early-stage embryos.


Structural requirements of pyrimidine, thienopyridine and ureido thiophene carboxamide-based inhibitors of the checkpoint kinase 1: QSAR, docking, molecular dynamics analysis.
Our focus of current research is directed toward clarification of novel inhibitors (pyrazolo[1,5-a] pyrimidine (PP), thienopyridines (TP) and 2-ureido thiophene carboxamide (UTC) derivatives) targeting Checkpoint kinase 1 (CHK(1)), which is an oncology target of significant current interest. Our computational approaches include: (i) QSAR analysis was carried out on the computed steric/electrostatic/hydrophobic/hydrogen bond donor/hydrogen bond acceptor interactions with the pseudoreceptor surface, which yielded predictive models capable of explaining much of the variance of inhibitors. The resultant optimum QSAR/CoMFA models exhibited (N(training) = 51, N(test) = 16, R(cv) (2) = 0.47, R(pred) (2) = 0.7) for PP, (N(training) = 45, N(test) = 9, R(cv) (2) = 0.52, R(pred) (2) = 0.75) for TP and (N(training) = 58, N(test) = 15, R(cv) (2) = 0.67, R(pred) (2) = 0.88) for UTC. (ii) Molecular docking and molecular dynamics simulations experiments of the inhibitors into the binding site of CHK(1) aided the interpretation of the QSAR models and demonstrated the binding modes in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding interactions, which indicated that a set of critical residues (Cys87, Glu91, Glu85, Ser147, Asp148, Glu17, Leu84 and Asn135) played a key role in the drug-target interactions. The obtained results in the present work will be fruitful for the design of new potent and selective inhibitors of CHK(1).


Variation in selection pressures on the goldenrod gall fly and the competitive interactions of its natural enemies.
Larvae of the tephritid fly Eurosta solidaginis induce ball-shaped galls on the stem of tall goldenrod, Solidago altissima. Survival probability depends on gall size; in small galls the larva is vulnerable to parasitoid oviposition, whereas larvae in large galls are more frequently eaten by avian predators. Fly populations from 20 natural old fields in central Pennsylvania were monitored in 1983 and 1984 to examine the distribution of the selection intensity imposed by natural enemies, the parasitoids Eurytoma gigantea and E. obtusiventris, the inquiline Mordellistena unicolor, and the predatory birds Dendrocopus pubescens and Parus atricapillus. Mordellistena and E. obtusiventris are able to attack galls of all diameters while E. gigantea and the predatory birds preferentially assaulted small and large diameter galls, respectively. Eurosta in intermediate sized galls had the highest survivorship, hence selection had a stabilizing component. However, parasitoid attack was more frequent than bird attack, and the two did not exactly balance, thus there was also a directional component. The mean directional selection intensity on gall size was 0.21 standard deviations of the mean, indicating that larger gall size was favored. Interactions among the insect members of the Eurosta natural enemy guild are complex and frequent.


A new two-disulphide intermediate in the refolding of reduced bovine pancreatic trypsin inhibitor.
The apparently complete refolding of reduced bovine pancreatic trypsin inhibitor (BPTI) is shown to produce a mixture of two species. One of these is native BPTI, but the other lacks the disulphide bond between cysteines 30 and 51. The latter species has a folded conformation very like that of native BPTI, and is oxidized by air to native BPTI on warming in aqueous solution. The two unreactive cysteine thiol groups appear to be buried in the interior of the molecule, which restricts access by reagents that can alkylate them or oxidize them to form the disulphide bond. The implications of this intermediate and its conformation for the understanding of protein folding are discussed.


Self-assembled organic nanotube promoted allylation of ketones in aqueous phase.
A self-assembled organic nanotube was found to promote the allylation of ketones in the aqueous phase.


Influence of loperamide on the internal anal sphincter in the opossum.
The objective of this study was to examine the influence of the commonly used antidiarrheal agent loperamide on the internal anal sphincter of anesthetized opossums. Loperamide caused a rise in internal anal sphincter pressures, and a decrease in the rectal distention-induced internal anal sphincter relaxation. To define the mechanism of decrease in the rectal distention response of the internal anal sphincter, we examined the effects of sacral efferent nerve stimulation, local intramural stimulation, and ganglionic stimulant (which acts at the postganglionic inhibitory neuron). Loperamide caused a significant decrease in the internal anal sphincter relaxation caused by sacral nerve stimulation, but not in that caused by local intramural stimulation and nicotine. These effects of loperamide on the internal anal sphincter were antagonized by naloxone. These findings suggest that the therapeutic effects of loperamide on the internal anal sphincter as an antidiarrheal agent are due to a rise in the tone of the sphincter and the inhibition of its relaxation in response to rectal distention. Both of these actions are mediated by activation of opioid receptors. The inhibition of internal anal sphincter relaxation induced by rectal distention (which mimicks recto-anal reflex) is due to inhibition of release of neurotransmitter from the preganglionic sacral nerve fibers.


Why do not all hip- and knee patients facing long waiting times accept re-referral to hospitals with short waiting time? Questionnaire study.
Patients' preferences are often assumed to be homogeneous and to favour hospitals with a short waiting time and high quality. Due to long waiting times (6 months) for artificial hip or knee implantation a Danish county in 1999-2000 offered patients on a waiting list a choice between remaining on the local hospital's waiting list with the long waiting time, or re-referral to a hospital outside the county with a shorter waiting time. Fewer patients than expected took advantage of the offer of re-referral ("accepters"): 89 of 149 patients (60%). In 2003, we asked patients about the reasons for their choice: 87% of patients responded. Respondents and non-respondents were similar by decision, choice of hospital, diagnosis and age; men were significantly more likely to respond than women. Accepters and decliners were similar by age, sex, diagnosis and the presence of a car in the household. Short distance, short transport time and previous experience with the nearby hospital were the most important reasons for choosing that hospital. Some patients appeared to be willing to accept a long waiting time, if they were told exactly when they would undergo surgery. The results of this study question the validity of the conventional wisdom, that patients are willing to travel long distances in order to receive treatment with short waiting time.


