Novel computer aided diagnostic models on multimodality medical images to differentiate well differentiated liposarcomas from lipomas approached by deep learning methods.
Deep learning methods have great potential to predict tumor characterization, such as histological diagnosis and genetic aberration. The objective of this study was to evaluate and validate the predictive performance of multimodality imaging-derived models using computer-aided diagnostic (CAD) methods for prediction of MDM2 gene amplification to identify well-differentiated liposarcoma (WDLPS) and lipoma. All 127 patients from two institutions were included with 89 patients in one institution for model training and 38 patients in the other institution for external validation between January 2012 and December 2018. For each modality, handcrafted radiomics analysis with manual segmentation was applied to extract 851 features for each modality, and six pretrained convolutional neural networks (CNNs) extracted 512-2048 deep learning features automatically. Extracted imaging-based features were selected via univariate filter selection methods and the recursive feature elimination algorithm, which were then classified by support vector machine for model construction. Integrated with two significant clinical variables, age and LDH level, a clinical-radiological model was constructed for identification WDLPS and lipoma. All differentiation models were evaluated using the area under the receiver operating characteristics curve (AUC) and their 95% confidence interval (CI). The multimodality model on deep learning features extracted from ResNet50 algorithm (RN-DL model) performed great differentiation performance with an AUC of 0.995 (95% CI 0.987-1.000) for the training cohort, and an AUC of 0.950 (95% CI 0.886-1.000), accuracy of 92.11%, sensitivity of 95.00% (95% CI 73.06-99.74%), specificity of 88.89% (95% CI 63.93-98.05%) in external validation. The integrated clinical-radiological model represented an AUC of 0.996 (95% CI 0.989-1.000) for the training cohort, and an AUC of 0.942 (95% CI 0.867-1.000), accuracy of 86.84%, sensitivity of 95.00% (95% CI 73.06-99.74%), and specificity of 77.78% (95% CI 51.92-92.63%) in external validation. Imaging-based multimodality models represent effective discrimination abilities between WDLPS and lipoma via CAD methods, and might be a practicable approach in assistance of treatment decision.


New therapeutic horizons for plasma phospholipid transfer protein (PLTP): Targeting endotoxemia, infection and sepsis.
Phospholipid Transfer Protein (PLTP) transfers amphiphilic lipids between circulating lipoproteins and between lipoproteins, cells and tissues. Indeed, PLTP is a major determinant of the plasma levels, turnover and functionality of the main lipoprotein classes: very low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL). To date, most attention has been focused on the role of PLTP in the context of cardiometabolic diseases, with additional insights in neurodegenerative diseases and immunity. Importantly, beyond its influence on plasma triglyceride and cholesterol transport, PLTP plays a key role in the modulation of the immune response, with immediate relevance to a wide range of inflammatory diseases including bacterial infection and sepsis. Indeed, emerging evidence supports the role of PLTP, in the context of its association with lipoproteins, in the neutralization and clearance of bacterial lipopolysaccharides (LPS) or endotoxins. LPS are amphipathic molecules originating from Gram-negative bacteria which harbor major pathogen-associated patterns, triggering an innate immune response in the host. Although the early inflammatory reaction constitutes a key step in the anti-microbial defense of the organism, it can lead to a dysregulated inflammatory response and to hemodynamic disorders, organ failure and eventually death. Moreover, and in addition to endotoxemia and acute inflammation, small amounts of LPS in the circulation can induce chronic, low-grade inflammation with long-term consequences in several metabolic disorders such as atherosclerosis, obesity and diabetes. After an updated overview of the role of PLTP in lipid transfer, lipoprotein metabolism and related diseases, current knowledge of its impact on inflammation, infection and sepsis is critically appraised. Finally, the relevance of PLTP as a new player and novel therapeutic target in the fight against inflammatory diseases is considered.


Synthesis, anti-thymidine phosphorylase activity and molecular docking of 5-thioxo-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ones.
In our lead finding program, a series of 5-thioxo-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ones and their 5-thio-alkyl derivatives were designed and synthesized which contained different substituents at ortho-position of 2-phenyl ring attached to the fused ring structure. The preliminary pharmacological evaluation demonstrated that the synthesized compounds exhibited a varying degree of inhibitory activity towards thymidine phosphorylase (TP), comparable to reference compound, 7-Deazaxanthine (7-DX, 2) (IC50 value=42.63 μM). The study also inferred that the ortho-substituted group at the phenyl ring and 5-thio-alkyl moiety imparted steric hindrance effects in the binding site of the enzyme, leading to a reduced inhibitory response. In addition, compound 3a was identified as a mixed-type inhibitor of TP. Moreover, computational docking study was performed to illustrate the important structural information on the plausible ligand-enzyme binding interactions.


Safety of intramuscular COVID-19 vaccination in patients with haemophilia.
Guidelines recommend that patients with haemophilia should preferably receive vaccination subcutaneously. COVID-19 and other vaccines, however, are only licenced for intramuscular application. To assess the safety of intramuscular COVID-19 vaccination in patients living with haemophilia. Part A of this prospective observational study enrolled consecutive patients with haemophilia A (HA) and B (HB) of all ages and severities and assessed injection site bleeding and other complications within 30 days of vaccination. Part B enrolled patients providing informed consent for detailed data collection including medication and prophylaxis around the time of vaccination. Logistic regression was performed to assess potential risk factors for bleeding. Four hundred and sixty-one patients were enrolled into part A. The primary endpoint injection site bleeding occurred in seven patients (1.5%, 95% confidence interval .7-3.1%). Comprehensive analysis of 214 patients (404 vaccinations, part B) revealed that 97% of patients with severe haemophilia had prophylaxis before vaccination, either as part of their routine prophylaxis or using additional doses. 56% and 30% of patients with moderate and mild haemophilia, respectively, received prophylaxis before vaccination. Among the seven bleeds recorded, three occurred when intramuscular vaccination was done without prophylaxis (odds ratio 12). This is the first prospective study reporting on the safety of intramuscular vaccination in haemophilia. The rate of injection site bleeding was low in mild haemophilia, and in moderate and severe haemophilia if patients received factor prophylaxis.


Transmission and infection risk of COVID-19 when people coughing in an elevator.
People in cities use elevators daily. With the COVID-19 pandemic, there are more worries about elevator safety, since elevators are often small and crowded. This study used a proven CFD model to see how the virus could spread in elevators. We simulated five people taking in an elevator for 2 min and analyzed the effect of different factors on the amount of virus that could be inhaled, such as the infected person's location, the standing positions of the persons, and the air flow rate. We found that the position of the infected person and the direction they stood greatly impacted virus transmission in the elevator. The use of mechanical ventilation with a flow rate of 30 ACH (air changes per hour) was effective in reducing the risk of infection. In situations where the air flow rate was 3 ACH, we found that the highest number of inhaled virus copies could range from 237 to 1186. However, with a flow rate of 30 ACH, the highest number was reduced to 153 to 509. The study also showed that wearing surgical masks decreased the highest number of inhaled virus copies to 74 to 155.


West Nile virus encephalitis during pregnancy.
West Nile virus is an emerging pathogen in the United States. Although most cases are subclinical, serious infection can occur in the form of fulminant meningoencephalitis. We present a case of West Nile virus meningoencephalitis complicating pregnancy. The patient presented in the second trimester with fever, nuchal rigidity, and mental status changes. The diagnosis was made by demonstrating the presence of immunoglobulin M antibody to West Nile virus in the cerebrospinal fluid. Gradual clinical improvement was noted after several days of supportive care. No obvious fetal consequences of infection were noted after birth. Obstetricians and health care providers need to be mindful of West Nile virus infection in pregnant women presenting with fever and neurological signs, particularly in endemic areas.


