CmBES1 is a regulator of boundary formation in chrysanthemum ray florets.
Chrysanthemum (Chrysanthemum morifolium) is an ideal model species for studying petal morphogenesis because of the diversity in the flower form across varieties; however, the molecular mechanisms underlying petal development are poorly understood. Here, we show that the brassinosteroid transcription factor BRI1-EMS-SUPPRESSOR 1 (CmBES1) in chrysanthemum (C. morifolium cv. Jinba) is important for organ boundary formation because it represses organ boundary identity genes. Chrysanthemum plants overexpressing CmBES1 displayed increased fusion of the outermost ray florets due to the loss of differentiation of the two dorsal petals, which developed simultaneously with the ventral petals. RNA-seq analysis of the overexpression lines revealed potential genes and pathways involved in petal development, such as CUP-SHAPED COTYLEDON (CUC2), CYCLOIDEA 4 (CYC4), genes encoding MADS-box transcription factors and homeodomain-leucine zippers (HD-Zips) and auxin pathway-related genes. This study characterizes the role of CmBES1 in ray floret development by its modulation of flower development and boundary identity genes in chrysanthemum.


Ultrasensitive bioanalytical assays using time-resolved fluorescence detection.
This article reviews the use of time-resolved fluorimetric detection of lanthanide chelate luminescence as a detection method for ultrasensitive bioanalytical assays. Assay formats and detection methods, and the principle of time-resolved fluorimetric detection, are described. Detection systems, assay formats, reagents, and instrumentation for time-resolved fluorimetric detection are outlined. A review of published and commercially available immunoassays and DNA hybridization assays using time-resolved fluorimetric detection of lanthanide chelate luminescence is given.


The relationship between perioperative blood transfusion and overall mortality in patients undergoing radical cystectomy for bladder cancer.
The relationship between perioperative blood transfusion (PBT) and oncologic outcomes is controversial. In patients undergoing surgery for colon cancer and several other solid malignancies, PBT has been associated with an increased risk of mortality. Yet, the urologic literature has a paucity of data addressing this topic. We sought to evaluate whether PBT affects overall survival following radical cystectomy (RC) for patients with bladder cancer. The medical records of 777 consecutive patients undergoing RC for urothelial carcinoma of the bladder were reviewed. PBT was defined as transfusion of red blood cells during RC or within the postoperative hospitalization. The primary outcome was overall survival. Clinical and pathologic variables were compared using χ(2) tests, and Cox multivariate survival analyses were performed. A total of 323 patients (41.6%) underwent PBT. In the univariate analysis, PBT was associated with increased overall mortality (HR 1.40, 95% CI 1.11-1.78). Additionally, an independent association was demonstrated in a non-transformed Cox regression model (HR, 95% CI 1.01-1.36) but not in a model utilizing restricted cubic splines (HR 1.03, 95% CI 0.77-1.38). The c-index was 0.78 for the first model and 0.79 for the second. In a traditional multivariate model, mirroring those that have been applied to this question in the general surgery literature, we demonstrated an association between PBT and overall mortality after RC. However, this relationship is not observed in a second statistical model. Given the complex nature of adequately controlling for confounding factors in studies of PBT, a prospective study will be necessary to fully elucidate the independent risks associated with PBT.


Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality.
The purpose of this study was to test whether mitochondrial dysfunction is causative of sepsis sequelae, a mouse model of peritonitis sepsis induced by cecal ligation and perforation. Inhibition of mitochondrial permeability transition was achieved by means of pharmacological drugs and overexpression of the antiapoptotic protein B-cell leukemia (Bcl)-2. Sepsis is the leading cause of death in critically ill patients and the predominant cause of multiple organ failure. Although precise mechanisms by which sepsis leads to multiple organ dysfunction are unknown, growing evidence suggests that perturbations of key mitochondrial functions, including adenosine triphosphate production, Ca2+ homeostasis, oxygen-derived free radical production, and permeability transition, might be involved in sepsis pathophysiology. Heart and lung functions were evaluated respectively by means of isolated heart preparation, bronchoalveolar lavage fluid protein concentration, lung wet/dry weight ratio, lung homogenate myeloperoxidase activity, and histopathologic grading. Respiratory fluxes, calcium uptake, and membrane potential were evaluated in isolated heart mitochondria. Peritonitis sepsis induced multiple organ dysfunction, mitochondrial abnormalities, and increased mortality rate, which were reduced by pharmacological inhibition of mitochondrial transition by cyclosporine derivatives and mitochondrial Bcl-2 overexpression. Our study provides strong evidence that mitochondrial permeability transition plays a critical role in septic organ dysfunction. These studies demonstrate that mitochondrial dysfunction in sepsis is causative rather than epiphenomenal and relevant in terms of vital organ function and outcome. Regarding the critical role of heart failure in the pathophysiology of septic shock, our study also indicates a potentially new therapeutic approach for treatment of sepsis syndrome.


Tetanus immunity in long-term care facilities.
To investigate the correlates of tetanus immunity in the elderly residing in a long-term care facility in Hawaii. Cross-sectional. A nursing home in Honolulu, Hawaii. Sixty subjects aged 65 and older: 30 men and 30 women. The interview included demographic information, immunization history, military service information, and other potential risk factors for tetanus. Serum tetanus antibody titers were measured. The data showed that 76.7% (46/60) had adequate tetanus titers. This is in stark contrast to previous studies, which have reported immunity rates of 27% to 46% in similar populations. There were significant associations between immunity and prior history of military service. There were no significant associations between immunity and past history of immunization, education, socioeconomic status, or sex. History of immunization from patients, families, or medical charts may be unreliable indicators of tetanus immunity. Recognizing patterns of and barriers to immunization could have important consequences for public health policy in long-term care institutions.


Ischaemic heart disease, and vehicle travel.
Mathematical data are presented supporting a relationship between road accident deaths (RAD), male and female, and ischaemic heart disease (IHD) deaths, male and female, in Australia. It is suggested that RAD on a national scale are a function of vehicle usage, for both males and females, and in turn, vehicle usage creates stress on bodily function resulting in IHD.


MANAGEMENT OF AUTOLOGUS RETINAL TRANSPLANT COMPLICATIONS: A CASE SERIES.
To present representative cases of the most common complications associated with an autologous retinal transplant (ART) for macular hole repair. A retrospective, consecutive case series on patients who underwent an ART by a single provider (Tamer H. Mahmoud). Four cases were included in this review. Each suffered an ART-specific complication, including graft displacement and dislocation, sub-ART perfluoron, and a delayed proliferative vitreoretinopathy-associated retinal detachment. Because more surgeons use ART to treat atypical macular holes, an adequate understanding of surgery-specific complications and techniques to treat those complications is increasingly necessary.


Production, bioprocessing and antiproliferative activity of camptothecin from Aspergillus terreus, endophyte of Cinnamomum camphora: restoring their biosynthesis by indigenous microbiome of C. camphora.
Fungal producing potency of camptothecin (CPT) raise the hope for their usage to be a platform for industrial production of CPT, nevertheless, attenuation of their productivity of CPT with the subculturing and preservation is the challenge. So, screening for novel endophytic fungal isolates with a reliable CPT-biosynthetic stability was the objective. Among the isolated endophytic fungi from the tested medicinal plants, Aspergillus terreus OQ642314.1, endophyte of Cinnamomum camphora, exhibits the highest yield of CPT (89.4 μg/l). From the NMR, FT-IR and LC-MS/MS analyses, the extracted CPT from A. terreus gave the same structure and molecular mass fragmentation pattern of authentic CPT (349 m/z). The putative CPT had a significant activity against MCF7 (0.27 µM) and HEPG-2 (0.8 µM), with a strong affinity to inhibits the human Topoisomerase 1 activity (IC50 0.362 μg/ml) as revealed from the Gel-based DNA relaxation assay. The purified CPT displayed a strong antimicrobial activity for various bacterial (E. coli and B. cereus) and fungal (A. flavus and A. parasiticus) isolates, ensuring the unique tertiary, and stereo-structure of A. terreus for penetrating the microbial cell walls and targeting the topoisomerase I. The higher dual activity of the purified CPT as antimicrobial and antitumor, emphasize their therapeutic efficiency, especially with growth of the opportunistic microorganisms due to the suppression of human immune system with the CPT uses in vivo. The putative CPT had an obvious activity against the tumor cell (MCF7) metastasis, and migration as revealed from the wound healing assay. The overall yield of A. terreus CPT was maximized with the Blackett-Burman design by twofolds increment (164.8 μg/l). The CPT yield by A. terreus was successively diminished with the multiple fungal subculturing, otherwise, the CPT productivity of A. terreus was restored, and increased over the zero culture upon coculturing with C. camphora microbiome (1.5% w/v), ensuring the restoring of CPT biosynthetic potency of A. terreus by the plant microbiome-derived chemical signals "microbial communication". This is the first report exploring the feasibility of A. terreus "endophyte of C. camphora" to be a preliminary platform for commercial production of CPT with a reliable sustainability upon uses of indigenous C. camphora microbiome.


Nifedipine-resistant Ca(++)-induced contraction in tail artery of spontaneously hypertensive rats.
Nifedipine-resistant Ca(++)-induced contractions (NR-Ca(++)-contraction) were compared in the tail arteries from SHRs and WKYs (5 and 13 week old). NR-Ca(++)-contraction of tail artery was defined as follows: Ca(++)-induced contraction in the presence of norepinephrine (NE) (10(-5) M) or 5-hydroxytryptamine (5-HT) (10(-5) M) in Ca(++)-free medium containing EGTA (0.1 mM) and nifedipine (10(-6) M). NR-Ca(++)-contractions in arteries from 5 week old SHRs and WKYs were not different. In contrast, NR-Ca(++)-contractions in arteries from 13 week old SHRs were about 2-fold greater than in arteries from 13 week old WKYs. In arteries from 13 week old WKYs and SHRs, nitroglycerin (10(-5) M) significantly reduced the NR-Ca(++)-contraction in the presence of 5-HT but not in the presence of NE. The reduction was inhibited by the presence of methylene blue (3 x 10(-6) M). 8-Bromo-cGMP (10(-4) M) reduced significantly the NR-Ca(++)-contraction in the presence of 5-HT in arteries from 13 week old SHRs and WKYs. The present experiments clearly demonstrated that the NR-Ca(++)-contractions (both in the presence of NE and 5-HT) in 13 week old SHRs were significantly greater than those in arteries from 13 week old WKYs. These results suggest that in addition to an increase in voltage-operated Ca++ mobilization reported by others, an increase in NR-Ca++ mobilization may contribute to the development of hypertension in SHR.