High density lipoprotein cholesterol in male relatives of patients with coronary heart disease.
To study factors that play a role in the familial occurrence of coronary heart disease, very low density lipoprotein (VLDL) triglycerides, low density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol were measured after preparative ultracentrifugation in first degree male relatives of coronary patients and in control subjects. The HDL cholesterol concentration was significantly lower in relatives of 20--71 years old than in controls. No increase of serum and LDL cholesterol was found. A low level of HDL cholesterol was observed even in the younger relatives who are less likely to have cardiovascualr disease. In older relatives low HDL cholesterol was found in the presence or absence of clinical evidence of coronary artery disease. The HDL-cholesterol concentration was inversely related to the VLDL triglycerides both in relatives and controls, but the regression lines were different ((P less than 0.001) for the relative (y = --0.166x + 0.43) and for the controls (y = 0.191x + 0.49). A low HDL cholesterol level appears to be a marker of relatives of coronary patients.


Granulation at the porta hepatis following hepatic portoenterostomy for biliary atresia: the healing of experimental hepatoenterostomy.
After hepatic portoenterostomy for biliary atresia, granulation that formed at the porta hepatis caused biliary obstruction in seven out of 27 patients (26%). Six of the seven developed the complication during the first 6 weeks after surgery. The mortality rate was 29% (2/7). Among the same group, the incidence and mortality rate of ascending cholangitis was 19% (5/27) and 20% (1/5), respectively. The features characteristic of biliary obstruction caused by granulation, as compared with those of ascending cholangitis, were the absence of signs of infection and the lack of response to medical treatment. Quantitative analysis of the healing process of an experimental hepatoenterostomy in the rat showed that the mean thickness of the granulation formed at the anastomotic site (area, 5 x 20 mm) decreased almost constantly--from 1.49 mm on day 7 to 0.64 mm on day 42. Mucosa covered 20% of the granulation on day 7, 55% on day 14, 63% on day 21, 76% on day 28, and 92% on day 42. The increase in coverage was greatest during the second postoperative week. The results suggested that the healing of the hepatoenteostomy should be almost complete within 6 weeks. The operative method and postoperative management to prevent excessive granulation should be chosen so as to decrease the incidence of postoperative biliary obstruction.


Endocytosed BCRs sequentially regulate MAPK and Akt signaling pathways from intracellular compartments.
Binding of antigen to the B cell antigen receptor (BCR) triggers both BCR signaling and endocytosis. How endocytosis regulates BCR signaling remains unknown. Here we report that BCR signaling was not extinguished by endocytosis of BCRs; instead, BCR signaling initiated at the plasma membrane continued as the BCR trafficked intracellularly with the sequential phosphorylation of kinases. Blocking the endocytosis of BCRs resulted in the recruitment of both proximal and downstream kinases to the plasma membrane, where mitogen-activated protein kinases (MAPKs) were hyperphosphorylated and the kinase Akt and its downstream target Foxo were hypophosphorylated, which led to the dysregulation of gene transcription controlled by these pathways. Thus, the cellular location of the BCR serves to compartmentalize kinase activation to regulate the outcome of signaling.


Vulnerability to stressor-induced disturbances in self-stimulation from the dorsal and ventral A10 area: differential effects of intraventricular D-Ala2-Met5-enkephalinamide, D-Ala2, N-Me-Phe4, Gly-Ol5-enkephalin, and D-Pen2, D-Pen5-enkephalin administration.
D-Ala2-Met5-enkephalinamide (DALA) (1.0 microg/microl) was administered intraventricularly to mice responding for electrical stimulation from the dorsal or ventral aspects of the VTA immediately prior to footshock (Experiment 1). Predictably, footshock reduced self-stimulation from the dorsal but not the ventral VTA immediately, 24, and 168 h following the stressor. Intraventricular DALA administration effected a partial attenuation of stressor-induced self-stimulation reductions from the dorsal VTA immediately and 24 h poststressor. Deficits appeared among DALA-Shocked mice responding for brain stimulation from the ventral VTA during comparable test intervals. The long-term depressant influence of footshock on self-stimulation from the dorsal VTA was abolished among DALA-treated mice and DALA-associated reductions in self-stimulation from the ventral A10 region among stressed mice were not evident 1 week later. Administration of D-Ala2, N-Me-Phe4, Gly-Ol5-enkephalin (DAGO) (0.01 microg/microl) or D-Pen2, D-Pen5-enkephalin (DPDPE) (1.0 microg/microl) intraventricularly prior to footshock effected an immediate and a delayed antagonism, respectively, of the stressor on self-stimulation from the dorsal VTA, which persisted for 1 week. Prophylactic administration of 0.001 microg/microl DAGO or 0.01 microg/microl DPDPE prior to the stressor failed to influence self-stimulation from the ventral VTA (Experiment 2). Administration of 0.01 microg/microl DAGO or 1.0 microg/microl DPDPE among mice responding for brain stimulation from the dorsal VTA following footshock produced a weak therapeutic effect immediately poststressor, but effected protracted amelioration of footshock-induced reductions of self-stimulation from the dorsal VTA (Experiment 3). Taken together, mu, delta, and mu-delta activation influenced self-stimulation differentially from the dorsal and ventral VTA according to the temporal order of opioid peptide challenge relative to stressor imposition. These data are discussed with respect to stressors, motivational alterations, and the putative modulating influence of endogenous enkephalin activity in subareas of the VTA.


Alkaline phosphatase to treat ischaemia-reperfusion injury in living-donor kidney transplantation: APhIRI I feasibility pilot study.
Ischemia-reperfusion injury (IRI) during kidney transplant procedures is associated with adverse outcome. Alkaline phosphatase (AP) is an enzyme that has the potential to dampen IRI. Prior to this study, it had not been tested in the setting of kidney transplantation. This study aimed to evaluate the safety and feasibility of peri-procedural AP administration in living donor kidney transplantation. In this double blind, randomized, placebo-controlled, single-center pilot study, all eligible recipients of living donor kidneys were asked to give informed consent. AP (bRESCAP) or a placebo was administered intravenously over 24 hours after the transplantation procedure. The primary outcome-graft function at 1 year-was represented by iohexol measured glomerular filtration rate (mGFR). Serum and urine biomarkers within seven days after surgery were used as surrogate markers of kidney function and injury. Eleven patients were enrolled of whom five were treated with bRESCAP and six with placebo. After 1 year, mGFR was not different between groups. No specific adverse events were observed in the bRESCAP group. Urine expression of injury biomarkers CCL14, NGAL and Cystatin C was lower in the bRESCAP group at day seven. This was statistically significant. This study illustrates that bRESCAP treatment is feasible in kidney transplantation, might have a dampening effect on IRI induced renal inflammation, and raises no safety concerns. Future research will evaluate the effects of bRESCAP treatment in donation after circulatory death kidney transplantation where IRI is more pronounced.