Young patients with shoulder chondrolysis following arthroscopic shoulder surgery treated with total shoulder arthroplasty.
Chondrolysis following shoulder arthroscopy is a devastating complication, often seen in young patients. After nonoperative measures have been exhausted, there are few treatment options available that reliably improve pain and function. The purpose of this study is to examine the intra-operative findings, radiographic features, and clinical outcomes of a series of patients with chondrolysis following arthroscopic surgery managed with a total shoulder arthroplasty. A retrospective review was performed on 11 patients (average age 39) with shoulder chondrolysis following arthroscopy. Attention was focused on review of the index arthroscopy, radiographs, and functional outcome scores prior to total shoulder arthroplasty, as well as intra-operative cultures, histology, radiographs, and functional outcomes from most recent follow-up. All patients were treated with total shoulder arthroplasty at an average of 26 months after the index arthroscopy. Preoperative and postoperative radiographs were reviewed, and outcomes were compared using validated measurements. Statistically significant improvements in shoulder abduction (89 degrees -123 degrees , P = .027), external rotation (26 degrees -48 degrees , P = .037), total ASES scores (30-77.5, P = .0039), and SST scores (3-8, P = .0078) were noted. Ten patients subjectively rated their outcomes as good or excellent, with 1 as satisfactory. Chondrolysis after shoulder arthroscopy has a rapid clinical progression and is likely multifactorial in etiology. Early results of total shoulder arthroplasty show an opportunity for improvements in pain and function; however, progressive glenoid radiolucencies may develop in these patients.


Growing Tungsten Nanophases on Carbon Spheres Doped with Nitrogen. Behaviour as Electro-Catalysts for Oxygen Reduction Reaction.
This work shows the preparation of carbon nanospheres with a high superficial nitrogen content (7 wt.%), obtained by a simple hydrothermal method, from pyrocatechol and formaldehyde, around which tungsten nanophases have been formed. One of these nanophases is tungsten carbide, whose electro-catalytic behavior in the ORR has been evaluated together with the presence of nitrogen surface groups. Both current and potential kinetic density values improve considerably with the presence of tungsten, despite the significant nitrogen loss detected during the carbonization treatment. However, the synergetic effect that the WC has with other electro-catalytic metals in this reaction cannot be easily evaluated with the nitrogen in these materials, since both contents vary in opposite ways. Nevertheless, all the prepared materials carried out oxygen electro-reduction by a mixed pathway of two and four electrons, showing remarkable electro-catalytic behavior.


Deciphering the brewing process of Cantonese-style rice vinegar: Main flavors, key physicochemical factors, and important microorganisms.
Cantonese-style rice vinegar is one of the most important Chinese rice vinegars and is quite popular all over the southeast coast of China, especially in Guangdong. This study identified 31 volatile compounds, including 11 esters, 6 alcohols, 3 aldehydes, 3 acids, 2 ketones, 1 phenol, and 5 alkanes, using headspace solid-phase microextraction-gas chromatography-mass spectrometry. Six organic acids were detected by high performance liquid chromatography. The ethanol content was detected by gas chromatography. During acetic acid fermentation, physicochemical analysis showed that the initial concentrations of reducing sugar and ethanol were 0.0079 g/L and 23.81 g/L, respectively, and the final value of total acid was 46.5 g/L, and the pH value was stable at 3.89. High-throughput sequencing was used to identify the microorganisms, and Acetobacter, Komagataeibacter, and Ralstonia were the top three bacterial genera. Quantitative real-time polymerase chain reaction revealed patterns that were different from those of high-throughput sequencing. The co-occurrence network of microorganisms and the correlation analysis between microorganisms and flavor substances indicate that Acetobacter and Ameyamaea played crucial roles as the main functional AAB, and the failure of Cantonese-style rice vinegar fermentation can be attributed to the abnormal increase in Komagataeibacter. Microbial co-occurrence network analysis indicated that Oscillibacter, Parasutterella, and Alistipes were the top three microorganisms. Redundancy analysis disclosed that total acid and ethanol were the key environmental factors influencing the microbial community. Fifteen microorganisms closely related to the metabolites were identified using the bidirectional orthogonal partial least squares model. Correlation analysis showed that these microorganisms were strongly associated with flavor metabolites and environmental factors. The findings of this study deepen our understanding of the fermentation of traditional Cantonese-style rice vinegar.


Perinatal sulfur dioxide exposure alters brainstem parasympathetic control of heart rate.
Sulfur dioxide (SO₂) is an air pollutant that impedes neonatal development and induces adverse cardiorespiratory health effects, including tachycardia. Here, an animal model was developed that enabled characterization of (i) in vivo alterations in heart rate and (ii) altered activity in brainstem neurons that control heart rate after perinatal SO₂ exposure. Pregnant Sprague-Dawley dams and their pups were exposed to 5 parts per million SO₂ for 1 h daily throughout gestation and 6 days postnatal. Electrocardiograms were recorded from pups at 5 days postnatal to examine changes in basal and diving reflex-evoked changes in heart rate following perinatal SO₂ exposure. In vitro studies employed whole-cell patch-clamp electrophysiology to examine changes in neurotransmission to cardiac vagal neurons within the nucleus ambiguus upon SO₂ exposure using a preparation that maintains fictive inspiratory activity recorded from the hypoglossal rootlet. Perinatal SO₂ exposure increased heart rate and blunted the parasympathetic-mediated diving reflex-evoked changes in heart rate. Neither spontaneous nor inspiratory-related inhibitory GABAergic or glycinergic neurotransmission to cardiac vagal neurons was altered by SO₂ exposure. However, excitatory glutamatergic neurotransmission was decreased by 51.2% upon SO₂ exposure. This diminished excitatory neurotransmission was tetrodotoxin-sensitive, indicating SO₂ exposure impaired the activity of preceding glutamatergic neurons that synapse upon cardiac vagal neurons. Diminished glutamatergic, but unaltered inhibitory neurotransmission to cardiac vagal neurons provides a mechanism for the observed SO₂-induced elevated heart rate via an impairment of brainstem cardioinhibitory parasympathetic activity to the heart.


The anatomical positioning change of retroperitoneal organs in prone and lateral position: an assessment for single-prone position lateral lumbar surgery.
There are reports that performing lateral lumbar interbody fusion (LLIF) in a prone, single position (single-prone LLIF) can be done safely in the prone position because the retroperitoneal organs reflect anteriorly with gravity. However, only a few study has investigated the safety of single-prone LLIF and retroperitoneal organ positioning in the prone position. We aimed to investigate the positioning of retroperitoneal organs in the prone position and evaluate the safety of single-prone LLIF surgery. A total of 94 patients were retrospectively reviewed. The anatomical positioning of the retroperitoneal organs was evaluated by CT in the preoperative supine and intraoperative prone position. The distances from the centre line of the intervertebral body to the organs including aorta, inferior vena cava, ascending and descending colons, and bilateral kidneys were measured for the lumbar spine. An "at risk" zone was defined as distance less than 10 mm anterior from the centre line of the intervertebral body. Compared to supine preoperative CTs, bilateral kidneys at the L2/3 level as well as the bilateral colons at the L3/4 level had statistically significant ventral shift with prone positioning. The proportion of retroperitoneal organs within the at-risk zone ranged from 29.6 to 88.6% in the prone position. The retroperitoneal organs shifted ventrally with prone positioning. However, the amount of shift was not large enough to avoid risk for organ injuries and substantial proportion of patients had organs within the cage insertion corridor. Careful preoperative planning is warranted when considering single-prone LLIF.


