Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver.
The aim of this study was to discover cis- and trans-acting factors significantly affecting mRNA expression and catalytic activity of human hepatic UDP-glucuronosyltransferases (UGTs). Transcription levels of five major hepatic UGT1A (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) and five UGT2B (UGT2B4, UGT2B7, UGT2B10, UGT2B15 and UGT2B17) genes were quantified in human liver tissue samples (n = 125) using real-time PCR. Glucuronidation activities of 14 substrates were measured in 47 livers. We genotyped 167 tagSNPs (single-nucleotide polymorphisms) in UGT1A (n = 43) and UGT2B (n = 124), as well as the known functional UGT1A1*28 and UGT2B17 CNV (copy number variation) polymorphisms. Transcription levels of 15 transcription factors (TFs) known to regulate these UGTs were quantified. We found that UGT expression and activity were highly variable among the livers (median and range of coefficient of variations: 135%, 74-217% and 52%, 39-105%, respectively). CAR, PXR and ESR1 were found to be the most important trans-regulators of UGT transcription (median and range of correlation coefficients: 46%, 6-58%; 47%, 9-58%; and 52%, 24-75%, respectively). Hepatic UGT activities were mainly determined by UGT gene transcription levels. Twenty-one polymorphisms were significantly (FDR-adjusted P < 0.05) associated with mRNA expression and/or activities of UGT1A1, UGT1A3 and UGT2B17. We found novel SNPs in the UGT2B17 CNV region accounting for variability in UGT2B17 gene transcription and testosterone glucuronidation rate, in addition to that attributable to the UGT2B17 CNV. Our study discovered novel pharmacogenetic markers and provided detailed insight into the genetic network regulating hepatic UGTs.


Systems genetics identifies miRNA-mediated regulation of host response in COVID-19.
Individuals infected with SARS-CoV-2 vary greatly in their disease severity, ranging from asymptomatic infection to severe disease. The regulation of gene expression is an important mechanism in the host immune response and can modulate the outcome of the disease. miRNAs play important roles in post-transcriptional regulation with consequences on downstream molecular and cellular host immune response processes. The nature and magnitude of miRNA perturbations associated with blood phenotypes and intensive care unit (ICU) admission in COVID-19 are poorly understood. We combined multi-omics profiling-genotyping, miRNA and RNA expression, measured at the time of hospital admission soon after the onset of COVID-19 symptoms-with phenotypes from electronic health records to understand how miRNA expression contributes to variation in disease severity in a diverse cohort of 259 unvaccinated patients in Abu Dhabi, United Arab Emirates. We analyzed 62 clinical variables and expression levels of 632 miRNAs measured at admission and identified 97 miRNAs associated with 8 blood phenotypes significantly associated with later ICU admission. Integrative miRNA-mRNA cross-correlation analysis identified multiple miRNA-mRNA-blood endophenotype associations and revealed the effect of miR-143-3p on neutrophil count mediated by the expression of its target gene BCL2. We report 168 significant cis-miRNA expression quantitative trait loci, 57 of which implicate miRNAs associated with either ICU admission or a blood endophenotype. This systems genetics study has given rise to a genomic picture of the architecture of whole blood miRNAs in unvaccinated COVID-19 patients and pinpoints post-transcriptional regulation as a potential mechanism that impacts blood traits underlying COVID-19 severity. The results also highlight the impact of host genetic regulatory control of miRNA expression in early stages of COVID-19 disease.


3'-Deoxy-3'-18F-fluorothymidine PET predicts response to (V600E)BRAF-targeted therapy in preclinical models of colorectal cancer.
Selective inhibition of oncogenic targets and associated signaling pathways forms the basis of personalized cancer medicine. The clinical success of (V600E)BRAF inhibition in melanoma, coupled with the emergence of acquired resistance, underscores the importance of rigorously validating quantitative biomarkers of treatment response in this and similar settings. Because constitutive activation of BRAF leads to proliferation in tumors, we explored 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET to noninvasively quantify changes in tumor proliferation that are associated with pharmacologic inhibition of (V600E)BRAF downstream effectors and that precede changes in tumor volume. Human colorectal cancer (CRC) cell lines expressing (V600E)BRAF were used to explore relationships between upregulation of p27 and phosphorylation of BRAF downstream effectors on small-molecule (V600E)BRAF inhibitor exposure. Athymic nude mice bearing (V600E)BRAF-expressing human CRC cell line xenografts were treated with a small-molecule (V600E)BRAF inhibitor (or vehicle) daily for 10 d. Predictive (18)F-FLT PET was conducted before changes in tumor volume occurred. Correlations were evaluated among PET, inhibition of phosphorylated MEK (p-MEK) and phosphorylated-ERK (p-ERK) by Western blot, tumor proliferation by histology, and small-molecule exposure by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). Treatment of CRC cell lines with PLX4720 reduced proliferation associated with target inhibition and upregulation of p27. In vivo, PLX4720 treatment reduced (18)F-FLT uptake, but not (18)F-FDG uptake, in Lim2405 xenografts before quantifiable differences in xenograft volume. Reduced (18)F-FLT PET reflected a modest, yet significant, reduction of Ki67 immunoreactivity, inhibition of p-MEK and p-ERK, and elevated tumor cell p27 protein levels. Both (18)F-FLT PET and (18)F-FDG PET accurately reflected a lack of response in HT-29 xenografts, which MALDI imaging mass spectrometry suggested may have stemmed from limited PLX4720 exposure. We used preclinical models of CRC to demonstrate (18)F-FLT PET as a sensitive predictor of response to (V600E)BRAF inhibitors. Because (18)F-FLT PET predicted reduced proliferation associated with attenuation of BRAF downstream effectors, yet (18)F-FDG PET did not, these data suggest that (18)F-FLT PET may represent an alternative to (18)F-FDG PET for quantifying clinical responses to BRAF inhibitors.


Behavioral therapy for overactive bladder.
What is behavioral therapy? On the one hand there is no consensus in the literature as to the definition of the treatment or the optimal mode of delivery. On the other hand, it is possibly the "best" single treatment for urinary incontinence when viewed from a risk:benefit analysis. There is general agreement that within this framework wide variations exist in intensity of treatment, expertise required to deliver the treatment, and the subsequent cost of therapy. A definition of behavioral therapy should include at least the following techniques: first, education and explanation of normal lower urinary tract function; second, micturition charts and diaries; and finally, timed voiding/bladder training regimens. All of the behavioral methods are demonstrably effective, with improvement rates in incontinence episodes uniformly in excess of 50%. Our challenge is to define the critical parts of behavioral therapy and develop algorithms that can be delivered to the incontinent population in the most cost-effective manner.


Differential binding of glycine- and taurine-conjugated bile acids to insoluble calcium phosphate.
It is demonstrated that bile acids bind to insoluble calcium phosphate at pH values beyond 5.5. Significant binding occurs with glycine-conjugated dihydroxy bile acids. Results indicate that these bile acids are bound in a micellar mode. Taurine conjugation almost completely inhibits the binding of these bile acids to insoluble calcium phosphate. Since glycine-conjugated dihydroxy bile acids are predominant in the rabbit, but not in the rat, our results suggest an explanation for the intriguing species-dependence of casein-induced hypercholesterolaemia, which is high in the rabbit but absent in the rat.


Cigarette smoke attenuates the RIG-I-initiated innate antiviral response to influenza infection in two murine models.
Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Despite this association, the mechanisms underlying the increased susceptibility to respiratory virus infection are poorly understood. Retinoic acid-inducible gene I (RIG-I) is an important regulator of influenza virus-induced expression of antiviral cytokines, mainly interferons (IFNs), which are necessary to clear viral infections. In this study, we compared the innate cytokine responses of two mouse CS exposure models following a challenge with influenza A virus (IAV): 1) exposure of the mice to cigarette smoke extract (CSE) intratracheally and 2) exposure of the mice to CS in a whole body exposure chamber. Both intratracheal CSE treatment and whole body CS exposure caused antiviral immunosuppression in these mice, and both CS exposure methods inhibited RIG-I induction. CS attenuated influenza-induced antiviral IFNs and IP-10 expression in vivo. However, we did not find that CS inhibited induction of the proinflammatory cytokines IL-6 and TNF-α, whose expression was induced by IAV. Interestingly, IAV infection also increased Toll-like receptor 3 (TLR3) expression in mouse lung, but CS exposure did not impact TLR3 induction in these mice. Together, the results support our previous finding in a human lung organ culture model that the suppression of RIG-I induction and antiviral cytokine responses by CS are likely important in the enhanced susceptibility of smokers to influenza infection in the lung.


Skeletal muscle Ras-related GTP binding B mRNA and protein expression is increased after essential amino acid ingestion in healthy humans.
Essential amino acids (EAAs) are potent stimulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis. However, regulators upstream of mTORC1 that are responsive to EAA availability are not well described, especially in human skeletal muscle. The purpose of this study was to determine changes in leucyl-tRNA synthetase (LARS/LARS) and Ras-related GTP binding B (RAGB/RAGB) mRNA and protein expression in healthy human skeletal muscle after acute EAA ingestion. Muscle biopsies sampled from the vastus lateralis were obtained from 13 young adults (7 males, 6 females; aged 22.9 ± 0.9 y; body mass index 21.7 ± 0.9 kg/m(2)) in the fasting state (baseline) and 1 and 3 h after EAA (13 g; 2.4 g of Leu) ingestion. Real-time quantitative polymerase chain reaction and Western blotting were used to determine changes in LARS/LARS and RAGB/RAGB mRNA and protein expression, respectively. Stable isotope tracers and gas chromatography mass spectrometry were used to determine Leu intracellular concentrations and muscle protein synthesis. EAA ingestion increased RAGB/RAGB mRNA (∼60%) and protein (∼100%) abundance in adult skeletal muscle (P ≤ 0.05). EAAs also increased muscle Leu concentrations (∼130%), mTOR phosphorylation (∼30%), and muscle protein synthesis (∼50%; P ≤ 0.05) but did not alter muscle LARS/LARS abundance (P > 0.05). We conclude that acute EAA ingestion is capable of increasing RAGB expression in human skeletal muscle. Future work is needed to determine whether this adaptive response is important to promote muscle protein anabolism in humans. This trial was registered at clinicaltrials.gov as NCT01669590.