Reactivity of locally produced CSF antibodies in patients with neurosyphilis against antigens of Treponema pallidum.
The reactivity and specificity of locally produced cerebrospinal fluid (CSF) antibodies against antigens of Treponema pallidum were assessed by Western blotting in patients with clinical signs of parenchymal or meningovascular neurosyphilis. All nine patients showed local production of treponeme-specific antibodies in the central nervous system (CNS). In most of the patients serum and CSF antibodies were bound to the same antigens: the common treponemal 48/45 kDa protein and the putative specific T. pallidum protein in the range of 12-14 kDa. In some patients the intensity of staining obtained by CSF antibodies was higher than that derived from serum, indicating locally produced antibodies. In contrast to other more acute inflammatory CNS diseases, no expanded or different antigen binding of the CSF antibodies compared with serum antibodies was found in neurosyphilic patients. The results presented are discussed with regard to the role of the blood-brain barrier in antibody concentrations of CSF and serum.


Measuring intellectual ability in cerebral palsy: The comparison of three tests and their neuroimaging correlates.
Standard intelligence scales require both verbal and manipulative responses, making it difficult to use in cerebral palsy and leading to underestimate their actual performance. This study aims to compare three intelligence tests suitable for the heterogeneity of cerebral palsy in order to identify which one(s) could be more appropriate to use. Forty-four subjects with bilateral dyskinetic cerebral palsy (26 male, mean age 23 years) conducted the Raven's Coloured Progressive Matrices (RCPM), the Peabody Picture Vocabulary Test-3rd (PPVT-III) and the Wechsler Nonverbal Scale of Ability (WNV). Furthermore, a comprehensive neuropsychological battery and magnetic resonance imaging were assessed. The results show that PPVT-III gives limited information on cognitive performance and brain correlates, getting lower intelligence quotient scores. The WNV provides similar outcomes as RCPM, but cases with severe motor impairment were unable to perform it. Finally, the RCPM gives more comprehensive information on cognitive performance, comprising not only visual but also verbal functions. It is also sensitive to the structural state of the brain, being related to basal ganglia, thalamus and white matter areas such as superior longitudinal fasciculus. So, the RCPM may be considered a standardized easy-to-administer tool with great potential in both clinical and research fields of bilateral cerebral palsy.


One-year follow-up of ischemic index changes after intravitreal dexamethasone implant for diabetic macular edema: an ultra-widefield fluorescein angiography study.
To investigate late changes in peripheral ischemia in patients affected by diabetic macular edema (DME) and treated with repeated dexamethasone (DEX) intravitreal implants over a 1-year period. In this retrospective cohort study, patients older than 18 years of age and with type 2 non-proliferative treatment-naïve diabetic retinopathy (DR) and DME at baseline were included. All patients were treated with two intravitreal DEX implants within 1 year of follow-up. A minimum of two annual ultra-widefield fluorescein angiography (UWF FA) were required to ensure that all cases had a baseline UWF FA (< 2 weeks before first treatment with dexamethasone) and a UWF FA performed at 12 months of follow-up. On baseline and 1-year UWFA images, peripheral retinal ischemia was quantified using the ischemic index (ISI). Six eyes of five patients (two males, three females) met the inclusion criteria and were enrolled in this study. Best-corrected visual acuity was 0.34 ± 0.22 LogMAR at baseline and improved to 0.21 ± 0.14 logMAR at the 1-year follow-up visit (P = 0.050). Mean ± SD central macular thickness was 467.6 ± 63.0 μm at baseline and 272.0 ± 14.7 μm at the 1-year follow-up visit (P = 0.043). Mean ± SD ISI was 26.7 ± 14.1% at baseline and reduced to 12.2 ± 5.0% at the 1-year follow-up visit (P = 0.012). Improvement in retinal perfusion is still maintained 1 year after starting treatment with DEX implants. This improvement in retinal perfusion might be related to DEX implant-related positive effects on leukostasis.


Middle ear infection due to vibrio alginolyticus. Bacteriological characterization.
A 47-year-old male suffering from chronic purulent ear discharge was investigated bacteriologically in autumn 1977. The isolated strain was identified as Vibrio alginolyticus. The fact that the patient spent his vacation at a Black-Sea resort every year strongly pleads for a direct inoculation of the halophilic Vibrio.


Speech-in-noise detection is related to auditory working memory precision for frequency.
Speech-in-noise (SiN) perception is a critical aspect of natural listening, deficits in which are a major contributor to the hearing handicap in cochlear hearing loss. Studies suggest that SiN perception correlates with cognitive skills, particularly phonological working memory: the ability to hold and manipulate phonemes or words in mind. We consider here the idea that SiN perception is linked to a more general ability to hold sound objects in mind, auditory working memory, irrespective of whether the objects are speech sounds. This process might help combine foreground elements, like speech, over seconds to aid their separation from the background of an auditory scene. We investigated the relationship between auditory working memory precision and SiN thresholds in listeners with normal hearing. We used a novel paradigm that tests auditory working memory for non-speech sounds that vary in frequency and amplitude modulation (AM) rate. The paradigm yields measures of precision in frequency and AM domains, based on the distribution of participants' estimates of the target. Across participants, frequency precision correlated significantly with SiN thresholds. Frequency precision also correlated with the number of years of musical training. Measures of phonological working memory did not correlate with SiN detection ability. Our results demonstrate a specific relationship between working memory for frequency and SiN. We suggest that working memory for frequency facilitates the identification and tracking of foreground objects like speech during natural listening. Working memory performance for frequency also correlated with years of musical instrument experience suggesting that the former is potentially modifiable.