Autophagy protects against ischemia/reperfusion-induced lung injury through alleviating blood-air barrier damage.
Understanding the role and underlying regulation mechanism of autophagy in ischemia/reperfusion (I/R)-induced lung injury may provide potentially new pharmacologic targets for treatment of acute lung injury. The aim of this study was to adjust autophagy with pharmacologic agents to determine its functional significance in I/R-induced lung injury. Human pulmonary microvascular endothelial cells (HPMVECs) and mice were pre-conditioned with autophagy inhibitor chloroquine or promoter rapamycin before they were challenged with oxygen-glucose deprivation/oxygen-glucose restoration (OGD) and lung I/R, respectively. Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 was pre-injected into I/R-induced mice to test the role of ERK1/2 in regulating autophagy. OGD caused tight conjunction damage and cell death in HPMVECs, which was further aggravated by blocking autophagy, yet ameliorated through promoting autophagy. On a consistent basis, inhibiting autophagy aggravated I/R-induced lung edema and tissue inflammation, which was significantly alleviated by promoting autophagy with rapamycin. In addition, inhibition of ERK1/2 increased expression of active mammalian target-of-rapamycin and thus decreased I/R-induced autophagy. It appears that autophagy plays a protective role in I/R-induced lung injury and this effect may be enhanced by moderately improving autophagy level. Meanwhile, the ERK1/2 signal pathway has a positively regulating role in lung I/R-induced autophagy.


In vitro acaricidal effect of Melia azedarach and Artemisia herba-alba extracts on Hyalomma dromedarii (Acari: Ixodidae): embryonated eggs and engorged nymphs.
The present study aimed to evaluate the in vitro efficacy of four medicinal plant extracts: petroleum ether and ethyl alcohol extracts of the ripen fruits of Melia azedarach and whole aerial parts of Artemisia herba-alba against the two inactive stages of the camel tick Hyalomma dromedarii, embryonated eggs and engorged nymphs in comparison to reference acaricide Butox®5.0 (Deltamethrin). Egg and nymphal immersion tests at four concentrations with three replicates were used. The deformity in larvae hatched from treated eggs and adults moulted from treated nymphs were observed and photographed by light microscope (LM) and scanning electron microscope (SEM). The results showed that M. azedarach and A. herba-alba extracts revealed higher significant toxic effects on embryonated eggs and engorged nymphs comparing with the reference acaricide (Butox®5.0) and control. In egg emmersion test, the LC50 of petroleum ether extracts of M. azedarach and A. herba-alba was 3.14 and 3.91%, respectively and LC50 of the respective ethyl alcohol extracts was 1.77 and 2.45%. In nymphal immersion test, LC50 of petroleum ether extracts of M. azedarach and A. herba-alba was 0.26 and 1%, respectively, and LC50 of the respective ethyl alcohol extracts was 4.17 and 8.7%. Abnormalities were observed by LM and SEM in the larvae hatched from the treated eggs as incomplete development of legs and mouth parts as well as shrinkage mainly in legs and mouthparts of adults emerged from treated nymphs. In conclusion, all extracts and petroleum ether extracts of the two plants have great potential to be developed as a novel acaricidal for controlling eggs and nymphs of H. dromedarii, respectively.


Association of serotonin concentration to behavior and IQ in autistic children.
Twenty-five boys meeting DSM-III criteria for infantile autism were evaluated for IQ, age, and behavior score on the Autism Behavior Checklist (ABC), in order to determine the ability to predic platelet-rich plasma (PRP) serotonin concentrations. Multiple regression techniques were used to adjust the PRP serotonin concentration for medication and whole blood platelet count to allow meaningful comparisons of serotonin concentrations among the autistic children. Though we found no significant correlation between the adjusted serotonin concentration and the IQ, or between the adjusted serotonin concentration and the various ABC scale scores, four individual items of the ABC did correlate with the adjusted serotonin concentration. Individuals with all of these items appear to be more severely affected with the disorder of autism and have a tendency to higher adjusted PRP serotonin concentration.


Genetic analysis of the CHD7 gene in Korean patients with CHARGE syndrome.
CHARGE syndrome is an autosomal dominant congenital disorder known to be caused by the haploinsufficiency of the CHD7 gene. Heterozygous mutations in the CHD7 gene have been identified in approximately 60-70% of patients clinically diagnosed with CHARGE syndrome. Although there have been many reports on the mutational spectrum of the CHD7 gene in patients with CHARGE syndrome worldwide, little is known about this syndrome in the Korean population. In this study, three Korean patients with CHARGE syndrome including one patient with Patau syndrome were evaluated for genetic analysis of the CHD7 gene using direct sequencing of all 38 exons and the flanking intronic regions. One nonsense and two novel missense mutations were identified in the CHD7 gene. Clinical symptoms caused by the missense mutations were much milder compared to the nonsense mutation, confirming the previously determined genotype-phenotype correlation in CHARGE syndrome. Our study demonstrates the importance of mutational screening of CHD7 in patients who have been diagnosed with other syndromes but display clinical features of CHARGE syndrome.


Single-cell transcriptome atlas of human mesenchymal stem cells exploring cellular heterogeneity.
The heterogeneity of mesenchymal stem cells (MSCs) is poorly understood, thus limiting clinical application and basic research reproducibility. Advanced single-cell RNA sequencing (scRNA-seq) is a robust tool used to analyse for dissecting cellular heterogeneity. However, the comprehensive single-cell atlas for human MSCs has not been achieved. This study used massive parallel multiplexing scRNA-seq to construct an atlas of > 130 000 single-MSC transcriptomes across multiple tissues and donors to assess their heterogeneity. The most widely clinically utilised tissue resources for MSCs were collected, including normal bone marrow (n = 3), adipose (n = 3), umbilical cord (n = 2), and dermis (n = 3). Seven tissue-specific and five conserved MSC subpopulations with distinct gene-expression signatures were identified from multiple tissue origins based on the high-quality data, which has not been achieved previously. This study showed that extracellular matrix (ECM) highly contributes to MSC heterogeneity. Notably, tissue-specific MSC subpopulations were substantially heterogeneous on ECM-associated immune regulation, antigen processing/presentation, and senescence, thus promoting inter-donor and intra-tissue heterogeneity. The variable dynamics of ECM-associated genes had discrete trajectory patterns across multiple tissues. Additionally, the conserved and tissue-specific transcriptomic-regulons and protein-protein interactions were identified, potentially representing common or tissue-specific MSC functional roles. Furthermore, the umbilical-cord-specific subpopulation possessed advantages in immunosuppressive properties. In summary, this work provides timely and great insights into MSC heterogeneity at multiple levels. This MSC atlas taxonomy also provides a comprehensive understanding of cellular heterogeneity, thus revealing the potential improvements in MSC-based therapeutic efficacy.


Cochlear kainate receptors.
Synaptic transmission between the cochlear hair cell and its afferent fiber is mediated by glutamate receptors. While kainate receptors are known to be present in the spiral ganglion, little is known of their distribution or functional role. We have detected all five kainate receptor subunits in the mouse cochlea with quantitative RT-PCR and with immunohistochemistry. We observed kainate receptors on afferent terminals co-localized with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA: ) receptors at the afferent synapse. Individual terminals innervating a single hair cell varied in their ratios of AMPA: to kainate receptor immunoreactivity. Infusion of the mouse cochlea via the scala tympani with UBP296, a recently developed antagonist with high specificity for the GluK1 kainate receptor (compared to the AMPA: receptor), reduced the compound action potential and elevated auditory neural thresholds without affecting the distortion product otoacoustic emission thresholds. Thus, the pharmacological evidence suggests that kainate receptors may contribute to the response to transmitter released from the hair cell during acoustic stimulation. It is plausible that afferent transmission at this synapse is mediated by a mix of AMPA: and kainate receptors.