Dating of ballpoint pen ink.
In this paper we describe a case in which a cash book, dated of the year 2000, was sent to the Forensic Science Division, Document Laboratory, Zurich Canton Police in March 2003. The questioned document was a list of 29 pages containing a consecutive handwritten numbering and dated entries (payments) made of blue ballpoint pen ink. By definition, a cash book has to be written by hand and the entries have to be made daily. The questioned document was suspected to have been written within a short period (e.g., a few hours) and backdated. The document lab was asked to determine the date of the entries of the questioned list. On one hand, we were asked, if the cash book had been kept on account consecutively during the period of one year, and on the other hand, the judges were interested in knowing, if the document could have been written in 2003 and back dated to 2000. To answer these questions, the document was examined for latent elements by electrostatic detection device (ESDA). The relative dating of the entries was performed by the quantification of the ballpoint pen ink dyes and their degradation products using HPLC. Results show that it is possible to determine the relative age of entries written by ballpoint pen within a relatively short time scale, if storage and supporting material of the different samples are the same or at least similar.


Surge Capacity and Mass Casualty Incidents Preparedness of Emergency Departments in a Metropolitan City: a Regional Survey Study.
Emergency departments (EDs) generally receive many casualties in disaster or mass casualty incidents (MCI). Some studies have conceptually suggested the surge capacity that ED should have; however, only few studies have investigated measurable numbers in one community. This study investigated the surge capacity of the specific number of accommodatable patients and overall preparedness at EDs in a metropolitan city. This cross-sectional study officially surveyed surge capacity and disaster preparedness for all regional and local emergency medical centers (EMC) in Seoul with the Seoul Metropolitan Government's public health division. This study developed survey items on space, staff, stuff, and systems, which are essential elements of surge capacity. The number of patients acceptable for each ED was investigated by triage level in ordinary and crisis situations. Multivariate linear regression analysis was performed on hospital resource variables related to surge capacity. In the second half of 2018, a survey was conducted targeting 31 EMC directors in Seoul. It was found that all regional and local EMCs in Seoul can accommodate 848 emergency patients and 537 non-emergency patients in crisis conditions. In ordinary situations, one EMC could accommodate an average of 1.3 patients with Korean Triage and Acuity Scale (KTAS) level 1, 3.1 patients with KTAS level 2, and 5.7 patients with KTAS level 3. In situations of crisis, this number increased to 3.4, 7.8, and 16.2, respectively. There are significant differences in surge capacity between ordinary and crisis conditions. The difference in surge capacity between regional and local EMC was not significant. In both ordinary and crisis conditions, only the total number of hospital beds were significantly associated with surge capacity. If the hospital's emergency transport system is ideally accomplished, patients arising from average MCI can be accommodated in Seoul. However, in a huge disaster, it may be challenging to handle the current surge capacity. More detailed follow-up studies are needed to prepare a surge capacity protocol in the community.


Human cytomegalovirus productively infects primary differentiated macrophages.
Monocytes are one of the predominant cell types in the peripheral blood that are infected by human cytomegalovirus (HCMV). Although virus can be detected in these cells in vivo, HCMV replication in cultured monocytes has been unsuccessful. In this study, we demonstrate efficient HCMV replication in cultured monocytes. HCMV permissiveness in these cells was dependent on nonadherent cell-induced stimulation of the monocyte, with subsequent morphological differentiation into macrophages. Approximately 40% of the cells infected by virus were detected by immunofluorescent staining with both immediate-early and late antibodies. In addition, viral plaque assays demonstrated significant productive infection of macrophages. These observations are consistent with the suggestion that the monocyte/macrophage serves as a source of viral amplification and dissemination.


Vaccination with adenovirus serotypes 35, 26, and 48 elicits higher levels of innate cytokine responses than adenovirus serotype 5 in rhesus monkeys.
Adenovirus (Ad) vaccine vectors have proven highly immunogenic in multiple experimental models, but the innate immune responses induced by these vectors remain poorly characterized. Here we report innate cytokine responses to 5 different Ad vectors in 26 rhesus monkeys. Vaccination with adenovirus serotype 35 (Ad35), Ad26, and Ad48 induced substantially higher levels of antiviral (gamma interferon [IFN-γ], 10-kDa gamma interferon-induced protein [IP-10]) and proinflammatory (interleukin 1 receptor antagonist [IL-1RA], IL-6) cytokines than vaccination with Ad5 on day 1 following immunization. In vitro studies with capsid chimeric vectors and receptor-blocking monoclonal antibodies suggested that fiber-receptor interactions, as well as other capsid components, were critical for triggering these innate responses. Moreover, multiple cell populations, including dendritic cells, monocytes/macrophages, and T lymphocytes, contributed to these innate cytokine profiles. These data demonstrate that Ad35, Ad26, and Ad48, which utilize CD46 as their primary cellular receptor, induce significantly greater innate cytokine responses than Ad5, which uses the coxsackievirus and adenovirus receptor (CAR). These differences in innate triggering result in markedly different immunologic milieus for the subsequent generation of adaptive immune responses by these vaccine vectors.


Predicting Regioselectivity of AO, CYP, FMO, and UGT Metabolism Using Quantum Mechanical Simulations and Machine Learning.
Unexpected metabolism in modification and conjugation phases can lead to the failure of many late-stage drug candidates or even withdrawal of approved drugs. Thus, it is critical to predict the sites of metabolism (SoM) for enzymes, which interact with drug-like molecules, in the early stages of the research. This study presents methods for predicting the isoform-specific metabolism for human AOs, FMOs, and UGTs and general CYP metabolism for preclinical species. The models use semi-empirical quantum mechanical simulations, validated using experimentally obtained data and DFT calculations, to estimate the reactivity of each SoM in the context of the whole molecule. Ligand-based models, trained and tested using high-quality regioselectivity data, combine the reactivity of the potential SoM with the orientation and steric effects of the binding pockets of the different enzyme isoforms. The resulting models achieve κ values of up to 0.94 and AUC of up to 0.92.


Molecular Design Strategy in Developing Titanyl Phthalocyanines as Dopant-Free Hole-Transporting Materials for Perovskite Solar Cells: Peripheral or Nonperipheral Substituents?
We demonstrate a molecular design strategy to enhance the efficiency of phthalocyanine (Pc)-based hole-transporting materials (HTMs) in perovskite solar cells (PSCs). Herein, two titanyl phthalocyanine (TiOPc) derivatives are designed and applied as dopant-free HTMs in planar n-i-p-structured PSCs. The newly developed TiOPc compounds possess eight n-hexylthio groups attached to either peripheral (P-SC6-TiOPc) or nonperipheral (NP-SC6-TiOPc) positions of the Pc ring. Utilizing these dopant-free HTMs in PSCs with a mixed cation perovskite as the light-absorbing material and tin oxide (SnO2) as the electron-transporting material (ETM) results in a considerably enhanced efficiency for NP-SC6-TiOPc-based devices compared to PSCs using P-SC6-TiOPc. Hence, all of the photovoltaic parameters, including power conversion efficiency (PCE), fill factor, open-circuit voltage, and short-circuit current density, are remarkably improved from 5.33 ± 1.01%, 33.34 ± 3.45%, 0.92 ± 0.18 V, and 17.33 ± 2.08 mA cm-2 to 15.83 ± 0.44%, 69.03 ± 1.59%, 1.05 ± 0.01 V, and 21.80 ± 0.36 mA cm-2, respectively, when using the nonperipheral-substituted TiOPc derivative as the HTM in a PSC. Experimental and computational analysis suggests more compact molecular packing for NP-SC6-TiOPc than P-SC6-TiOPc in the solid state due to stronger π-π interactions, leading to thin films with better quality and higher performance in hole extraction and transportation. PSCs with NP-SC6-TiOPc also offer much higher long-term stability than P-SC6-TiOPc-based devices under ambient conditions with a relative humidity of 75%.


The antidepressant effect of 4-hydroxybenzyl alcohol 2-naphthoate through monoaminergic, GABAergic system and BDNF signaling pathway.
Gastrodigenin, also known as 4-hydroxybenzyl alcohol (HBA), is one of the main components of Gastrodia elata, which is a perfect lead compound of natural products. In order to get new active compounds, we modified the structure of HBA through esterification with carboxylic acid, and got a series of derivatives in which 4-hydroxybenzyl alcohol 2-naphthoate (NHBA) showed stronger antidepressant activity than HBA. In this paper, we firstly evaluated the antidepressant activity of NHBA by tail suspension test (TST) and forced swimming test (FST). Then, we carried out the biochemical assay and western blot to determine its mechanism. The results displayed that NHBA could increase the content of serotonin, dopamine, norepinephrine, γ-aminobutyric acid, brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in mice brain. It suggested that NHBA exhibited an antidepressant-like effect through monoaminergic system, GABAergic system and BDNF/TrkB signaling pathways.


Molecular properties of muscarinic acetylcholine receptors.
Muscarinic acetylcholine receptors, which comprise five subtypes (M1-M5 receptors), are expressed in both the CNS and PNS (particularly the target organs of parasympathetic neurons). M1-M5 receptors are integral membrane proteins with seven transmembrane segments, bind with acetylcholine (ACh) in the extracellular phase, and thereafter interact with and activate GTP-binding regulatory proteins (G proteins) in the intracellular phase: M1, M3, and M5 receptors interact with Gq-type G proteins, and M2 and M4 receptors with Gi/Go-type G proteins. Activated G proteins initiate a number of intracellular signal transduction systems. Agonist-bound muscarinic receptors are phosphorylated by G protein-coupled receptor kinases, which initiate their desensitization through uncoupling from G proteins, receptor internalization, and receptor breakdown (down regulation). Recently the crystal structures of M2 and M3 receptors were determined and are expected to contribute to the development of drugs targeted to muscarinic receptors. This paper summarizes the molecular properties of muscarinic receptors with reference to the historical background and bias to studies performed in our laboratories.