The microheterogeneity of androgen-binding protein in rat serum and epididymis is due to differences in glycosylation of their subunits.
The microheterogeneity of androgen-binding protein (ABP) from rat serum and epididymis was examined by subjecting purified native or deglycosylated preparations to analysis by one- or two-dimensional polyacrylamide gel electrophoresis (PAGE) followed by electrophoretic transfer to nitrocellulose and immunochemical localization. Analysis of native ABP by one-dimensional sodium dodecyl sulfate-PAGE confirmed earlier observations that it is composed of subunits and that the subunits of serum ABP had higher apparent molecular weights than those of epididymal ABP. Treatment with neuraminidase, N-glycanase, or O-glycanase, alone or in combination, resulted in decreases in the apparent molecular weight of the subunits. These analyses indicated that terminal sialic acid residues and Asn-linked oligosaccharides were present on both subunits of ABP from the two sources. The fact that the greatest reduction in the Mr of the heavy subunit occurred following treatment with all three enzymes provides evidence that O-linked sugars are present on it. While enzyme treatment did not result in the appearance of a single subunit, chemical deglycosylation did (Mr 39,600). The carbohydrate composition of the heavy and light subunits of intact serum and epididymal ABP was 22 and 9% and 19 and 8%, respectively. Analysis by two-dimensional PAGE indicated that both subunits of the ABPs were composed of isoelectric variants. Although ABP from the two sources had several variants in common, differences were also observed. Treatment of the ABPs with the enzymes resulted in a shift of the pI values to a more basic pH range, indicating that carbohydrate removal also removed charged moieties. The most dramatic shift in the pI values of the isoforms occurred when O-glycanase was present in the enzyme mixture, providing further evidence for the presence of O-linked oligosaccharides on ABP. Isoelectric variants were present even after chemical deglycosylation of ABP.


Predicting the performance of existing pre-cast concrete pipes using destructive and non-destructive testing techniques.
One of the most significant and critical urban assets for a sustainable community is the sewer pipeline network and water distribution system. Water sewer networks and distribution systems have a definite service life span to provide continuous facilities to end users. Therefore, it is pertinent to continuously evaluate the condition of water and sewer concrete pipelines to ensure the reliable, sustainable, and cost-efficient transport of water and sewerage for the safety of society. The condition assessment is commonly carried out by visual observations followed by some non-destructive testing methods. However, it is the need of the hour to shift assessment methods to advance assessment techniques to save time and money for our community. Currently, in this project, the condition assessment of pre-cast concrete pipes was carried out by destructive and non-destructive methods. Different test trials i.e., ultra-sonic pulse velocity, Schmidt hammer also known as rebound hammer test, visual inspection, three edge bearing test, and core cutting test on the old buried and new concrete pipes were performed. It was observed that concrete used for the construction of existing precast concrete pipes still has better quality indices after 20 years as compared to that of concrete of new pipes. However, steel has deteriorated with time and clear corrosion of steel was identified in existing pre-cast concrete pipes. At the same time, it was observed that there should be an automated mechanism to continuously asses the condition of pre-cast existing pipes which will address the sustainable development goals (SDG 6, 9, 11). Consequently, it can be said that condition assessment of pre-cast concrete pipes will lead to sustainable societies and infrastructure.


Use of size-dependent electron configuration fingerprint to develop general prediction models for nanomaterials.
Due to the lack of nano descriptors that can appropriately represent the wide chemical space of engineered nanomaterials (ENMs), applicability domain of nano-quantitative structure-activity relationship models are limited to certain types of ENMs, such as metal oxides, metals, carbon-based nanomaterials, or quantum dots. In this study, a size-dependent electron configuration fingerprint (SDEC FP) was introduced to estimate the quantity of electrons based on the core, doping, and coating materials of ENMs in different sizes. SDEC FP was used in prediction model development and nanostructure similarity analysis on datasets including metal and carbon-based nanomaterials with and without surface modifications. Cytotoxicity and zeta potential prediction models developed with SDEC FP achieved good prediction accuracies on test set. Nanostructure similarity analysis was performed through principal component analysis which showed that structural similarity between ENMs measured by SDEC FP was highly correlated with their properties.


Orbital post-septal hyaluronic acid: An iatrogenic etiology compounding lower eyelid steatoblepharon.
The stark rise in the incidence of dermal filler-related adverse sequelae has given rise to a variety of cosmetic distortions related to improper filler placement that include dynamic and static contour deformities of the face. In this article, we describe two instances of post-septal hyaluronic acid filler aggravating existing steatoblepharon and outline potential causative mechanisms responsible for this condition.


Modelling the impact of a high-uptake bivalent booster scenario on the COVID-19 burden and healthcare costs in New York City.
Uptake of the COVID-19 bivalent booster vaccine (targeting the original SARS-CoV-2 strain and subvariants BA.4 and BA.5 of the Omicron variant) among eligible residents of New York City (NYC) has been modest and declining. Assessing the impact of improved population-level booster coverage with bivalent vaccines in NYC can help inform investment towards vaccination and potential cost-savings. We calibrated an agent-based model of disease transmission to confirmed and probable cases of COVID-19 in NYC and simulated it to project outcomes under two scenarios. In the base case scenario, we assumed that vaccination continued with the average daily rate of 92 vaccine doses per 100,000 administered during December 2022. In the counterfactual scenario, we modeled a high-uptake scenario between January 1, 2023 and March 31, 2023, with an average daily rate of 296 vaccine doses per 100,000 population that increased bivalent coverage in NYC to match the age-specific influenza vaccine coverage of the 2020-2021 season. Vaccination rate outside the campaign duration remained the same as the base case scenario. Compared to the base case, the high-uptake scenario averted 88,274 (95% Confidence Interval [CI]: 77,097-100,342) cases, and prevented 2,917 (95% CI: 2,557-3,267) hospitalizations between January 1 through the end of June 2023. Averted outcomes resulted in net savings of $217.2 (95% CI: 190.0-242.2) million in direct healthcare costs. We estimated that the high-uptake scenario would avert 72,879 (95% CI: 63,894-82,228) days of student absenteeism from schools due to COVID-19 illness. Our results illustrate the continued benefits of COVID-19 vaccines in preventing severe health outcomes, averting healthcare costs, and maintaining educational continuity in NYC. The Canadian Institutes of Health Research, The Natural Sciences and Engineering Research Council of Canada, NIH, Centers for Disease Control and Prevention (CDC), NSF, The Commonwealth Fund, and The Notsew Orm Sands Foundation.


Subsets of symptomatic hand osteoarthritis in community-dwelling older adults in the United Kingdom: prevalence, inter-relationships, risk factor profiles and clinical characteristics at baseline and 3-years.
To compare the population prevalence, inter-relationships, risk factor profiles and clinical characteristics of subsets of symptomatic hand osteoarthritis (OA) with a view to understanding their relative frequency and distinctiveness. 1076 community-dwelling adults with hand symptoms (60% women, mean age 64.7 years) were recruited and classified into pre-defined subsets using physical examination and standardised hand radiographs, scored with the Kellgren & Lawrence (K&L) and Verbruggen-Veys grading systems. Detailed information on selected risk factors was obtained from direct measurement (Body Mass Index (BMI)), self-complete questionnaires (excessive use of hands, previous hand injury) and medical record review (hypertension, dyslipidaemia, type 2 diabetes). Hand pain and disability were self-reported at baseline and 3-year follow-up using Australian/Canadian Osteoarthritis Hand Index (AUSCAN). Crude population prevalence estimates for symptomatic hand OA subsets in the adult population aged 50 years and over were: thumb base OA (22.4%), nodal interphalangeal joint (IPJ) OA (15.5%), generalised hand OA (10.4%), non-nodal IPJ OA (4.9%), erosive OA (1.0%). Apart from thumb base OA, there was considerable overlap between the subsets. Erosive OA appeared the most distinctive with the highest female: male ratio, and the most disability at baseline and 3-years. A higher frequency of obesity, hypertension, dyslipidaemia, and metabolic syndrome was observed in this subset. Overlap in the occurrence of hand OA subsets poses conceptual and practical challenges to the pursuit of distinct phenotypes. Erosive OA may nevertheless provide particular insight into the role of metabolic and cardiovascular risk factors in the pathogenesis of OA.


Metals in Plant Functional Types of Ombrotrophic Peatlands in the Sudetes (SW Poland).
The Sudetes are remarkable for the variety and number of peat bogs which receive nutrients via precipitation from atmospheric deposition as the only source of minerals. As this type of peat bogs with a very low buffering capacity is affected in the Sudetes by long-range exhausts from the former Black Triangle, strong response to atmospheric contamination may be expected. Therefore these peat bogs are highly suitable for bioindication purposes. As a result, metal levels in peat and plants should be controlled to evaluate potential ecological damage and to devise treatment strategies. The aim of this study was to evaluate the concentration of Cd, Cr, Cu, Fe, Hg, Mn, Ni, Pb, and Zn in species from different plant functional types (PFTs): shrubs, evergreen dwarf shrubs, deciduous dwarf shrubs, tussock sedges, non-tussock sedges, forbs, Sphagnum mosses, brown mosses, liverworts, and algae collected from peat bogs of the Izera, Karkonosze, and Bystrzyckie Mountains. PFTs of the Karkonosze peat bogs situated above the upper forest line contained higher metal concentrations than those of the Izera and Bystrzyckie peat bogs from lower altitudes and surrounded by forests. Of all PFTs, the algae Zygogonium ericetorum accumulated the highest levels of Fe, Pb, and Zn. The PFTs of Sphagnum mosses were also very effective bioindicators of Cd, Cr, Fe, Hg, and Pb deposition to peat bog ecosystems. Pb, Fe, and Cr found in the examined vascular PFTs originated from atmospheric deposition. The results showed that airborne contaminants, including the ones connected with long-range transport, can make a significant contribution to a load of trace metals in peat bogs located above the upper forest line. These airborne depositions facilitate better recognition of the transport of contaminants carried over great distances and should be taken into account in monitoring and environmental protection programs. In particular, the results, first of all, show the differences in the bioaccumulation of metals in PFTs and their response to trace metal levels in such habitats. Of all PFTs, algae and Sphagnum mosses were the best choices for bioindication of trace metal pollution in ombrotrophic mountain mires. PFTs have not been used so far for investigating ombrotrophic mountain mires in Europe. Thus results of this investigation could be extended to this type of peat bogs in the mountains of Central Europe for better selection of PFTs for bioindication purposes.