Central neurogenic hyperventilation in a conscious man with CSF dissemination from a pineal glioblastoma.
A 40-year old conscious man developed central neurogenic hyperventilation (CNH). He had tumor dissemination to the brainstem 10 months after undergoing partial removal of a pineal glioblastoma. To the best of our knowledge, this is the first report of CNH caused by the cerebrospinal fluid dissemination of a tumor. The authors suggest that multiple lesions from an infiltrative tumor in the brainstem may give rise to CNH and further our understanding of the pathogenesis of CNH.


Interventional therapy for neonates with critical congenital heart disease.
Transcatheter interventional therapies for children continue to evolve at a remarkable rate. Perhaps no where are these procedures more important than in the critically ill newborn. In this core curriculum review article several of the most commonly performed interventions performed in critically ill newborns are discussed with regards to technique and outcomes.


Standardization of reticulocyte counts in the athlete biological passport: A practical update.
The athlete biological passport monitors blood variables over time to uncover blood doping. With the phasing in of a new series of blood analyzers, the Sysmex XN series, it was necessary to examine the comparability of results with the previously employed XT/XE series. A previous comparison between XN and XT/XE series suggested a small but significant bias between the two instruments in the measurements of RET%. Here, we examined the comparability of RET% on the XN and XT/XE platform using data collected over the first year since the transition. The comparability of results obtained from XN and XT/XE instruments was assessed using three datasets: (i) 767 blood samples measured on both instrument series in 22 WADA-accredited laboratories, (ii) 27 323 samples measured on either instrument across 31 laboratories, and (iii) 119 clinical samples and 110 anti-doping samples measured on both instruments in a single laboratory. Analysis of the three datasets confirms the previous observation of a bias toward higher RET% values for samples measured on Sysmex XN instruments compared with the XT/XE series. Using data across a larger number of XN instruments and a larger athlete population, the current work suggests that the bias is proportional and slightly higher than previously observed across most of the range RET% values. A model is proposed for the comparison of data across XN and XT/XE technologies whereby the instrument bias increases proportionally with RET% measured on Sysmex XN Series, but where the rate of increase is negatively related to IRF%.


Dimensional analysis for modeling oxygen transfer in rotating biological contactor.
In rotating biological contactors (RBC), the oxygen mass transfer coefficient (KLa) is often inadequately predicted by the available models. Hence, dimensional analysis based empirical models were developed for predicting KLa and the component of KLa due to turbulence (KLat) using data available in the literature. The overall oxygen transfer number (OTN) and its component due to turbulence (OTNt) were defined as dimensionless groups based on KLa and KLat, respectively. They were expressed as a function of dimensionless groups, formed using disc diameter (D), area of discs (Ad), rotational speed (omega) and cross-sectional area of the tank (At). OTN was also a function of thickness of the water film on the disc (delta) and working volume of the reactor (V). Decrease in number of discs and decrease in (Ad/At) resulted in decreasing OTN but increasing OTNt. Both OTNt and OTN increased with increase in omega. The proposed empirical models will facilitate scale-up of RBCs.


Efficient refolding of the bifunctional therapeutic fusion protein VAS-TRAIL by a triple agent solution.
VAS-TRAIL is a bifunctional fusion protein that combines anti-angiogenic activity with tumor-selective apoptotic activity for enhanced anti-tumor efficacy. VAS-TRAIL is expressed as inclusion body in Escherichia coli, but protein refolding is difficult to achieve and results in low yields of bioactive protein. In this study, we describe an efficient method for VAS-TRAIL refolding. The solubilization of aggregated VAS-TRAIL was achieved by a triple agent solution, which consists of an alkaline solution (pH 11.5) containing 0.4M l-arginine and 2M urea. The solubilized protein showed high purity and preserved secondary structure according to fluorescence properties. VAS-TRAIL refolding was performed through stepwise dialysis and resulted in more than 50% recovery of the soluble protein. The function of l-arginine was additive with alkaline pH, as shown by the significant improvement in refolding yield (≈30%) by l-arginine-containing solubilization solutions compared with alkaline solubilization solutions without l-arginine. The refolded VAS-TRAIL also showed β-sheet structures and the propensity for oligomerization. Bioassays showed that the refolded fusion protein exhibited the expected activities, including its apoptotic activities toward tumor and endothelial cells, which proposed its promising therapeutic potential.


Costs versus earnings in colon surgery and coronary artery bypass grafting under a prospective payment system: Sufficient financial incentives to reduce surgical site infections?
Based on a surgical site infection (SSI) cohort at an academic center, we showed a median potentially preventable loss per non-SSI case of $17,916 in colon surgery and of $34,741 in coronary artery bypass grafting.


Bovine dental pulp collagens: characterization of types III and V collagen.
Pulp was essentially solubilized by partial pepsin digestion. The various genetic types of collagens were isolated by differential salt precipitation and extraction. Types I, III and V collagen represented 56, 41 and 2% of the total collagen, respectively. The type V collagen comprised two different molecular species consisting of [alpha 1(V)]2 alpha 2(V) and alpha 1(V) alpha 2(V) alpha 3(V), the ratio of which was approx. 1:1.3. The major portion of the type III collagen was present as a high molecular weight aggregate which released alpha 1(III) chains upon reduction with 2-mercaptoethanol.


Identifying a molecular profile to predict the risk of recurrence in high-intermediate risk endometrial cancer.
Patients with high-intermediate risk endometrial cancer (H-IR EMCA) have an elevated risk of recurrence compared to low-risk counterparts. Many H-IR EMCA patients are treated with radiation or chemotherapy, but their overall survival is not significantly impacted by treatment. The objective of this study was to compare molecular profiles of H-IR EMCA patients with disease recurrence to those without to identify characteristics that could better predict patient outcomes. Tissue was acquired from H-IR EMCA patients with disease recurrence (n=15) and without disease recurrence (n=15) who had not received adjuvant therapy and performed DNA and RNA analyses. In recurrent population, 5 patients had matchingrecurrent and initial tumor tissues. Of note, 5/7 (71%) African Americanpatients had disease recurrence compared to 10/23 (43%) White patients. Inaddition, several new mutations were found in individual patient's recurrentcompared to initial tumors. Currently the treatment ofendometrial cancer is rapidly changing with molecular profiling becoming partof the standard of care. Additionally, it and is being incorporated intoclinical trials in this group of patients. The specific gene mutations and RNAexpression signatures that were observed in our small cohort need to bevalidated in larger cohorts to determine their impact.


The optic nerve and visual pathways.
We review the clinical examination of the optic disc and assessment of the integrity of the visual pathways: assessment of vision in the infant and child, assessment of disc size and configuration, detection of abnormalities such as cupping or disc swelling and their significance, visual field examination in the child, and the various field defects which result from pathology affecting the visual pathway anywhere along its course. Congenital anomalies of the optic disc, their systemic associations and significance are discussed. We also review the presentation of the visually impaired child, the significance of nystagmus in this context, the differential diagnosis and investigation.


