Retinal Oxygen Saturation in Patients with Primary Open-angle Glaucoma Using a Non-flash Hypespectral Camera.
Purpose/Aim: To investigate retinal vessel blood oxygen saturation in patients with primary open-angle glaucoma (POAG) and healthy controls. A novel non-flash hyperspectral retinal camera was used to image 17 healthy individuals (mean age 69.3 ± 6.1 years) and 22 patients with stable POAG (mean age 69.2 ± 5.8 years) at 548, 569, 586, 600, 605, and 610 nm wavelengths. POAG patients were grouped as mild-moderate (n = 13) and moderate-severe (n = 9) based on Humphrey 24-2 visual field results (mean deviation [MD] < -6 and MD ≥ -6; respectively). Optical density values were extracted using Image-J software for blood oxygen saturation (SO2) determination. Arteriolar and venular SO2 were measured within 1.5 optic nerve head diameters from the disc margin along the vessels in the inferior temporal quadrant of the tested eye per subject. Analysis of variance (ANOVA), student t-test, and Pearson's correlation were used for statistical analysis of the data (p < 0.05). Venular, arteriolar, and arteriovenous (AV) differences in SO2 measurements were not significantly different between controls and the combined POAG groups (p > 0.06 for all). However, mean venular SO2 was significantly higher in the POAG with MD ≥ -6 dB when compared to controls and patients with mild glaucoma (p = 0.005). The AV differences were significantly lower in patients with more severe field defect (p = 0.006) compared to the remaining groups. No differences were found in the mean arteriolar SO2 between the groups (p = 0.155). Significant correlations were found only between higher visual field MD values and higher venular SO2 (p = 0.048) but not the remaining SO2 measurements. Patients with POAG and moderate-severe visual field defect had higher venular SO2 compared to those with mild-moderate defect and controls. This would indicate reduced oxygen consumption in more advanced glaucoma likely as a result of ganglion cell degeneration.


Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model.
Cancer-associated fibroblasts (CAFs) are the key components of the densely proliferated stroma in pancreatic ductal adenocarcinoma (PDAC) and contribute to tumor progression and drug resistance. CAFs comprise heterogeneous subpopulations playing unique and vital roles. However, the commonly used mouse models have not been able to fully reproduce the histological and functional characteristics of clinical human CAF. Here, we generated a human cell-derived stroma-rich CDX (Sr-CDX) model, to reproduce the clinical tumor microenvironment. By co-transplanting human adipose-derived mesenchymal stem cells (AD-MSCs) and a human PDAC cell line (Capan-1) into mice, the Sr-CDX model recapitulated the characteristics of clinical pancreatic cancer, such as accelerated tumor growth, abundant stromal proliferation, chemoresistance, and dense stroma formed from the heterogeneous CAFs. Global RNA sequencing, single-cell based RNA sequencing, and histological analysis of CAFs in the Sr-CDX model revealed that the CAFs of the Sr-CDX mice were derived from the transplanted AD-MSCs and composed of heterogeneous subpopulations of CAF, including known and unknown subtypes. These lines of evidences suggest that our new tumor-bearing mouse model has the potential to address an open question in CAF research, that is the mechanism of CAF differentiation.


[Selected parameters of bone metabolism in hemodialyzed and peritoneally dialyzed patients].
Renal osteodystrophy is a metabolic bone disease occurring in patients with end-stage renal failure. The aim of the study was to compare serum concentrations of some bone markers in hemodialysed (HD) patients and in patients undergoing continuous ambulatory peritoneal dialysis (CADO). We studied two groups of patients with end-stage renal failure: 52 hemodialysed individuals aged 24-74 years and 19 peritoneally dialysed patients aged 20-70 years. Serum calcium and phosphate concentration, cholesterol, triglycerides, total protein, albumin, alkaline phosphatase, urea before and after HD, urea in CADO patients were determined by standard laboratory methods. Serum PTH, osteocalcin, 1,25(OH)2D3 and insulin-like growth factor (IGF-1) concentrations were measured by commercially available radioimmunoassay. Serum tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1) concentrations were measured by ELISA. There were no differences between serum concentrations of the studied bone markers in hemodialysed patients and CAPD patients. All dialysed patients presented high concentrations of serum PTH, osteocalcin, alkaline phosphatase activity, lower serum IGF-1 concentration and normal serum calcitriol concentration. High serum PTH and osteocalcin concentrations may indicate intensification of bone synthesis, what is typical for osteitis fibrosa.


A Novel Error Correction Approach to Improve Standard Point Positioning of Integrated BDS/GPS.
To improve the standard point positioning (SPP) accuracy of integrated BDS (BeiDou Navigation Satellite System)/GPS (Global Positioning System) at the receiver end, a novel approach based on Long Short-Term Memory (LSTM) error correction recurrent neural network is proposed and implemented to reduce the error caused by multiple sources. On the basis of the weighted least square (WLS) method and Kalman filter, the proposed LSTM-based algorithms, named WLS-LSTM and Kalman-LSTM error correction methods, are used to predict the positioning error of the next epoch, and the prediction result is used to correct the next epoch error. Based on the measured data, the results of the weighted least square method, the Kalman filter method and the LSTM error correction method were compared and analyzed. The dynamic test was also conducted, and the experimental results in dynamic scenarios were analyzed. From the experimental results, the three-dimensional point positioning error of Kalman-LSTM error correction method is 1.038 m, while the error of weighted least square method, Kalman filter and WLS-LSTM error correction method are 3.498, 3.406 and 1.782 m, respectively. The positioning error is 3.7399 m and the corrected positioning error is 0.7493 m in a dynamic scene. The results show that the LSTM-based error correction method can improve the standard point positioning accuracy of integrated BDS/GPS significantly.


Evaluation of Strength Properties of Sand Modified with Organic Polymers.
Due to weak physical properties of sand, chemical reinforcement methods are widely used to improve sand properties to meet the engineering requirements. However, most of the traditional additives cause environmental problems. Therefore, non-traditional additives such as liquid polymers, enzymes, ions, and lignin derivatives have been studied extensively. In this study, organic polymer is used as a soil stabilizer to reinforce the sand. To evaluate the effectiveness of the organic polymer as soil stabilizer, a series of unconfined compression strength (UCS) tests, direct shear tests, and tensile tests were carried out on reinforced sand with different polymer concentrations and dry densities of sand. The reinforcement mechanism was analysed with scanning electron microscopy (SEM) images. The results indicated that the polymer concentration and dry density of sand had significant effects on the strength characteristics of reinforced sand specimens. The unconfined compressive strength, cohesion, and tensile strength of specimens with the same dry density increased with the increasing polymer concentration. The polymer membranes-formed by the mixture of polymer and water-enwrap the sand particles and interlink them to form a stable structure. The efficiency of this stabilization changed with dry sand density.


Using a trauma-informed framework to care for incarcerated women.
Available health and social services in women's correctional facilities often do not consider the interrelationship of gender, trauma, and mental illness. As a result, preexisting health issues are often exacerbated, leaving women to reenter their communities with more complex health needs. We propose that a trauma-informed framework can be used to guide clinical interactions with female inmates. A case study is presented as an example of proposed best clinical practice. Future trauma-related practice implications are provided.


Lafutidine changes levels of somatostatin, calcitonin gene-related peptide, and secretin in human plasma.
We examined the effects of the histamine H2-receptor antagonist, lafutidine, on the levels of gastrointestinal peptides (somatostatin, calcitonin gene-related peptide (CGRP), gastrin, secretin, and motilin) in plasma from healthy subjects. After a single oral administration of lafutidine (10 mg), the plasma lafutidine level (186 +/- 13.4ng/ml) was highest in the 60-min sample after administration and then the plasma level fell. Lafutidine caused significant increase in plasma somatostatin levels at 20 to 120 min and in CGRP levels at 40 to 120 min, compared with a placebo group. The physiological release of plasma secretin was reduced by administration of lafutidine, but the medicine did not alter the level of gastrin or motilin. These results suggest that the pharmacological effects of lafutidine on regulation of gastrointestinal functions closely relate to changes of somatostatin-, CGRP- and secretin-immunoreactive substance levels in human plasma.


Density detection in dependent left lung region using transesophageal echocardiography.
Densities in dependent lung regions worsen oxygenation in patients with acute respiratory distress syndrome. Identification of these densities requires examination using computed tomography (CT). In this study, the authors evaluated the use of transesophageal echocardiography (TEE) to estimate densities in the dependent lung. Forty consecutive patients with acute lung injury or acute respiratory distress syndrome who underwent CT and TEE examination were included in this study. Densities in the lower left lung area were detected through the descending aorta by TEE. Density areas observed by TEE were compared with those obtained by CT. The effect of positive end-expiratory pressure (PEEP) application on density area was also evaluated. Density areas in the dependent lung region measured by TEE were 12.0+/-6.1 cm2 (mean +/- SD) at mid esophageal position. Density areas evaluated using TEE in the left lung correlated significantly with those estimated with CT in the left and right lungs (P < 0.01 in both lungs). In addition, the authors observed a significant correlation between PaO2/FIO2 and density areas estimated using TEE (P < 0.05). During positive end-expiratory pressure application, the area of density estimated with TEE decreased and PaO2 improved. The authors clearly demonstrated that it is possible to estimate the density area of the dependent left lung regions in patients with acute lung injury or acute respiratory distress syndrome using TEE. It is also possible to observe the changes of density areas during application of positive end-expiratory pressure.


Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix.
We describe the pharmacological profile in rats and monkeys of degarelix (FE200486), a member of a new class of long-acting gonadotropin-releasing hormone (GnRH) antagonists. At single subcutaneous injections of 0.3 to 10 microg/kg in rats, degarelix produced a dose-dependent suppression of the pituitary-gonadal axis as revealed by the decrease in plasma luteinizing hormone (LH) and testosterone levels. Duration of LH suppression increased with the dose: in the rat, significant suppression of LH lasted 1, 2, and 7 days after a single subcutaneous injection of degarelix at 12.5, 50, or 200 microg/kg, respectively. Degarelix fully suppressed plasma LH and testosterone levels in the castrated and intact rats as well as in the ovariectomized rhesus monkey for more than 40 days after a single 2-mg/kg subcutaneous injection. In comparative experiments, degarelix showed a longer duration of action than the recently developed GnRH antagonists abarelix, ganirelix, cetrorelix, and azaline B. The in vivo mechanism of action of degarelix was consistent with competitive antagonism, and the prolonged action of degarelix was paralleled by continued presence of radioimmunoassayable degarelix in the general circulation. In contrast to cetrorelix and similarly to ganirelix and abarelix, degarelix had only weak histamine-releasing properties in vitro. These results demonstrate that the unique and favorable pharmacological properties of degarelix make it an ideal candidate for the management of sex steroid-dependent pathologies requiring long-term inhibition of the gonadotropic axis.