Polymer chain generation for coarse-grained models using radical-like polymerization.
A versatile method is proposed to generate configurations of coarse-grained models for polymer melts. This method, largely inspired by chemical "radical polymerization," is divided in three stages: (i) nucleation of radicals (reacting molecules caching monomers), (ii) growth of chains within a solvent of monomers and (iii) termination: annihilation of radicals and removal of residual monomers. The main interest of this method is that relaxation is performed while chains are generated. Pure mono and polydisperse polymer melts are generated and compared to the configurations generated by the push off method from Auhl et al. [J. Chem. Phys. 119, 12718 (2003)]. A detailed study of the static properties (radius of gyration, mean square internal distance, entanglement length) confirms that the radical-like polymerization technique is suitable to generate equilibrated melts. Moreover, the method is flexible and can be adapted to generate nanostructured polymers, namely, diblock and triblock copolymers.


Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury.
Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.


Effect of long-term administration of rebamipide on Helicobacter pylori infection in mice.
It has been suggested that chronic, persistent, uncontrolled inflammations in the stomach could provide the basic step for the beginning of carcinogenesis. One of the potential clinical applications of rebamipide is the inhibition of the immunoinflammatory response in gastric mucosa imposed by Helicobacter pylori. To determine the implications of long-term rebamipide treatment in H. pylori infection, we studied the underlying moleculo-pathological changes in gastric lesions in mice infected with H. pylori (SS1 strain), following this treatment. C57BL/6 mice were sacrificed 24 and 50 weeks after H. pylori infection, respectively. Colonization rates of H. pylori, degree of gastric inflammation and other pathological changes including atrophic gastritis and metaplasia, serum levels of IL-1beta, TNF-alpha, IFN-gamma and IL-10, mRNA transcripts of various mouse cytokines and chemokines, and NF-kappaB binding activities, and finally the presence of gastric adenocarcinoma were compared between an H. pylori infected group (HP), and an H. pylori infected group administered with long-term rebamipide-containing pellet diets (HPR). Serum levels of IL-1beta, IFN-gamma and TNF-alpha, the gastric mucosal expression of ICAM-1, HCAM and MMP, and transcriptional regulation of NF-kappaB-DNA binding were all significantly decreased in the HPR group compared with the HP group. An RNase protection assay showed, in the rebamipide administered group, significantly decreased mRNA levels of apoptosis-related genes such as caspase-8, FasL, Fas, TRAIL and various cytokines genes such as IFN-gamma, RANTES, TNF-alpha, TNFR p75, IL-1beta. In the experiment designed to provoke gastric cancer through MNU treatment with H. pylori infection, the incidence of gastric carcinoma was not different in either group. However, long-term administration of rebamipide showed the advantage of decreasing precancerous lesions like chronic atrophic gastritis and showed molecular evidence of attenuation of proliferation. The long-term administration of rebamipide should be considered in the treatment of H. pylori since it demonstrated molecular and biological advantages like a lessening of gastric inflammation and a possible chemopreventive effect.


Identification of antimicrobial peptide genes from transcriptomes in Mandarin fish (Siniperca chuatsi) and their response to infection with Aeromonas hydrophila.
Mandarin fish (Siniperca chuatsi) is a valuable freshwater fish species widely cultured in China. Its aquaculture production is challenged by bacterial septicaemia, which is one of the most common bacterial diseases. Antimicrobial peptides (AMPs) play a critical role in the innate immune system of fish, exhibiting defensive and inhibitory effects against a wide range of pathogens. This study aimed to identify the antimicrobial peptide genes in mandarin fish using transcriptomes data obtained from 17 tissue in our laboratory. Through nucleotide sequence alignment and protein structural domain analysis, 15 antimicrobial peptide genes (moronecidin, pleurocidin, lysozyme g, thymosin β12, hepcidin, leap 2, β-defensin, galectin 8, galectin 9, apoB, apoD, apoE, apoF, apoM, and nk-lysin) were identified, of which 9 antimicrobial peptide genes were identified for the first time. In addition, 15 AMPs were subjected to sequence characterization and protein structure analysis. After injection with Aeromonas hydrophila, the number of red blood cells, hemoglobin concentration, and platelet counts in mandarin fish showed a decreasing trend, indicating partial hemolysis. The expression change patterns of 15 AMP genes in the intestine after A. hydrophila infection were examined by using qRT-PCR. The results revealed, marked up-regulation (approximately 116.04) of the hepcidin gene, down-regulation of the piscidin family genes expression. Moreover, most AMP genes were responded in the early stages after A. hydrophila challenge. This study provides fundamental information for investigating the role of the different antimicrobial peptide genes in mandarin fish in defense against A. hydrophila infection.


Enhancing tsetse fly refractoriness to trypanosome infection--a new IAEA coordinated research project.
To date, IAEA-supported Sterile Insect Technique (SIT) projects for tsetse and trypanosomiasis control have been in areas without human sleeping sickness, but future projects could include areas of actual or potential human disease transmission. In this context it would be imperative that released sterile tsetse flies are incompetent to transmit the disease-causing trypanosome parasite. Therefore, development of tsetse fly strains refractory to trypanosome infection is highly desirable as a simple and effective method of ensuring vector incompetence of the released flies. This new IAEA Coordinated Research Project (CRP) focuses on gaining a deeper knowledge of the tripartite interactions between the tsetse fly vectors, their symbionts and trypanosome parasites. The objective of this CRP is to acquire a better understanding of mechanisms that limit the development of trypanosome infections in tsetse and how these may be enhanced.


Short-term effects of potassium fertilization on the hydraulic conductance of Laurus nobilis L.
This study reports experimental evidence on the effect of short-term potassium fertilization on potassium uptake, tissue concentration and hydraulic conductance of pot-grown laurel plants. Potassium uptake and loading into the xylem of laurel seedlings increased within 24 h after fertilization. Potassium was not accumulated in roots and leaves, but the [K(+)] of xylem sap was 80% higher in fertilized plants (+K) than in potassium-starved plants (-K), as a likely result of recirculation between xylem and phloem. Increased xylem sap [K(+)] resulted in a 45% increase in transpiration rate, a 30% increase in plant hydraulic conductance (K(plant)) and a 120% increase in leaf-specific conductivity of the shoot (k(shoot)). We suggest that this increase was due to ion-mediated up-regulation of xylem hydraulics, possibly caused by the interaction of potassium ions with the pectic matrix of intervessel pits. The enhancement of hydraulic conductance following short-term potassium fertilization is a phenomenon that can be of advantage to plants for maintaining cell turgor, stomatal aperture and gas exchange rates under moderate drought stress. Our data provide additional support for the important role of potassium nutrition in agriculture and forestry.


Glutamate and aspartate binding sites are enriched in synaptic junctions isolated from rat brain.
The binding of the putative excitatory transmitters glutamate (Glu) and aspartate (Asp) was measured in various subcellular fractions in order to assess their degree of localization in synaptic junctions (SJs). For both ligands, specific binding levels increased in the order, whole particulate membranes--crude mitochondrial pellet membranes (P2)--synaptic plasma membranes (SPM), and were highly enriched in SJs, with values approximately 9 times greater than the values in whole particulate membranes. The recovery of binding sites in SJs suggested that the majority of sites in SPMs were junctional in nature. Specific binding sites were found also in other subcellular fractions, such as microsomal membranes, "light" SPMs, and mitochondrial membranes. Sodium ions were able to stimulate the specific binding of both ligands (Asp greater than Glu), the magnitude of the effect between subcellular fractions being in the order, whole particulate membranes greater than P2 greater than SPM. This effect was absent in SJs. Calcium and magnesium ions also enhanced the binding (Glu greater than Asp) in the order, whole particulate membranes greater than or equal to P2 greater than or equal to SPM greater than SJ. The results indicate that Glu and Asp binding sites have a specific synaptic localization and support a role for Glu and Asp receptors in synaptic transmission.


Advances in targeting the extracellular matrix for glaucoma therapy: current updates.
Elevated intraocular pressure (IOP) is a well-recognized risk factor for development of primary open angle glaucoma (POAG), a leading cause of irreversible blindness. Ocular hypertension is associated with excessive extracellular matrix (ECM) deposition in trabecular meshwork (TM) resulting in increased aqueous outflow resistance and elevated IOP. Hence, therapeutic options targeting ECM remodeling in TM to lower IOP in glaucomatous eyes are of considerable importance. This paper discusses the complex process of ECM regulation in TM and explores promising therapeutic targets. The role of Transforming Growth Factor-β as a central player in ECM deposition in TM is discussed. We elaborate the key regulatory processes involved in its activation, release, signaling, and cross talk with other signaling pathways including Rho GTPase, Wnt, integrin, cytokines, and renin-angiotensin-aldosterone. Further, we summarize the therapeutic agents that have been explored to target ECM dysregulation in TM. Targeting molecular pathways to reduce ECM deposition and/or enhance its degradation are of considerable significance for IOP lowering. Challenges lie in pinpointing specific targets and designing drug delivery systems to precisely interact with pathologically active/inactive signaling. Recent advances in monoclonal antibodies, fusion molecules, and vectored nanotechnology offer potential solutions.


Traffic jam functions in a branched pathway from Notch activation to niche cell fate.
The niche directs key behaviors of its resident stem cells, and is thus crucial for tissue maintenance, repair and longevity. However, little is known about the genetic pathways that guide niche specification and development. The male germline stem cell niche in Drosophila houses two stem cell populations and is specified within the embryonic gonad, thus making it an excellent model for studying niche development. The hub cells that form the niche are specified early by Notch activation. Over the next few hours, these individual cells then cluster together and take up a defined position before expressing markers of hub cell differentiation. This timing suggests that there are other factors for niche development yet to be defined. Here, we have identified a role for the large Maf transcription factor Traffic jam (Tj) in hub cell specification downstream of Notch. Tj downregulation is the first detectable effect of Notch activation in hub cells. Furthermore, Tj depletion is sufficient to generate ectopic hub cells that can recruit stem cells. Surprisingly, ectopic niche cells in tj mutants remain dispersed in the absence of Notch activation. This led us to uncover a branched pathway downstream of Notch in which Bowl functions to direct hub cell assembly in parallel to Tj downregulation.