Modulation of sensory nerve fiber excitability by transcutaneous cathodal direct current stimulation.
To assess the lasting effects on sensory nerve membrane excitability of transcutaneous peripheral nerve stimulation with cathodal direct currents (pDCS). We performed pDCS in 10 healthy subjects with the active electrode placed over the distal right forearm and the reference electrode on the back of the right hand. We used 5×5cm rubber electrodes and the current applied was 2.5mA during 15min. Three pDCS sessions were performed on the same day: first, a baseline stimulation was performed, followed by a sham stimulation and lastly a cathodal stimulation. Median sensory nerve excitability measurements were performed at baseline and immediately after each pDCS session using the TRONDNF nerve excitability protocol of the QTRAC program (measurement on the second finger). The protocol was completed and well tolerated in all subjects. RRP (relative refractory period) and refractoriness at 2.5ms were significantly different across the three study conditions, with a significant increase of RRP immediately following cathodal stimulation compared with baseline assessment (mean 4.2 versus 5.3, P=0.002). Other measurements were not modulated by the intervention. Sham-stimulation did not change axonal excitability. Cathodal pDCS stimulation increased RRP of sensory fibers, but no other consistent long-lasting effect was observed. This finding might suggest a reduction of sensory fiber excitability induced by cathodal pDCS.


The effect of environmental stimulation upon the stereotyped behavior of autistic children.
Two groups of three autistic children, equated for chronological age but differing in IQ and performance MA, were observed for 20-minute sessions. Total duration of time subjects engaged in stereotyped behavior was recorded for each minute. During minutes 6--15, subjects were provided with either minimal or high environmental stimulation. High environmental stimulation was found to increase the mean duration of time the low-IQ group engaged in stereotyped behavior but to decrease the duration for the high-IQ group. The theoretical implications are discussed.


Evaluation of a novel device to assess obstructive sleep apnea and body position.
Obstructive sleep apnea is a prevalent disease with well-known complications when left untreated. Advances in sleep-disordered breathing diagnosis may increase detection and appropriate treatment. The Wesper device is a recently developed portable system with specialized wearable patches that can measure respiratory effort, derived airflow, estimated air pressure, and body position. This study sought to compare the diagnostic ability of the novel Wesper device with the gold standard of polysomnography. Patients enrolled in the study underwent simultaneous polysomnography and Wesper device testing in a sleep laboratory setting. Data were collected and scored by readers blinded to all patient information, and the primary reader was blinded to testing method. The accuracy of the Wesper device was determined by calculation of the Pearson correlation and Bland-Altman limits of agreement of apnea-hypopnea indices between testing methods. Adverse events were also recorded. A total of 53 patients were enrolled in the study and 45 patients were included in the final analysis. Pearson correlation between polysomnography and Wesper device apnea-hypopnea index determinations was 0.951, which met the primary endpoint goal (P = .0003). The Bland-Altman 95% limits of agreement were -8.05 and 6.38, which also met the endpoint goal (P < .001). There were no adverse events or serious adverse events noted. The Wesper device compares favorably with gold-standard polysomnography. Given the lack of safety concerns, we advocate for further study regarding its utility in diagnosis and management of sleep apnea in the future. Raphelson JR, Ahmed IM, Ancoli-Israel S, et al. Evaluation of a novel device to assess obstructive sleep apnea and body position. J Clin Sleep Med. 2023;19(9):1643-1649.


Bone/cartilage targeted hydrogel: Strategies and applications.
The skeletal system is responsible for weight-bearing, organ protection, and movement. Bone diseases caused by trauma, infection, and aging can seriously affect a patient's quality of life. Bone targeted biomaterials are suitable for the treatment of bone diseases. Biomaterials with bone-targeted properties can improve drug utilization and reduce side effects. A large number of bone-targeted micro-nano materials have been developed. However, only a few studies addressed bone-targeted hydrogel. The large size of hydrogel makes it difficult to achieve systematic targeting. However, local targeted hydrogel still has significant prospects. Molecules in bone/cartilage extracellular matrix and bone cells provide binding sites for bone-targeted hydrogel. Drug delivery systems featuring microgels with targeting properties is a key construction strategy for bone-targeted hydrogel. Besides, injectable hydrogel drug depot carrying bone-targeted drugs is another strategy. In this review, we summarize the bone-targeted hydrogel through application environment, construction strategies and disease applications. We hope this article will provide a reference for the development of bone-targeted hydrogels. We also hope this article could increase awareness of bone-targeted materials.


Pregna-5,17(20)-dien-21-oyl amides affecting sterol and triglyceride biosynthesis in Hep G2 cells.
Synthesis of series [17(20)Z]- and [17(20)E]-pregna-5,17(20)-dien-21-oyl amides, containing polar substituents in amide moiety, based on rearrangement of 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one caused by amines, is presented. The titled compounds were evaluated for their potency to regulate sterol and triglyceride biosynthesis in human hepatoma Hep G2 cells in comparison with 25-hydroxycholesterol. Three [17(20)E]-pregna-5,17(20)-dien-21-oyl amides at a concentrations of 5 μM inhibited sterol biosynthesis and stimulated triglyceride biosynthesis; their regulatory potency was dependent on the structure of amide moiety; the isomeric [17(20)Z]-pregna-5,17(20)-dien-21-oyl amides were inactive.


Chronic effects of fractionated renal irradiation on the pharmacokinetics of intravenous methotrexate.
the chronic effects of renal irradiation on the pharmacology of methotrexate was studied in a rat model. Unanesthetized rats received 2 doses of bilateral fractionated kidney irradiation (16.2 Gy or 19.8 Gy in 9 fractions). Alterations in renal function were first seen at 3 months in the 19.8 Gy group and 12 months in the 16.2 Gy groups. Life table analysis showed a shift in the survival curve of about 3 months between the 2 radiation doses. The pharmacokinetics of i.v. methotrexate showed an increase in the area under the plasma curve beginning at 9 months in the 19.8 Gy group and at 15 months in the 16.2 Gy group. The volume of distribution of methotrexate was smaller in the irradiated rats than in unirradiated controls. Multiple linear regression models showed significant correlations between parameters of methotrexate clearance and certain renal function tests. Nevertheless, no set of renal function tests consistently predicted alteration in methotrexate clearance in the 2 radiation groups. Furthermore, time after irradiation remained a highly significant variable indicating that renal irradiation causes time dependent change in methotrexate pharmacokinetics that can not be accounted for by the usual tests of renal function.


Targeted activation of transcription in vivo through hairpin-triplex forming oligonucleotide in Saccharomyces cerevisiae.
Triplex forming oligonucleotides (TFO) are known to be potential agents for modifying gene function. In most instances they are utilized for repression of transcription. However hybrid molecules containing cis-acting elements in a duplex DNA in a hairpin form contiguously with the TFO can bind transcription factors in vitro. In the present manuscript we demonstrate that hairpin-TFO can be employed in vivo for targeted activation of gene expression of two genes mapping on chromosome XI of Saccharomyces cerevisiae. The cis-acting GAL4 protein-binding site contained in the hairpin-TFO is targeted in vivo to the 5' upstream sequence of STE6 and CBT1 genes that are transcribed in opposite directions and share a poly(pu/py) sequence that can form triple helical structure. The hairpin-TFO is targeted to this site and promotes the activation of both the genes. These results demonstrate four important aspects relating to activation of gene expression: (i) accessibility of duplex DNA packaged into chromatin to triplex forming sequences in vivo, (ii) the potential use of hairpin-TFO in therapeutics by activation of transcription in vivo, (iii) Sharing of transcription factors between two genes transcribed in opposite directions and (iv) specific activation of genes even when their cognate site is not covalently linked to the gene being activated.


Quantitative DWI implemented after DCE-MRI yields increased specificity for BI-RADS 3 and 4 breast lesions.
To assess if specificity can be increased when semiautomated breast lesion analysis of quantitative diffusion-weighted imaging (DWI) is implemented after dynamic contrast-enhanced (DCE-) magnetic resonance imaging (MRI) in the workup of BI-RADS 3 and 4 breast lesions larger than 1 cm. In all, 120 consecutive patients (mean-age, 48 years; age range, 23-75 years) with 139 breast lesions (≥1 cm) were examined (2010-2014) with 1.5T DCE-MRI and DWI (b = 0, 50, 200, 500, 800, 1000 s/mm2 ) and the BI-RADS classification and histopathology were obtained. For each lesion malignancy was excluded using voxelwise semiautomated breast lesion analysis based on previously defined thresholds for the apparent diffusion coefficient (ADC) and the three intravoxel incoherent motion (IVIM) parameters: molecular diffusion (Dslow ), microperfusion (Dfast ), and the fraction of Dfast (ffast ). The sensitivity (Se), specificity (Sp), and negative predictive value (NPV) based on only IVIM parameters combined in parallel (Dslow , Dfast , and ffast ), or the ADC or the BI-RADS classification by DCE-MRI were compared. Subsequently, the Se, Sp, and NPV of the combination of the BI-RADS classification by DCE-MRI followed by the IVIM parameters in parallel (or the ADC) were compared. In all, 23 of 139 breast lesions were benign. Se and Sp of DCE-MRI was 100% and 30.4% (NPV = 100%). Se and Sp of IVIM parameters in parallel were 92.2% and 52.2% (NPV = 57.1%) and for the ADC 95.7% and 17.4%, respectively (NPV = 44.4%). In all, 26 of 139 lesions were classified as BI-RADS 3 (n = 7) or BI-RADS 4 (n = 19). DCE-MRI combined with ADC (Se = 99.1%, Sp = 34.8%) or IVIM (Se = 99.1%, Sp = 56.5%) did significantly improve (P = 0.016) Sp of DCE-MRI alone for workup of BI-RADS 3 and 4 lesions (NPV = 92.9%). Quantitative DWI has a lower NPV compared to DCE-MRI for evaluation of breast lesions and may therefore not be able to replace DCE-MRI; when implemented after DCE-MRI as problem solver for BI-RADS 3 and 4 lesions, the combined specificity improves significantly. J. Magn. Reson. Imaging 2016;44:1642-1649.