Berberine decreased N-acetylation of 2-aminofluorene through inhibition of N-acetyltransferase gene expression in human leukemia HL-60 cells.
Previous studies have demonstrated that berberine decreases N-acetyltransferase (NAT) activity in human leukemia HL-60 cells, however, NAT gene expression has not been investigated. In this study, berberine was selected for testing the inhibition of N-acetylation of 2-aminofluorene (AF) and NAT gene expression in human HL-60 cells. The N-acetylation of AF was determined and quantitated by high performance liquid chromatography (HPLC). The data showed that a 24-hour berberine treatment decreased the amount of N-acetylation of AF in HL-60 cells. The NAT enzymes were stained and examined by Western blotting and flow cytometry. The results indicated that berberine decreased the levels of NAT protein in HL-60 cells. The expression of NAT gene (mRNAT NAT1) was determined by polymerase chain reaction (PCR), and it was found that berberine had inhibited the expression of mRNA NAT1 in human HL-60 cells.


Comprehensive comparisons of the current human, mouse, and rat RefSeq, Ensembl, EST, and FANTOM3 datasets: identification of new human genes with specific tissue expression profile.
Our understanding of functional genetic elements in the genomes is continuously growing and new entries are entered in various databases on a regular basis. We have here merged the genetic elements in RefSeq, Ensembl, FANTOM3, HINV, and NCBI:s ESTdb using the genome assemblies in order to achieve a comprehensive picture of the current status of the identity and gene number in human, mouse, and rat. The number of human protein coding genes has not increased (25,043) while the increased sequencing of mouse transcripts has provided the considerably higher number of protein coding genes (31,578) in mouse. The results indicate large discrepancies between the datasets, as considerable numbers of unique transcripts can be found in each dataset. Despite the high number of ncRNA (38,129 in mouse) there are also almost 20,000 EST clusters in both mouse and humans with more than one EST that do not overlap any transcript suggesting that several new genetic elements are still to be found. We also demonstrated presence of new genes by identifying new human ones that have specific tissue profiles, using RT-PCR on rat tissues.


The impact of bioactive lipids on cardiovascular development.
Lysophospholipids comprise a group of bioactive molecules with multiple biological functions. The cardinal members of this signalling molecule group are sphingosylphosphorylcholine (SPC), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) which are, at least in part, homologous to each other. Bioactive lipids usually act via G-protein coupled receptors (GPCRs), but can also function as direct intracellular messengers. Recently, it became evident that bioactive lipids play a role during cellular differentiation development. SPC induces mesodermal differentiation of mouse ES cells and differentiation of promyelocytic leukemia cells, by a mechanism being critically dependent on MEK-ERK signalling. LPA stimulates the clonal expansion of neurospheres from neural stem/progenitor cells and induces c-fos via activation of mitogen- and stress-activated protein kinase 1 (MSK1) in ES cells. S1P acts on hematopoietic progenitor cells as a chemotactic factor and has also been found to be critical for cardiac and skeletal muscle regeneration. Furthermore, S1P promotes cardiogenesis and similarly activates Erk signalling in mouse ES cells. Interestingly, S1P may also act to maintain human stem cell pluripotency. Both LPA and S1P positively regulate the proliferative capacity of murine ES cells. In this paper we will focus on the differential and developmental impact of lysophospholipids on cardiovascular development.


An Optimized Dihydrodibenzothiazepine Lead Compound (SBI-0797750) as a Potent and Selective Inhibitor of Plasmodium falciparum and P. vivax Glucose 6-Phosphate Dehydrogenase 6-Phosphogluconolactonase.
In Plasmodium, the first two and rate-limiting enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase (G6PD) and the 6-phosphogluconolactonase, are bifunctionally fused to a unique enzyme named GluPho, differing structurally and mechanistically from the respective human orthologs. Consistent with the enzyme's essentiality for malaria parasite proliferation and propagation, human G6PD deficiency has immense impact on protection against severe malaria, making PfGluPho an attractive antimalarial drug target. Herein we report on the optimized lead compound N-(((2R,4S)-1-cyclobutyl-4-hydroxypyrrolidin-2-yl)methyl)-6-fluoro-4-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide (SBI-0797750), a potent and fully selective PfGluPho inhibitor with robust nanomolar activity against recombinant PfGluPho, PvG6PD, and P. falciparum blood-stage parasites. Mode-of-action studies have confirmed that SBI-0797750 disturbs the cytosolic glutathione-dependent redox potential, as well as the cytosolic and mitochondrial H2O2 homeostasis of P. falciparum blood stages, at low nanomolar concentrations. Moreover, SBI-0797750 does not harm red blood cell (RBC) integrity and phagocytosis and thus does not promote anemia. SBI-0797750 is therefore a very promising antimalarial lead compound.


Faculty Perceptions of Formative Feedback from Medical Students.
Phenomenon: Feedback given by medical students to their teachers during a clerkship has the potential to improve learning by communicating students' needs and providing faculty with information on how to adjust their teaching. Aligning student learning needs and faculty teaching approach could result in increased student understanding and skill development before a clerkship's end. However, little is known about faculty perceptions of formative feedback from medical students and how faculty might respond to such feedback. Approach: In this qualitative study, semistructured interviews of 24 third-year clerkship faculty were conducted to explore faculty opinions about receiving formative feedback from students. Transcripts of these interviews were reviewed, and content analysis was performed. Findings: Faculty endorsed the idea of obtaining formative feedback from medical students. However, probing revealed factors that would significantly influence their receptivity and response to the feedback provided, including (a) who would be giving the feedback, (b) what content was included in the feedback, (c) how the feedback was framed, and (d) why the feedback was given. Although participants endorsed the concept of receiving formative feedback from medical students, their accounts of how they might respond to it presented a mixed picture of receptivity, acceptance, and response. Insights: These findings have practical implications. If formative feedback from medical students to faculty is to be encouraged, institutions need to find ways of creating a feedback culture in which more dialogic models become "the norm" and work with faculty to increase their receptivity to and acceptance of student feedback. This is essential for students to feel safe and be safe from retribution when providing insights into how faculty can better meet their learning needs.


Linking Multi-Modal MRI to Clinical Measures of Visual Field Loss After Stroke.
Loss of vision across large parts of the visual field is a common and devastating complication of cerebral strokes. In the clinic, this loss is quantified by measuring the sensitivity threshold across the field of vision using static perimetry. These methods rely on the ability of the patient to report the presence of lights in particular locations. While perimetry provides important information about the intactness of the visual field, the approach has some shortcomings. For example, it cannot distinguish where in the visual pathway the key processing deficit is located. In contrast, brain imaging can provide important information about anatomy, connectivity, and function of the visual pathway following stroke. In particular, functional magnetic resonance imaging (fMRI) and analysis of population receptive fields (pRF) can reveal mismatches between clinical perimetry and maps of cortical areas that still respond to visual stimuli after stroke. Here, we demonstrate how information from different brain imaging modalities-visual field maps derived from fMRI, lesion definitions from anatomical scans, and white matter tracts from diffusion weighted MRI data-provides a more complete picture of vision loss. For any given location in the visual field, the combination of anatomical and functional information can help identify whether vision loss is due to absence of gray matter tissue or likely due to white matter disconnection from other cortical areas. We present a combined imaging acquisition and visual stimulus protocol, together with a description of the analysis methodology, and apply it to datasets from four stroke survivors with homonymous field loss (two with hemianopia, two with quadrantanopia). For researchers trying to understand recovery of vision after stroke and clinicians seeking to stratify patients into different treatment pathways, this approach combines multiple, convergent sources of data to characterize the extent of the stroke damage. We show that such an approach gives a more comprehensive measure of residual visual capacity-in two particular respects: which locations in the visual field should be targeted and what kind of visual attributes are most suited for rehabilitation.


Evaluation of myopathy risk for HMG-CoA reductase inhibitors by urethane infusion method.
Purpose of the present study was to evaluate the myopathy risk using a urethane infusion method following oral administration of five kinds of commercial HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (HCRIs), (pravastatin (PV), simvastatin (SV), cerivastatin (CeV), atorvastatin (AV), and fluvastatin (FV)) alone or with coadministration of bezafibrate (BF). The solubility of HCRIs in various solvents was determined as a criterion of the physicochemical property. The plasma creatine phosphokinase (CPK) level as a marker of myopathy in normal rats was screened under urethane infusion after oral administration of HCRI alone or with BF coadministration. Also, renal tissue specimens were prepared and the myoglobin remaining in the tissue was visualized by the labeled avidin-biotin technique. The plasma CPK level in normal rats under urethane infusion following oral administration of five kinds of HCRI increased as the dose of HCRI increased, and coadministration of BF further increased the CPK level for each drug. The risk of myopathy evaluated from the CPK level was ranked as follows: CeV>FV>AV>SV>PV. Myoglobin deposition was observed in the cast of proximal tubules, cytoplasm of distal tubules and collecting ducts of rat kidney extracted from rats treated with HCRIs under urethane infusion. Histopathological findings showed that the extent of myoglobin deposition increased on coadministration of BF with each drug. The correlation was found for myopathy risk evaluated by CPK level using the urethane infusion method and drug lipophilicity, ie., the water/n-octanol partition coefficient except for the case of SV. Histopathological findings for the kidney following HCRI treatment also reflected the CPK level in rats under urethane infusion.