Immunoproteomic identification of secretory and subcellular protein antigens and functional evaluation of the secretome fraction of Mycobacterium immunogenum, a newly recognized species of the Mycobacterium chelonae-Mycobacterium abscessus group.
Mycobacterium immunogenum has been associated with occupational pulmonary disease hypersensitivity pneumonitis (HP). The aim of this study was to identify immunogenic proteins (antigens) in this pathogen as a first step toward understanding its virulence factors and role in HP etiology. Immunoproteomic profiling of secreted and subcellular protein fractions using a combination of two-dimensional electrophoresis (2-DE), immunoblotting, and matrix-assisted laser desorption/ionization-Time of flight (MALDI-TOF) led to the identification of 33 immunoreactive proteins, comprising of 4 secretory, 6 cell wall-associated, 11 membranous, and 12 cytosolic proteins. Of these, eight immunoreactive proteins represented homologues of the known mycobacterial antigens, namely heat shock protein GroEL, antigen 85A, elongation factor Tu (EF-Tu), L-asparaginase, polyketide synthase, PE-PGRS, PPE, and superoxide dismutase (SOD). Global functional search revealed that the remaining 25 novel mycobacterial antigens in M. immunogenum showed homology with hypothetical proteins (11 antigens) and other bacterial proteins (14 antigens) with a role in virulence, survival, and/or diverse metabolic functions. To understand immunogenicity of the secretome in M. immunogenum, the major protein spot on the secretome 2D-gel (consisting of multiple secretory antigens such as OtsB and CtpA, among others) was eluted and subjected to functional characterization in terms of induction of innate immune response in murine alveolar macrophages. The secretome eluate caused up-regulation of the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IL-18 and down-regulation of the anti-inflammatory cytokine IL-10, implying a potential of the secreted antigens to cause host immune response underlying the M. immunogenum-induced lung disease HP. This is the first report on identification of antigens in M. immunogenum as well as on the potential of its secretome proteins to induce host response. The identified antigens could have likely roles in virulence and/or diagnosis and serve as potential targets for drug, biocide, and/or vaccine development.


12-channel receive array with a volume transmit coil for hand/wrist imaging at 7 T.
To develop a coil configuration for high-resolution imaging of different regions of the hand and wrist at 7 T. A quadrature bandpass birdcage and a 12-channel high density receive array were developed for imaging metacarpus and wrist. Workbench and magnetic resonance imaging (MRI) measurements were done to characterize the coil and obtain in vivo images. Electromagnetic simulations were performed to assess the uniformity of transmit profile and calculate the specific absorption rate (SAR). The results obtained show that the constructed transmit coil can be used in combination with receive arrays, without the need to retune the same. The developed wrist array was used to produce images of ultrahigh resolution (0.19 × 0.19 × 0.5 mm(3) ), revealing fine anatomical details. Simulations show that a near-uniform transmit profile is possible throughout the hand. No inhomogeneities were observed in the transmit profile, unlike a human head or abdomen at 7 T, due to the small volume of the hand and its low conductive regions. While transceive arrays are usually preferred at 7 T due to issues related to decrease in wavelength, it is shown in this study that with regard to hand-imaging optimized high-density receive arrays are a good solution to obtain images of extremely fine resolution of different regions.


A PEGylated fibrin hydrogel-based antimicrobial wound dressing controls infection without impeding wound healing.
Combat injuries are associated with a high incidence of infection, and there is a continuing need for improved approaches to control infection and promote wound healing. Due to the possible local and systemic adverse effects of standard 1% cream formulation (Silvadene), we had previously developed a polyethylene glycol (PEGylated) fibrin hydrogel (FPEG)-based wound dressing for the controlled delivery of silver sulfadiazine (SSD) entrapped in chitosan microspheres (CSM). In this study, we have evaluated the antimicrobial and wound healing efficacy of SSD-CSM-FPEG using a full-thickness porcine wound infected with Pseudomonas aeruginosa. Infected wounds treated with a one-time application of the SSD-CSM-FPEG wound dressing demonstrated significantly reduced bacterial bioburden over time (99·99% of reduction by day 11; P < 0·05) compared with all the other treatment groups. The epithelial thickness and granulation of the wound bed was significantly better on day 7 (150·9 ± 13·12 µm), when compared with other treatment groups. Overall, our findings demonstrate that the SSD-CSM-FPEG wound dressing effectively controls P. aeruginosa infection and promotes wound healing by providing a favourable environment that induces neovascularisation. Collectively, sustained release of SSD using fibrin hydrogel exhibited enhanced benefits when compared with the currently available SSD treatment, and this may have significant implications in the bacterial reduction of infected wounds in military and civilian populations.


[Expression of FOXP3 in CD4+ CD39+ T cells of patients with systemic lupus erythematosus and dynamic observation of treatment with glucocorticoid].
To investigate the level of FOXP3 expressed in CD4+ CD39+ T cells in peripheral blood of patients with systemic lupus erythematosus (SLE) and observe the regulation of glucocorticoid on it. Frequencies of CD4+ CD25+ CD39+, CD4 CD25+ FOXP3+ and CD4+ CD39+ FOXP3+ T cells and levels of FOXP3 protein were analyzed by flow cytometry of 47 SLE patients (including 29 untreated/active SLE) and 22 healthy controls. Meanwhile, correlations among three groups and influences of glucocorticoid were analyzed. Percents of CD4+ CD25+ CD39+ T cells expressed in active SLE, inactive SLE and healthy controls were (1.3 +/- 0.5)%, (1.9 +/- 0.8)% and (2.3 +/- 1.0)% respectively, the level decreased in active SLE compared with inactive SLE and healthy controls P < 0.05 in each group, but it had no significant difference between the latter two groups (P > 0.05). In active SLE, levels of FOXP3 protein expressed in CD4+ CD25+, CD4+ CD25high and CD4+ CD39+ T cells were (45 +/- 12)%, (65 +/- 14)% and (70 +/- 14)% respectively. Levels of FOXP3 expressed in CD4+ CD25high and CD4+ CD39+ T cells were higher than that expressed in CD4+ CD25+ T cells (P < 0.01), while it had no significant difference between CD4 CD25high T cells and CD4+ CD39+ T cells (P > 0.05). These results demonstrate that CD39 may be a better surface marker of regulatory T cells, and that deficiency of CD39+ Treg cells may play an important role in the pathogenesis of SLE.


High-performance liquid chromatography of non-polar retinoid isomers.
Normal-phase high-performance liquid chromatograms of retinal, retinol and retinyl palmitate isomers using n-heptane-tert.-butyl methyl ether as mobile phase are presented. Methods for the synthesis of various isomers of these retinoids are described. This enables one to produce standard chromatograms and to select various isomers for cochromatography and the identification of the various peaks under study. Assignment of the peaks is based on chromatograms published previously in this journal. For the main isomers it is possible to get baseline separation of the commonly occurring isomeric forms in a reasonably short analysis time.


Secondary follicular mucinosis associated with systemic lupus erythematosus.
A 61-year-old woman presented with a five-month history of an intermittent eruption of papules and nodules on her face and neck. Past medical history included systemic lupus erythematosus. Histopathologic examination was consistent with secondary follicular mucinosis in association with systemic lupus erythematosus. This rare entity has been described in one prior report as a precursor to the clinical onset of systemic lupus erythematosus. Follicular mucinosis occurs as either a primary idiopathic form or a secondary form associated with either benign inflammatory processes or malignant conditions, such as cutaneous T-cell lymphoma. Numerous treatments for primary follicular mucinosis have been described, which include isotretinoin and glucocorticoids, whereas treatment of the underlying disease is necessary in the secondary form. The association with lymphoma mandates long-term clinical monitoring of patients with particularly recalcitrant, widespread, or chronic follicular mucinosis.


Chondroblastoma of the distal femur resected through a small fenestra via computed tomography navigation and endoscopy: a case report.
Chondroblastoma is a benign bone tumor with a relatively high incidence in older children and adolescents during the period of active epiphyseal growth. It is generally regarded as a benign neoplasm, but sometimes it grows aggressively or recurs. To prevent recurrence, complete curettage is important; however, such an approach can be extremely difficult to perform precisely when the chondroblastoma arises deep in the epiphysis. In our patient's case, we used a computed tomography-based navigation system with registration technique involving skin marker fiduciaries and endoscopic curettage of the lesion. A 16-year-old Japanese girl presented to our facility with left knee joint pain, which started nine months before her initial examination. Computed tomography and magnetic resonance imaging studies of the left knee showed a radiolucent lesion with marginal sclerosis and lobular homogeneous hypo-intensity and hyper-intensity signals in the distal epiphysis of the left femoral epiphysis, carried through to the growth plate. To prevent recurrence of chondroblastoma and growth disturbance, we used a computed tomography-based navigation system with registration technique involving skin marker fiduciaries and endoscopic curettage of the lesion. Wide excision with total removal of the chondroblastoma in the distal femur often requires large exposure with associated drawbacks, where a wide excision near the growth plate can potentially lead to growth disturbance. Therefore, in an accessible location in the distal femur, endoscopic excision of chondroblastoma under navigation system guidance can be performed with minimal operative damage. In the setting of a benign intra-osseous lesion infiltrating the growth plate, arthroscopic retrieval or excision under a computed tomography-based navigation system should be considered before proceeding with open surgery.