Establishment and characterization of ferret cells in culture.
Cells derived from the brain of a 6 wk-old ferret have been subcultured over 100 times and have undergone over 400 population doublings in vitro. These cells, referred to as Mpf cells, have an absolute efficiency of colony formation in excess of 45%, exhibit a mean population doubling time of 12.5 h, possess ferret-specific antigens, and have isozymes with electrophoretic properties that are the same as those of isozymes found in ferret liver. The cells exhibit a cytopathic effect and support the synthesis of progeny virus when they are infected with the viruses of lymphocytic choriomeningitis, Newcastle disease, pseudorabies, Sindbis, vaccinia, and vesicular stomatitis. The passage level of the Mpf cells, their elapsed number of population doublings, their possession of ferret-specific antigens, and the comigration of four isozymes obtained from these cells and ferret liver define the cells as an established line of ferret cells.


Genipap (Genipa americana L.) juice intake biomarkers after medium-term consumption.
Genipap (Genipa americana L.) is an exotic fruit largely consumed and well known, in Amazonian pharmacopeia, to treat anemia, measles and uterine cancer. It is also used as a diuretic, digestive, healing, laxative and antiseptic. The aim of this study was to apply an untargeted metabolomics strategy to determine biomarkers of food intake after short-term consumption of genipap juice. Sixteen healthy adult men were administered jenipap juice (250 mL) twice a day for three weeks. Before and after the three weeks of consumption. the subjects drank a control drink, and they consumed a standard diet. Urine was collected after 0-6 h, 6-12 h and 12-24 h. An ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics approach was applied to analyze the urine samples. Principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were performed to highlight experimental differences between groups. The value of the area under the curve (AUC) of the receiver operator characteristic (ROC) curve validated the identified biomarkers. Thirty-one statistically affected urinary metabolites were putatively identified and were mainly related to iridoids family, medium-chain fatty acids, and polyphenols. Also a group of urinary markers including dihydrocaffeic acid (DHCA), 1-(4-hydroxyphenyl)-1,2-propanediol and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid were established as biomarkers of genipap consumption. Our findings have established a comprehensive panel of changes in the urinary metabolome and provided information to monitor endogenous alterations that are linked to genipap juice intake. These data should be used in further studies to understand the health implications of genipap juice consumption.


Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis, in vitro biological evaluation, molecular docking study and in silico ADME prediction.
Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a-m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50 value=13.16μM), 5d (IC50 value=15.66μM) and 5j (IC50 value=19.16μM) had shown good PDF inhibition activity. The compounds 5a (MIC range=11.00-15.83μg/mL), 5b (MIC range=23.75-28.50μg/mL) and 5j (MIC range=7.66-16.91μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range=25-50μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a-m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.


Evaluation of an educational video providing key messages for doctors to counsel families following a first afebrile seizure.
The aim was to evaluate an educational video in educating doctors on the key messages and follow-up pathways following a first afebrile seizure presentation. A multidisciplinary expert team developed the video (http://www.pennsw.org.au/families/resources/first-seizure-pack-and-video) based on available evidence and best-practice. It contains a role-play between the parent/child and physician. It addresses: key messages to impart following a first seizure, seizure first aid, safety messages including necessary precautions post-discharge, contents of the First Seizure Pack for families, follow-up pathway and issues for discussion with the paediatrician at a later appointment. Paediatric/Emergency department (ED) trainees across three Australian sites were recruited during terms 1 and 2, 2019. A repeated measures design was used. Multilevel modelling analyses were performed. The primary outcome was clinician knowledge. Secondary outcomes were confidence in answering questions and counselling families. Qualitative data on the utility, strengths and weaknesses of the video were evaluated. A total of 127 participants consented, one withdrew prior to commencing. A total of 126 baseline surveys, 115 follow-up surveys and 45 1-month follow-up surveys were returned. Viewing the video significantly improved knowledge of key messages at immediate follow-up (P < 0.001) and 1-month follow-up (P = 0.048). Likewise, confidence was significantly improved; 96.5% of responders found the video useful, 90.3% were likely to use the resource in the future and 82% would change their approach to counselling. Most liked aspects of the resource were clarity/conciseness of the information (n = 70) and comprehensiveness (n = 38). This education video significantly improved clinician knowledge and confidence in counselling families following first seizure.


Traumatic stress symptoms after the November 13th 2015 Terrorist Attacks among Young Adults: The relation to media and emotion regulation.
A major terror attack occurred in the Paris region on 13th November 2015. This event was widely showed, described, and commented in the media. Media consumption may lead to a widespread diffusion of trauma-related symptoms following a collective trauma. These effects may depend on the type of media and emotion regulation strategies used by the media consumer. Trauma history, traumatic symptoms, media consumption, psychological distress, and emotion regulation strategies of 451 young adults were assessed by an online survey. Findings reveal the joint role of social networks use and dysfunctional emotion regulation strategies on anxiety, depression, and somatization symptoms and also on cognitive and emotional alteration among traumatic symptoms. Consistent with the emotional contagion hypothesis, individuals who reported spending more time on social networks were also those who were experiencing more psychological distress.


Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke.
To review the literature on carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known carcinogens in tobacco smoke and include urinary metabolites, DNA adducts, and blood protein adducts. Published reviews and the current literature were searched for relevant articles. The most consistently elevated biomarker in people exposed to SHS was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc), urinary metabolites of the tobacco specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The tobacco specificity of this biomarker as well as its clear relation to an established lung carcinogen are particularly appropriate for its application in studies of SHS exposure. The results of the available carcinogen derived biomarker studies provide biochemical data which support the conclusion, based on epidemiologic investigations, that SHS causes lung cancer in non-smokers.


Machine learning derived echocardiographic image quality in patients with left ventricular systolic dysfunction: insights on the echo views of greatest image quality.
We sought to determine the cardiac ultrasound view of greatest quality using a machine learning (ML) approach on a cohort of transthoracic echocardiograms (TTE) with abnormal left ventricular (LV) systolic function. We utilize an ML model to determine the TTE view of highest quality when scanned by sonographers. A random sample of TTEs with reported LV dysfunction from 09/25/2017-01/15/2019 were downloaded from the regional database. Component video files were analyzed using ML models that jointly classified view and image quality. The model consisted of convolutional layers for extracting spatial features and Long Short-term Memory units to temporally aggregate the frame-wise spatial embeddings. We report the view-specific quality scores for each TTE. Pair-wise comparisons amongst views were performed with Wilcoxon signed-rank test. Of 1,145 TTEs analyzed by the ML model, 74.5% were from males and mean LV ejection fraction was 43.1 ± 9.9%. Maximum quality score was best for the apical 4 chamber (AP4) view (70.6 ± 13.9%, p<0.001 compared to all other views) and worst for the apical 2 chamber (AP2) view (60.4 ± 15.4%, p<0.001 for all views except parasternal short-axis view at mitral/papillary muscle level, PSAX M/PM). In TTEs scanned by professional sonographers, the view with greatest ML-derived quality was the AP4 view.


A pilot study of the relationship between multiple sclerosis and the physical environment in northwest Ireland.
Multiple sclerosis (MS) is a neurological disease of unknown origin, but it is though likely to have an environmental component in addition to genetic predisposition. It appears common in areas with underlying radon-producing granites. Radon exposure before the age of 15 years is postulated as a contributory cause in genetically susceptible individuals. Pilot studies were undertaken, with results which indicate that radon exposure may be a factor, and that the hypothesis warrants further investigation.