Myocardin related transcription factors are required for coordinated cell cycle progression.
Myocardin related transcription factors A and B (MRTFs) activate serum response factor-driven transcription in response to Rho signaling and changes in actin dynamics. Myocardin and MRTFs have been implicated in anti-proliferative effects on a range of cell types. The precise mechanisms, however, remained elusive. We employed double knockdown of MRTF-A and MRTF-B in NIH 3T3 fibroblasts to evaluate its effects on cell cycle progression and proliferation. We show that transient depletion of MRTFs conveys a modest anti-proliferative effect and impinges on normal cell cycle progression, resulting in significantly shortened G 1 phase and slightly extended S and G 2 phase under normal growth conditions. Under serum-starved conditions we observed aberrant entry into the S and G 2 phases without subsequent cell division. This was accompanied by downregulation of cyclin-CDK inhibitors p27Kip1, p18Ink4c and 19Ink4d as well as upregulation of p21Waf1 and cyclin D1. Extended knockdown led to increased formation of micronuclei, while cells stably depleted of MRTFs tend to become aneuploid and polyploid. Thus, MRTFs are required for accurate cell cycle progression and maintenance of genomic stability in fibroblast cells.


Development and optimization of a diode laser for photodynamic therapy.
This study demonstrated the development of a laser system for cancer treatment with photodynamic therapy (PDT) based on a 635 nm laser diode. In order to optimize efficacy in PDT, the ideal laser system should deliver a homogeneous nondivergent light energy with a variable spot size and specific wavelength at a stable output power. We developed a digital laser beam controller using the constant current method to protect the laser diode resonator from the current spikes and other fluctuations, and electrical faults. To improve the PDT effects, the laser system should deliver stable laser energy in continuous wave (CW), burst mode and super burst mode, with variable irradiation times depending on the tumor type and condition. The experimental results showed the diode laser system described herein was eminently suitable for PDT. The laser beam was homogeneous without diverging and the output power increased stably and in a linear manner from 10 mW to 1500 mW according to the increasing input current. Variation between the set and delivered output was less than 7%. The diode laser system developed by the author for use in PDT was compact, user-friendly, and delivered a stable and easily adjustable output power at a specific wavelength and user-set emission modes.


Diosgenin From Dioscorea Nipponica Rhizoma Against Graves' Disease-On Network Pharmacology and Experimental Evaluation.
Dioscorea nipponica rhizoma (DNR) is commonly used for the cure of hyperthyroidism resulting from Graves' disease (GD) or thyroid nodules. However, its therapeutic mechanism remains unclear. This study aimed to utilize network pharmacology integrated molecular docking and experimental verification to reveal the potential pharmacological mechanism of DNR against GD. First, the active componds of DNR were collected from the HERB database and a literature search was conducted. Then, according to multisource database, the predicted genes of DNR and GD were collected to generate networks. The analysis of protein-protein interaction and GO enrichment and KEGG pathway were employed to discover main mechanisms associated with therapeutic targets. Moreover, molecular docking simulation was applied in order to verify the interactions between the drug and target. Finally, our experiments validated the ameliorated effects of diosgenin, the main component of DNR, in terms of phosphorylation deactivation in IGF-1R, which in turn inhibited the phosphorylation and activation of PI3K-AKT and Rap1-MEK signaling pathways, promoting cell apoptosis and GD remission. Our present study provided a foundation for further investigation of the in-depth mechanisms of diosgenin in GD and will provide new scientific evidence for clinical application.


MAGE-E1, a new member of the melanoma-associated antigen gene family and its expression in human glioma.
To unearth glioma-specific genes in human glioblastoma, the serial analysis of gene expression technique was applied to a primary glioblastoma, using cultured human astrocytes as a normal control. Among the top 147 most-expressed tags in glioblastoma, we found a tag, TTTTGGGTAT, that originated from an unidentified gene and which was not detected in human astrocyte cultures. Real-time quantitative reverse transcription-PCR showed that MAGE-E1 expression was 2.6-15-fold enriched in glioblastoma relative to human astrocytes. Expressed sequence tags containing this tag were homologous to the melanoma-associated antigen gene (MAGE) family, and this new cDNA, named MAGE-E1, was cloned by the 5'-rapid amplification of cDNA ends technique. Three alternatively spliced variants (MAGE-E1a-c) were found, and deduced amino acid sequence showed that MAGE-E1a and -E1b shared the MAGE-conserved region, whereas -E1c did not. This suggests that although MAGE-E1c is expressed from one of the MAGE family, it has distinct functions from other members. Tissue distribution analysis showed that MAGE-E1 was distinct from other MAGEs. MAGE-E1 expression was detected only in brain and ovary among normal tissues. Interestingly, MAGE-E1a and/or -E1b were specifically expressed in glioma cells among cancer cells. These results indicate that MAGE-E1 is a novel and glioma-specific member of MAGE family.


Analytical method for camera calibration from a single image with four coplanar control lines.
An analytical method to calibrate a camera's extrinsic parameters and effective focal lengths is presented. We used a single image with four coplanar control lines. Unique solutions of the camera's extrinsic parameters and the two effective focal lengths are derived linearly and analytically. If the effective focal lengths are known, unique solutions of the extrinsic parameters can be derived more easily. Our method can easily be implemented and has better precision than the analogous method by use of control points. The results of simulated experiments are presented.


Enteral nutritional therapy: application of quality indicators.
Monitor the adequacy of enteral nutritional therapy at the intensive care unit aiming to improve the quality of nutritional assistance. Prospective and observational study developed at the adult intensive care unit from 2005 to 2008. Patients over 18 years of age with exclusive enteral nutritional therapy for over 72h participated in the sample. The average values and the percentile adequacy of energy and proteins calculated, prescribed and administered in each year were analyzed. The factors responsible for the non-conformity of the administration planned were classified into intensive care unit extrinsic or intrinsic causes. The quality indicators proposed by the ILSI Brazil were applied, and expressed into percentile goals. In the statistic analyses, confidence interval and the t Student e Mann-Whitney (p<0.05) tests were used, according to the Epi Info program. One hundred and sixteen patients were followed up. There were statically difference in values of energy and protein administered in 2005 and in 2006, when compared to those in 2008. The adequacy calculated/prescribed remained close to 100% in all the surveys and the adequacy administered/prescribed increased from 74% in 2005, to 89% in 2008. An increase in interruptions of enteral nutritional therapy for external factors and the decrease in interruptions for intensive care unit internal factors were verified. The quality indicators equally reflect the evolution of the patient care. In the four yearly surveys, a progressive enhancement of nutritional support was verified. Quality indicators allow nutritional care evolution monitoring, the comparison to other services data, and are a new perspective for enteral nutritional therapy assessment.


Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein-associated O-GlcNAc.
Increased levels of protein O-linked N-acetylglucosamine (O-GlcNAc) have been shown to increase cell survival following stress. Therefore, the goal of this study was to determine whether in isolated neonatal rat ventricular myocytes (NRVMs) an increase in protein O-GlcNAcylation resulted in improved survival and viability following ischemia-reperfusion (I/R). NRVMs were exposed to 4 h of ischemia and 16 h of reperfusion, and cell viability, necrosis, apoptosis, and O-GlcNAc levels were assessed. Treatment of cells with glucosamine, hyperglycemia, or O-(2-acetamido-2-deoxy-D-glucopyranosylidene)-amino-N-phenylcarbamate(PUGNAc), an inhibitor of O-GlcNAcase, significantly increased O-GlcNAc levels and improved cell viability, as well as reducing both necrosis and apoptosis compared with untreated cells following I/R. Alloxan, an inhibitor of O-GlcNAc transferase, markedly reduced O-GlcNAc levels and exacerbated I/R injury. The improved survival with hyperglycemia was attenuated by azaserine, which inhibits glucose metabolism via the hexosamine biosynthesis pathway. Reperfusion in the absence of glucose reduced O-GlcNAc levels on reperfusion compared with normal glucose conditions and decreased cell viability. O-GlcNAc levels significantly correlated with cell viability during reperfusion. The effects of glucosamine and PUGNAc on cellular viability were associated with reduced calcineurin activation as measured by translocation of nuclear factor of activated T cells, suggesting that increased O-GlcNAc levels may attenuate I/R induced increase in cytosolic Ca(2+). These data support the concept that activation of metabolic pathways leading to an increase in O-GlcNAc levels is an endogenous stress-activated response and that augmentation of this response improves cell survival. Thus strategies designed to activate these pathways may represent novel interventions for inducing cardioprotection.


Cosmetic rehabilitation.
Appearance is one of the most powerful factors influencing social interactions with others. What patients with disfigurements experience from society on a daily basis is a very real stigma. Cosmetic rehabilitation is a system of cosmetic techniques devised for patients to use to assist themselves to cope constructively with the psychological and physical trauma of their disfigurements.


Case report: restorative options in regional odontodysplasia.
A case of regional odontodysplasia in a 13 year old female is reported. The restorative options in this case are considered along with the rational for providing a dentine bonded all-porcelain bridge. This approach restored both function and aesthetics with minimum destruction to the hypoplastic tooth tissue of the abutment.


BMP and mTOR signaling in heterotopic ossification: Does their crosstalk provide therapeutic opportunities?
Heterotopic ossification (HO) refers to the pathological formation of ectopic bone in soft tissues, it occurs following severe trauma or in patients with a rare genetic disorder known as fibrodysplasia ossificans progressiva. The pathological process of HO formation is a two-step mechanism: inflammation and destruction of connective tissues, followed by bone formation. The latter is further subdivided into three stages: fibroproliferation/angiogenesis, chondrogenesis, and osteogenesis. Currently, therapeutic options for HO are limited. New potential therapeutics will most likely arise from a more detailed understanding of the signaling pathways implicated in each stage of ectopic bone formation and molecular targets that may be effective at both the early and late stages of HO. Bone morphogenetic protein (BMP) signaling is believed to play a key role in the overall HO process. Recently, the mammalian target of rapamycin (mTOR) signaling pathway has received attention as a critical pathway for chondrogenesis, osteogenesis, and HO. Inhibition of mTOR signaling has been shown to block trauma-induced and genetic HO. Intriguingly, recent studies have revealed crosstalk between mTOR and BMP signaling. Moreover, mTOR has emerged as a factor involved in the early hypoxic and inflammatory stages of HO. We will summarize the current knowledge of the roles of mTOR and BMP signaling in HO, with a particular focus on the crosstalk between mTOR and BMP signaling. We also discuss the activation of AMP activated protein kinase (AMPK) by the most widely used drug for type 2 diabetes, metformin, which exerts a dual negative regulatory effect on mTOR and BMP signaling, suggesting that metformin is a promising drug treatment for HO. The discovery of an mTOR-BMP signaling network may be a potential molecular mechanism of HO and may represent a novel therapeutic target for the pharmacological control of HO.