The effects of triacetyloleandomycin and oleandomycin phosphate on the glucocorticoid receptor in cultured skin fibroblasts.
Triacetyloleandomycin (TAO) has been described as a "steroid-sparing" drug in that poorly controlled asthmatic patients can be stabilized or improved with the addition of TAO despite decreasing dosages of steroids, specifically methylprednisolone (MP). It is not clear whether the beneficial effects of TAO are due to decreased MP clearance or are due to enhanced glucocorticoid effect peripherally. We tested the latter possibility by studying the interaction of TAO and oleandomycin phosphate (OLEO), the active metabolite of TAO in vivo, with glucocorticoid receptors in dispersed, intact cultured human skin fibroblasts. With the use of cells incubated with [3H]dexamethasone at 22 degrees C, we examined the competitive binding properties of TAO and OLEO (at varying concentrations) with and without MP as compared with several other steroids and MP alone. We also studied the effects on cellular glucocorticoid receptor number and affinity when TAO at a concentration of 4 X 10(-5) alone, at 10(-5) M in combination with a receptor saturating concentration of MP (5 X 10(-8) M), with MP alone, or with OLEO (10(-5) M) combined with MP was added to fibroblasts in the growth phase 1 wk before assay. TAO and OLEO did not compete for the binding of [3H]dexamethasone to the fibroblast glucocorticoid receptor, nor did they alter the binding properties of MP. With prolonged cellular exposure, TAO alone did not alter the number of glucocorticoid receptors (per cell) or their affinity for [3H]dexamethasone. Interestingly, prolonged exposure to saturating concentrations of MP alone decreased glucocorticoid receptor density; this effect was not altered by the presence of TAO or OLEO.(ABSTRACT TRUNCATED AT 250 WORDS)


Desmoplastic trichoepithelioma and intradermal nevus: a combined malformation.
We studied 13 desmoplastic trichoepitheliomas associated with intradermal nevi. Ten intradermal nevi were found among 76 new cases of desmoplastic trichoepithelioma (13%); three additional examples of the combined malformation were seen in consultation. Clinically, desmoplastic trichoepithelioma associated with an intradermal nevus was typically a small, firm or hard, sometimes annular, nodule on the face, particularly the cheek, of a relatively young woman. Microscopically, the combined malformation contained narrow strands of basaloid cells and keratinous cysts in a desmoplastic stroma, intimately mixed with intradermal nests of nevocytes. Melanocytic nevi have been associated with epidermal hyperplasia resembling seborrheic keratoses, follicular cysts, trichostasis spinulosa, syringomas, basal cell carcinomas, and hair follicle formation on the soles. The frequency of the occurrence of intradermal nevus with desmoplastic trichoepithelioma and the close anatomic association of the two elements may indicate that this combined malformation is another example of epithelial induction by melanocytic nevi.


Plant cell wall profiling by fast maximum likelihood reconstruction (FMLR) and region-of-interest (ROI) segmentation of solution-state 2D 1H-13C NMR spectra.
Interest in the detailed lignin and polysaccharide composition of plant cell walls has surged within the past decade partly as a result of biotechnology research aimed at converting biomass to biofuels. High-resolution, solution-state 2D 1H-13C HSQC NMR spectroscopy has proven to be an effective tool for rapid and reproducible fingerprinting of the numerous polysaccharides and lignin components in unfractionated plant cell wall materials, and is therefore a powerful tool for cell wall profiling based on our ability to simultaneously identify and comparatively quantify numerous components within spectra generated in a relatively short time. However, assigning peaks in new spectra, integrating them to provide relative component distributions, and producing color-assigned spectra, are all current bottlenecks to the routine use of such NMR profiling methods. We have assembled a high-throughput software platform for plant cell wall profiling that uses spectral deconvolution by Fast Maximum Likelihood Reconstruction (FMLR) to construct a mathematical model of the signals present in a set of related NMR spectra. Combined with a simple region of interest (ROI) table that maps spectral regions to NMR chemical shift assignments of chemical entities, the reconstructions can provide rapid and reproducible fingerprinting of numerous polysaccharide and lignin components in unfractionated cell wall material, including derivation of lignin monomer unit (S:G:H) ratios or the so-called SGH profile. Evidence is presented that ROI-based amplitudes derived from FMLR provide a robust feature set for subsequent multivariate analysis. The utility of this approach is demonstrated on a large transgenic study of Arabidopsis requiring concerted analysis of 91 ROIs (including both assigned and unassigned regions) in the lignin and polysaccharide regions of almost 100 related 2D 1H-13C HSQC spectra. We show that when a suitable number of replicates are obtained per sample group, the correlated patterns of enriched and depleted cell wall components can be reliably and objectively detected even prior to multivariate analysis. The analysis methodology has been implemented in a publicly-available, cross-platform (Windows/Mac/Linux), web-enabled software application that enables researchers to view and publish detailed annotated spectra in addition to summary reports in simple spreadsheet data formats. The analysis methodology is not limited to studies of plant cell walls but is amenable to any NMR study where ROI segmentation techniques generate meaningful results.Please see Research Article: http://www.biotechnologyforbiofuels.com/content/6/1/46/.


The actions of vasoactive compounds in the foetus and the effect of perfusion through the placenta on their biological activity.
In acute experiments on the in utero foetal lamb, angiotensin II was a more potent pressor agent that either noradrenaline or adrenaline, and the response to angiotensin II was not consistently modified by the combined administration of alpha and beta-adrenergic blocking agents. A significant reduction in the pressor response of the foetus to angiotensin II and noradrenaline occurred with infusion of these compounds to the foetus by the umbilical artery when compared with the response obtained with infusions of the same doses of these drugs by the umbilical vein. Moreover, the concentration of angiotensin II (pg. ml-1) present in the foetal circulation was less following umbilical arterial infusions compared with umbilical vein infusions of the same doses. A similar reduction in the pressor activity of adrenaline and the cardio-stimulant effect of isoprenaline occurred when these drugs were infused by the umbilical artery. It is concluded that the foetus, like the adult animal, is more sensitive to angiotensin II than to catecholamines and that the biological activities of noradrenaline, angiotensin II, adrenaline and isoprenaline are reduced by perfusion through the foetal placenta.


The muscle reflex and chemoreflex interaction: ventilatory implications for the exercising human.
We examined the interactive influence of the muscle reflex (MR) and the chemoreflex (CR) on the ventilatory response to exercise. Eleven healthy subjects (5 women/6 men) completed three bouts of constant-load single-leg knee-extension exercise in a control trial and an identical trial conducted with lumbar intrathecal fentanyl to attenuate neural feedback from lower-limb group III/IV muscle afferents. The exercise during the two trials was performed while breathing ambient air ([Formula: see text] ~97%, [Formula: see text]~84 mmHg, [Formula: see text] ~32 mmHg, pH ~7.39), or under normocapnic hypoxia ([Formula: see text] ~79%, [Formula: see text] ~43 mmHg, [Formula: see text] ~33 mmHg, pH ~7.39) or normoxic hypercapnia ([Formula: see text] ~98%, [Formula: see text] ~105 mmHg, [Formula: see text] ~50 mmHg, pH ~7.26). During coactivation of the MR and the hypoxia-induced CR (O2-CR), minute ventilation (V̇e) and tidal volume (VT) were significantly greater compared with the sum of the responses to the activation of each reflex alone; there was no difference between the observed and summated responses in terms of breathing frequency (fB; P = 0.4). During coactivation of the MR and the hypercapnia-induced CR (CO2-CR), the observed ventilatory responses were similar to the summated responses of the reflexes (P ≥ 0.1). Therefore, the interaction between the MR and the O2-CR exerts a hyperadditive effect on V̇e and VT and an additive effect on fB, whereas the interaction between the MR and the CO2-CR is simply additive for all ventilatory parameters. These findings reveal that the MR:CR interaction further augments the ventilatory response to exercise in hypoxia.NEW & NOTEWORTHY Although the muscle reflex and the chemoreflex are recognized as independent feedback mechanisms regulating breathing during exercise, the ventilatory implications resulting from their interaction remain unclear. We quantified the individual and interactive effects of these reflexes during exercise and revealed differential modes of interaction. Importantly, the reflex interaction further amplifies the ventilatory response to exercise under hypoxemic conditions, highlighting a potential mechanism for optimizing arterial oxygenation in physically active humans at high altitude.


A three-year follow-up study of psoriasis patients treated with low dosages of etretinate orally and corticosteroids topically.
Etretinate 0.5 mg/kg body weight combined with 0.1% triamcinolone acetonide and 5% salicylic acid in an O/W cream gave more than 70% improvement in 62% of 75 patients. Of this satisfactorily improved group, at least 41% were still in the same condition after 3 years on a maintenance dose of, on average, 0.3 mg/kg body weight etretinate daily and 20 g weekly of a relatively strong corticosteroid cream. The side effects were acceptable and the convenience for the patients is great as compared with other treatment.


Ethnic differences in thermal pain responses: a comparison of South Asian and White British healthy males.
The expression and report of pain is influenced by social environment and culture. Previous studies have suggested ethnically determined differences in report of pain threshold, intensity and affect. The influence of ethnic differences between White British and South Asians has remained unexplored. Twenty age-matched, male volunteers in each group underwent evaluation. Cold and warm perception and cold and heat threshold were assessed using an ascending method of limits. Magnitude estimation of pain unpleasantness and pain intensity were investigated with thermal stimuli of 46, 47, 48 and 49 degrees C. Subjects also completed a pain anxiety questionnaire. Data was analysed using t-test, Mann-Whitney and repeated measures analysis of variance as appropriate. There were no differences in cold and warm perception between the two groups. There was a statistically significant difference between the two groups for heat pain threshold (P=0.006) and heat pain intensity demonstrated a significant effect for ethnicity (F=13.84, P=0.001). Although no group differences emerged for cold pain threshold and heat unpleasantness, South Asians demonstrated lower cold pain threshold and reported more unpleasantness at all temperatures but this was not statistically significant. Our study shows that ethnicity plays an important role in heat pain threshold and pain report, South Asian males demonstrated lower pain thresholds and higher pain report when compared with matched White British males. There were no differences in pain anxiety between the two groups and no correlations were identified between pain and pain anxiety Haemodynamic measures and anthropometry did not explain group differences.


Isolation of a thiol-dependent serine protease in peanut and investigation of its role in the complement and the allergic reaction.
A serine protease activity was detected in aqueous peanuts seeds extracts, partially purified and characterized as a thiol-dependent serine protease. The potential role of this proteolytic activity on allergic reaction to peanuts was prospected through complement activation studies in human plasma and serum, and MDCK cells to investigate a possible occludin degradation in tight junctions. The peanut protease activity induced the production of anaphylatoxins C3a and C5a, and of the terminal membrane attack complex SC5b-9 whatever the complement activation pathway. The protease activity was also involved in the partial digestion of occludin within tight junctions, with for result, an increase of the epithelial permeability to antigen absorption.


Direct excitatory effects of neuropeptide Y (NPY) on rat hippocampal neurones in vitro.
Intracellular recordings from granule cells of the rat dentate gyrus show neuropeptide Y (NPY) applied by pressure ejection from pipettes containing 1.2-12 microM by pressures of less than 200 kPa for 1-5 s in duration to consistently evoke membrane depolarisations accompanied by a reduction in membrane resistance. The depolarisations were accompanied by an increase in excitability. Since the depolarisations evoked by NPY were not attenuated by either tetrodotoxin or kynurenic acid a direct excitatory action of NPY is postulated.