New treatment method for refractory gastroesophageal reflux disease (GERD): C-BLART (clip band ligation anti-reflux therapy)-a short-term study.
C-BLART (clip band ligation anti-reflux therapy) has been reported as a new alternative endoscopic treatment for refractory gastroesophageal reflux disease (GERD). This study evaluated the short-term efficacy of C-BLART for controlling GERD symptoms, esophageal acid exposure, esophagitis, and quality of life. Patients with refractory GERD were recruited for a nonrandomized concurrent comparison, with 60 patients in the C-BLART with tailored PPI use group and 43 patients in the BID proton pump inhibitor (PPI) group. The primary outcomes were esophageal acid exposure and the lower esophageal sphincter (LES) pressure. The GERD-Q score, esophagitis grade, and adherence degree were also recorded. Crossover from the BID PPI group to the C-BLART with tailored PPI use group was allowed after 6 months. The LES pressure and GERD-Q score improved more in the C-BLART with tailored PPI use group (P < 0.001) after 6 months, with no significant difference in the decrease in esophagitis compared with the baseline endoscopic results (P = 0.268). Treatment with PPIs had been halted in 43% of the patients at 6 months after C-BLART. At 12 months after C-BLART, the DeMeester score showed a significant improvement compared with the baseline measurements (P = 0.025). The GERD-Q score and LES pressure did not significantly improve compared with the baseline values (P = 0.102, P = 0.184) in C-BLART with tailored PPI use group. At 6 to 12 months, n = 6 (10%) patients had undergone laparoscopic fundoplication to control their symptoms in all the patients after C-BLART. C-BLART is a novel treatment for controlling refractory GERD symptoms, esophageal acid exposure, and LES pressure according to this short-term analysis, safely performed endoscopically to create an anti-reflux barrier with ligated bands. Despite improvements in DeMeester score, LES pressure, and GERD-Q scores in the C-BLART with tailored PPI use group, many patients continue to demonstrate objective evidence of GERD.


Validation of the PHQ-9 depression scale in Ethiopian cancer patients attending the oncology clinic at Tikur Anbessa specialized hospital.
Although depression is highly prevalent among cancer patients, it is often underdiagnosed and poorly managed particularly in developing nations. These shortcomings can have substantial adverse effects not only on the disease prognosis but also on patients' quality of life. The Patient Health Questionnaire-9 is a widely used depression screening tool but it has not been validated among patients with chronic illnesses such as cancer in Ethiopia. We aim to validate the PHQ-9 among Ethiopian cancer patients in an outpatient setting. A cross-sectional study was conducted among cancer patients attending the oncology clinic at Tikur Anbessa Specialized Hospital (TASH). We assessed criterion validity and performance of the PHQ-9 test against the gold standard Mini-International Neuropsychiatric Interview (MINI) diagnostic tool among patients with cancer. The MINI was administered by psychiatric nurses who were blind to the initial PHQ-9 screening tool. A total of 163 patients completed the 2 stages of a diagnostic interview in the study. The majority (64%) of the participants were women, the mean age was 46 (13.5) years. Using the gold standard MINI test the prevalence of Major Depressive Episode (MDE) was 15%. The internal consistency (Cronbach's α) for PHQ-9 was 0.78 suggesting good (acceptable) internal consistency for the reliability of the test scores. When the total PHQ-9 score was used to identify cases of MDE, the Area under the Curve (AUC) was 0.93 (95% confidence interval [CI], 0.88-0.97) on Receiver Operating Characteristic (ROC) analysis. This shows evidence for the excellent discriminating power of the PHQ-9 between cases and non-cases of MDE. At cutoff point ≥4, the PHQ-9 had a sensitivity of 88% and specificity of 78.1% on the ROC curve to detect MDE. PHQ-9 is a reliable and valid instrument to detect MDE among individuals with chronic conditions such as cancer patients in outpatient settings and it can be used in resource-limited settings for early diagnosis and proper therapy of such patients.


Lower Extremity Biomechanical Examination of Athletes.
A comprehensive lower extremity examination is a critical examination component for any type of injury in an athlete but should also be part of a preseason or preventive care program. Identification and treatment of biomechanical abnormalities and association with evidence-based risk factors for lower extremity disorders can be incorporated to potentially reduce risk or prevent acute and chronic injuries.


Indocyanine green localization for laparoscopic duodenal web excision.
A duodenal web refers to partial or complete obstruction of the duodenum due to a membranous web. When looking at the serosal side of the intestine during duodenal web excision, especially during laparoscopic surgery, determining the web origin might be challenging. This study aimed to determine the efficacy of intraduodenum indocyanine green injection and near-infrared light during laparoscopic surgery in enhancing the ability to identify duodenal web localization. We used intraduodenum indocyanine green injection to unequivocally recognize the duodenal web and facilitate laparoscopic excision. The clinical analysis was based on a male neonatal case with duodenal web admitted to our hospital. After the patient was placed in the supine position, 5 mL of ICG was injected via a 6-Fr nasogastric tube. The fluorescence was visualized in the white light and near-infrared light dual-mode of the camera system, localizing the duodenal precisely and in real-time. Laparoscopically, the duodenal web was accurately identified and removed with intraduodenum indocyanine green visualization under near-infrared light. The procedure was completed successfully, and the patient showed good postoperative outcomes. Intraduodenum indocyanine green injection during laparoscopic surgery is a feasible adjuvant for duodenal web localization, showing improvements in terms of outcomes compared to previous methods of determining the duodenal web location.


Vaccinia virus as a subhelper for AAV replication and packaging.
Adeno-associated virus (AAV) has been widely used as a gene therapy vector to treat a variety of disorders. While these vectors are increasingly popular and successful in the clinic, there is still much to learn about the viruses. Understanding the biology of these viruses is essential in engineering better vectors and generating vectors more efficiently for large-scale use. AAV requires a helper for production and replication making this aspect of the viral life cycle crucial. Vaccinia virus (VV) has been widely cited as a helper virus for AAV. However, to date, there are no detailed analyses of its helper function. Here, the helper role of VV was studied in detail. In contrast to common belief, we demonstrated that VV was not a sufficient helper virus for AAV replication. Vaccinia failed to produce rAAV and activate AAV promoters. While this virus could not support rAAV production, Vaccinia could initiate AAV replication and packaging when AAV promoter activation is not necessary. This activity is due to the ability of Vaccinia-driven Rep78 to transcribe in the cytoplasm and subsequently translate in the nucleus and undergo typical functions in the AAV life cycle. As such, VV is subhelper for AAV compared to complete helper functions of adenovirus.