Twenty-four hour efficacy with the dorzolamide/timolol-fixed combination compared with the brimonidine/timolol-fixed combination in primary open-angle glaucoma.
The aim of this study is to compare the 24-hour efficacy of dorzolamide/timolol-fixed combination (DTFC) and brimonidine/timolol-fixed combination (BTFC) in primary open-angle glaucoma (POAG). One eye each of 77 POAG patients was included in this prospective, observer-masked, crossover comparison. Following a 2-month timolol run-in period, patients had three intraocular pressure (IOP) measurements at 1000, 1200 and 1400 h while on timolol treatment. Patients showing at least a 20% IOP reduction on timolol were randomised to 3 months of therapy with DTFC or BTFC, and then were crossed over to the opposite therapy. Sixty POAG patients completed the study. The mean 24-hour IOP was significantly reduced with both the fixed combinations compared with the timolol-treated diurnal IOP (P < 0.001). When the two fixed combinations were compared directly, DTFC demonstrated a lower mean 24-hour IOP level as compared with BTFC (mean difference: -0.7 mm Hg, 95% confidence interval (CI): (-1.0, -0.3), P < 0.001). At two individual time points, DTFC significantly reduced IOP more than BTFC: at 1800 h (-1.0 mm Hg, 95% CI (-1.6,-0.5), P = 0.001) and at 0200 (-0.9 mm Hg, 95% CI: (-1.4,-0.5), P = 0.001). No significant difference existed for the other time points. Both the fixed combinations significantly reduce 24-hour IOP in POAG. DTFC provided significantly better 24-hour efficacy.


Accelerated fractionation with a concurrent boost for early stage breast cancer.
Hypofractionated radiation refers to treatment with greater than 2 Gy per fraction, usually in fewer number and an overall shorter treatment period, compared to conventional radiation fractionation. Randomized prospective trials of hypofractionated whole breast irradiation (WBI) have demonstrated comparable outcomes as conventional fractionation in early stage postlumpectomy radiation in selected groups of patients. These data have changed the traditional radiobiology estimation of the alpha/beta ratio that predicted fractionation sensitivity for breast cancer, suggesting that further increase in dose per fraction is possible for early stage breast cancer without significantly increasing late effects. Many questions remain regarding hypofractionated WBI and span from optimal patient selection to radiation technique including dose planning optimization and the incorporation of a tumor bed boost. A concurrent radiation boost has been studied in a number of single institution studies and has shown to be feasible with acceptable acute and short-term late toxicity. A phase III trial by the Radiation Therapy Oncology Group (RTOG 1005) in North America and other trials in Europe are currently studying in-breast cancer control from hypofractionated WBI with a concurrent tumor bed boost. Results from these current trials could improve the acceptance and broaden the applicability of hypofractionation treatment courses for the treatment of patients with early stage breast cancer.


An evaluation of the Minnesota Multiphasic Personality Inventory as a discriminator of primary organic and primary psychogenic impotence in diabetic males.
The ability of the MMPI to discriminate between primary psychogenic impotence and primary organic impotence in males with diabetes mellitus was assessed. In order to provide the MMPI with the optimal situation to discriminate between the two groups, we attempted to form a homogeneous sample in terms of physical conditions. Thirty impotent diabetic males were classified as primary organic or primary psychogenic based on nocturnal penile tumescence data. Beutler et al.'s MMPI decision rules yielded a 63% misclassification of the two groups. Possible explanations for the lack of discriminative power of the MMPI with this sample of diabetic males were discussed in relation to previous findings. The power of nocturnal penile tumescence to classify men as having primary organic or primary psychogenic impotence was examined with reference to other vascular and endocrine variables.


Influence of perpendicular external magnetic field on microstructures of monolayer composed of ferromagnetic particles: analysis by means of quasi-two-dimensional Monte Carlo simulation.
We investigated the influences of the magnetic field strength and particle areal density on the microstructure of a quasi-two-dimensional monolayer composed of ferromagnetic particles by means of a Monte Carlo simulation. The magnetic field was applied along a direction perpendicular to the plane of the monolayer. Microstructures of the monolayer obtained in the simulations were analyzed in terms of radial distribution and orientational distribution functions. Formation of the microstructures is discussed from the perspective of particle-particle interaction energy and the perpendicular magnetic susceptibility of the monolayer was calculated from simulated magnetization curves. The obtained results are summarized as follows. For small areal density of particles, formation of chain-like structures is prevented by the repulsive magnetic interaction between particles due to orientations of the magnetic moments in the particles along the magnetic field direction. For intermediate areal density of particles, the chain-like structures remain even when a relatively strong magnetic field is applied, because contributions of the attractive magnetic interactions increase. For large areal density of particles, mixtures of chain-like and locally ordered structures appear due to the anisotropic attractive magnetic interactions in the absence of the magnetic field. However, when a sufficiently strong magnetic field is applied, the magnetic interactions between particles change to isotropic repulsive interactions, which results in the short-range repulsive steric interactions between particles becoming dominant with the appearance of hexagonal close packed structures.


Primiparous women's knowledge of diastasis recti abdominis, concerns about abdominal appearance, treatments, and perceived abdominal muscle strength 6-8 months postpartum. A cross sectional comparison study.
Diastasis recti abdominis (DRA) is a prevalent condition in the postpartum period. To date, there is scant knowledge on how DRA influences physical, mental, and emotional health. This study investigates primiparous women`s knowledge about DRA, concerns about abdominal appearance, and perceived abdominal muscle strength, comparing women with and without reported DRA. This was a cross-sectional comparison study. Data were collected by a web-based questionnaire, mainly through social media in Norway. To be included in the study women had to be primiparous 6-8 months postpartum. The questionnaire contained questions regarding women`s knowledge about DRA, perceived protrusion, received treatment, concerns with abdominal appearance and muscle strength. Abdominal body image was measured through the shape concern questions from The Eating Disorder Examination questionnaire (EDE-Q 6.0). Demographic and other descriptive variables are presented as means with standard deviations (SD) or as frequencies with percentages. Chi-square test of independence and independent sample t-tests were used to compare differences between women with and without abdominal protrusion for categorical and continuous variables, respectively. Our sample consisted of 460 women. Knowledge about DRA was reported by 415/440 (94.3%) women. A total of 73.3% reported to have been worried during pregnancy about abdominal appearance postpartum. Mean degree of concern about present abdominal appearance was 5.5/10 (SD 2.4). Almost 80% experienced weaker abdominal muscles than pre-pregnancy. Ninety-six women (20.9%) reported a protrusion along the midline of their abdomen. Significantly more women with protrusion reported weaker abdominal muscles than women without protrusion. The most frequent treatment women with protrusion reported were exercises for the abdominal muscles (92.6%). Mean score on the EDE-Q, shape concern questions, was higher in women with reported protrusion (mean score: 2.37 (SD 1.6) than women without protrusion (mean score: 2.14 (SD 1.4), p = 0.175. Primiparous women are concerned about abdominal appearance both during pregnancy and after birth. Those reporting abdominal protrusion are less satisfied with their abdominal appearance and they report weaker abdominal muscles than women without protrusion. This study may contribute to improved knowledge about women`s health concerns, and assessment of DRA should be part of routine follow-up of postpartum women.


Reduced CNS exposure of memantine in a triple transgenic mouse model of Alzheimer's disease assessed using a novel LC-MS technique.
A sensitive and robust LC-MS method for quantifying memantine (MEM) concentrations in mouse brain homogenate and perfusate was developed and validated. The developed LC-MS method exhibited good linearity between response and MEM concentrations in both perfusate and brain homogenate (r(2)=0.98-0.99) with mean accuracy and precision values of 105.6% and 7.7% (for perfusate) and 99.0% and 9.5% (for brain homogenate). This assay was then applied to determine the impact of reported blood-brain barrier (BBB) alterations in Alzheimer's disease (AD) on the CNS exposure of the anti-AD drug, MEM. The brain uptake of MEM was measured in 12-13 and 17-19 month old wild-type (WT) and triple transgenic (3 × Tg) AD mice using the developed LC-MS assay and a transcardiac perfusion technique. The transcardiac perfusion technique was validated in our laboratory with marker compounds (each representing different mechanisms of transport across the BBB) to ascertain that the physical and functional properties of the BBB were maintained using this technique. While the brain uptake of MEM was not significantly different between WT and 3 × Tg mice at 12-13 months, MEM brain uptake was significantly (p<0.05) decreased by 43% in 17-19 month old 3 × Tg mice relative to WT mice. Using this novel LC-MS technique, the CNS exposure of a therapeutically-relevant drug, MEM, has been shown to be decreased in AD, implying a need to assess the impact of this disorder on the brain uptake of other therapeutically-relevant compounds.