Responses of feline caudal hypothalamic cardiorespiratory neurons to hypoxia and hypercapnia.
Several studies have suggested that the caudal hypothalamus modulates responses to hypercapnia and hypoxia. In addition, this area of the hypothalamus contains neurons that have a sympathoexcitatory discharge. The purpose of the present study was to determine whether the basal discharge of caudal hypothalamic neurons that are stimulated by hypercapnia or hypoxia is related to cardiovascular (sympathetic discharge and/or the cardiac cycle) and/or respiratory activity (phrenic nerve discharge). Hypothalamic single unit activity, phrenic nerve activity, and cervical sympathetic nerve activity were recorded in anesthetized cats. Computer averaging techniques were used to compare temporally the discharge of hypothalamic neurons with cardiovascular and/or respiratory activity. Cardiorespiratory and hypothalamic neuronal responses to ventilation with hypoxic (10% O2/90% N2) and hypercapnic (5% CO2/95% O2) gases were determined in intact and in peripherally-chemodenervated, barodenervated cats. Thirty-two percent of hypothalamic neurons were stimulated by a hypercapnic stimulus in intact cats; of those that were stimulated by hypercapnia, all had a basal discharge related to cardiovascular and/or respiratory activity. Hypoxia significantly increased the discharge rate of 21% of hypothalamic units in intact animals; 90% of those had a cardiovascular and/or respiratory-related rhythm. Only 13% of the neurons were stimulated by both hypoxia and hypercapnia. Similar results were found in barodenervated, peripherally chemodenervated cats. Neurons excited by these stimuli in both the intact and denervated cats were found to be concentrated in the posterior hypothalamic area. The results of this study suggest that a group of caudal hypothalamic neurons contribute to the cardiorespiratory responses to hypoxia and hypercapnia, but via separate subpopulations of neurons. In addition, input from peripheral baroreceptor and chemoreceptor afferents is not required for this modulation.


Emulsifying Capacity of Cowpea Protein Isolates. Effect of Thermal and Hydrolytic Treatment.
In this work, modifications due to the effect of thermal treatments (TT 70 and 90 °C) and partial hydrolysis by digestion with alcalase (LH) on the emulsifying properties of cowpea protein isolates (CPIs) extracted at pH 8 and 10 were analyzed. In addition, the influence of protein concentration [0.1 and 1% (w/v)] was evaluated. Emulsions (O:W) were prepared and particle size, stability, interfacial composition, and microstructure were studied. Fresh emulsions formulated with TT CPIs presented lower values of volume-weighted mean droplet size (D4.3), with the increase in temperature and treatment time, compared to the untreated CPIs. After seven days of storage, D4.3 and the indexes of flocculation (FI) and coalescence (CI) increased, mainly at 90 °C. On the other hand, the emulsions with LH CPIs presented lower D4.3 values compared to all the conditions tested, remaining unchanged during the storage time. The destabilization process in the TT CPIs emulsions revealed coalescence at 0.1% (w/v) and cremated-flocculation at 1% (w/v). The presence of polypeptides of low molecular mass (MM) at the interface would be responsible for the better stability found in emulsions with LH CPIs, compared to those formulated with untreated and TT CPIs. Increasing the protein concentration resulted in a significant improvement of all emulsifying properties.


Effect of modulators of cytoskeletal function on desensitization and recovery of PGE2-responsive ovarian adenylate cyclase.
Exposure of cultured Graafian follicles to PGE2 for 20 h resulted in a loss of the cyclic AMP response to fresh hormone. This desensitization was prevented by addition to the medium of D2O (25--50%) or Li+ (0.6--6 mM), agents believed to stabilize microtubules, as well as by phalloidin (1.0--10 microM), believed to stabilize the polymerized state of actin, in a dose-dependent manner. The spontaneous recovery of responsiveness to PGE2 upon incubation of refractory follicles for 6 h in hormone-free medium was prevented by addition to the medium of cytochalasin B (CB; 3 microgram/ml) or of the actin-binding myosin subfragment HMM S-1 (80 microgram/ml) or of anti-actin serum; viz. by agents likely to interfere with microfilament function. D2O (50%) caused morphological damage to the inner layer of the membrana granulosa and severe depression of protein synthesis. The other drugs used (phalloidin, LiCl and cytochalasin B) had no such effects. Resensitization of refractory follicles was also prevented by cycloheximide (10 micrograms/ml) and by actinomycin D (10 micrograms/ml). It is speculated that the recovery process may involve the insertion of a newly synthesized protein, such as PG-receptor, into the membrane by a mechanism dependent on microfilament action. These findings provide suggestive evidence for the hypothesis that cytoskeletal elements associated with the cell membrane take part in the modulation of the adenylate cyclase response to hormones.


A micro-method for PHA-induced stimulation of human lymphocytes. II. communication: effect of splenectomy on the inhibitory activity of serum in patients with Hodgkin's disease.
Lymphocytes of 19 unselected patients with Hodgkin's disease were stimulated with PHA in vitro using a microculture system. The sera of these donors were simultaneously tested for their ability to support PHA-induced stimulation of normal lymphocytes as compared to sera drawn from healthy volumteers. Wheras DNA synthesis in Hodgkin's disease using normal sera was almost uniformly decreased, transformation of normal lymphocytes was suppressed in 9 of 11 sera from patients with Hodgkin's disease without splenectomy, but only in 1 of 8 sera from patients tested after removal of the spleen. 3 donors could be tested both before and after splenectomy, 2 showed a complete disappearance of inhibiting substances in their sera. These findings are discussed as to the immunological significance of inhibiting factors and splenectomy in Hodgkin's disease.


The natural history of recently diagnosed autonomic neuropathy over a period of 2 years.
Patients with diabetic autonomic neuropathy (DAN) have an increased cardiovascular mortality rate compared with normals or diabetic patients without DAN. Indices of standard cardiovascular autonomic function tests and heart rate variability (HRV) are reliable markers of the presence and severity of DAN. The present prospective study investigated the natural history of values of HRV indices and cardiovascular reflex tests in patients with recently diagnosed asymptomatic DAN, over a period of 2 years, at 3 month intervals. A total of 30 consecutive patients (nine men and 21 women), of median age 51 (range 25-65) years, eight with type 1 and 22 with Type 2 diabetes mellitus, were included in the study, at the time that the presence of DAN was confirmed, as this was established if at least two of cardiovascular autonomic function tests became abnormal. The expiration/inspiration (E/I) ratio. S.D. and mean circular resultant of R-R intervals, the Valsalva index, the 30:15 ratio, and the blood pressure response to standing as well as normalised spectral power indices of HRV were used. All measured indices, except the Valsalva index, deteriorated in all 30 patients during the 2 year follow-up. Most of HRV indices values deteriorated significantly in comparison to baseline at month 12, while the values of cardiovascular reflex tests displayed significant deterioration, in comparison to baseline, between months 15 and 21. Fourteen patients developed symptoms of DAN during the 2 year period. Patients with better glycemic control exhibited deterioration of DAN markers at the same time period with those with poor glycemic control. Our data suggest that the progression of DAN is significant during the 2 years subsequent to its discovery. This was defined by the deterioration of the mean values of HRV indices and standard cardiovascular autonomic function tests, and by the development of autonomic symptoms in some patients. HRV indices are the earlier markers of DAN deterioration.


Identification of SPRYD4 as a tumour suppressor predicts prognosis and correlates with immune infiltration in cholangiocarcinoma.
Cholangiocarcinoma (CCA) is an aggressive solid tumour with a 5-year survival rate ranging from 7% to 20%. It is, therefore, urgent to identify novel biomarkers and therapeutic targets to improve the outcomes of patients with CCA. SPRY-domain containing protein 4 (SPRYD4) contains SPRY domains that modulate protein-protein interaction in various biological processes; however, its role in cancer development is insufficiently explored. This study is the first to identify that SPRYD4 is downregulated in CCA tissues using multiple public datasets and a CCA cohort. Furthermore, the low expression of SPRYD4 was significantly associated with unfavourable clinicopathological characteristics and poor prognosis in patients with CCA, indicating that SPRYD4 could be a prognosis indicator of CCA. In vitro experiments revealed that SPRYD4 overexpression inhibited CCA cells proliferation and migration, whereas the proliferative and migratory capacity of CCA cells was enhanced after SPRYD4 deletion. Moreover, flow cytometry showed that SPRYD4 overexpression triggered the S/G2 cell phase arrest and promoted apoptosis in CCA cells. Furthermore, the tumour-inhibitory effect of SPRYD4 was validated in vivo using xenograft mouse models. SPRYD4 also showed a close association with tumour-infiltrating lymphocytes and important immune checkpoints including PD1, PD-L1 and CTLA4 in CCA. In conclusion, this study elucidated the role of SPRYD4 during CCA development and highlighted SPRYD4 as a novel biomarker and tumour suppressor in CCA.


An occurrence of Synthesiomyia nudiseta (Wulp) (Diptera: Muscidae) from a human corpse in a high-rise building in Malaysia: a case report.
This is the first report of Synthesiomyia nudiseta (Wulp) (Diptera: Muscidae) on a human corpse discovered in a high-rise building in Malaysia. On 5 March 2008, a decomposing body of an adult female was found on the top floor of a thirteen-story building in Kuala Lumpur, Malaysia. Her body was colonized by S. nudiseta larvae, which were normally associated with corpses found indoors at ground level. The post-mortem interval (PMI) was estimated at approximately 5 to 9 days. This case is significant as it demonstrates that this species can locate a dead body even in a high-rise building. Further findings of fly distribution especially in high-rise buildings should be reported to assist entomologists in PMI analysis.


NMR structure of the 101-nucleotide core encapsidation signal of the Moloney murine leukemia virus.
The full length, positive-strand genome of the Moloney Murine Leukemia Virus contains a "core encapsidation signal" that is essential for efficient genome packaging during virus assembly. We have determined the structure of a 101-nucleotide RNA that contains this signal (called mPsi) using a novel isotope-edited NMR approach. The method is robust and should be generally applicable to larger RNAs. mPsi folds into three stem loops, two of which (SL-C and SL-D) co-stack to form an extended helix. The third stem loop (SL-B) is connected to SL-C by a flexible, four-nucleotide linker. The structure contains five mismatched base-pairs, an unusual C.CG base-triple platform, and a novel "A-minor K-turn," in which unpaired adenosine bases A340 and A341 of a GGAA bulge pack in the minor groove of a proximal stem, and a bulged distal uridine (U319) forms a hydrogen bond with the phosphodiester of A341. Phylogenetic analyses indicate that these essential structural elements are conserved among the murine C-type retroviruses.