4-Octyl itaconate restricts STING activation by blocking its palmitoylation.
The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens and maintaining immune homeostasis. While substantial advances have been made in understanding the metabolic changes that occur during macrophage activation, little is known about how these metabolic changes affect the cGAS-STING axis. In this study, we identify that 4-octyl itaconate (4-OI), a derivative of itaconate, inhibits the activation of cGAS-STING. Furthermore, we show that 4-OI inhibits cGAS-STING-related antiviral immune responses and autoimmune inflammation. However, we find that endogenous itaconate does not affect cGAS-STING activation, indicating that 4-OI and itaconate function differently. Mechanistically, we find that 4-OI directly alkylates STING at Cys91, blocking STING palmitoylation and oligomerization. The alkylation of STING by 4-OI represents another type of post-translational modifications (PTMs) of STING. Our findings reveal a mechanism by which cGAS-STING function is regulated through 4-OI alkylation and provide insights into the crosstalk between different kinds of PTMs.


Trace Elemental Characterization of Chalk Dust and Their Associated Health Risk Assessment.
It is evident that chalk produces dust on use, i.e., particulate matter, which will alter the air quality of classrooms and can cause health hazards in teachers. The possible causes for health effects of chalk dust on teachers are still unclear. Hence, the aim of this study is to estimate the concentration of trace elements (Al, Cr, Mn, Fe, Co, Ni, Si, Pb) in chalk dust collected from classrooms by using ICP-MS. Both suspended and settled chalk dust was collected from selected classrooms. Suspended chalk dust was collected with PM2.5 filter paper using fine dust sampler, and settled chalk dust was collected by placing petriplates at a distance of 3 m from the board for a duration period of 30 min. Scanning electron microscopy images of chalk dust were taken up. Potential health risk analysis was also assessed. Results showed that Al, Fe, and Mn are in higher concentration (>1000 μg kg-1) in both settled and suspended chalk dust. Cr, Mn, Fe, Co, and Ni were beyond the minimal risk levels in both settled and suspended chalk dust. There are no minimal risk levels for the elements Al, Si, and Pb. The concentration of trace elements in suspended chalk dust was higher than that in settled chalk dust. The SEM images of PM2.5 filter papers (suspended chalk dust) showed that all pores of the sampled filter papers are clogged with chalk dust. The few SEM images of the settled chalk dust showed fibrous shape which is associated with good-quality chalk whereas others showed circular and more aggregated nature of chalk dust from low-quality chalk from which the dust production will be very high. As observed from the result that the trace elements concentration was high in the suspended chalk dust, the fact can be correlated with the SEM images which have shown high density of absorbed chalk dust. With reference to human health risk, dermal exposure was the main route of exposure followed by inhalation and ingestion. Al (aluminum), Fe (iron), Si (silicon), and Mn (manganese) are the major contributors for the non-carcinogenic effects. For all the elements, the carcinogenic effect calculated (LADD) is within the global acceptable limit (10-6-10-4).


Every contact leaves a trace: Documenting contamination in lithic residue studies at the Middle Palaeolithic sites of Lusakert Cave 1 (Armenia) and Crvena Stijena (Montenegro).
Investigations of organic lithic micro-residues have, over the last decade, shifted from entirely morphological observations using visible-light microscopy to compositional ones using scanning electron microscopy and Fourier-transform infrared microspectroscopy, providing a seemingly objective chemical basis for residue identifications. Contamination, though, remains a problem that can affect these results. Modern contaminants, accumulated during the post-excavation lives of artifacts, are pervasive, subtle, and even "invisible" (unlisted ingredients in common lab products). Ancient contamination is a second issue. The aim of residue analysis is to recognize residues related to use, but other types of residues can also accumulate on artifacts. Caves are subject to various taphonomic forces and organic inputs, and use-related residues can degrade into secondary compounds. This organic "background noise" must be taken into consideration. Here we show that residue contamination is more pervasive than is often appreciated, as revealed by our studies of Middle Palaeolithic artifacts from two sites: Lusakert Cave 1 in Armenia and Crvena Stijena in Montenegro. First, we explain how artifacts from Lusakert Cave 1, despite being handled following specialized protocols, were tainted by a modern-day contaminant from an unanticipated source: a release agent used inside the zip-top bags that are ubiquitous in the field and lab. Second, we document that, when non-artifact "controls" are studied alongside artifacts from Crvena Stijena, comparisons reveal that organic residues are adhered to both, indicating that they are prevalent throughout the sediments and not necessarily related to use. We provide suggestions for reducing contamination and increasing the reliability of residue studies. Ultimately, we propose that archaeologists working in the field of residue studies must start with the null hypothesis that miniscule organic residues reflect contamination, either ancient or modern, and systematically proceed to rule out all possible contaminants before interpreting them as evidence of an artifact's use in the distant past.


Adherent-invasive Escherichia coli LF82 aggravated intestinal inflammation in colitis mice by affecting the gut microbiota and Th17/Treg cell differentiation balance.
The imbalance of Th17 and Treg cell differentiation, intestinal flora imbalance, and intestinal mucosal barrier damage may be important links in the occurrence and development of inflammatory bowel disease (IBD) since Th17 and Treg differentiation are affected by the intestinal flora. This study aimed to explore the effect of Escherichia coli (E. coli) LF82 on the differentiation of Th17 and Treg cells and the role of the intestinal flora in mouse colitis. The effects of E. coli LF82 infection on intestinal inflammation were evaluated by analyzing the disease activity index, histology, myeloperoxidase activity, FITC-D fluorescence value, and claudin-1 and ZO-1 expression. The effects of E. coli LF82 on the Th17/Treg balance and intestinal flora were analyzed by flow cytometry and 16S rDNA sequencing. Inflammatory markers, changes in the intestinal flora, and Th17/Treg cells were then detected after transplanting fecal bacteria from normal mice into colitis mice infected by E. coli LF82. We found that E. coli LF82 infection can aggravate the intestinal inflammation of mice colitis, destroy their intestinal mucosal barrier, increase intestinal mucosal permeability, and aggravate the imbalance of Th17/Treg differentiation and the disorder of intestinal flora. After improving the intestinal flora imbalance by fecal bacteria transplantation, intestinal inflammation and intestinal mucosal barrier damage were reduced, and the differentiation balance of Th17 and Treg cells was restored. This study showed that E. coli LF82 infection aggravates intestinal inflammation and intestinal mucosal barrier damage in colitis by affecting the intestinal flora composition and indirectly regulating the Th17 and Treg cell differentiation balance.