Fragile Gene WWOX Guides TFAP2A/TFAP2C-Dependent Actions Against Tumor Progression in Grade II Bladder Cancer.
The presence of common fragile sites is associated with no-accidental chromosomal instability which occurs prior to carcinogenesis. The WWOX gene spans the second most active fragile site: FRA16D. Chromosomal breakage at this site is more common in bladder cancer patients who are tobacco smokers which suggests the importance of WWOX gene loss regarding bladder carcinogenesis. Tryptophan domains of WWOX are known to recognize motifs of other proteins such as AP-2α and AP-2γ allowing protein-protein interactions. While the roles of both AP-2 transcription factors are important for bladder carcinogenesis, their nature is different. Based on the literature, AP-2γ appears to be oncogenic, whereas AP-2α mainly exhibits tumor suppressor character. Presumably, the interaction between WWOX and both transcription factors regulates thousands of genes, hence the aim of the present study was to determine WWOX, AP-2α, and AP-2γ function in modulating biological processes of bladder cancer. RT-112 cell line (grade II bladder cancer) was subjected to two stable lentiviral transductions. Overall, this resulted in six variants to investigate distinct WWOX, AP-2α, or AP-2γ function as well as WWOX in collaboration with a particular transcription factor. Cellular models were examined with immunocytochemical staining and in terms of differences in biological processes using assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, migration, activity of metalloproteinases and 3D culture growth. WWOX overexpression increased apoptosis but decreased cell viability, migration and large spatial colonies. AP-2α overexpression decreased tumor cell viability, migratory potential, matrix metalloproteinase-2 activity and clonogenicity. AP-2γ overexpression decreased matrix metalloproteinase-2 activity but increased wound healing, adhesion, clonogenicity and spatial colony formation. WWOX and AP-2α overexpression induced apoptosis but decreased cell viability, adhesion, matrix metalloproteinase-2 activity, overall number of cultured colonies and migration rate. WWOX and AP-2γ overexpression decreased tumor cell viability, proliferation potential, adhesion, clonogenicity and the ability to create spatial structures, but also increased apoptosis or migration rate. Co-overexpression of WWOX with AP-2α or WWOX with AP-2γ resulted in a net anti-tumor effect. However, considering this research findings and the difference between AP-2α and AP-2γ, we suggest that this similarity is due to a divergent behavior of WWOX.


Meteorological conditions and the diagnosis of occupationally related contact sensitizations.
An accurate diagnosis of (occupational) contact sensitization by patch testing is a prerequisite for efficient preventive management. However, previously observed seasonal fluctuations in patch-test reactions indicate some influence of meteorological conditions. The present analysis aims at quantifying the possible impact of temperature and humidity on patch-test reactions to occupationally related allergens. Clinical data from 61 780 patients tested with standard series allergens potentially related to occupational exposure from 1993 through 2001 were collected by a contact sensitization surveillance network.The association between the patch-test results and meteorological data (air temperature and humidity) collected at the time and the approximate location of the testing was analyzed in a multinomial logistic regression analysis. For three allergens (a dye and two biocides), the odds of irritant or doubtful allergic reactions increased during cold and arid conditions. Two of them (pphenylenediamine and formaldehyde) also showed an association between weak positive allergic reactions and such weather. In contrast, reactions to various adhesive, plastic, and rubber-related allergens were not associated with weather conditions. An overall increase in skin irritation, brought on by cold and dry conditions, may instigate an increase in positive reactions by leading doubtful allergic reactions to be (falsely) categorized as allergic for at least two of the considered allergens. For the most part, however, weather conditions were not associated with reactions to occupational allergens. Thus the validity of patch testing does not largely seem to be compromised by ambient meteorological conditions.


Respiratory tract infections and gut microbiome modifications: A systematic review.
Respiratory tract infections (RTIs) are extremely common and can cause gastrointestinal tract symptoms and changes to the gut microbiota, yet these effects are poorly understood. We conducted a systematic review to evaluate the reported evidence of gut microbiome alterations in patients with a RTI compared to healthy controls (PROSPERO: CRD42019138853). We systematically searched Medline, Embase, Web of Science, Cochrane and the Clinical Trial Database for studies published between January 2015 and June 2021. Studies were eligible for inclusion if they were human cohorts describing the gut microbiome in patients with an RTI compared to healthy controls and the infection was caused by a viral or bacterial pathogen. Dual data screening and extraction with narrative synthesis was performed. We identified 1,593 articles and assessed 11 full texts for inclusion. Included studies (some nested) reported gut microbiome changes in the context of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (n = 5), influenza (H1N1 and H7N9) (n = 2), Tuberculosis (TB) (n = 4), Community-Acquired Pneumonia CAP (n = 2) and recurrent RTIs (rRTI) (n = 1) infections. We found studies of patients with an RTI compared to controls reported a decrease in gut microbiome diversity (Shannon) of 1.45 units (95% CI, 0.15-2.50 [p, <0.0001]) and a lower abundance of taxa (p, 0.0086). Meta-analysis of the Shannon value showed considerable heterogeneity between studies (I2, 94.42). Unbiased analysis displayed as a funnel plot revealed a depletion of Lachnospiraceae, Ruminococcaceae and Ruminococcus and enrichment of Enterococcus. There was an important absence in the lack of cohort studies reporting gut microbiome changes and high heterogeneity between studies may be explained by variations in microbiome methods and confounder effects. Further human cohort studies are needed to understand RTI-induced gut microbiome changes to better understand interplay between microbes and respiratory health.


Development of a systems-based in situ multiplex biomarker screening approach for the assessment of immunopathology and neural tissue plasticity in male rats after traumatic brain injury.
Traumatic brain injuries (TBIs) pose a massive burden of disease and continue to be a leading cause of morbidity and mortality throughout the world. A major obstacle in developing effective treatments is the lack of comprehensive understanding of the underlying mechanisms that mediate tissue damage and recovery after TBI. As such, our work aims to highlight the development of a novel experimental platform capable of fully characterizing the underlying pathobiology that unfolds after TBI. This platform encompasses an empirically optimized multiplex immunohistochemistry staining and imaging system customized to screen for a myriad of biomarkers required to comprehensively evaluate the extent of neuroinflammation, neural tissue damage, and repair in response to TBI. Herein, we demonstrate that our multiplex biomarker screening platform is capable of evaluating changes in both the topographical location and functional states of resident and infiltrating cell types that play a role in neuropathology after controlled cortical impact injury to the brain in male Sprague-Dawley rats. Our results demonstrate that our multiplex biomarker screening platform lays the groundwork for the comprehensive characterization of changes that occur within the brain after TBI. Such work may ultimately lead to the understanding of the governing pathobiology of TBI, thereby fostering the development of novel therapeutic interventions tailored to produce optimal tissue protection, repair, and/or regeneration with minimal side effects, and may ultimately find utility in a wide variety of other neurological injuries, diseases, and disorders that share components of TBI pathobiology.


Deleterious Effect of Crossfostering in Rat Pups on Hypoxic-Ischaemic Injury Tolerance and Hypothermic Neuroprotection.
We study the effect of hypothermia (HT) following hypoxic-ischaemic (HI) brain injury in postnatal day 7 (P7) rats. In 2015, new European Union animal transport regulations prompted a change in practice at the breeding facility, which henceforth crossfostered P3 litters to P8 older lactating dams prior to transportation. It is generally assumed that crossfostering does not significantly affect the experimental results. The aim of this study was to examine whether crossfostering affects our model consistency by modifying injury susceptibility and hypothermic neuroprotection. We analysed 219 pups from 11 experiments conducted between 2013 and 2015: 73 non-crossfostered and 146 crossfostered pups. At P7, all pups underwent unilateral common carotid artery ligation followed by 50 min of hypoxia (8% O2, 36°C). Immediately after this mild insult, the pups were randomized to post-insult normothermia or HT treatment. Pups were culled at P14. Injury was assessed by area loss of the ipsilateral hemisphere and histopathology scoring of the hippocampus, cortex, thalamus, and basal ganglia. Crossfostered pups had double the injury compared to non-crossfostered pups irrespective of the treatment group. Hypothermic neuroprotection was statistically significant, but with a smaller and less consistent effect in crossfostered pups (relative neuroprotection 16% vs. 31% in non-crossfostered). These results demonstrate hypothermic neuroprotection following a mild HI insult. A representative subset of 41 animals was also assessed for evidence of microglial reactivity; however, no detectable difference in microglial reactivity was observed between any of the groups. In conclusion, crossfostering alters outcomes in our established model through reduced insult tolerance and variable neuroprotection. Crossfostering as a common breeding practice is a largely unexplored variable in animal research that may result in invalid research conclusions if inadequately adjusted for by larger group sizes. As a result, crossfostering is likely to be inconsistent with the principles of replacement, reduction, and refinement.


Health status, neighborhood socioeconomic context, and premature mortality in the United States: The National Institutes of Health-AARP Diet and Health Study.
We examined whether the risk of premature mortality associated with living in socioeconomically deprived neighborhoods varies according to the health status of individuals. Community-dwelling adults (n = 566,402; age = 50-71 years) in 6 US states and 2 metropolitan areas participated in the ongoing prospective National Institutes of Health-AARP Diet and Health Study, which began in 1995. We used baseline data for 565,679 participants on health behaviors, self-rated health status, and medical history, collected by mailed questionnaires. Participants were linked to 2000 census data for an index of census tract socioeconomic deprivation. The main outcome was all-cause mortality ascertained through 2006. In adjusted survival analyses of persons in good-to-excellent health at baseline, risk of mortality increased with increasing levels of census tract socioeconomic deprivation. Neighborhood socioeconomic mortality disparities among persons in fair-to-poor health were not statistically significant after adjustment for demographic characteristics, educational achievement, lifestyle, and medical conditions. Neighborhood socioeconomic inequalities lead to large disparities in risk of premature mortality among healthy US adults but not among those in poor health.