Hand-assisted approach to laparoscopic myomectomy and hysterectomy.
In this series we discuss the feasibility of hand-assisted approach to laparoscopic myomectomy and hysterectomy. The hand-assisted approach is a useful technique bridging the benefits of minimally invasive surgery and an open approach. We present the largest series to date of 15 patients: 10 hand-assisted hysterectomies and 5 myomectomies. All 15 cases were performed by the team of surgeons at a large academic medical center in the northeastern United States. We provide a detailed description of the hand-assisted technique along with patient demographic data, surgical outcomes, and complications. Operating times ranged from 86 to 269 minutes, and estimated blood loss ranged from 30 to 4000 mL. On the basis of preliminary outcomes, the hand-assisted technique appears to be beneficial in challenging laparoscopic cases, yet careful patient selection and vigilance are required to ensure successful outcomes.


Meningeal Whole Mounts for Imaging CNS Fungal Infection.
Invasive fungal infections may involve the brain and central nervous system (CNS), leading to often fatal meningitis in immunocompromised individuals. Recent technological advances have allowed us to move beyond studying the brain parenchyma to understanding the immune mechanisms of the meninges, the protective layer that surrounds the brain and spinal cord. Specifically, advanced microscopy techniques have enabled researchers to begin to visualize the anatomy of the meninges and the cellular mediators of meningeal inflammation. In this chapter, we describe how to make meningeal tissue mounts for imaging by confocal microscopy.


Birth Experiences, Breastfeeding, and the Mother-Child Relationship: Evidence from a Large Sample of Mothers.
It is a priority for public health professionals to improve global breastfeeding rates, which have remained low in Western countries for more than a decade. Few researchers have addressed how maternal perceptions of birth experiences affect infant feeding methods. Furthermore, mixed results have been shown in research regarding breastfeeding and mother-child bonding, and many studies are limited by small sample sizes, representing a need for further investigation. We aimed to examine the relationship between subjective birth experiences and breastfeeding outcomes, and explored whether breastfeeding affected mother-infant bonding. 3,080 mothers up to three years postpartum completed a cross - sectional survey. Mothers who had more positive birth experiences were more likely to report breastfeeding their babies. Moreover, mothers who perceived their birth as more positive were more likely to breastfeed their child for a longer period (over 9 months) than those who had more negative experiences. In line with recent research, breastfeeding behaviours were not associated with reported mother-infant bonding. Mothers who reported better birth experiences were most likely to breastfeed, and breastfeed for longer. We find no evidence to suggest that feeding methods are associated with bonding outcomes.


Corrigendum: Online Mental Health Survey in a Medical College in China During the COVID-19 Outbreak.
[This corrects the article DOI: 10.3389/fpsyt.2020.00459.].


Spatial variations in diffusive methane fluxes and the role of eutrophication in a subtropical shallow lake.
Shallow lakes account for most of the diffusive CH4 emissions from global lakes, and they also suffer from eutrophication worldwide. Determining the effect of eutrophication on diffusive CH4 fluxes is fundamental to understanding CH4 emissions in shallow lakes. This study aimed to investigate the spatial variations in diffusive CH4 fluxes and explore the role of eutrophication in Lake Chaohu, a large and shallow eutrophic lake in the lower reaches of the Yangtze River. A one-year field observation was carried out to examine CH4 concentrations in the sediment and water and the diffusive fluxes of CH4 across the sediment-water interface (Fs-w) and water-air interface (Fw-a). Both Fs-w (0.306-1.56 mmol m-2 d-1) and Fw-a (0.097-0.529 mmol m-2 d-1) were upward and showed significant spatial heterogeneity and were significantly positively correlated. Parameters related to eutrophication had significant positive relationships with Fw-a, and the total phosphorus distribution in the water explained the greatest proportion of the spatial variation in Fw-a. Distance to shore and water depth were inversely correlated with Fw-a and modified the effects of eutrophication. Overall, the results provide direct evidence of the key role of eutrophication in shaping the spatial distribution of diffusive CH4 fluxes and a scientific basis for predicting changes in CH4 emissions with future eutrophication changes in shallow lakes in subtropical zones.


Effect of neoadjuvant chemotherapy on locally advanced upper tract urothelial carcinoma: A systematic review and meta-analysis.
The role of neoadjuvant chemotherapy (NAC) for the management of upper tract urothelial carcinoma (UTUC) remains controversial. The aim of present study was to evaluate the contemporary role of NAC for patients with locally advanced UTUC through systematic review and meta-analysis of the literature. Systematic literature searches were conducted in PubMed/Medline and Embase for all studies that examined the role of chemotherapy for UTUC. We performed this study according to the Preferred Reported Items for Systematic Reviews and Meta-analysis guidelines. Endpoints were overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). A total of four trials on 318 patients were included in this study. Each of the included studies was retrospective. Compared to controls, NAC improved OS, CSS, and PFS by 57% (95% confidence interval [CI], 0.25-0.73; p = 0.002), 59% (95% CI, 0.27-0.57; p < 0.00001), and 45% (95% CI, 0.50-0.60; p < 0.00001), respectively. The absolute increases in OS, CSS, and PFS were 11%, 18%, and 13%, respectively, and these increases are equivalent to numbers-needed-to-treat of 9, 5.5, and 7.6, respectively. Pooled odds ratio for the effect of NAC on downstaging was 0.21 (95% CI, 0.09-0.60; p = 0.004), which indicates that NAC group had a 4.76-fold higher probability of having pathologic N stage 0 than control group. NAC treatment before radical nephroureterectomy might provide better survival outcomes in patients with locally advanced UTUC. Prospective randomized studies are needed to confirm the benefits of NAC in locally advanced UTUC patients.


Synergistic effect ofSacoglottis gabonensis bark extract.
Aflatoxin B1 metabolism was studied using microsomal and cytosolic fractions isolated from weanling male Fischer F344 rats given in drinking water for 7 days an aqueous extract ofSacoglottis gabonensis bark, 0.1% ethanol solution, or a solution containing both extract and ethanolad libitum. Microsomal production of aflatoxin B1-dihydrodiol, aflatoxin Q1, aflatoxin M1, aflatoxin Pi and proteinaflatoxin adduct formation, and cytosolic aflatoxin B1-glutathione conjugation were assayed. Pretreatment with the extract alone or together with ethanol caused significant increases in aflatoxin M1 production as compared to controls given only water, but aflatoxin Q1 production was enhanced only by pretreatment with both extract and ethanol. All the three treatments caused significant reductions in liver glutathione content. The highest aflatoxin B1 metabolising activity as determined by aflatoxin M1 and aflatoxin Q1 production was observed in rats pretreated with both ethanol and the extract, suggesting synergism. The findings suggest that at relatively mild doses,S. gabonensis extract alone or in concert with ethanol may influence response to aflatoxin.


Crayfish tissue metabolomes effectively distinguish impacts of wastewater and agriculture in aquatic ecosystems.
Environmental metabolomics has been proposed as a tool for biomonitoring because organisms regulate production or consumption of metabolites in response to environmental conditions. We evaluated the efficacy of the metabolome of three tissues (hepatopancreas, gill, and tail muscle) from the northern crayfish (Faxonius virilis) to detect and differentiate between impacts of human activities (i.e., reference, municipal wastewater, and agriculture). We conducted a reciprocal transfer study exposing crayfish for 1 or 2 weeks in three streams with different amounts and types of human activities in southern Manitoba, Canada. Tissue samples were analyzed using nuclear magnetic resonance spectroscopy to generate a metabolic profile. Findings indicated the gill tissue metabolome best detected and differentiated between human activities. In particular, the gill metabolome was able to rapidly integrate abrupt changes in environmental conditions associated with municipal wastewater activity. In contrast, the tail metabolome best differentiated between crayfish collected at the reference site from those collected at the two impacted sites. Metabolites extracted from hepatopancreas tissue showed limited and inconsistent detection of among site differences. Based on our findings, we conclude that the metabolome of the northern crayfish can be an effective biomonitoring tool, but monitoring purpose will dictate tissue selection. Indeed, we recommend the gill metabolome be used for short-term assays aimed at detecting acute effects, whereas the tail be applied for survey monitoring aimed at detecting deviations in ecological condition at test sites from reference site conditions.


New perspectives in the drug treatment of Kawasaki disease.
Kawasaki disease (KD) has become the leading cause of acquired heart disease in developed countries. Conventional therapy for KD includes intravenous gammaglobulin (2 g/kg as a single dose over 12 hours) and aspirin (acetylsalicylic acid; high dose until the fourteenth day of illness then low dose). Therapy administered within the first 10 days of the onset of the illness has been shown to reduce arterial wall inflammation and thereby prevent the development of coronary artery aneurysm formation. The majority of patients with KD will respond to conventional therapy. However, the management of nonresponders and patients with complications (such as acute thrombosis and chronic coronary artery changes) remains controversial. In this review article, we address some of these controversies and also describe newer treatment modalities that have been used in the management of patients with KD, both in the acute and convalescent stages of the disease.


Mechanism of integration of the broad-host-range plasmid RP4 into the chromosome of Myxococcus xanthus.
The site-specific recombination mechanism through which the plasmid RP4 has been previously shown to integrate into the chromosome of Myxococcus xanthus has been investigated further. Once integrated in one of the numerous chromosomal sites from two different strains, through a precise site on the plasmid, the latter can be excised either precisely or after a definite 14.5-kb deletion. In some cases, the integration is followed by different DNA rearrangements that yield a higher rate of excision and integration. A model for the site-specific integration and excision of the plasmid is proposed.


Stakeholder Development of an Online Program to Track Arthritis-Related Patient-Reported Outcomes Longitudinally: Live Yes! INSIGHTS.
Patient-reported outcome measures (PROMs) are increasingly used in clinical settings but may not provide benefits to patients outside of health encounters. The Arthritis Foundation's Live Yes! Network provides an opportunity for PROM use by individuals and the network that assists individuals with managing their arthritis between encounters. Our objective was to develop a patient-reported outcomes platform for the network, Live Yes! INSIGHTS, using mixed methods and extensive stakeholder input. A mixed methods longitudinal transformation design was used, starting with semistructured interviews to specify the main priorities of the program, literature review to identify potential PROMs, modified Delphi and nominal group technique to select final PROMs, and focus groups to guide program implementation, messaging, and use of results. We gathered input from 93 participants, including from individuals living with arthritis (74% of participants), caregivers, providers, researchers, and measurement experts. Our mixed methods study resulted in the selection of Patient-Reported Outcomes Measurement Information System (PROMIS)-29, PROMIS Emotional Support Short Form v2.0, and the Health Care Empowerment Questionnaire, to be deployed through a Qualtrics platform. Triangulation of data resulted in identification of potential risks and benefits, including confidentiality, ability to personally track and share data, and an opportunity to contribute to research. An accessible measurement system backed by psychometrically strong PROMs, created with robust stakeholder engagement, and linked to a national patient network sets the stage for individuals with arthritis to better monitor and improve health outcomes both outside and inside health care settings and for the network to customize programming to meet needs.