City-scale model for COVID-19 epidemiology with mobility and social activities represented by a set of hidden Markov models.
SARS-CoV-2 emerged by the end of 2019 and became a global pandemic due to its rapid spread. Various outbreaks of the disease in different parts of the world have been studied, and epidemiological analyses of these outbreaks have been useful for developing models with the aim of tracking and predicting the spread of epidemics. In this paper, an agent-based model that predicts the local daily evolution of the number of people hospitalized in intensive care due to COVID-19 is presented. An agent-based model has been developed, taking into consideration the most relevant characteristics of the geography and climate of a mid-size city, its population and pathology statistics, and its social customs and mobility, including the state of public transportation. In addition to these inputs, the different phases of isolation and social distancing are also taken into account. By means of a set of hidden Markov models, the system captures and reproduces virus transmission associated with the stochastic nature of people's mobility and activities in the city. The spread of the virus in the host is also simulated by following the stages of the disease and by considering the existence of comorbidities and the proportion of asymptomatic carriers. As a case study, the model was applied to Paraná city (Entre Ríos, Argentina) in the second half of 2020. The model adequately predicts the daily evolution of people hospitalized in intensive care due to COVID-19. This adequacy is reflected by the fact that the prediction of the model (including its dispersion), as with the data reported in the field, never exceeded 90% of the capacity of beds installed in the city. In addition, other epidemiological variables of interest, with discrimination by age range, were also adequately reproduced, such as the number of deaths, reported cases, and asymptomatic individuals. The model can be used to predict the most likely evolution of the number of cases and hospital bed occupancy in the short term. By adjusting the model to match the data on hospitalizations in intensive care units and deaths due to COVID-19, it is possible to analyze the impact of isolation and social distancing measures on the disease spread dynamics. In addition, it allows for simulating combinations of characteristics that would lead to a potential collapse in the health system due to lack of infrastructure as well as predicting the impact of social events or increases in people's mobility.


Moral Intuitions About Stigmatizing Practices and Feeding Stigmatizing Practices: How Haidt's Moral Foundations Theory Relates to Infectious Disease Stigma.
Despite extensive stigma mitigation efforts, infectious disease stigma remains common. So far, little attention has been paid to the moral psychology of stigmatizing practices (i.e. beliefs, attitudes, actions) rather than the experience of being stigmatized. Addressing the moral psychology behind stigmatizing practices seems necessary to explain the persistence of infectious disease stigma and to develop effective mitigation strategies. Our article proposes building on Jonathan Haidt's moral foundations theory, which states that moral judgements follow from intuitions rather than conscious reasoning. Conceptual analysis was conducted to show how Haidt's five moral foundations can be connected to (i) moral judgements about stigmatizing practices and (ii) stigmatizing practices themselves. We found that care/harm, fairness/cheating, loyalty/betrayal and sanctity/degradation intuitions can inform moral judgements about stigmatizing practices. Loyalty/betrayal and sanctity/degradation intuitions can sometimes also feed stigmatizing practices. Authority/subversion intuitions can inform moral judgements and stigmatizing practices towards people who disrespect authoritative rules meant to protect public health. Moral dumbfounding and posthoc reasoning might explain the persistence of stigmatizing practices. In conclusion, this study demonstrates the relevance of Haidt's approach to infectious disease stigma research and mitigation strategies. We hope that this study motivates researchers to further test and assess this approach.


Glutamate-gated chloride channels inhibit juvenile hormone biosynthesis in the cockroach, Diploptera punctata.
Juvenile hormone (JH) synthesized and released from endocrine gland corpus allatum (CA) plays an important role in insect metamorphosis, vitellogenesis and reproduction. Glutamate is a major neurotransmitter in the nervous system and its activated receptors possess excitatory and inhibitory forms in muscle fibers of invertebrates. Previously, we have shown that the rise of intracellular calcium through excitatory glutamate receptors, N-methyl-d-aspartate (NMDA) and non-NMDA-type channels stimulates JH synthesis in the cockroach, Diploptera punctata. Here, we demonstrate the occurrence of inhibitory chloride permeable glutamate (GluCl) receptors on CA cell membranes. Application of the GluCl channel activators, ibotenic acid (Ibo) and ivermectin, but not gamma-aminobutyric acid caused a decline in JH synthesis in glands of either high or low activity during the gonadotrophic cycle. Also, while recording the membrane potential of the isolated whole CA glands intracellularly, Ibo induced a hyperpolarizated response. Both changes in the membrane potential and inhibition of JH synthesis could be abolished by the application of the chloride channel blocker picrotoxin. Finally, we found both excitatory and inhibitory glutamate receptors cause antagonistic effects on rates of JH synthesis. These results indicate a novel function of GluCl channels in the inhibition of JH synthesis that could be a potential pathway for developing a new generation of insecticides.


[Prevalence of human papillomavirus genotypes: comparison between three detection methods in patients of Pernambuco, Brazil].
to compare three methods for the detection of HPV infection and to determine the prevalence of the genotypes found. a total of 120 cervical scrape samples from patients with cervical intraepithelial neoplasia were analyzed by the conventional polymerase chain reaction using the MY09/11 and GP05+/06+ primers, and by the Nested polymerase chain reaction. The samples were subjected to DNA amplification with the GH20 and PC04 primers (β-globin) to verify DNA quality and also by polymerase chain reaction and Nested polymerase chain reaction. The amplicons were visualized in 1.2% agarose gel stained with Blue Green Loading Dye I. Positive samples also were sequenced using the automatic DNA sequencer "MegaBACE 1000". The Χ2 and Fisher tests were used for statistical analysis with the level of significance set at 5%. fifteen samples were eliminated from the study because they failed to amplify the β-globin gene. Of the remaining samples, 40% (42/105) were positive using primers MY09/11, 98% (103/105) using primers GP05+/06+, and 92% (97/105) using Nested-PCR. With the MY09/11 and GP05+/06+ techniques, it was possible to obtain 100% HPV-positive samples. In this study, the prevalence of the genotypes found was 57, 23, 5, 4 and 3% for HPV genotypes 16, 18, 31, 33 and 56, respectively. HPVs 67 and 83 were present in 2%, and genotypes 6, 11, 58 and candHPV85 were present in 1% each. The prevalence of the more common genotypes (HPV 16 and 18) in this study agrees with that reported worldwide (IC95%=0.4657-0.8976). to obtain more reliable results, it is necessary the use of more than one primer system to detect HPV infections. We believe that the three techniques studied are important and suitable for the clinical diagnosis of HPV, when they are appropriately combined.