Intrapersonal and populational heterogeneity of the chemokine RANTES.
Current immunoassays for the chemokine RANTES (regulated on activation, normal T-cell expressed and secreted) are not tailored for specific isoforms that exist endogenously, despite the fact that variants with modified activity are known to exist. This is surprising in view of this protein's ubiquitous increased presence in many diseases and that the 2 established isoforms are truncated by enzymes also correlated to disease. An in-depth population survey of RANTES heterogeneity in the context of multiple diseases via a mass spectrometric immunoassay (MSIA) may resolve this issue. We developed an MSIA for RANTES and endogenous variants apparent in human plasma. Samples from multiple cohorts of individuals (type 2 diabetes, congestive heart failure, history of myocardial infarction, and cancer patients) were run in parallel with samples from healthy individuals (239 people total). We used 230 microL of plasma per individual and tabulated relative percent abundance (RPA) values for identified isoforms. We detected at least 19 variants, including the dipeptidyl peptidase IV (DPP-IV)-truncated variant. The majority of variants were unreported in the literature. Identifiable modifications included N- and/or C-terminal truncations, oxidation, glycation, and glycosylation. We observed statistically significant differences in RPA values for multiple variants between disease cohorts and recognized prospective disease-specific protein profiles for RANTES. Because of widespread interest in the clinical value of RANTES, the protein diversity established here may aid in the design of future, fully quantitative assays. Equally important, an inclusive qualitative understanding of RANTES heterogeneity may present new insights into the relationship between RANTES and disease.


Revision Hip Arthroscopy for Graft Retear and Residual Cam Lesion in a Previously Labral Reconstructed Hip.
Persistent pain after hip arthroscopy may be due to residual impingement, hip dysplasia, osteoarthritis progression, labral injury, or insufficient capsular closure. A patient's history, physical examination findings, and imaging studies should be used to determine whether revision hip arthroscopy is indicated. If surgical management is chosen, careful preoperative planning is essential. During revision hip arthroscopy, the presence and location of adhesions should be considered during interportal capsulotomy and T-capsulotomy creation and while applying traction sutures. The presence of a residual cam or pincer lesion and the adequacy of the labrum or labral graft should be assessed and properly addressed. If capsular redundancy is recognized, capsular plication may be performed. The purpose of this Technical Note is to describe an approach to revision hip arthroscopy for labral repair and residual cam lesion resection.


Whole-Brain Radiotherapy Combined With Anlotinib for Multiple Brain Metastases From Non-small Cell Lung Cancer Without Targetable Driver Mutation: A Single-Arm, Phase II Study.
Existing evidence demonstrates that radiotherapy and antiangiogenic drugs have synergistic antitumour effects and may be a promising treatment option for patients with solid tumour. Thus, we performed a phase II trial to evaluate the efficacy and safety of whole-brain radiotherapy (WBRT) combined with anlotinib for multiple brain metastases (BMs) from non-small cell lung cancer (NSCLC) without targetable driver mutations. Patients with multiple BMs (⩾3) from NSCLC without targetable driver mutations who failed to respond to at least first-line chemotherapy were enrolled. Eligible patients received WBRT (30 Gy/10 f, 5 f/week) and anlotinib (12 mg/day, day 1-14 of 21 days per cycle, 2 cycles) until disease progression or treatment intolerance. The primary endpoint was intracranial objective response rate (iORR) and secondary endpoints included intracranial progression-free survival (iPFS), disease control rate (DCR), overall survival (OS), and safety. Between April 2019 and March 2021, 21 patients were enrolled in the trial, of which 12 were aged ⩾60 years (57.1%), 13 were men (61.9%), 7 had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 (81.0%), 18 had adenocarcinoma (85.7%), and 11 had ⩾6 BMs (52.4%). Of the 21 evaluable patients, the iORR was 66.7% (1 complete response + 13 partial response [PR]), and 28.6% (7PR) had extracerebral lesions. The DCRs for intracerebral and extracerebral lesions were 90.5% and 81.0%, respectively. The iPFS and OS were 10.3 months (95% confidence interval [CI]: 0-24.8 months) and 13.4 months (95% CI: 0-27.9 months), respectively. The most frequently observed toxicities were loss of appetite (61.9%), hypertension (52.4%), fatigue (47.6%), diarrhoea (28.6%), vomiting (19.0%), dizziness (42.9%), and headache (33.3%). None of the patients developed grade 4 or higher grade adverse reactions. Anlotinib combined with WBRT is effective and well tolerated in patients with multiple BMs (⩾3) from NSCLC without targetable driver mutations. Therefore, further validation studies are required.Clinical trial registration number: ChiCTR 1900027769.


Cytosolic Ca2+ measurements by ratiometric fluorescence microscopy in melanoma cells.
Cytosolic Ca2+ levels are maintained at low nanomolar concentrations, and disruption of Ca2+ homeostasis is associated with cell/tissue damage. Thus, methods have been developed to accurately assess cellular Ca2+ levels, each with intrinsic advantages and disadvantages. Here, we present in detail a ratiometric fluorometric method for cytosolic Ca2+ measurement in cultured melanoma cells using Fura 2-AM cell loading and fluorescence microscopy imaging. For complete details on the use and execution of this protocol, please refer to Esteves et al. (2020).


Serum fibroblast growth factor-23 (FGF-23) levels are independently associated with left ventricular mass and myocardial performance index in maintenance haemodialysis patients.
Fibroblast growth factor-23 (FGF-23) is a phosphorus-regulating substance. Circulating FGF-23 levels increase markedly in dialysis patients and are independently associated with increased risk of mortality. Given the fact that cardiovascular disease is the leading cause of death in dialysis patients, the aim of this study was to test if elevated FGF-23 levels might be associated with left ventricular mass index (LVMI) and left ventricular index of myocardial performance (MPI) in maintenance haemodialysis patients. In this cross-sectional study, plasma FGF-23 concentrations were measured using a C-terminal human enzyme-linked immunosorbent assay kit, and echocardiography was performed in 128 maintenance haemodialysis patients (65 women and 63 men, mean age: 55.5 ± 13 years, mean haemodialysis vintage: 52 ± 10 months, all patients are on haemodialysis thrice a week) and 40 control subjects (21 women and 19 men; mean age: 54 ± 11 years) with normal kidney function (eGFR > 90 mL/min/1.73 m(2)). Serum FGF-23 levels were elevated when compared with age- and gender-matched controls with preserved kidney function [(median 958 RU/mL; interquartile range 106-1894 RU/mL) vs (median 27 RU/mL; interquartile range 11-35), P < 0.0001]. Patients with a history of coronary artery disease and aortic valve calcifications had higher levels of log FGF-23 than those without (3.00 ± 0.22 vs 2.82 ± 0.26, P = 0.002; and 3.06 ± 0.19 vs 2.83 ± 0.26, P = 0.0001, respectively). Patients with MPI > 0.47 had higher serum FGF-23 levels than those with MPI < 0.47 [(median 1156 RU/mL; interquartile range 396-1894 RU/mL) vs (median 657 RU/mL; interquartile range 106-1102 RU/mL), P = 0.0001]. Significant correlations were recorded between log FGF-23 levels and LVMI (r = 0.281, P = 0,007) and MPI (r = 0.555, P = 0.0001). Multivariable-adjusted regression analyses revealed that increased log FGF-23 concentrations were independently associated with increased left ventricular mass index (30% increase per 1-SD increase in log FGF-23 concentration, P = 0.002) and increased MPI (28.5% increase per 1-SD increase in log FGF-23 concentration, P = 0.001). Plasma FGF-23 concentration is independently associated with LVMI and MPI in maintenance haemodialysis patients. Further prospective studies are needed to clarify whether increased serum FGF-23 level is a marker or a potential mechanism for left ventricular involvement in patients with end-stage renal disease.


Historic changes of occupational work load and mortality from peptic ulcer in Germany.
The occurrence of peptic ulcer disease appears to be associated with the amount of occupational work load. Worldwide the number of hospital admissions, surgical operations, and death rates from gastric and duodenal ulcer have declined during recent decades. This communication examines the probability of a correlation between the time trends of gastric and duodenal ulcer mortality in Germany and changes in the occupational work load between 1870 and 1984. Lifetime cumulative hours of work declined for all consecutive cohorts of the population born between 1840 and 1955. The fall occurred similarly in all age groups. However, lifetime cumulative energy expenditure originating from industrial blue collar work showed a peak for the cohorts born during the last quarter of the 19th century. A marked decline occurred in all cohorts born after 1905. A similar birth-cohort pattern was found for mortality from peptic ulcer disease, with those born at the turn of the century showing a higher risk of dying from peptic ulcer disease than any previous or subsequent generation. The coincidence of the birth-cohort patterns of both mortality from peptic ulcer and occupational energy expenditure suggests that birth-cohort pattern of peptic ulcer may be related to the trends of occupational work load that occurred during the industrial revolution. The amount of work hours appears to be a less sensitive measure for the occupational work load. The superimposition of two counteracting historic changes, namely the increased industrial work force and the decreased occupational work load due to legislative regulations, industrial automation, and mechanization may have shaped the rise and fall in the occurrence of peptic ulcer disease.


The use of surgical drains in orthopedics.
The use of postsurgical drains have a long history in thoracic and abdominal surgery. In orthopedics these devices have been used to decrease local edema, lessen the potential for hematoma or seroma formation, and to aid in the efflux of infection. However, the role of postoperative surgical drains in clean, elective cases has not been firmly established. In fact, most studies fail to show a statistical difference in outcome between drained and undrained patients. Despite the paucity of clinical evidence demonstrating any benefit supporting their use, drains continue to be placed after elective orthopedic procedures.


[Identification of clinically isolated fungi and their culture collection system in Japan].
Due to the serious financial condition of the health care insurance system in Japan, many clinical microbiology laboratories in hospitals have been forced to close or downsize, and therefore identification of pathogenic fungi isolated in these hospitals has become more and more difficult. This problem becomes even more serious when rare but clinically important fungi are the causative agents. For the smooth and accurate identification of the fungi, formation of a collaborative network among hospital laboratories, private clinical laboratory test centers and university research laboratories is now required. In contrast, the culture collection system of pathogenic fungi for deposit and distribution has been significantly improved in the past few years largely due to the support of the National BioResource Program. The most important part of this kind of system is its longevity, and further improvement is warranted to keep the system viable even after the end of the Program.