Diagnostic accuracy of antigen-based immunochromatographic rapid diagnostic tests for the detection of Salmonella in blood culture broth.
In low resource settings, Salmonella serovars frequently cause bloodstream infections. This study investigated the diagnostic performance of immunochromatographic rapid diagnostic tests (RDTs), which detect Salmonella antigens, when applied to stored grown blood culture broth. The SD Bioline One Step Salmonella Typhi Ag Rapid Detection Kit (Standard Diagnostics, Republic of Korea), marketed for the detection of Salmonella enterica serovar Typhi (Salmonella Typhi) in stool and the Salmonella Ag Rapid Test (Creative Diagnostics, USA), marketed for the detection of all Salmonella serotypes in stool, were selected for evaluation based on a pre-test evaluation of six RDT products. The limits of detection (LOD) for culture suspensions were established and the selected RDT products were assessed on 19 freshly grown spiked blood culture broth samples and 413 stored clinical blood culture broth samples, collected in Cambodia and the Democratic Republic of the Congo. The LOD of both products was established as 107-108 CFU/ml. When applied to clinical blood culture broth samples, the diagnostic sensitivity and specificity of the SD Bioline RDT were respectively 100% and 79.7% for the detection of Salmonella Typhi; 94.4% (65/69) of false-positive results were caused by Salmonella Enteritidis. When considering the combined detection of Salmonella Typhi and Enteritidis (both group D Salmonella), sensitivity and specificity were 97.9% and 98.5% respectively. For Creative Diagnostics, diagnostic sensitivity was 78.3% and specificity 91.0% for all Salmonella serotypes combined; 88.3% (53/60) of false negative results were caused by Salmonella Paratyphi A. When applied to grown blood culture broths, the SD Bioline RDT had a good sensitivity and specificity for the detection of Salmonella Typhi and Salmonella Enteritidis. The Creative Diagnostics product had a moderate sensitivity and acceptable specificity for the detection of all Salmonella serovars combined and needs further optimization. A RDT that reliably detects Salmonella Paratyphi A is needed.


Iron isotope composition of particles produced by UV-femtosecond laser ablation of natural oxides, sulfides, and carbonates.
The need for femtosecond laser ablation (fs-LA) systems coupled to MC-ICP-MS to accurately perform in situ stable isotope analyses remains an open question, because of the lack of knowledge concerning ablation-related isotopic fractionation in this regime. We report the first iron isotope analysis of size-resolved, laser-induced particles of natural magnetite, siderite, pyrrhotite, and pyrite, collected through cascade impaction, followed by analysis by solution nebulization MC-ICP-MS, as well as imaging using electron microscopy. Iron mass distributions are independent of mineralogy, and particle morphology includes both spheres and agglomerates for all ablated phases. X-ray spectroscopy shows elemental fractionation in siderite (C-rich agglomerates) and pyrrhotite/pyrite (S-rich spheres). We find an increase in (56)Fe/(54)Fe ratios of +2‰, +1.2‰, and +0.8‰ with increasing particle size for magnetite, siderite, and pyrrhotite, respectively. Fe isotope differences in size-sorted aerosols from pyrite ablation are not analytically resolvable. Experimental data are discussed using models of particles generation by Hergenröder and elemental/isotopic fractionation by Richter. We interpret the isotopic fractionation to be related to the iron condensation time scale, dependent on its saturation in the gas phase, as a function of mineral composition. Despite the isotopic variations across aerosol size fractions, total aerosol composition, as calculated from mass balance, confirms that fs-LA produces a stoichiometric sampling in terms of isotopic composition. Specifically, both elemental and isotopic fractionation are produced by particle generation processes and not by femtosecond laser-matter interactions. These results provide critical insights into the analytical requirements for laser-ablation-based stable isotope measurements of high-precision and accuracy in geological samples, including the importance of quantitative aerosol transport to the ICP.


Double-blind, multicenter, randomized trial to compare the effect of two doses of adrenocorticotropic hormone versus placebo in controlling delayed emesis after high-dose cisplatin in adult patients with cancer.
To compare, in a double-blind, placebo-controlled, randomized trial, the efficacy of two different doses of the depot formulation of adrenocorticotropic hormone (ACTH) in controlling delayed emesis after cisplatin. One hundred fifty-two patients were enrolled onto the study. On day 1, all patients received cisplatin (60 to 120 mg/m2) and a combination of dexamethasone 20 mg plus ondansetron or metoclopramide to prevent acute emesis. On day 2 (24 hours after cisplatin administration), patients were randomized to receive placebo, or ACTH 1 mg intramuscularly (I.M.), or ACTH 2 mg I.M. plus one additional dose of 1 mg on day 4. Details of vomiting, nausea, and adverse effects were recorded daily for every 24-hour period from day 2 to day 6. In a subset of patients, serum cortisol levels were measured between 20 and 72 hours after cisplatin administration. One hundred fifty patients were assessable. Over the 5 days of the study, delayed vomiting occurred less frequently in the patients treated with ACTH 2 mg plus 1 mg than in those treated with ACTH 1 mg or placebo (28%, 38%, and 65%, respectively; P = .001). The greatest observed differences were seen on days 2 (24 to 48 hours; P = .01) and 3 (48 to 72 hours; P = .01). On days 4, 5, and 6 (96 to 144 hours), no significant differences were observed among the three arms. The severity of delayed emesis expressed as the mean number of emetic episodes per day was 0.48, 0.70, and 0.80, respectively (P = .002). Patients treated with the higher dose of ACTH had the least nausea on day 3 (P = .02) and day 4 (P = .03). Adrenal cortisol secretion rapidly increased after ACTH injection, but was suppressed for approximately 44 hours in the placebo group. Toxicity was mild and transient in all groups. ACTH reduces the incidence and severity of delayed vomiting and nausea after cisplatin. A dose of 2 mg 24 hours after cisplatin is better than one of 1 mg. Whether the activity of ACTH is mediated only by adrenal corticosteroids needs to be verified.


Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.


Relationships between Community Festival Participation, Social Capital, and Subjective Well-Being in a Cross-Cultural Context.
This study explores the relationships among social capital, community festival participation, and subjective well-being (SWB). It examines the mediating role of festival participation between social capital and SWB. The dataset Social Well-being Survey in Asia from the Philippines and Thailand was collected using nationwide surveys in 2016. The total number of respondents was 1057 in the Philippines and 982 in Thailand. The results affirm several determinants related to SWB, which is composed of happiness and overall life satisfaction. The models show significant relationships among festival participation, social capital, and SWB. The results indicate strong associations among social capital with family and relatives, festival participation, and SWB. The interaction effects between the two countries are included. Structural and cognitive social capital with kinship groups were important determinants in facilitating festival participation, and positively associated with SWB. Moreover, the results identify the mediating effect of festival participation between social capital with family and relatives and SWB. The results can provide similarities and differences in the relationships among social capital and kinship groups, community festival participation, and SWB between the Philippines and Thailand. This study offers important empirical evidence of a cross-cultural study in the context of the Philippines and Thailand.


How Should Organizations and Clinicians Help Marginalized Patients Manage Loneliness as a Harm of Climate Change?
This commentary on a case outlines 4 interventions that would help to prevent or mitigate illness and attendant loneliness affecting vulnerable patients during extreme weather events. It suggests that an individualistic approach to the collective problem of climate change is inadequate and that health professionals and health organizations should (1) transition from reactive climate change strategies to integrating disaster preparedness into daily operations and (2) advocate for changes in society that address harms and begin to mitigate the negative effects of climate change, especially on marginalized people.


Adherence to the European Code Against Cancer in relation to long-term cancer mortality: intercohort comparisons from the Seven Countries Study.
Within the Seven Countries Study, we investigated whether population differences in 25-year cancer mortality and mortality due to cancer of the lung, stomach, and colorectum could be explained by population differences in adherence to the European Code Against Cancer. Baseline surveys were carried out around 1960 on 12,763 middle-aged men constituting 16 cohorts in seven countries; small samples of the cohorts kept dietary records. In 1987, food equivalent composites representing the average food intake of each cohort at baseline were collected locally and analyzed in one central laboratory. The vital status of all participants was verified after 25 years of follow-up. Overall adherence to the first four recommendations of the European Code Against Cancer was inversely related to 25-year total cancer mortality but not to all-cause mortality. The association with cancer mortality was essentially due to the inverse association for adherence to the guideline on smoking only. Each decrease in the percentage of smokers of 3.4% (10% of range) was associated with a relative risk of 0.93 of dying from cancer. Adherence to the recommendation on consumption of vegetables, fruits, and fiber-rich cereals was inversely related to stomach cancer mortality, whereas adherence to the recommendation on body weight, physical activity, and intake of fat was associated with higher stomach cancer mortality.


Cost-effectiveness of treatments for non-osteoarthritic knee pain conditions: A systematic review.
Knee pain is common in adolescents and adults and is associated with an increased risk of developing knee osteoarthritis. The aim of this systematic review was to gather and appraise the cost-effectiveness of treatment approaches for non-osteoarthritic knee pain conditions. A systematic review was conducted according to the PRISMA guidelines and registered on PROSPERO (CRD42016050683). The literature search was done in MEDLINE via PubMed, EMBASE, The Cochrane Library, and the National Health Service Economic Evaluation Database. Study selection was carried out by two independent reviewers and data were extracted using a customized extraction form. Study quality was assessed using the Consensus on Health Economic Criteria list. Fifteen studies were included. The majority regarded the treatment of anterior cruciate ligament (ACL) injuries, but we also identified studies evaluating other knee pain conditions such as meniscus injuries, cartilage defects, and patellofemoral pain syndrome. Study interventions were categorized as surgical or non-surgical interventions. The surgical interventions included ACL reconstruction, chondrocyte implantation, meniscus scaffold procedure, meniscal allograft transplantation, partial meniscectomy, microfracture, and different types of autografts and allografts. The non-surgical management consisted of physical therapy, rehabilitation, exercise, counselling, bracing, and advice. In general, for ACL injuries surgical management alone or in combination with rehabilitation appeared to be cost-effective. The quality of the economic evaluations was of moderate to high quality. There was insufficient evidence to give a firm overview of cost-effective interventions for non-osteoarthritic knee pain, but surgical treatment of acute ACL injury appeared cost-effective. There is very little data regarding the cost-effectiveness of non-surgical interventions for non-traumatic knee conditions.