Aberrant waste disposal in neurodegeneration: why improved sleep could be the solution.
Sleep takes up a large percentage of our lives and the full functions of this state are still not understood. However, over the last 10 years a new and important function has emerged as a mediator of brain clearance. Removal of toxic metabolites and proteins from the brain parenchyma generated during waking activity and high levels of synaptic processing is critical to normal brain function and only enabled during deep sleep. Understanding of this process is revealing how impaired sleep contributes an important and likely causative role in the accumulation and aggregation of aberrant proteins such as β-amyloid and phosphorylated tau, as well as inflammation and neuronal damage. We are also beginning to understand how brain slow-wave activity interacts with vascular function allowing the flow of CSF and interstitial fluid to drain into the body's lymphatic system. New methodology is enabling visualization of this process in both animals and humans and is revealing how these processes break down during ageing and disease. With this understanding we can begin to envisage novel therapeutic approaches to the treatment of neurodegeneration, and how reversing sleep impairment in the correct manner may provide a way to slow these processes and improve brain function.


Sintering mode of a translucent Y-TZP: Effects on its biaxial flexure fatigue strength, surface morphology and translucency.
This investigation evaluated the effect of two sintering modes of a translucent zirconia (Y-TZP) on its surface roughness, topography, phase-transformation (t → m), translucency and biaxial flexure fatigue strength. To do so, 50 Y-TZP discs (Ø = 15 mm; thickness = 1.2 mm; IPS e.max ZirCAD LT) were prepared and divided into two groups: Standard mode (SM) and Fast mode (FM). Staircase fatigue testing was performed (piston-on-three balls set-up, ISO 6872:2015), as well as surface roughness, profilometry, scanning electron microscopy (SEM-FEG), energy dispersive X-ray spectroscopy (EDX), phase transformation (t → m) using X-ray diffraction analysis (XRD), translucency parameter analysis (TP and TP00 ) and fractography. The results showed no statistical significant differences for roughness parameters (p > 0.05, SM: Ra = 0.13 ± 0.02, Rz = 1.21 ± 0.26 and RSm = 24.91 ± 2.19; FM: Ra = 0.14 ± 0.03, Rz = 1.32 ± 0.25 and RSm = 24.68 ± 2.16) or flexural fatigue strength (SM: 512 (464-560) MPa; FM: 542 (472-611) MPa) between the groups. In addition, similarity in surface morphological features (SEM and profilometry), composition and phases (EDX and XRD) was observed between the firing protocols. Fractography showed that the failure origin occurred on the tensile side. Sintering mode did not affect the TP (F = 0.001, p = 0.97) and TP00 (F = 0.12, p = 0.72). Therefore, the fast-sintering mode is suggested as a viable alternative to the standard mode since it does not influence the evaluated surface morphology, microstructure, fatigue strength and translucency of a translucent monolithic zirconia. The fast sintering mode is a viable alternative for zirconia without compromising its topography, microstructure, mechanical performance or translucency.


Dynamic expression of Erbb pathway members during early mammary gland morphogenesis.
Similar to other epithelial appendages, mammary anlagen progress from stratified epithelium through placode and bud stages. Embryonic mammary morphogenesis is elicited by a combination of local cell migration, adhesion changes and proliferation, and these same developmental processes impact breast cancer etiology. The Erbb signaling network plays important roles in postnatal mammary gland morphogenesis and carcinogenesis. Neuregulin3 (Nrg3), an Erbb family ligand, has recently been shown to be involved in the specification of mammary glands in mice. To further examine the possible involvement of other Erbb family members and their ligands in early mammary morphogenesis, we have characterized their expression patterns during this process. We used whole mount in situ hybridization to analyze the expression patterns of these genes at stages prior to and during mammary placode formation. Immunohistochemistry was used to examine expression patterns at later bud stages. The Neuregulin ligands, Nrg1, Nrg2, Nrg3, Nrg4 and the receptors, Erbb1, Erbb2, Erbb3, Erbb4, were expressed either at stages prior to morphological appearance of the mammary placode or from the time that the placode is first morphologically distinct through to later bud stages. The expression patterns presented here suggest that multiple members of this signaling network are potential mediators of early mammary morphogenesis.


Increased incidence of pathologically nonorgan confined prostate cancer in African-American men eligible for active surveillance.
To compare the clinicopathologic findings of African-American (AA) and White-American (WA) men with prostate cancer (PCa) who were candidates for active surveillance (AS) and underwent radical prostatectomy (RP). Prospectively maintained database of men who underwent RP from 2 academic centers were analyzed retrospectively. Postoperative pathologic characteristics of patients who met the AS inclusion criteria of the University of California, San Francisco (UCSF) and National Comprehensive Cancer Network (NCCN) were evaluated. After RP, the rate of pathological upstaging and Gleason upgrading were compared between AA and WA men. In the AA cohort, 196 and 124 men met the UCSF and NCCN criteria for AS, respectively. With respect to WA patients, 191 and 148 fulfilled the AS criteria for UCSF and NCCN, respectively. AA men had a higher percentage of maximum biopsy core than WA men (15.3%-20.4% vs 11.5%-15.0%, P <.05, respectively) in both cohorts. In addition, a greater proportion of AA men had multiple positive biopsy cores compared to WA men (45.2% vs 33.1%, P = .046) under the NCCN criteria. A higher proportion of AA men were upstaged (≥pT3) compared to WA men (19.4% vs 10.1%, P = .037). A multivariate regression test revealed that age, preoperative PSA, and number of positive cores were independent predictors of more advanced disease (upstaging and/or upgrading) in AA men. AA men who were candidates for AS criteria had worse clinicopathological features on final surgical pathology than WA men. These results suggest that a more stringent AS criteria should be considered in AA men with prostate cancer.