Structural Approaches to Control Interlayer Interactions in 2D Covalent Organic Frameworks.
The ability to design and synthesize monomers can affect fundamental aspects in 2D covalent organic frameworks, such as dimensionality, topology, and pore size. Besides this, the structure of the monomers can also affect interlayer interactions, which provide an additional means to influence crystallinity, layer arrangement, interlayer distances, and exfoliability. Herein, some of the effects that the structure of monomers can have on the interlayer interactions in 2D covalent organic frameworks and related materials are illustrated.


Comparison of algometry and palpation in the recognition of temporomandibular disorder pain complaints.
To determine the construct validity of algometry and to compare it with that of palpation, and to compare tenderness of masticatory muscle sites and the temporomandibular joint (TMJ) on palpation and on algometry. Two hundred fifty subjects, 148 with temporomandibular disorder (TMD) pain complaints, underwent a standardized blinded physical examination that included pain-intensity measures on palpation and pressure pain threshold measures on algometry of masseter muscle sites, temporalis muscle sites, and the TMJ. Logistic regression analysis indicated that the recognition of TMD pain complaints based on pressure algometry was comparable to that of palpation (R2 = 0.22 and R2 = 0.21, respectively). The masseter muscles were most tender to palpation and algometry, followed by the TMJs and the temporalis muscles. Construct validity of algometry in the recognition of TMD pain complaints is comparable to that of palpation, and differences in tenderness on palpation and on algometry are found between masticatory muscle sites and the TMJ.


Ethics in the marketing of medical services.
This paper deals with the ethics of marketing medical services by physicians, medical groups, hospitals and other mainstream medical caregivers in the United States. It does not deal with pharmaceutical marketing, since that raises a number of special issues, some of them legal and some having to do with the unique culture of pharmaceutical marketing, which really ought to be dealt with separately. Nor does it touch on the little-explored field of marketing alternative and complementary medicine. It begins with a general description of what is included in "the marketing process." It then briefly tours some of the difficulties faced by those who would market medical services ethically, and ends with some comments on the relevance of professionalism to ethical marketing.


Tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy: a novel and successful strategy to predict survival.
Histopathologic tumor regression grades (TRGs) after neoadjuvant chemotherapy predict survival in different cancers. In bladder cancer, corresponding studies have not been conducted. Fifty-six patients with advanced invasive urothelial bladder cancer received neoadjuvant chemotherapy before cystectomy and lymphadenectomy. TRGs were defined as follows: TRG1: complete tumor regression; TRG2: >50% tumor regression; TRG3: 50% or less tumor regression. Separate TRGs were assigned for primary tumors and corresponding lymph nodes. The prognostic impact of these 2 TRGs, the highest (dominant) TRG per patient, and competing tumor features reflecting tumor regression (ypT/ypN stage, maximum diameter of the residual tumor) were determined. Tumor characteristics in initial transurethral resection of the bladder specimens were tested for response prediction. The frequency of TRGs 1, 2, and 3 in the primary tumors were n=16, n=19, and n=21; corresponding data from the lymph nodes were n=31, n=9, and n=16. Interobserver agreement in determination of the TRG was strong (κ=0.8). Univariately, all evaluated parameters were significantly (P ≤ 0.001) related to overall survival; however, the segregation of the Kaplan-Meier curves was best for the dominant TRG. In multivariate analysis, only dominant TRG predicted overall survival independently (P=0.035). In transurethral resection specimens of the chemotherapy-naive bladder cancer, the only tumor feature with significant (P<0.03) predictive value for therapy response was a high proliferation rate. In conclusion, among all parameters reflecting tumor regression, the dominant TRG was the only independent risk factor. A favorable chemotherapy response is associated with a high proliferation rate in the initial chemotherapy-naive bladder cancer. This feature might help personalize neoadjuvant chemotherapy.


Utilization patterns of central nervous system drugs: A cross-sectional study among the critically ill patients.
Critically ill patients often receive central nervous system drugs due to primary disorder or complications secondary to multiorgan failure. The aim of the study was to evaluate the current utilization pattern of central nervous system drugs among patients in the medical intensive care unit. A prospective observational study carried out over a period of 1 year. The relevant data on drug prescription of each patient was collected from the inpatient case record. Drugs were classified into different groups based on WHO-ATC classification. The demographic data, clinical data, and utilization of different classes of drugs as well as individual drugs were analyzed. A total of 325 consecutive patients were included for the analysis; 211 (65%) patients were males; 146 patients (45%) were above 55 years of age. Encephalopathy [63(19.38%)] and stroke [62(19%)] were the common central nervous system diagnoses. In a total of 1237 drugs, 68% of the drugs were prescribed by trade name. Midazolam (N05CD08) 142 (43.69%), morphine (N02AA01) 201 (61.84%), and atracurium (M03AC04) 82 (25.23%) were the most commonly used sedative, analgesic, and neuromuscular blocker, respectively. Phenytoin (N03AB02) 151 (46.46%) had maximum representation among antiepileptic agents. Utilization of drugs from multiple central nervous system drug classes was noticed. Rational use of drugs can be encouraged by prescription by brand name.


Association between Gamma-Glutamyl Transferase and Coronary Atherosclerotic Plaque Vulnerability: An Optical Coherence Tomography Study.
Gamma-glutamyl transferase (GGT) has been detected in coronary plaques. However, the association between serum GGT levels and coronary atherosclerotic plaque vulnerability in patients with coronary artery disease (CAD) as detected by optical coherence tomography (OCT) has not been investigated. We performed a retrospective study of consecutively enrolled CAD patients undergoing preintervention OCT examination during coronary angiography. Plaque vulnerability was defined as the presence of ruptured plaques or thin-cap fibroatheroma (TCFA) upon OCT. The association between serum GGT levels and coronary plaque vulnerability was evaluated using multivariate logistic regression analysis. A total of 142 patients were included in our analysis. OCT examination detected ruptured plaques in 16 patients, nonruptured plaques with TCFA in 17 patients, and nonruptured plaques and non-TCFA in 109 patients. Univariate analyses showed that gender, diabetes, Apolipoprotein A1 (ApoA1) and high-density lipoprotein cholesterol (HDL-c), and diagnosis of acute coronary syndrome (ACS) were associated with plaque vulnerability (P all < 0.05). Patients grouped according to serum GGT tertiles did not differ statistically in baseline characteristics or OCT findings. Results of multivariate logistic analyses showed that diabetes and diagnosis of ACS were associated with plaque rupture and TCFA (P < 0.05). GGT serum levels were not associated with OCT detected coronary vulnerability in our cohort of CAD patient.


Distribution model of the surface roughness in magnetorheological jet polishing.
Magnetorheological jet polishing (MJP) plays an important role in polishing complex cavities and special optical elements with high precision. However, the roughness distribution function that describes the variation with polishing time of the roughness value of every area in the polishing area has not been studied deeply. In this paper, the influence of the roughness distribution on the removal function of MJP in optics (with a roughness of less than 10 nm) and its evolution model in the spatial and time domains are studied. With the increase of polishing time, the surface roughness of the central area linearly increases, forming surface defects, such as pits. The roughness of the polishing area exhibits a limited growth trend. Verification experiments are carried out on BK7 glass. The results of the roughness distribution on the removal function prove the correctness of the model. The model laid a foundation; therefore, it has important guidance and reference value for the application to the whole aperture polishing.


Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis.
The mammalian target of rapamycin (mTOR) regulates cell growth in response to various intracellular and extracellular signals. It assembles into two multiprotein complexes: the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-insensitive mTORC2. In this study, we inactivated mTORC1 in mice by deleting the gene encoding raptor in the progenitors of the developing CNS. Mice are born but never feed and die within a few hours. The brains deficient for raptor show a microcephaly starting at E17.5 that is the consequence of a reduced cell number and cell size. Changes in cell cycle length during late cortical development and increased cell death both contribute to the reduction in cell number. Neurospheres derived from raptor-deficient brains are smaller, and differentiation of neural progenitors into glia but not into neurons is inhibited. The differentiation defect is paralleled by decreased Stat3 signaling, which is a target of mTORC1 and has been implicated in gliogenesis. Together, our results show that postnatal survival, overall brain growth, and specific aspects of brain development critically depend on mTORC1 function.


Prostaglandin E2 induces expression of MAPK phosphatase 1 (MKP-1) in airway smooth muscle cells.
Prostaglandin E2 (PGE2) is a prostanoid with diverse actions in health and disease. In chronic respiratory diseases driven by inflammation, PGE2 has both positive and negative effects. An enhanced understanding of the receptor-mediated cellular signalling pathways induced by PGE2 may help us separate the beneficial properties from unwanted actions of this important prostaglandin. PGE2 is known to exert anti-inflammatory and bronchoprotective actions in human airways. To date however, whether PGE2 increases production of the anti-inflammatory protein MAPK phosphatase 1 (MKP-1) was unknown. We address this herein and use primary cultures of human airway smooth muscle (ASM) cells to show that PGE2 increases MKP-1 mRNA and protein upregulation in a concentration-dependent manner. We explore the signalling pathways responsible and show that PGE2-induces CREB phosphorylation, not p38 MAPK activation, in ASM cells. Moreover, we utilize selective antagonists of EP2 (PF-04418948) and EP4 receptors (GW 627368X) to begin to identify EP-mediated functional outcomes in ASM cells in vitro. Taken together with earlier studies, our data suggest that PGE2 increases production of the anti-inflammatory protein MKP-1 via cAMP/CREB-mediated cellular signalling in ASM cells and demonstrates that EP2 may, in part, be involved.


Precise marker excision system using an animal-derived piggyBac transposon in plants.
Accurate and effective positive marker excision is indispensable for the introduction of desired mutations into the plant genome via gene targeting (GT) using a positive/negative counter selection system. In mammals, the moth-derived piggyBac transposon system has been exploited successfully to eliminate a selectable marker from a GT locus without leaving a footprint. Here, we present evidence that the piggyBac transposon also functions in plant cells. To demonstrate the use of the piggyBac transposon for effective marker excision in plants, we designed a transposition assay system that allows the piggyBac transposition to be visualized as emerald luciferase (Eluc) luminescence in rice cells. The Eluc signal derived from piggyBac excision was observed in hyperactive piggyBac transposase-expressing rice calli. Polymerase chain reaction, Southern blot analyses and sequencing revealed the efficient and precise transposition of piggyBac in these calli. Furthermore, we have demonstrated the excision of a selection marker from a reporter locus in T0 plants without concomitant re-integration of the transposon and at a high frequency (44.0% of excision events), even in the absence of negative selection.