Enduring mental health morbidity and social function impairment in world trade center rescue, recovery, and cleanup workers: the psychological dimension of an environmental health disaster.
The World Trade Center (WTC) attacks exposed thousands of workers to hazardous environmental conditions and psychological trauma. In 2002, to assess the health of these workers, Congress directed the National Institute for Occupational Safety and Health to establish the WTC Medical Monitoring and Treatment Program. This program has established a large cohort of WTC rescue, recovery, and cleanup workers. We previously documented extensive pulmonary dysfunction in this cohort related to toxic environmental exposures. Our objective in this study was to describe mental health outcomes, social function impairment, and psychiatric comorbidity in the WTC worker cohort, as well as perceived symptomatology in workers' children. Ten to 61 months after the WTC attack, 10,132 WTC workers completed a self-administered mental health questionnaire. Of the workers who completd the questionnaire, 11.1% met criteria for probable post-traumatic stress disorder (PTSD), 8.8% met criteria for probable depression, 5.0% met criteria for probable panic disorder, and 62% met criteria for substantial stress reaction. PTSD prevalence was comparable to that seen in returning Afghanistan war veterans and was much higher than in the U.S. general population. Point prevalence declined from 13.5% to 9.7% over the 5 years of observation. Comorbidity was extensive and included extremely high risks for impairment of social function. PTSD was significantly associated with loss of family members and friends, disruption of family, work, and social life, and higher rates of behavioral symptoms in children of workers. Working in 9/11 recovery operations is associated with chronic impairment of mental health and social functioning. Psychological distress and psychopathology in WTC workers greatly exceed population norms. Surveillance and treatment programs continue to be needed.


Hospital patient discharge process: an evaluation.
Medication discrepancies for patients after discharge from hospital are well documented. They have been shown to cause unnecessary harm to patients and can result in hospital readmission. To improve patient discharge, the current process of discharging patients from hospital (the discharge process) needs evaluating to determine where and why medication issues occur. This study aimed to identify and evaluate the discharge process used in a range of acute National Health Service hospitals across the North West of England. This qualitative study involved semi-structured telephone interviews with 13 chief pharmacists or an appropriately nominated member of the hospital pharmacy team. Thematic analysis of the transcribed interview data was performed. Data analysis revealed eight main themes which all impacted on the discharge process. The study was successful in identifying the discharge process across the range of hospitals as well as key issues and examples of good practice. The hospitals involved in the study were found to have similar discharge processes with issues common to all. One significant finding was a lack of patient involvement in the discharge process. To improve the patient discharge process, innovative solutions are required to overcome the current issues. In future work, the study findings will be used to develop a new model of care for patient discharge from hospital.


Salt and acid studies on canine lingual epithelium.
A section of dog tongue just anterior to the circumvallate papillae was placed in an Ussing chamber and characterized with respect to monovalent cation transport pathways, response to HCl, and the interaction between salt and acid for the purposes of determining whether ion transport through the tongue is related to the transduction process. The primary findings of this work follow. The stimulation of the short-circuit current (Isc) with decreasing pH on the dorsal surface results from a net Cl- efflux through an amiloride- and ouabain-insensitive pathway that changed its selectivity from cationic at neutral pH to anionic at lower pH values. The stimulation is abolished at isotonic NaCl concentrations. This behavior would not be predicted from the proton-binding model to a "sour receptor" as suggested by Beidler (Handbook of Sensory Physiology; Berlin: Springer-Verlag, 1971). In symmetrical solutions of Krebs-Henseleit buffer, Isc is inhibited 30% by 10(-4) M amiloride on the mucosal side and 100% by 10(-3) M ouabain on the serosal side. These results coupled with net Cl- and Na+ flux measurements show that Isc is due to a net Cl- efflux. With 1.0 M NaCl on the dorsal side, 10(-4) M amiloride inhibits Isc 84%. In contrast, when the mucosal surface is bathed in KCl (1.0 M), CsCl (1.0 M), or HCl (10(-3) M), Isc is insensitive to both 10(-4) M amiloride and/or 10(-3) M ouabain. These data suggest that K+, Cs+, and H+ traverse the tongue through different pathways from Na+ and are not energized by a Na+ gradient.


[Assisted suicide in psychiatry; current situation and notes on a recent case].
The Dutch legal system grants psychiatric patients the right to assisted suicide but imposes strict conditions. The matter, however, remains controversial. Many psychiatrists are reluctant to become involved in assisted suicide because they are not familiar with the procedure that has to be followed, nor are they clear about the precise meaning of 'acting responsibly'. To provide an overview of the procedure to be followed and of the criteria to be met when a psychiatrist is wondering whether to grant a patient's request for assistance with suicide. We analyse the law, jurisprudence and medical ethics and the special problems that arise in the case of psychiatric patients. We describe the developments in law and psychiatric practice which have led to greater recognition of the autonomy of the patient. The final decision depends on an assessment of the patient's competence and his ability to articulate his request clearly and on the hopelessness engendered by unbearable suffering. In the future there may be an increase in the number of cases of assisted suicide in psychiatry now that procedures and criteria have been established which are in accordance with the Dutch legal system.


Neighborhood-based differences in physical activity: an environment scale evaluation.
This study evaluated a neighborhood environment survey and compared the physical activity and weight status of the residents in 2 neighborhoods. On 2 occasions, 107 adults from neighborhoods with differing "walkability" were selected to complete a survey on their neighborhood environment. Physical activity was assessed by self-report and by accelerometer; height and weight were assessed by self-report. Neighborhood environment characteristics had moderate to high test-retest reliabilities. Residents of high-walkability neighborhoods reported higher residential density, land use mix, street connectivity, aesthetics, and safety. They had more than 70 more minutes of physical activity and had lower obesity prevalence (adjusted for individual demographics) than did residents of low-walkability neighborhoods. The reliability and validity of self-reported neighborhood environment subscales were supported. Neighborhood environment was associated with physical activity and overweight prevalence.


On selection mechanisms during initial evolution and on the possible role of ionic balance.
Initial evolution at the molecular level can proceed through mechanisms that enhance either the generation or the survival of certain molecules. Phenomena related to ionic balance can be the basis for both generative and survival selection mechanisms that may have driven the initial evolution of macromolecules. An important advantage of mechanisms based on ionic balance phenomena is that they can conceivably generate spatial and temporal inhomogeneities in semi-enclosed spaces within cavities of porous materials and/or membranes. Under certain circumstances, such inhomogeneities are required for initial evolution to proceed.


Melatonin influences human balance.
In order to evaluate a possible correlation between melatonin, the cerebellum and, consequently, human balance, a double-blind pilot study was performed in 5 subjects with random administration of different doses of melatonin. Before and 1 h after a single administration, a complete otoneurological examination was performed. This first pilot study revealed that melatonin had effects on human equilibrium although these effects were not dosage related and were different in individual subjects. On the basis of these results, a second study was performed. Fourteen healthy volunteers were investigated before and 1 h after administration of a single dose of 10 mg melatonin. The otoneurological examination was restricted to the evaluation of: horizontal saccades, horizontal sinusoidal smooth pursuit, eyes open, eyes closed and head retroflexed static posturography. All subjects showed a decrease in posturographic performances, especially in the simplest test (eyes open) and half of them (6 out of 13) showed also impairment of eye movements. These results confirm the role of melatonin in the control of sensorimotor performances, and the cerebellar receptors might be correlated with the control of human balance.


Thyroid control over membrane processes in rat heart.
We have studied the effects of hypo- and hyperthyroidism on sarcolemmal (SL) and sarcoplasmic reticular (SR) ion transport processes and mitochondrial energy production in rat heart. The following conclusions were derived. 1) Compared with euthyroid state, hyperthyroidism led to increased SR Ca(2+)-accumulation. In SL, the activities of Ca(2+)-stimulated adenosine triphosphatase (ATPase), ATP-dependent Ca2+ pumping, and Na(+)-Ca2+ exchanger were not affected; but ouabain-sensitive Na(+)-K(+)-ATPase activity was enhanced. 2) Hypothyroidism resulted in depressed activities of Ca2+ pumps both in SL and SR. In SL, the Na(+)-K(+)-ATPase activity was decreased, but Na(+)-Ca2+ exchange was unaltered. 3) Thus slower relaxation of the hypothyroid myocardium may be attributed to depressed functioning of Ca2+ pumps in SR and SL, whereas faster relaxation of the hyperthyroid heart may be based on increased Ca(2+)-pumping activity of SR. 4) Hyperthyroidism and hypothyroidism, respectively, led to enhanced and decreased rates of mitochondrial phosphocreatine synthesis. The thyroid state appears to control the functional coupling between mitochondrial creatine kinase and ATP-ADP translocase: the energy of oxidative phosphorylation was transformed into phosphocreatine more effectively in mitochondria from hypothyroid hearts than in those from hyperthyroid hearts.


Ethological aspects of psychiatry.
Studies of non-verbal behaviour with respect to mentally ill patients is a relatively neglected aspect of psychiatry. Probably the main reason for this has been the lack of relevant methods. In recent years ethological techniques have emerged enabling the facial expressions, body postures and gestures of animals and humans to be objectively measured so that the functional importance is laid open for analysis. This article discusses the way ethological ideas and techniques can contribute to an understanding of the behaviour of the mentally ill. Examples are drawn from studies of flight behaviour which encompass those behavioural strategies associated with withdrawal or avoidance of a source of danger or harm. It is argued that much of the non-verbal behaviour in psychotic patients reflects blocked escape and that this is one of the reasons why such individuals are socially withdrawn. The application of ethology to the psychiatric assessment of patients is also demonstrated on the basis of ethological profiles from some selected patients. It is concluded that psychiatrists and ethologists should cooperate in the future evaluation of therapeutic measures including new drugs developed on the basis of ethological tests.


Trench-parallel flow beneath the nazca plate from seismic anisotropy.
Shear-wave splitting of S and SKS phases reveals the anisotropy and strain field of the mantle beneath the subducting Nazca plate, Cocos plate, and the Caribbean region. These observations can be used to test models of mantle flow. Two-dimensional entrained mantle flow beneath the subducting Nazca slab is not consistent with the data. Rather, there is evidence for horizontal trench-parallel flow in the mantle beneath the Nazca plate along much of the Andean subduction zone. Trench-parallel flow is attributale utable to retrograde motion of the slab, the decoupling of the slab and underlying mantle, and a partial barrier to flow at depth, resulting in lateral mantle flow beneath the slab. Such flow facilitates the transfer of material from the shrinking mantle reservoir beneath the Pacific basin to the growing mantle reservoir beneath the Atlantic basin. Trenchparallel flow may explain the eastward motions of the Caribbean and Scotia sea plates, the anomalously shallow bathymetry of the eastern Nazca plate, the long-wavelength geoid high over western South America, and it may contribute to the high elevation and intense deformation of the central Andes.