Platelet and red blood cell phagocytosis kinetics are differentially controlled by phosphatase activity within mononuclear cells.
Anti-D treatment is effective in increasing platelet (PLT) counts in patients with autoimmune thrombocytopenic purpura (AITP); however, the exact mechanism of action is unknown. Previous results have suggested that anti-D-coated red blood cells (RBCs) affect reticuloendothelial system phagocytosis by stimulating agents (e.g., reactive oxygen species) that alter signaling pathways within the phagocyte. To address this, a flow cytometric assay was used to compare the kinetics and signaling pathways responsible for opsonized PLT and RBC phagocytosis. Human RBCs or PLTs were labeled with the fluorescent dye CM-Green, opsonized with Rh immune globulin or anti-MHC, respectively, and incubated with THP-1 monocytes with or without signal transduction inhibitors and intracellular fluorescence was analyzed. Compared with opsonized PLTs, phagocytosis of opsonized RBCs was significantly slower (p<0.0001) and, within 2 hours, induced a state of phagocytic refractoriness; resting the mononuclear cells (MNCs) for up to 24 hours did not rescue their ability to further mediate PLT phagocytosis. Inhibitors of phosphatidylinositol 3-kinase (wortmannin, LY294002, myricetin, and quercetin), protein kinase C (staurosporine), and Syk kinase (piceatannol) inhibited both opsonized RBC and opsonized PLT phagocytosis. In contrast, opsonized RBC phagocytosis was significantly (p<0.0001) enhanced by the tyrosine phosphatase inhibitor phenyl arsine oxide, whereas PLT phagocytosis was significantly reduced (p<0.0001). Of interest, phosphatase inhibition during opsonized RBC phagocytosis induced a longer (48 hr) phagocytic refractoriness period in the MNCs. These results suggest that the early kinetics and signaling events related to phosphatase activity regulate how mononuclear phagocytes engulf opsonized RBCs and induce phagocytic refractoriness for further PLT phagocytosis.


Oxidative treatment of NOM by selective oxidants in drinking water treatment and its impact on DBP formation in postchlorination.
Natural organic matter (NOM), as a ubiquitous component in aqueous environments, has raised continuous scientific concerns due to its role as an organic precursor to disinfection by-products (DBPs) in the subsequent chlorination process. Selective oxidants, including ozone (O3), chlorine dioxide (ClO2), permanganate (Mn(VII)), and ferrate (Fe(VI)) are widely used in the preoxidation stage in drinking water treatment. The selective reactivity of those oxidants toward NOM is expected to alternate NOM properties and consequently DBP formation in postchlorination. Despite extensive studies on the interactions of NOM with selective oxidants, there is currently a lack of an overview of this area. To fill this gap, this study presents the current knowledge of the modification of NOM properties by selective oxidants and its impact on DBP formation in postchlorination. The NOM property changes in three aspects, including bulk property (e.g., total organic carbon, ultraviolet absorbance), fractional constituent (e.g., molecular size, hydrophilicity/hydrophobicity), and elemental composition (e.g., functional group) by the four selective oxidants (i.e., O3, ClO2, Mn(VII), and Fe(VI)) were discussed. Thereafter, the impacts of alteration of NOM properties by those selective oxidants on DBP formation in the subsequent chlorination were summarized, wherein the key influencing factors were discussed. Finally, the future perspectives in this area were forwarded, which highlighted the significance of process optimization, the attention to the less studied but more toxic DBPs, and the need for the identification of unknown DBPs. This review presented a state-of-the-art knowledge pool of the fate of NOM in oxidation and chlorination processes, promoted our understanding of the relationship between NOM properties and DBP formation, and identified further research needs in this area.


Chronic treatment with melatonin attenuates serotonergic degeneration in the striatum and olfactory tubercle of zitter mutant rats.
The effects of chronic treatment with the antioxidant hormone melatonin on degeneration of serotonergic fibers were studied in the striatum and olfactory tubercle of the zitter rat, which shows a loss-of-function mutation of the glycosylated transmembrane protein attractin. In these animals, serotonergic fibers in the striatum and olfactory tubercle undergo spontaneous and progressive degeneration as a result of abnormal metabolism of reactive oxygen species. Homozygous zitter (zi/zi) rats were provided ad libitum access to drinking water containing melatonin for 9 months (M) after weaning. High-performance liquid chromatography analysis revealed that melatonin treatment significantly increased serotonin in the caudate-putamen, (CPU), nucleus accumbens (NA) and olfactory tubercle (OT). Immunohistochemical staining for serotonin was consistent with the neurochemical data and further demonstrated substantially increased numbers of serotonergic nerve terminals in these areas. Aberrant serotonergic fibers characterized by swollen varicosities (>1 microm in diameter) were observed in the CPU and NA of 10 M zi/zi rats. The number of these fibers decreased after melatonin treatment ended. Furthermore, hyperinnervation of serotonergic fibers was observed in the OT of melatonin-treated zi/zi rats. These results suggest that melatonin protects serotonergic fibers and terminals in zitter rats and/or promotes their neuroplasticity.


Health effects of occupational exposure to printer emissions on workers in China: Cardiopulmonary function change.
Printers emitted nanoparticles (NPs), ozone (O3) and volatile organic chemicals (VOCs) during operation that elicited adverse effects on indoor air quality of the printing room, which may affect the health of exposed workers. The aim of this work was to explore the health effects of occupational exposure to printer emissions on workers, especially cardiovascular and lung function. We sampled particles in the print shop for characterization, including particle size distribution and elemental composition, and measured PM1 number concentrations in print shops and other workplaces. We assessed blood pressure, heart rate and pulmonary function in 53 printing room workers and 54 controls in Beijing, China. Multiple linear regression analysis were used to examine health effects of exposure to printer emissions. The PM1 number concentration in the print shop was more than 2 times that of the control group. Compared with controls, the exposed workers with lower education and income had heavier workload with a median of 7 days per week and 12 h per day on working days, and presented cardiopulmonary function injury with increased the diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP). The most significant changes of cardiopulmonary function were found in exposed workers with more than 10 years of working age. Multiple linear regression also showed printer emissions exposure was associated with increased SBP and MAP, while decreased lung function indices. This study found changes in the cardiopulmonary function of staff members exposed to printer emissions, which prompted the necessity and urgency of improving the environment of printing rooms and protecting the health of exposed workers.