Cryopreservation of adult unrelated donor products in hematopoietic cell transplantation: the OneMatch experience and systematic review of the literature.
The frequency of cryopreserving blood stem or progenitor products from unrelated donors is not known and the underlying reasons are poorly documented. Greater insight is needed to develop policies on cryopreservation that balance donor safety with patient needs. Cryopreservation requests between January 1, 2014, and May 31, 2016, at the OneMatch Stem Cell and Marrow Network at Canadian Blood Services were reviewed and a systematic review of the literature was performed. Thirty products of 719 (4.2%) unrelated donor collections facilitated by OneMatch were cryopreserved. Patient-related reasons were most common and included the need to delay transplant for continued antimicrobial treatment (six patients), patient too deconditioned to proceed with scheduled transplant (five patients), and/or need for more treatment for relapsed disease (three patients). Donor-related issues leading to cryopreservation requests were less common (five cases), mainly due to lack of donor availability after attempting to reschedule. Cryopreservation of a product that was never infused occurred infrequently (two cases, 7%). In our systematic review of the literature, 993 cases were identified in 32 published reports. Both patient-related and donor-related reasons were cited but not specifically reported, precluding quantitative insight regarding the relative frequency of causes. The impact of cryopreservation on hematopoietic engraftment appears negligible when compared to controls in a subset of studies; however, reporting of outcomes was inconsistent. Future studies with standard outcome measures are needed to clarify the impact of cryopreservation on engraftment and other transplant outcomes. International guidelines that consider the ethical framework surrounding requests for donor product cryopreservation are needed.


Extent of surrounding edema does not correlate with acute complications after radiosurgery for melanoma brain metastases.
To assess whether extent of surrounding edema correlates with acute adverse clinical outcomes within 3 months after stereotactic radiosurgery (SRS) for melanoma brain metastases (BM). Patients with melanoma BM treated with SRS were included in a single center retrospective analysis. A contrast-enhanced magnetic resonance image (MRI) brain was acquired on the day of treatment and used to calculate the volume of the largest lesion (the index BM) and total volume of all BM. Their corresponding volume of surrounding edema was defined based on the fluid attenuated inversion recovery (FLAIR) sequence. After SRS, MRI was performed every 3 months for at least 2 years if the patient remained well enough to do so. Adverse neurologic events after SRS were defined using common terminology criteria for adverse events (CTCAE) version 5.0. Multivariate regression analyses assessed for associations between BM size and edema at baseline with increasing edema and neurologic adverse events within 3 months after SRS. Mean volume of the index BM reduced from 2.2 to 0.5 cm3 at 3 months after SRS (p = 0.03). Mean volume of edema surrounding the index BM was 6.4 cm3 at baseline, 10.2 cm3 at 3 months and 5.5 cm3 at 6 months. There were 7/43 (16%) patients that experienced an adverse neurological event within 3 months (attributable to any cause) and 4/43 (9%) were associated with an increase in BM edema. On univariate and multivariate analyses, there were no correlations between any baseline factors and volume of edema at 3 months. However, SRS dose delivered and systemic therapy use within 4 weeks of SRS both correlated with a reduction in edema surrounding the index BM. A transient increase in mean volume of edema was apparent at 3 months after SRS. However, this resolved by 6 months and did not correlate with adverse events or dexamethasone requirement. Thus, the clinical significance is uncertain.


Bladder calculi enveloped by extensive cystitis glandularis: case report.
We report a case of 2 large calculi encased within a 15 gm. tumor of cystitis cystica and cystitis glandularis. The patient presented with acute right epididymitis. An excretory urogram showed 2 bladder calculi. Cystoscopy revealed a mass around the stones resembling adenocarcinoma of the bladder base. Transurethral resection of the tumor and cystolitholapaxy were performed. The final diagnosis was bladder calculi within a mass of cystitis cystica and cystitis glandularis. A review of the literature failed to reveal a similar case.


Invest conflicts of adult predators.
Parental care is incorporated into a prey-predator model in which immature predators are taken care of by their parents. It is assumed that adult predators confront the problem to stay home to protect offspring or to go out to forage. The global dynamics of the mathematical model is analyzed by means of analytical methods and numerical simulations. Conditions for the extinction of predator populations are established and the manners in which predators become extinct are revealed. Bifurcation analysis shows that the model admits changes from the extinction of predators to stable coexistence at a positive equilibrium point, and then to stage-structure induced oscillations. It is shown that optimal invest of adult predators can be achieved.


Possible role of prolactin in the induction of hypogonadism by chronic alcohol treatment in the male rat.
Treatment of adult male rats with ethanol for a period of six weeks resulted in a numerical but not significant increase in plasma prolactin levels together with a reduction in plasma luteinizing hormone (LH) levels. Although basal plasma testosterone (T) levels were not affected in ethanol-treated animals, testicular weight was reduced and seminiferous tubules exhibited signs of atrophy. The responses of LH to luteinizing hormone releasing hormone (LHRH) and T to hCG were significantly impaired in ethanol-treated rats (p less than 0.01). Treatment with bromocriptine (1 mg/kg body weight/day), resulted in the expected decrease in plasma levels of prolactin and an increase in basal plasma LH levels to the levels found in control groups. Basal plasma T levels were not affected by bromocriptine. However, both plasma LH responses to LHRH and plasma T responses to hCG were significantly improved by bromocriptine treatment in alcoholic rats and became similar to the responses measured in control animals. The results suggest that bromocriptine-induced suppression of prolactin release has a beneficial effect on ethanol-induced hypogonadism.


Multi-approach assessment for the evaluation of spatio-temporal estrogenicity in fish from effluent-dominated surface waters under low instream flow.
Current practices employed by most wastewater treatment plants (WWTP) are unable to completely remove endocrine disrupting compounds (EDCs) from reclaimed waters, and consistently discharge these substances to receiving systems. Effluent-dominated and dependent surface waters, especially during low instream flows, can increase exposure and risks to aquatic organisms due to adverse biological effects associated with EDCs. Given the ecological implications that may arise from exposure to such compounds, the present a multi-approach study examined spatio-temporal estrogenic potential of wastewater effluent to fish in East Canyon Creek (ECC), Utah, USA, a unique urban river with instream flows seasonally influenced by snowmelt. Juvenile rainbow trout (Oncorhynchus mykiss) were caged at different upstream and downstream sites from an effluent discharge during the summer and fall seasons. In the summer, where approximately 50% of the streamflow was dominated by effluent, fish from the upstream and a downstream site, located 13 miles away from the effluent discharge, presented significantly elevated concentrations of plasma vitellogenin (VTG). Similarly, significantly high 17β-estradiol to 11-ketotestosterone ratios were measured in the summer across all sites and time points, compared to the fall. In the laboratory, juvenile fish and primary hepatocytes were exposed to concentrated effluent and surface water samples. Quantification of VTG, although in significantly lower levels, resembled response patterns observed in fish from the field study. Furthermore, analytical quantification of common EDCs in wastewater revealed the presence of estriol and estrone, though these did not appear to be related to the observed biological responses, as these were more significant in sites were no EDCs were detected. These combined observations suggest potential estrogenicity for fish in ECC under continuous exposures and highlight the advantages of following weight-of-evidence (WoE) approaches for environmental monitoring, as targeted analytically-based assessments may or may not support the identification of causative contaminants for adverse biological effects.


Gene diversity in Indian populations.
Gene frequency data of ten protein and enzyme loci in seven populations of India were collected from the literature. The gene differentiation among seven populations relative to total population was only 0.6%, indicating that the genic variation between populations was small compared to that within them. Using 29 common protein loci, the genetic distances between Indians and three major races of man, Caucasoids, Mongoloids, and Negroids were also determined. Indians are closer to Mongoloids than to Caucasoids or Negroids as indicated by the phylogenetic tree.


Single-emitter quantum key distribution over 175 km of fibre with optimised finite key rates.
Quantum key distribution with solid-state single-photon emitters is gaining traction due to their rapidly improving performance and compatibility with future quantum networks. Here we emulate a quantum key distribution scheme with quantum-dot-generated single photons frequency-converted to 1550 nm, achieving count rates of 1.6 MHz with [Formula: see text] and asymptotic positive key rates over 175 km of telecom fibre. We show that the commonly used finite-key analysis for non-decoy state QKD drastically overestimates secure key acquisition times due to overly loose bounds on statistical fluctuations. Using the tighter multiplicative Chernoff bound to constrain the estimated finite key parameters, we reduce the required number of received signals by a factor 108. The resulting finite key rate approaches the asymptotic limit at all achievable distances in acquisition times of one hour, and at 100 km we generate finite keys at 13 kbps for one minute of acquisition. This result is an important step towards long-distance single-emitter quantum networking.


Synthesis of β,β-diaryl propiophenones via palladium-catalyzed domino arylboronation, elimination and enone hydroarylation of enaminones.
The syntheses of β,β-diaryl aryl propiophenones have been realized via palladium-catalyzed domino reactions of dimethyl amino functionalized enaminones and aryl boronic acids. This is the first example of transition metal-catalyzed enaminone C-N bond conversion for the generation of a new C-C(aryl) structure.


Strong male-driven evolution of DNA sequences in humans and apes.
Studies of human genetic diseases have suggested a higher mutation rate in males than in females and the male-to-female ratio (alpha) of mutation rate has been estimated from DNA sequence and microsatellite data to be about 4-6 in higher primates. Two recent studies, however, claim that alpha is only about 2 in humans. This is even smaller than the estimates (alpha > 4) for carnivores and birds; humans should have a higher alpha than carnivores and birds because of a longer generation time and a larger sex difference in the number of germ cell cycles. To resolve this issue, we sequenced a noncoding fragment on Y of about 10.4 kilobases (kb) and a homologous region on chromosome 3 in humans, greater apes, and lesser apes. Here we show that our estimate of alpha from the internal branches of the phylogeny is 5.25 (95% confidence interval (CI) 2.44 to infinity), similar to the previous estimates, but significantly higher than the two recent ones. In contrast, for the external (short, species-specific) branches, alpha is only 2.23 (95% CI: 1.47-3.84). We suggest that closely related species are not suitable for estimating alpha, because of ancient polymorphism and other factors. Moreover, we provide an explanation for the small estimate of alpha in a previous study. Our study reinstates a high alpha in hominoids and supports the view that DNA replication errors are the primary source of germline mutation.