Evidence of recombination and genetic diversity in southern rice black-streaked dwarf virus.
Southern rice black-streaked dwarf virus (SRBSDV) causes one of the most serious viral diseases of rice in China and Vietnam. Sequence identities of S10, encoding the major capsid protein, were 98.0 %-100 % and 98.3 %-100 % at the nucleotide and amino acid level, respectively. Our results suggest that the codon at position 550 of S10 is under positive selection, while most of the other codons are under neutral evolution. Putative recombination events were identified in genomic RNA segments S1, 2, 4, 5, 6 and 10, which are rare in plant-infecting dsRNA viruses. This study reveals the current state of SRBSDV evolution.


Replication of genome-wide association studies of type 2 diabetes susceptibility in Japan.
In Europeans and populations of European origin, several groups have recently identified novel type 2 diabetes susceptibility genes, including FTO, SLC30A8, HHEX, CDKAL1, CDKN2B, and IGF2BP2, none of which were in the list of functional candidates. The aim of this study was to replicate in a Japanese population previously identified associations of single nucleotide polymorphisms (SNPs) within 10 candidate loci with type 2 diabetes using a relatively large sample size: 1921 subjects with type 2 diabetes and 1622 normal controls. A total of 15 SNPs were genotyped. Eight SNPs in five loci were found to be associated with type 2 diabetes: rs3802177 [odds ratio (OR) = 1.16 (95% confidence interval (CI) 1.05-1.27); P = 4.5 x 10(-3)] in SLC30A8; rs1111875 [OR = 1.27 (95% CI 1.14-1.40); P = 1.4 x 10(-5)] and rs7923837 [OR = 1.27 (95% CI 1.13-1.43); P = 1.0 x 10(-4)] in HHEX; rs10811661 [OR = 1.27 (95% CI 1.15-1.40); P = 1.9 x 10(-6)] in CDKN2B; rs4402960 [OR = 1.23 (95% CI 1.11-1.36); P = 8.1 x 10(-5)] and rs1470579 [OR = 1.18 (95% CI 1.07-1.31); P = 8.3 x 10(-4)] in IGF2BP2; and rs7754840 [OR = 1.28 (95% CI 1.17-1.41); P = 4.5 x 10(-7)] and rs7756992 [OR = 1.27 (95% CI 1.15-1.40); P = 9.8 x 10(-7)] in CDKAL1. The first and second strongest associations were found at variants in CDKAL1 and CDKN2B, both of which are involved in the regenerative capacity of pancreatic beta-cells. Some of these variants represent common type 2 diabetes-susceptibility genes in both Japanese and Europeans.


Clinical correlations of antibodies in pemphigus studied by radioimmunoassay.
Pemphigus antibodies of class G immunoglobulins (IgG) were studied with the use of a solid-phase radioimmunoassay (RIA) that utilizes COLO-16, a squamous cell tumor line, as the substrate. Sera from patients with pemphigus vulgaris and pemphigus vegetans showed greater average binding than did sera from patients with pemphigus foliaceus and pemphigus erythematosus. The patients were subgrouped according to their clinical presentations and were divided into patients with skin lesions only, those with mucous membrane lesions only, and those with both skin and mucous membrane lesions. No significant differences were observed between these groups. There was good correlation between IgG binding in the RIA and both the disease activity and the response to therapy. Blood group antigen absorbable "false positive" anti-intercellular substance antibodies were not detected in the RIA.


Improved chemical shift based fragment selection for CS-Rosetta using Rosetta3 fragment picker.
A new fragment picker has been developed for CS-Rosetta that combines beneficial features of the original fragment picker, MFR, used with CS-Rosetta, and the fragment picker, NNMake, that was used for purely sequence based fragment selection in the context of ROSETTA de-novo structure prediction. Additionally, the new fragment picker has reduced sensitivity to outliers and other difficult to match data points rendering the protocol more robust and less likely to introduce bias towards wrong conformations in cases where data is bad, missing or inconclusive. The fragment picker protocol gives significant improvements on 6 of 23 CS-Rosetta targets. An independent benchmark on 39 protein targets, whose NMR data sets were published only after protocol optimization had been finished, also show significantly improved performance for the new fragment picker (van der Schot et al. in J Biomol NMR, 2013).


Using a sensitivity study to facilitate the design of a multi-electrode array to measure six cardiac conductivity values.
When using the bidomain model to model the electrical activity of the heart, there are potentially six cardiac conductivity values involved: conductivity values in directions along and normal to the cardiac fibres with a sheet, as well as a conductivity value in the normal direction between the sheets, and these occur for both the extracellular and intracellular domains in the model. To date it has been common to assume that the two normal direction conductivity values are the same. However, recent work has demonstrated that six cardiac conductivity values, rather than four, are necessary for accurate modelling, which can then facilitate understanding of cardiovascular disease. To design a method to determine these conductivities, it is also necessary to design a suitable multi-electrode array, which can be used, in conjunction with an inversion technique, to retrieve conductivity values from measurements of potential made on the array. This work uses the results of a study, into the sensitivity of the measuring potentials to variability in the input conductivities, to facilitate the design of an array that could be used to retrieve six cardiac conductivity values, as well as fibre rotation angle. It is found that if an electrode in the array has a much lower value of potential than the other electrodes, then it tends to be much more sensitive to the input conductivities than the other electrodes. It also appears that inclusion of this type of electrode in the set of measuring electrodes is essential for accurately retrieving conductivity values. This technique is used to identify electrodes to be included in the array and using the final design it is demonstrated, using synthetic values of potential, that the six cardiac conductivity values, and the fibre rotation angle, can be retrieved very accurately.


Schistosoma mansoni: localization of calcium-detecting reagents in electron-lucent areas of specific preacetabular gland granules.
In an attempt to establish the exact location of calcium within the preacetabular glands of cercariae of Schistosoma mansoni, these larvae were exposed to reagents (potassium oxalate, potassium pyroantimonate, chloranilic acid, and silver nitrate) useful in the detection of calcium, and were subsequently observed with the aid of light and electron microscopes. Cercariae incubated in potassium oxalate and viewed in polarized light showed birefringence only in the preacetabular gland funduses. At the ultrastructural level, the preacetabular glands of potassium oxalate-treated cercariae had no electron-dense precipitate, but instead had translucent, irregularly shaped inclusions, similar to spaces left by volatilized calcium oxalate as described by others. Pyroantimonate treatment, on the other hand, localized the reaction in the electron-lucent areas of the light-spotted granules. The von Kossa silver nitrate procedure destroyed the secretory granules; therefore, an electron-dense precipitate was distributed throughout the gland. However, pretreatment with chloranilic acid before fixation preserved the granules, and subsequent exposure to the von Kossa silver nitrate gave a reaction identical to that obtained with the pyroantimonate alone. When viewed in polarized light, chloranilic acid-incubated cercariae showed birefringence in the fundus and duct areas.