Facilitators and barriers for vaccination in patients with inflammatory rheumatic musculoskeletal diseases: a prospective cohort study.
To identify facilitators and barriers towards vaccination in general and specifically against pneumococci, influenza and SARS-CoV-2 in patients with rheumatic musculoskeletal diseases (RMD). Between February and April 2021, consecutive patients with RMD were asked to complete a structured questionnaire on general knowledge about vaccination, personal attitudes and perceived facilitators and barriers towards vaccination. General facilitators (n=12) and barriers (n=15) and more specific ones for vaccination against pneumococci, influenza and SARS-CoV-2 were assessed. Likert scales had four response options: from 1 (completely disagree) to 4 (completely agree). Patient and disease characteristics, their vaccination records and attitudes towards vaccination against SARS-CoV-2 were assessed. 441 patients responded to the questionnaire. Knowledge about vaccination was decent in ≥70% of patients, but <10% of patients doubted its effectiveness. Statements on facilitators were generally more favourable than on barriers. Facilitators for SARS-CoV-2 vaccination were not different from vaccination in general. Societal and organisational facilitators were more often named than interpersonal or intrapersonal facilitators. Most patients indicated that recommendations of their healthcare professional would encourage them to be vaccinated-without preference for general practitioner or rheumatologists. There were more barriers towards SARS-CoV-2 vaccination than to vaccination in general. Intrapersonal issues were most frequently reported as a barrier. Statistically significant differences in response patterns to nearly all barriers between patients classified as definitely willing, probably willing and unwilling to receive SARS-CoV-2 vaccines were noted. Facilitators towards vaccination were more important than barriers. Most barriers against vaccination were intrapersonal issues. Societal facilitators identified support strategies in that direction.


Inhibition of fracture healing in the presence of contamination by Staphylococcus aureus: Effects of growth state and immune response.
Extremity injuries comprise a significant portion of trauma, affecting quality of life, financial burden, and return to duty. Bacterial contamination is commonly associated with failure to heal, despite antibiotic treatment, suggesting that additional therapies must be developed to combat these complications. Treatment failure is likely due to the presence of resistant microbial communities known as biofilms. Biofilm bacteria are able to elicit a direct inhibition of healing through a multitude of known factors. However, they likely also inhibit healing through alteration of the inflammatory response. As inflammation is a critical step in fracture healing, how the presence of biofilm bacteria shifts this response to one that is suboptimal for healing is an important consideration that is currently understudied. The profile of inflammatory factors in response to biofilm bacteria is unique and distinct from those induced during normal healing or by planktonic bacteria alone. This review will examine the presence of inflammatory factors during normal healing and those induced by contaminating bacteria, and will discuss how these differences may ultimately lead to nonunion. Specifically, this review will focus on the Th1/Th2/Th17 type inflammatory responses and how shifts in the balance of these responses during infection can lead to both ineffective clearance and disruption of fracture healing. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1845-1854, 2017.


Phase 2 open-label study of weekly docosahexaenoic acid-paclitaxel in cutaneous and mucosal metastatic melanoma patients.
Docosahexaenoic acid (DHA)-paclitaxel has a unique pharmacokinetic profile that allows high concentrations of paclitaxel to be delivered to melanoma cells for prolonged periods compared with paclitaxel. We investigated the response rate and safety of weekly DHA-paclitaxel in metastatic melanoma patients. We enrolled chemotherapy-naive patients with metastatic nonchoroidal melanoma using the two-stage Fleming design. At least one response was needed in the first stage to proceed to the second stage. DHA-paclitaxel (500 mg/m/week by 1-h intravenous infusion) was administered for 5 weeks every 6-week cycle until disease progression, intolerable toxicity, or treatment refusal. Response and toxicity were assessed every 6 weeks and weekly, respectively. Thirty patients were enrolled. The patients' median age was 67 years (range: 29-86 years). The median number of treatment cycles was 2 (range: 1-6 cycles). Three patients (10%) had partial responses; one lasted 4 months, and two lasted 5.6 months. Fifteen patients (50%) had stable disease with a median duration of 2.8 months (range: 2.6-8.9 months). The median survival was 14.8 months. Neutropenia (10%) and musculoskeletal pain (10%) were the most common grade 3 and 4 toxicities, and fatigue (73%), skin rash (70%), and diarrhea (60%) were the most common side effects. As a single-agent therapy, DHA-paclitaxel was well tolerated in metastatic melanoma patients. Its efficacy as a first-line therapy for metastatic melanoma does not exceed that seen with other single-agent chemotherapies such as dacarbazine. Further evaluation of DHA-paclitaxel in combination with other chemotherapy or targeted agents could be considered.


The Role of Placental Growth Factor, Soluble Endoglin, and Uterine Artery Diastolic Notch to Predict the Early Onset of Preeclampsia.
Reducing maternal mortality is one of the targets in the Millennium Development Goals (MDGs). In a systematic review, 4.6 per cent (95% CI 2.7-8.2) of pregnancies were complicated by preeclampsia worldwide. Preeclampsia occurs in around 10% of pregnancies in the world whereas developing countries contribute more than developed countries. In developing countries, there are 13 cases of preeclampsia in every 1,000 births, whereas in developed countries only 2-3 cases of preeclampsia are found in every 10,000 deliveries. Variations in prevalence among countries reflect, at least in part, differences in the distribution of maternal age and the proportion of nulliparous pregnant women in the population. We aimed to investigate the role of placental growth factor, soluble endoglin, and uterine artery diastolic notch to predict the early onset of preeclampsia. This study used an analytical study with a nested case-control design. The study was conducted at Bunda Thamrin Hospital, Tanjung Mulia Mitra Medika Hospital, Sundari Hospital and a private clinic, from March to November 2018 with a total sample of 70 research subjects. Uterine artery diastolic notch was not found in 50% of subjects. A total of 27 subjects (38.6%) had a unilateral diastolic notch, and 8 subjects (11.4%) had a bilateral diastolic notch. Cut-off point PIGF levels was 441 pg/ml, and Area Under Curve (AUC) 82.5% (95% CI 61.5%-100%), with sensitivity 80% and specificity 87.7%. The levels sEng in this study could not predict the incidence of early-onset preeclampsia (p = 0.113). Combined PlGF and pulsatile index of uterine arteries may predict early onset preeclampsia with sensitivity 40% and specificity 90.77%. From these results, pregnant women o 22-24 weeks of pregnancy, the levels of PlGF and the uterine artery pulsatility index can be a predictor of early-onset preeclampsia. Examination of PlGF levels alone is sufficient as a predictor of early-onset preeclampsia. From these results, it can be concluded that in pregnant women of 22-24 weeks, the diastolic notches in uterine arteries cannot predict the incidence of early-onset preeclampsia. PlGF levels and pulsatile index of uterine arteries can be used as predictors of early-onset preeclampsia although examination of PlGF levels alone is sufficient as a predictor of early-onset preeclampsia.


Antibiotics, obesity and the link to microbes - what are we doing to our children?
Childhood obesity and overweight are among the greatest health challenges in the pediatric population. Obese individuals exhibit marked differences in the composition of the intestinal microbial community as compared to lean subjects. These changes in the gut microbiota precede the clinical manifestation of overweight. Convincing experimental data suggest a causal role for intestinal microbes in the development of obesity and associated metabolic disorders. Exposure to antibiotics exerts a devastating impact on the intestinal microbial community. Epidemiological studies have provided evidence indicating that early or repeated childhood exposure to antibiotics is associated with increased risk of overweight later in childhood but the causal role of this exposure in obesity development is not clear. However, data from studies conducted using experimental animal models indicate that antibiotic-induced changes in the gut microbiota influence host metabolism and lead to fat accumulation. The intestinal microbiota perturbation caused by antibiotic exposure in the perinatal period appears to program the host to an obesity-prone metabolic phenotype, which persists after the antibiotics have been discontinued and the gut microbiota has recovered. These observations may have serious implications in the clinical setting, since a substantial number of human infants are subjected to antibiotic treatment through the mother during delivery or directly in the immediate neonatal period. The clinical significance of these exposures remains unknown. Prudent use of antibiotics is paramount not only to reduce the propagation of antibiotic-resistant organisms but also to minimize the potentially detrimental long-term metabolic consequences of early antibiotic exposure. Improved means of reliably detecting neonates with bacterial infection would reduce the need for empirical antibiotic exposure initiated based on nonspecific symptoms and signs or risk factors. Finally, means to support healthy microbial contact in neonates and infants requiring antibiotic treatment are needed.


Coding Local and Global Binary Visual Features Extracted From Video Sequences.
Binary local features represent an effective alternative to real-valued descriptors, leading to comparable results for many visual analysis tasks while being characterized by significantly lower computational complexity and memory requirements. When dealing with large collections, a more compact representation based on global features is often preferred, which can be obtained from local features by means of, e.g., the bag-of-visual word model. Several applications, including, for example, visual sensor networks and mobile augmented reality, require visual features to be transmitted over a bandwidth-limited network, thus calling for coding techniques that aim at reducing the required bit budget while attaining a target level of efficiency. In this paper, we investigate a coding scheme tailored to both local and global binary features, which aims at exploiting both spatial and temporal redundancy by means of intra- and inter-frame coding. In this respect, the proposed coding scheme can conveniently be adopted to support the analyze-then-compress (ATC) paradigm. That is, visual features are extracted from the acquired content, encoded at remote nodes, and finally transmitted to a central controller that performs the visual analysis. This is in contrast with the traditional approach, in which visual content is acquired at a node, compressed and then sent to a central unit for further processing, according to the compress-then-analyze (CTA) paradigm. In this paper, we experimentally compare the ATC and the CTA by means of rate-efficiency curves in the context of two different visual analysis tasks: 1) homography estimation and 2) content-based retrieval. Our results show that the novel ATC paradigm based on the proposed coding primitives can be competitive with the CTA, especially in bandwidth limited scenarios.