Host, technical, and environmental factors affecting QuantiFERON-TB Gold In-Tube performance in children below 5 years of age.
Interferon-gamma release assays performance can be impaired by host-related, technical and environmental factors, but data in young children are limited. We performed a cross-sectional study of children < 5 years-of-age at risk of tuberculosis (TB), using QuantiFERON-TB Gold In-Tube (QFT-GIT) assays. The impact of the following was evaluated: (i) host-related [age; hematological parameters; erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); and tobacco smoke exposure (TSE) based on serum cotinine concentrations], (ii) technical (pre-analytical delay) and (iii) environmental factors (annual season; monthly temperatures). Of 204 children, 35 (17.2%) were diagnosed with latent TB infection or TB disease. QFT-GIT results were indeterminate in 14 (6.9%) patients. In multivariate analysis, younger age and higher ESR were associated with lower positive control responses (beta: 0.247, p = 0.002 and - 0.204, p = 0.007, respectively), and increasing age was associated with lower rates of indeterminate QFT-GIT results [OR (95% CI) 0.948 (0.903-0.996) per month, p = 0.035]. In children with positive QFT-GIT results, average monthly temperatures correlated with antigen responses (r = 0.453, p = 0.020); also, antigen responses were lower in winter than in other seasons (p = 0.027). Serum cotinine concentrations determined in a subgroup of patients (n = 41) indicated TSE in 36 (88%), positive control responses being lower in children with TSE (p = 0.034). In children < 5 years-of-age, young age, elevated ESR, temperature, annual season and TSE can affect the performance of QFT-GIT assays.


Biomechanics of clear aligners: hidden truths & first principles.
Over the past two decades clear aligner-based treatment has received remarkableattention from the orthodontic profession and more so from general practitioners.Different companies have emerged using vigorous advertisement to promote theirproducts mainly to patients and clinicians through social media. A variety of concepts,methods, and adjuncts have been introduced to enhance the efficacy andeffectiveness of clear aligners. However, the accuracy of tooth movement (vspredicted) with aligners still hovers around 50%. Fixed appliances fare much better onaccuracy and predictability of treatment. Why is there a discrepancy betweenexpected and actual outcomes? This paper utilizes 'first principles' and the existingevidence to unravel some of the key drawbacks of aligner-based therapy. Severalshortcomings in the biomechanical properties of aligner material (thermoplastics) thataffect clinical performance are discussed. Based on the first principles of alignerbiomechanics, this paper provides clinical insights for improving predictability and effectiveness of aligner therapy.


Chemical pollutants in the respiratory zone of welders: Determination of concentrations and hazard analysis.
Welding pollutants have potentially dangerous effects on the health of welders. Analysis of exposure risks is an appropriate method for industrial hygiene occupational exposure. The present study aimed to determine the concentrations of exposure and risk evaluation of welders to fumes and gases in three common types of welding including Shielded Metal Arc Welding (SMAW), Gas Metal Arc Welding (GMAW) and Gas Tungsten Arc Welding (GTAW). This cross-sectional study was carried out at a steel company. Samples were taken from manganese, chromium and nickel fumes with NIOSH 7300 method and for NO, NO2, CO and O3 gases using direct reading instruments. SQRCA method was used to assess the level of exposure risk. Our study showed that the highest and lowest concentrations of exposure to gases were observed in MIG and GTAW welding, respectively. Also, the highest and lowest concentrations of exposure to metals were observed in SMAW and GTAW processes, respectively. Mean exposure to M, Cr and Ni metals was 2.302, 3.195, and 1.241 mg/m3, respectively. Also, mean exposure to CO, NO, NO2 and O3 was 43.05, 27.88, 4.30, and 0.41 ppm, respectively. Results of risk analysis showed that O3, NO2 and Cr had high and very high risk levels in all welding processes. MIG and SMAW welders have a high occupational exposure to metal and toxic gases in welding. Preventive measures such as assessment of workplace air, installation of the ventilation systems, and providing appropriate respiratory protection devices for welders should be taken.


Celecoxib significantly reduces opioid use after shoulder arthroplasty.
The opioid crisis has illuminated the risks of opioid use for pain management, with renewed interest in reducing opioid consumption after common orthopedic procedures. Anti-inflammatory medication is an important component of multimodal pain management for patients undergoing orthopedic surgery. The purpose of this study was to evaluate the effect of celecoxib on pain control and opioid use after shoulder surgery. Patients scheduled for either total shoulder replacement (group 1) or rotator cuff repair (group 2) were candidates for the study. The exclusion criteria included allergy to celecoxib, coagulopathy, use of anticoagulants, baseline use of long-acting opioids, and a history of medical conditions such as myocardial infarction or stroke. Consenting patients were randomized by type of procedure using block randomization to receive either placebo or celecoxib 1 hour prior to the procedure and for 3 weeks postoperatively. The primary outcome measure assessed was opioid utilization as measured by morphine-equivalent dose (MED). Secondary outcome measures included pain scores at 3 and 6 weeks postoperatively. Data were analyzed using multiple linear regression. Of 1081 patients scheduled for either total shoulder replacement or rotator cuff repair from February 2014 to February 2018, 78 were enrolled for arthroplasty (group 1, with 39 receiving celecoxib and 39 receiving placebo) and 79 were enrolled for rotator cuff repair (group 2, with 40 receiving celecoxib and 39 receiving placebo). Compared with the placebo arm, patients prescribed celecoxib took fewer MEDs by -168 (95% confidence interval [CI], -272 to -64; P < .01) at 3 weeks in the total population and by -197.7 (95% CI, -358 to -38; P = .02) in the arthroplasty group. Similarly, at 6 weeks, total MEDs used was -199 (95% CI, -356 to -42; P < .01) in the total population and -270 (95% CI, -524 to -16; P = .04) in the arthroplasty group. No statistically significant differences in opioid consumption were found between study arms in the cuff repair group, at either 3 or 6 weeks. Of note, preoperative opioid use was statistically associated with higher levels of opioid use in the total population and group 1 at 3 and 6 weeks (P < .01 for all) but not in group 2 (P > .05 for both). Use of morphine equivalents was statistically significantly less at 3 and 6 weeks in patients who took celecoxib in the total population and in the arthroplasty group. Patients prescribed celecoxib for 3 weeks after shoulder surgery took less opioid medication for pain at 3 and 6 weeks. Multimodal pain control using celecoxib is an effective way to reduce postoperative opioid use in shoulder arthroplasty patients. Preoperative opioid use is associated with higher levels of opioid use after shoulder arthroplasty.


Induction of ROS generation and NF-κB activation in MARC-145 cells by a novel porcine reproductive and respiratory syndrome virus in Southwest of China isolate.
Porcine reproductive and respiratory syndrome virus (PRRSV) is the cause of an economically important swine disease that has devastated the swine industry since the late 1980s. The aim of the present study was to investigate the interaction between reactive oxygen species (ROS) and NF-κB by PRRSV infection. We isolated the local strain of PRRSV from southwest China, designated YN-2011, then sequenced and analyzed the genome. YN-2011 was then used to evaluate the interaction of ROS and NF-κB. In PRRSV infected MARC-145 cells, there was a time-dependent increase in ROS and Maleic Dialdehyde (MDA). Accordingly, NF-κB activation was also increased as PRRSV infection progressed. Degradation of IκB mRNA was detected late in PRRSV infection, and overexpression of the dominant negative form of IκBα significantly suppressed NF-κB induced by PRRSV. The results indicate that the generation of ROS is involved in PRRSV replication and this progression is associated with the alteration in NF-κB activity induced by ROS. These results should extend our better understanding the interaction between PRRSV and host MARC-145 cells.


Intraspecific competition in Tridacna crocea, a burrowing bivalve.
Intraspecific competition for space and light occurred when Tridacna crocea burrowed into coralline substratum of boulders on leeward coral reefs in the central Great Barrier Reef near Townsville, Australia. Intensity of competition was linearly related to clam density. Above about 200 clams/m2, all clams physically contacted one another and all shells sustained damage. Mortality in isolated populations due to intraspecific competition was estimated at 40%. Principles of intraspecific competition in plants were tested for applicability to T. crocea populations. Juvenile mortality due to competitive stress was density dependent. Aggregated distributions of one year old clams changed to random or regular distribution of adults. Normal size-frequency distribution for juveniles became skewed for older groups. A bimodal size-frequency distribution of the population was related to selective mortality in 1-3 year old clams. Adult mortality due to crowding was less severe but significant. Growth rates were inhibited by competition. Deformations in morphology resulted from crowding. Intraspecific competition for space and light by adults inhibited recruitment of young. Animal adaptations to reduce mortality under crowded conditions were also important. Larvae aggregated on settling and oriented with posterior ends pointed away from nearest neighbors. Positional alignment within the substratum was selectively advantageous. Burrowing posteriorly was preferential, but anterior and sideways burrowing as well as twisting within the burrow were also observed. Movement within substratum served to reduce local damage to the shell. Proteinaceous deposits secreted through perforations in the shell reduced subsequent damage. T. crocea populations exhibited many animal adaptations that reduced mortality during the first years of life, but as cohorts matured, plant-like patterns of competitive interaction became more significant.


Quantification of intracellular and extracellular prostanoids stimulated by A23187 by liquid chromatography/electrospray ionization tandem mass spectrometry.
Prostanoids are bioactive substances that contribute to various biological and pathological processes. To evaluate both extracellular and intracellular levels of prostanoids at the same time, we developed methods for quantification of extracellular and intracellular levels of prostanoids, including prostaglandin E(2) (PGE(2)), PGD(2), PGF(2α), 6-keto PGF(1α), and TXB(2), in cultured cells using liquid chromatography/tandem mass spectrometry (LC/MS/MS), and we validated the LC/MS/MS methods. A solid-phase extraction cartridge was used for extraction of prostanoids. The prostanoids were separated by a C(18) column with an isocratic flow of acetonitrile/water/acetic acid (40:60:0.1, v/v/v). Calibration curves of extracellular measurement for the prostanoids were linear in the range from 0.1 to 100 ng/mL (r(2)>0.999), and those of intracellular measurement were linear in the range from 0.05 to 50 ng (r(2)>0.999). Validation assessment showed that both methods of extracellular and intracellular measurements were highly reliable with good accuracy and precision. We also applied the methods to human airway epithelial Calu-3 cells and human lung adenocarcinoma epithelial A549 cells.