The combined use of cell sheet fragments of periodontal ligament stem cells and platelet-rich fibrin granules for avulsed tooth reimplantation.
The aim of this study was to construct a cell transplant method consisting of cell sheet fragments of periodontal ligament stem cells (PDLSCs) and platelet-rich fibrin (PRF) granules to enhance periodontal healing in avulsed tooth reimplantation. To test this concept in vitro, human PDLSCs were isolated and characterized by colony forming unit assay, cell surface marker characterizations, and their osteogenic/adipogenic differentiation potential. The biological effects of autologous PRF as a growth factor-enriched endogenous scaffold on human PDLSCs were then investigated and quantified for statistical analyses, including cell viability and proliferation, alkaline phosphatase (ALP) activity, and the gene expression of bone sialoprotein (BSP), osteocalcin (OCN), collagen I (Col-I), and cementum protein 23 (CP23). It was found that the PRF induced a significant and continuous stimulation of proliferation in human PDLSCs throughout the 7-day incubation period. Furthermore, the PRF suppressed the osteoblastic differentiation of PDLSCs by decreasing ALP activity and the gene expression of BSP and OCN while up-regulating the mRNA expression levels of Col-I and CP23 during the testing period. To assess the potential application of the PDLSCs/PRF construct in tooth reimplantation, 36 incisors were extracted from 6 dogs. The incisors then underwent 2 h of dry storage and were randomly divided into four groups receiving different strategies of reimplantation, where the avulsed teeth were reimplanted with the use of the autologous PDLSCs/PRF construct (cell sheet fragments in combination with PRF granules), with the use of autologous PDLSCs or PRF alone, or without adjuvant use of PRF or PDLSCs. Eight weeks post-reimplantation, the PDLSCs/PRF group achieved a more effective periodontal healing, characterized by the regeneration of PDL-like tissues and a reduction of ankylosis and inflammation, compared with the other testing groups. These overall results suggest that the PDLSCs/PRF construct may be a useful tool for alveolar surgery that has the potential to improve the clinical outcomes in future avulsed tooth reimplantations.


Direct comparison of [13N]ammonia and [15O]water estimates of perfusion with quantification of regional myocardial blood flow by microspheres.
Both [13N]ammonia and [15O]water have been used to quantify myocardial blood flow with positron emission tomography using appropriate tracer kinetic models. A direct comparison of the two tracers with radioactive microspheres has not been performed in the same experimental preparation. The two tracers have been tested for myocardial blood flow quantification in closed-chest dogs with circumflex coronary stenosis or permanent occlusion at rest and during adenosine-induced hyperemia. [13N]ammonia- and [15O]water-derived myocardial blood flow values have been compared with radiolabeled microspheres. Validation studies consisted of simultaneous measurements of blood flow with positron emission tomography and microspheres over a wide range of flow values. Blood pool and regional tissue activity curves were fitted with a three-compartment model for [13N]ammonia with and without arterial metabolite correction and with a single-tissue-compartment model for [15O]water. A correction for finite-resolution effect before the fit was also applied. In large regions of interest (5 cm3), a good correlation between the microsphere method and [13N]ammonia (with metabolite correction) was obtained (y = 3 + 0.78x, r = 0.94). The correlation with microspheres was slightly better with [15O]water (y = -3 + 0.89x, r = 0.97). Similar correlations were achieved in smaller regions of interest (1 cm3) as well as in akinetic segments and in central infarct regions. Positron emission tomography with appropriate tracer kinetic models using [13N]ammonia and [15O]water provides an accurate quantitative method for measuring regional myocardial blood flow over a wide range of flow values in normally contracting or akinetic canine myocardium in the absence and in the presence of infarction.


Surgical Strategy of Endoscopically assisted Periradicular Surgery Using Novel Head-mounted Display System.
A novel head-mounted display offers high quality of endoscopic imagery in front of the eyes, irrespective of the head position. We present an application of the head-mounted display system as a personal integrated multi-image monitoring system in endoscopically assisted periradicular surgery. Our head-mounted display system displayed multiple forms of information as integrated, sharp, high-definition endoscope, biological monitor, and X-ray image (such as panoramic and computed tomography images) synchronously using a picture in picture. In addition, this system can cope with both the endoscopic field of view and the direct field of view. While monitoring the patient's general condition with a head-mounted display, the surgery was performed with endoscopic animation. We could also switch to the direct surgical field and endoscopic field of view smoothly without moving the head and without surgical interference. The availability of a head-mounted display system during endoscopically assisted periradicular surgery enabled the provision of a comfortable and appropriate surgical environment for the surgeon.


Sensitization to Bjerkandera adusta enhances severity of cough symptom in patients with fungus-associated chronic cough (FACC).
The aim of the present study was to clarify the influence of sensitization to Bjerkandera adusta (B. adusta) on the clinical manifestation in patients with fungus-associated chronic cough (FACC). Seventeen patients with FACC who underwent bronchoprovocation tests using an antigenic solution of B. adusta were selected from among 21 FACC patients. We compared the allergological findings and clinical characteristics of the FACC patients who showed a positive reaction to the bronchoprovocation test (Allergic fungal cough sensitized to B. adusta; AFC-Bj) with the remaining FACC patients (non AFC-Bj) retrospectively. The eleven patients with AFC-Bj had a median age of 52 (range, 22-70) years, and 45.5% were female. The respective values for six patients with non AFC-Bj were 47.5 (range, 36-60) years of age, and 33.3% were female. The positive ratios for an immediate cutaneous reaction (45.5%; p<0.05) and the lymphocyte stimulation test (63.6%; p<0.05) to B. adusta were found to be significantly higher in the AFC-Bj group than in the non AFC-Bj group. The total time required for complete remission of cough symptoms was longer (median 20, range 12-43 weeks; p=0.0009), and the recurrence ratio of coughing was more frequent in the AFC-Bj group in comparison to those in non AFC-Bj group (2, range 1-3 times and 0.5, range 0-1 times, respectively). This study demonstrated that B. adusta, a basidiomycetous is an environmental fungus attracting attention because of its possible role in enhancing the cough severity of FACC patients via the sensitization to this fungus.


The expression of microRNA-197-3p regulates the proliferation of ovarian granulosa cells through CUL3 in polycystic ovarian syndrome.
MicroRNAs (miR) have been shown to exhibit marked dysregulation in polycystic ovarian syndrome (PCOS). Additionally, granulosa cell proliferation and apoptosis are important in PCOS pathogenesis. Considering this, the current study aimed at characterization of the regulatory function of miR-197-3p on the growth and proliferation of ovarian granulosa cells at the molecular level. The results showed that miR-197-3p is significantly repressed (P<0.05) in PCOS tissues and granulosa cells. Granulosa cell proliferation was significantly (P<0.05) inhibited by miR-197-3p overexpression via induction of apoptosis. In silico analysis predicted cullin 3 (CUL3) as the regulatory target of miR-197-3p, which was also confirmed by the dual luciferase reporter assay. CUL3 was overexpressed in KGN ovarian granulosa cells, and its silencing mimicked the tumor suppressive effects of miR-197-3p. Taken together, miR-197-3p exhibits a negative regulatory role in regulating granulosa ovarian cell proliferation via posttranscriptional repression of CUL3 in PCOS.


Evidence for a Na/H Antiporter in Membrane Vesicles Isolated from Roots of the Halophyte Atriplex nummularia.
The ATP-dependent establishment of a positive membrane potential (measured as S(14)CN(-)-accumulation) in membrane vesicles isolated from the roots of Atriplex nummularia Lindl. was not inhibited by NaMes and KMes at concentrations up to 140 millimolar. On the other hand, the formation of DeltapH (measured as (14)C-methylamine accumulation or quenching of quinacrine fluorescence), was depressed by NaMes concentrations as low as 30 millimolar. Supply of NaMes after the DeltapH had been established brought about partial dissipation within 30 seconds. Extent of dissipation of DeltapH increased with NaMes concentration over the range tested (up to 180 millimolar). The H(+)/Na(+) exchange indicated by these results was not due to the creation of a Na(+) diffusion potential. Formation of DeltapH in these vesicles was stable to NO(3) (-) up to 100 millimolar; further, the dissipating effect of Na(+) supply was apparent on a DeltapH formed in the presence of 30 millimolar NO(3) (-). Additional evidence that the origin of the membrane vesicles observed in this investigation was not the tonoplast and was probably the plasmalemma included the vanadate sensitivity of the establishment of the membrane potential.


Identification of a proline residue as a transduction element involved in voltage gating of gap junctions.
Gap junction channels are structurally distinct from other ion channels in that they comprise two hemichannels which interact head-to-head to form an aqueous channel between cells. Intercellular voltage differences together with increased intracellular concentrations of H+ and Ca2+ cause closure of these normally patent channels. The relative sensitivity to voltage varies with the subunit (connexin) composition of the channels. The third of four transmembrane-spanning regions (M3) in connexins has been proposed to form the channel lining, and a global 'tilting' of the hemichannel subunits has been correlated with channel closure. But specific components involved in transduction of channel gating events have not been identified in either gap junctions or other ion channel classes (however, see model in ref. 5). We have examined a strictly conserved proline centrally located in M2 of connexin proteins. Mutation of this proline (Pro 87) in connexin 26 causes a reversal in the voltage-gating response when the mutant hemichannel is paired with wild-type connexin 26 in the Xenopus oocyte system. This suggests that the unique properties associated with this residue are critical to the transduction of voltage gating in these channels.


The transcriptional effects of the vesicants lewisite and sulfur mustard on human epidermal keratinocytes.
Sulfur mustard (SM) injury is a complex process that begins with extensive alkylation of critical cellular components and culminates in cell death and skin vesication. The mechanism of toxicity is not well understood since SM broadly alkylates cellular nucleophiles. However, two events appear integral-the formation of DNA cross-links and the release of proteases into the extracellular matrix. To identify genes directly involved in vesication, the transcriptional profile of SM was compared to the vesicant lewisite (L). Similarly, to identify genes directly involved in DNA damage, the transcriptional profile of SM was compared to the genotoxic agent cisplatin (c-Pt). Microarrays containing 7,075 sequence-verified human cDNAs were screened with mRNA from human epidermal keratinocytes treated with 200 mu M agent for 2 h. A large number of differentially expressed genes were identified, with many similarities observed between agents. Many genes not previously associated with SM and L injury were also identified, including a large percentage of unknown function. A comparison of the differential expression profiles revealed that L had the broadest and most robustly altered expression. Apoptotic transcripts were clearly evident in L but not in SM, suggesting a late stage in L injury.


Chemoprevention of prostate cancer: concepts and strategies.
Chemoprevention is the administration of agents to prevent induction and inhibit or delay progression of cancers. For prostate, as for other cancer targets, successful chemopreventive strategies require well-characterized agents, suitable cohorts, and reliable intermediate biomarkers of cancer for evaluating chemopreventive efficacy. Agent requirements are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the observed chemopreventive activity. On this basis, promising chemopreventive drugs in prostate include retinoids, antiandrogens, antiestrogens, steroid aromatase inhibitors, 5alpha-reductase inhibitors, vitamins D and E, selenium, lycopene, and 2-difluoromethylornithine. Phase II trials are critical for evaluating chemopreventive efficacy. Cohorts in these trials should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen as endpoints. Many cohorts proposed for phase II trials are patients with previous cancers or premalignant lesions. For such patients, trials should be conducted within the context of standard treatment. Two cohorts currently used in phase II prostate cancer chemoprevention trials are patients with PIN and patients scheduled for prostate cancer surgery. Biomarkers should fit expected biological mechanisms, be assayed reliably and quantitatively, measured easily, and correlate to decreased cancer incidence. Protocols for adequately sampling tissue are essential. Changes in PIN provide prostate biomarkers with the ability to be quantified and a high correlation to cancer. PIN measurements include nuclear polymorphism, nucleolar size and number of nucleoli/nuclei, and DNA ploidy. Other potentially useful biomarkers are associated with cellular proliferation kinetics (e.g. PCNA and apoptosis), differentiation (e.g. blood group antigens, vimentin), genetic damage (e.g. LOH on chromosome 8), signal transduction (e.g. TGFalpha, TGFbeta, IGF-I, c-erbB-2 expression), angiogenesis, and biochemical changes (e.g. PSA levels).


Protective effect of dietary capsaicin on induced oxidation of low-density lipoprotein in rats.
An animal study was carried out to examine the beneficial influence of the known hypocholesterolemic spice principle-capsaicin on the susceptibility of low-density lipoprotein to oxidation in normal and hypercholesterolemic condition. In rats rendered hypercholeterolemic by maintaining them on a cholesterol-enriched diet for eight weeks, inclusion of capsaicin (0.015%) in the diet, produced significant hypocholesterolemic effect. Oxidation of low-density lipoprotein was induced either by copper ion in vitro after its isolation, or by ferrous ion in vivo in experimental rats under either normal or hypercholesterolemic situation and the beneficial effect of dietary capsaicin on the same was evaluated. LDL oxidation was measured by the thiobarbituric acid reactive substances (TBARS) formed and relative electrophoretic mobility of oxidized LDL. Dietary capsaicin was found to be protective to the LDL oxidation in vitro in the case of normal rats as indicated by reduction in TBARS by more than 40%. In the case of LDL isolated from hypercholesterolemic rats the extent of copper induced LDL oxidation was significantly lower than that of LDL isolated from normal rats. Dietary capsaicin did not make any difference in the extent of LDL oxidation in vitro in hypercholesterolemic rats. Ferrous ion induced in vivo oxidation of LDL was 71% lower in capsaicin fed normal rats. In high cholesterol feeding, Fe-induced in vivo oxidation of LDL was 73% lower, while the same was still marginally lower in capsaicin fed hypercholesterolemic rats. Hepatic lipid peroxidation was significantly decreased by dietary capsaicin in normal rats. While a significantly decreased level of lipid peroxidation was observed in hypercholesterolemic rats compared to normal rats, the same was not significantly altered by dietary capsaicin. Results suggest that dietary spice principle capsaicin is protective to LDL oxidation both in vivo and in vitro under normal situation, while in hypercholesterolemic situation where the extent of LDL oxidation is already lowered, capsaicin does not offer any further reduction.


The influence of ammonium and chloride on potassium and nitrate absorption by barley roots depends on time of exposure and cultivar.
Net uptakes of K(+) and NO(3) (-) were monitored simultaneously and continuously for two barley (Hordeum vulgare) cultivars, Prato and Olli. The cultivars had similar rates of net K(+) and NO(3) (-) uptake in the absence of NH(4) (+) or Cl(-). Long-term exposure (over 6 hours) to media which contained equimolar mixtures of NH(4) (+), K(+), Cl(-), or NO(3) (-) affected the cultivars very differently: (a) the presence of NH(4) (+) as NH(4)Cl stimulated net NO(3) (-) uptake in Prato barley but inhibited net NO(3) (-) uptake in Olli barley; (b) Cl(-) inhibited net NO(3) (-) uptake in Prato but had little effect in Olli; and (c) NH(4) (+) as (NH(4))(2)SO(4) inhibited net K(+) uptake in Prato but had little effect in Olli. Moreover, the immediate response to the addition of an ion often varied significantly from the long-term response; for example, the addition of Cl(-) initially inhibited net K(+) uptake in Olli barley but, after a 4 hour exposure, it was stimulatory. For both cultivars, net NH(4) (+) and Cl(-) uptake did not change significantly with time after these ions were added to the nutrient medium. These data indicate that, even within one species, there is a high degree of genotypic variation in the control of nutrient absorption.


Postmortem Muscle Protein Changes as a Tool for Monitoring Sahraoui Dromedary Meat Quality Characteristics.
The effects of slaughter age (2 vs. 9 years) and postmortem time (6, 8, 10, 12, 24, 48 and 72 h) on the meat quality and protein changes of the longissimus lumborum muscles of the Algerian Sahraoui dromedary were investigated. Muscles of young dromedaries evidenced a slower acidification process and a significantly higher myofibrillar fragmentation index throughout the postmortem time. The SDS-PAGE of sarcoplasmic and myofibrillar proteins revealed that meat from young dromedaries was characterized by the lowest percentage of myoglobin (p < 0.001) and the highest percentage of desmin (p < 0.01). During postmortem time, a decrease was found for phosphoglucomutase (p < 0.01), α-actinin (p < 0.05) and desmin (p < 0.01) in meat from young dromedaries. Western blot revealed an intense degradation of troponin T in younger dromedaries, with an earlier appearance of the 28 kDa polypeptide highlighting differences in the proteolytic potential between dromedaries of different ages. Principal component analysis showed that meat from young dromedaries, starting from 24 h postmortem, was located in a zone of the plot characterized by higher levels of the myofibrillar fragmentation index, 30 kDa polypeptide and enolase, overall confirming greater proteolysis in younger animals. Data suggest that the investigation of the muscle proteome is necessary to set targeted interventions to improve the aging process of dromedary meat cuts.


Accelerated Partial Breast Irradiation (APBI): Where Are We Now?
Accelerated partial breast irradiation (APBI) is an alternative approach to breast conserving therapy (BCT) where radiation (RT) is delivered over a shorter period of time compared with whole breast irradiation (WBI), resulting in improved patient convenience and cost savings. APBI can be delivered using brachytherapy, intraoperative RT, or conformal external beam radiation therapy (EBRT) techniques. In this review, the authors appraise the latest modern randomized controlled trials (RCTs) of APBI and discuss the application of the data to clinical practice. The OCOG-RAPID and NSABP B-39/RTOG 0413 trials recently reported long-term outcomes of APBI. The OCOG-RAPID trial delivered 38.5 Gy/10 fractions twice daily (at least 6 h apart using EBRT) or WBI and demonstrated non-inferiority of APBI compared with WBI (8-year cumulative rate of ipsilateral breast tumor recurrence (IBTR) was 3% after APBI or 2.8% after WBI, HR 1.27, 90%CI: 0.84-1.91). While acute toxicity was reduced, late toxicity and breast cosmesis were worse with APBI. The NSABP B-39 trial included higher risk patients and was unable to demonstrate equivalence between APBI (38.5 Gy/10 fractions delivered twice daily using EBRT or brachytherapy techniques) and WBI. However, 10-year IBTR rates were low: 4.6% vs. 3.9%, respectively, HR 1.22, 90%CI: 0.94-1.58. The University of Florence demonstrated low rates of local recurrence at 10 years and overall excellent breast cosmetic outcomes when APBI was delivered using EBRT to a dose of 30 Gy/5 fractions delivered on non-consecutive days. Recent RCTs of APBI have shed light on important factors for the integration of APBI into clinical practice, including patient selection and treatment delivery. APBI should be limited to patients with low-risk ductal carcinoma in situ or early stage (T1) invasive ductal cancer with clear margins of excision, estrogen receptor positivity, and node negative disease. Ongoing research should focus on the optimal dose/fractionation for delivery of EBRT-based APBI.


Limited knee extension--a reliable indicator of a successful closed reduction of developmental dysplasia of hip.
A clinical observation of 49 hips in children who had closed reduction and application of hip spica for developmental dysplasia of hip (DDH) was undertaken in our department. A clinical sign of "Limited Extension at ipsilateral knee" was observed after successful closed reduction of the hip. This sign was absent if the hip was not reduced. This sign was due to hamstring tightness after successful closed reduction. We suggest that the presence of this sign is a reliable indicator of successful closed reduction and also an indicator of the vulnerability of the proximal femoral epiphysis to increased pressures during positions of immobilization.


Regression to normoglycaemia by fenofibrate in pre-diabetic subjects complicated with hypertriglyceridaemia: a prospective randomized controlled trial.
Lipotoxicity has recently been shown to be an important risk factor underlying the pathogenesis of pre-diabetes. However, clinical evidence supporting the treatment of pre-diabetes by improving lipotoxicity is lacking. Here, we conducted an open-label, randomized, controlled trial to investigate whether fenofibrate, the widely used hypolipidaemic agent, might benefit pre-diabetes, with metformin and diet control, the recommended intervention methods, as positive controls. Newly diagnosed pre-diabetes patients (n = 120) with hypertriglyceridaemia (plasma triglyceride levels between 1.8 and 4.5 mmol/l) were randomly assigned by computer-generated randomization sequence to either control group (no intervention), fenofibrate group (200 mg once a day), metformin group (500 mg three times a day) or diet-controlled group (diet recommendation). Plasma biochemistry examination was performed every 2 months. The primary endpoint was the outcome of the natural course of pre-diabetes, evaluated by oral glucose tolerance test after 6-month follow-up. Twenty subjects in the fenofibrate group, 24 subjects in the metformin group and 25 subjects in both the diet-controlled group and the control group finished the trial. Fenofibrate, metformin and diet control had protective effects on hypertriglyceridaemic pre-diabetes, evidenced by 53.3, 70 and 30% participants regressed to normoglycaemia, respectively. The effects of fenofibrate and metformin were comparable (P > 0.05), while diet control was less effective (P < 0.05). Liver damage occurred in six subjects in the fenofibrate group and gastrointestinal symptoms occurred in four subjects in the metformin group. No serious adverse events occurred. Controlling lipotoxicity by fenofibrate could effectively ameliorate the natural course of hypertriglyceridaemic pre-diabetes.


The stray capacitance effect in Kelvin probe force microscopy using FM, AM and heterodyne AM modes.
The effect of stray capacitance on potential measurements was investigated using Kelvin probe force microscopy (KPFM) at room temperature under ultra-high vacuum (UHV). The stray capacitance effect was explored in three modes, including frequency modulation (FM), amplitude modulation (AM) and heterodyne amplitude modulation (heterodyne AM). We showed theoretically that the distance-dependence of the modulated electrostatic force in AM-KPFM is significantly weaker than in FM- and heterodyne AM-KPFMs and that the stray capacitance of the cantilever, which seriously influences the potential measurements in AM-KPFM, was almost completely eliminated in FM- and heterodyne AM-KPFMs. We experimentally confirmed that the contact potential difference (CPD) in AM-KPFM, which compensates the electrostatic force between the tip and the surface, was significantly larger than in FM- and heterodyne AM-KPFMs due to the stray capacitance effect. We also compared the atomic scale corrugations in the local contact potential difference (LCPD) among the three modes on the surface of Si(111)-7 × 7 finding that the LCPD corrugation in AM-KPFM was significantly weaker than in FM- and heterodyne AM-KPFMs under low AC bias voltage conditions. The very weak LCPD corrugation in AM-KPFM was attributed to the artefact induced by topographic feedback.


Methyl-introduced A-ring analogues of 1alpha,25-dihydroxyvitamin D3: synthesis and biological evaluation.
The hormonally-active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1), has a wide variety of biological activities, which makes it a promising therapeutic agent for the treatment of cancer, psoriasis and osteoporosis. Insights into the structure-activity relationships of the A-ring of 1 are needed to assist the development of more potent and selective analogues, as well as to define the molecular mode of action. All possible A-ring stereoisomers of 2-methyl-1,25-dihydroxyvitamin D3 and 2,2-dimethyl-1,25-dihydroxyvitamin D3, which differ in stereochemistry at the C1-, C2- and C3-positions, were designed and efficiently synthesized by employing the convergent method. Biological evaluation of the analogues, in terms of the vitamin D receptor-binding affinity and HL-60 cell differentiation-inducing activity, as well as the transcriptional potency in ROS 17/2.8 cells, revealed the importance of substituents at the C2-position in certain orientations.


Molecular Immune-Inflammatory Connections between Dietary Fats and Atherosclerotic Cardiovascular Disease: Which Translation into Clinics?
Current guidelines recommend reducing the daily intake of dietary fats for the prevention of ischemic cardiovascular diseases (CVDs). Avoiding saturated fats while increasing the intake of mono- or polyunsaturated fatty acids has been for long time the cornerstone of dietary approaches in cardiovascular prevention, mainly due to the metabolic effects of these molecules. However, recently, this approach has been critically revised. The experimental evidence, in fact, supports the concept that the pro- or anti-inflammatory potential of different dietary fats contributes to atherogenic or anti-atherogenic cellular and molecular processes beyond (or in addition to) their metabolic effects. All these aspects are hardly translatable into clinics when trying to find connections between the pro-/anti-inflammatory potential of dietary lipids and their effects on CVD outcomes. Interventional trials, although providing stronger potential for causal inference, are typically small sample-sized, and they have short follow-up, noncompliance, and high attrition rates. Besides, observational studies are confounded by a number of variables and the quantification of dietary intakes is far from optimal. A better understanding of the anatomic and physiological barriers for the absorption and the players involved in the metabolism of dietary lipids (e.g., gut microbiota) might be an alternative strategy in the attempt to provide a first step towards a personalized dietary approach in CVD prevention.


A growth model for water distribution networks with loops.
Water distribution networks (WDNs) expand their service areas over time. These growth dynamics are poorly understood. One facet of WDNs is that they have loops in general, and closing loops may be a functionally important process for enhancing their robustness and efficiency. We propose a growth model for WDNs that generates networks with loops and is applicable to networks with multiple water sources. We apply the proposed model to four empirical WDNs to show that it produces networks whose structure is similar to that of the empirical WDNs. The comparison between the empirical and modelled WDNs suggests that the empirical WDNs may realize a reasonable balance between cost, efficiency and robustness in terms of the network structure. We also study the design of pipe diameters based on a biological positive feedback mechanism. Specifically, we apply a model inspired by Physarum polycephalum to find moderate positive correlations between the empirical and modelled pipe diameters. The difference between the empirical and modelled pipe diameters suggests that we may be able to improve the performance of WDNs by following organizing principles of biological flow networks.


Identification of Novel Circulating miRNA Biomarkers for the Diagnosis of Esophageal Squamous Cell Carcinoma and Squamous Dysplasia.
Circulating miRNAs have been identified as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC), but their efficacy in discovering early-stage ESCC is still unsatisfying. Esophageal squamous dysplasia (ESD) is the precursor lesion of ESCC. Notably, little is known about the role(s) of circulating miRNAs in identifying ESD. In this study, we, therefore, aimed to identify serum miRNAs as novel diagnostic markers for detecting ESD and ESCC. The genome-wide miRNA expression was profiled in 104 (52 ESCC and 52 controls) serum samples using microarray. Seven candidate miRNAs from the microarray assay were evaluated for their diagnostic performance in another cohort of 266 participants (96 ESCC, 92 ESD, and 78 healthy controls). The serum levels of miR-16-5p, miR-197-5p, miR-451a, and miR-92a-3p were associated with ESCC; the biomarker based on the panel of these four miRNAs could efficiently distinguish patients with ESCC from the controls [AUC = 0.856; 95% confidence interval (CI), 0.794-0.905; P < 0.001]. The serum levels of miR-16-5p, miR-320c, miR-638, and miR-92a-3p were significantly higher in patients with ESD than in controls, and this four-miRNA signature could efficiently differentiate patients with ESD from the controls (AUC = 0.842; 95% CI, 0.778-0.893; P < 0.001). In addition, compared with serum carcinoembryonic antigen and carbohydrate antigen 199, miRNA-based panels had a better diagnostic performance in distinguishing patients with ESCC and ESD from healthy controls. Our study identified two novel panels of circulating miRNAs with high efficiency in detecting ESCC and ESD, suggesting that circulating miRNAs, in particular the combination of them, might serve as noninvasive biomarkers for the early detection of ESCC. This study suggests the feasibility of using circular miRNA-based blood tests to aid in the detection of ESD and ESCC.


[Urinary stress incontinence: rehabilitation treatment of the pelvic floor].
The authors inspected 112 patients with diagnostic urogynecologic and urodynamic criteria. They suffered from urinary stress incontinence. Forty patients effected rehabilitative therapy of the pelvic floor with visits twice weekly with a method which included: pelvic muscle exercises, biofeedback and functional electrostimulation. The patients were divided into two groups in accordance with the kind of urinary stress incontinence: in the first group there were patients with genuine urinary stress incontinence, in the second group patients with mixed urinary stress incontinence. The results at the end of treatment reported a proportion of success of 66% in the first group and of 54% in the second group.


Hepatic arterial infusion combined with systemic chemotherapy induced complete response of metachronous liver metastases after resection of pancreatic insulinoma.
Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs). We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases to hepatic arterial infusion combined with systemic chemotherapy. A 58-year-old woman was admitted to our hospital following loss of consciousness. Examination revealed a pancreatic tumor, and she underwent distal pancreatectomy following diagnosis of insulinoma. Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3 months after surgery. Therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. We observed complete ablation of all metastatic liver nodules after 11 cycles of the chemotherapy using MRI. We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7 years after surgery.


Analysis of the Rate of Re-planning in Spot-Scanning Proton Therapy.
Finite proton range affords improved dose conformality of radiation therapy when patient regions-of-interest geometries are well characterized. Substantial changes in patient anatomy necessitate re-planning (RP) to maintain effective, safe treatment. Regularly planned verification scanning (VS) is performed to ensure consistent treatment quality. Substantial resources, however, are required to conduct an effective proton plan verification program, which includes but is not limited to, additional computed tomography (CT) scanner time and dedicated personnel: radiation therapists, medical physicists, physicians, and medical dosimetrists. Verification scans (VSs) and re-plans (RPs) of 711 patients treated with proton therapy between June 2015 and June 2018 were studied. All treatment RP was performed with the intent to maintain original plan integrity and coverage. The treatments were classified by anatomic site: brain, craniospinal, bone, spine, head and neck (H&N), lung or chest, breast, prostate, rectum, anus, pelvis, esophagus, liver, abdomen, and extremity. Within each group, the dates of initial simulation scan, number of VSs, number of fractions completed at the time of VS, and the frequency of RP were collected. Data were analyzed in terms of rate of RP and individual likelihood of RP. A total of 2196 VSs and 201 RPs were performed across all treatment sites. H&N and lung or chest disease sites represented the largest proportion of plan modifications in terms of rate of re-plan (RoR: 54% and 58%, respectively) and individual likelihood of RP on a per patient basis (likelihood of RP [RP%]: 46% and 39%, respectively). These sites required RP beyond 4 weeks of treatment, suggesting continued benefit for frequent, periodic VS. Disease sites in the lower pelvis demonstrated a low yield for RP per VS (0.01-0.02), suggesting that decreasing VS frequency, particularly late in treatment, may be reasonable. A large degree of variation in RoR and individual RP% was observed between anatomic treatment sites. The present retrospective analysis provides data to help develop anatomic site-based VS protocols.