Chemokines: signal lamps for trafficking of T and B cells for development and effector function.
Chemokines can act as signal lamps for trafficking of lymphocytes at the important crossing points of lymphoid tissues. Lymphoid progenitors at different differentiation stages are differentially localized in primary lymphoid tissues and have differential responsiveness to thymic or bone marrow chemokines: SDF-1, CKbeta-11/MIP-3beta/ELC, SLC/6Ckine/Exodus2, MIP-1beta, and TECK. Naive T cells and B cells circulate to secondary lymphoid tissues for possible activation. Chemokines, SDF-1, SLC/6Ckine/Exodus2, CKbeta-11/MIP-3beta/ELC, BLC/BCA-1, and DC-CK1/PARC, are expressed in the specialized microenvironments of secondary lymphoid tissues and regulate the migration of naive lymphocytes. Effector lymphocytes express a different set of chemokine receptors from naive lymphocytes. T helper (Th) 0 and 1 cells predominantly express CXCR3 and CCR5, whereas Th2 cells express CCR3, CCR4, and CCR8, which, with other factors such as expression patterns of adhesion molecules, likely determine the tissue-specific infiltration of effector lymphocytes.


Should analyses of large, national palliative care data sets with patient reported outcomes (PROs) be restricted to services with high patient participation? A register-based study.
There is an increased interest in the analysis of large, national palliative care data sets including patient reported outcomes (PROs). No study has investigated if it was best to include or exclude data from services with low response rates in order to obtain the patient reported outcomes most representative of the national palliative care population. Thus, the aim of this study was to investigate whether services with low response rates should be excluded from analyses to prevent effects of possible selection bias. Data from the Danish Palliative Care Database from 24,589 specialized palliative care admittances of cancer patients was included. Patients reported ten aspects of quality of life using the EORTC QLQ-C15-PAL-questionnaire. Multiple linear regression was performed to test if response rate was associated with the ten aspects of quality of life. The score of six quality of life aspects were significantly associated with response rate. However, in only two cases patients from specialized palliative care services with lower response rates (< 20.0%, 20.0-29.9%, 30.0-39.9%, 40.0-49.9% or 50.0-59.9) were feeling better than patients from services with high response rates (≥60%) and in both cases it was less than 2 points on a 0-100 scale. The study hypothesis, that patients from specialized palliative care services with lower response rates were reporting better quality of life than those from specialized palliative care services with high response rates, was not supported. This suggests that there is no reason to exclude data from specialized palliative care services with low response rates.


Application of a Serum Protein Signature for Pancreatic Cancer to Separate Cases from Controls in a Pancreatic Surveillance Cohort.
Pancreatic cancer (PC) surveillance is currently offered to individuals with a genetic predisposition to PC, but routinely used radiological screening modalities are not entirely reliable in detecting early-stage PC or its precursor lesions. We recently identified a discriminating PC biomarker signature in a sporadic patient cohort. In this study, we investigated if protein profiling can accurately distinguish PC from non-PC in a pancreatic surveillance cohort of genetically predisposed individuals. Serum samples of 66 individuals with a CDKN2A germline mutation who participated in the pancreatic surveillance program (5 cases, 61 controls) were obtained following a standardized protocol. After sample clean-up, peptide and protein profiles were obtained on an ultrahigh-resolution matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry platform. A discriminant score for each sample was calculated with a previously designed prediction rule, and the median discriminant scores of cases and controls were compared. Individuals with precursor lesions of PC (n = 4) and individuals with a recent diagnosis of melanoma (n = 4) were also separately considered. Cases had a higher median discriminant score than controls (0.26 vs 0.016; P = .001). The only individual with pathologically confirmed precursor lesions of PC could also be clearly distinguished from controls, and having a (recent) medical history of melanoma did not influence the protein signatures. Peptide and protein signatures are able to accurately distinguish PC cases from controls in a pancreatic surveillance setting. Mass spectrometry-based protein profiling therefore seems to be a promising candidate for implementation in the pancreatic surveillance program as an additional screening modality.


Membrane potential and resistance changes induced in salivary gland acinar cells by microiontophoretic application of acetylcholine and adrenergic agonists.
The effects of microiontophoretic applications of catecholamines and acetylcholine on parotid acinar cell membrane potential and resistance were investigated using intracellular microelectrode recording in superfused segments of mouse parotid or rat submandibular glands. Short pulses of acetylcholine and alpha-adrenergic agonists had similar effects, consisting of a marked decrease in membrane resistance accompanied by an initial depolization or hyperpolarization depending on the level of the resting membrane potential. This initial response was followed by a slow hyperpolarization occurring at a time when the resistance was increasing towards the prestimulation level. The equilibrium potential for the initial potential change caused by excitation of the cholinergic receptors was investigated directly by setting the membrane potential at different levels by injecting direct current and stimulating the same cell repeatedly with equal doses of acetylcholine. The equilibrium potential was found to be about -55 mV. The delayed hyperpolarization could not be reversed by passing hyperpolarizing current, but actually increased in size with higher membrane potentials. The minimum latency of the effect of acetylcholine or alpha-adrenergic agonists was 200-500 msec. Excitation of beta-adrenoceptors caused, after a long latency of several seconds, a small depolarization. Epinephrine induced a combined alpha- and beta-adrenergic response, with the alpha-component predominating. Blocking the alpha-adrenoceptors with phentolamine revealed the beta-adrenergic depolarization, while blocking the beta-adrenoceptors with propranolol caused the components of the alpha-adrenergic response to become more pronounced. All three receptors (alpha- and beta-adrenoceptors and cholinergic receptors) were present in individual acini.


Motor learning processes in a movement-scaling task in olivopontocerebellar atrophy and Parkinson's disease.
Nine Parkinson's disease (PD), seven olivopontocerebellar atrophy (OPCA) patients and two age-matched control groups learned a linear arm movement-scaling task over 2 days, requiring movements proportional in length to visually presented target-bars. Scaling was acquired through knowledge of results (KR concerning the direction and magnitude of errors) following every second acquisition trial. Initial acquisition of both groups was significantly worse than their respective controls (poorer movement scaling), but rapidly improved to nearly identical levels. Retention for the PD group's movement scaling was as good as controls initially, but markedly poorer after 24 h. The OPCA group did not show this deficit. Both patient groups extrapolated accurately to longer, previously unpracticed target distances (no KR provided), suggesting an unimpaired capacity to generate and use an internal representation of the movement scaling. They also rapidly learned a new scaling relationship when the gain was changed. Overall, the learning of this movement-scaling task was not adversely affected in OPCA, and the impairment was restricted primarily to longer-term retention in PD. The study suggests that: (1) the ability to acquire movement scaling in a task that requires conscious use of error feedback and no new coordination may depend little on the cerebellum, and (2) the basal ganglia may participate in longer-term storage of scaling information.


A trans-omic Mendelian randomization study of parental lifespan uncovers novel aging biology and therapeutic candidates for chronic diseases.
The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and aging-associated diseases. Here, we leveraged summary statistics of a genome-wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype-Tissue Expression project. Through a combination of multi-tissue transcriptome-wide association analyses and genetic colocalization, we identified novel genes that may be associated with parental lifespan. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan and chronic diseases offering new drug repositioning opportunities such as those targeting apolipoprotein-B-containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome-wide MR analyses were used to map genetically regulated genes, proteins and metabolites with other human traits as well as the disease-related phenome in the FinnGen cohorts (n = 135,638). Altogether, this study identified new candidate genes, circulating proteins and metabolites that may influence human aging as well as potential therapeutic targets for chronic diseases that warrant further investigation.


Histogram analysis based on diffusion kurtosis imaging: Differentiating glioblastoma multiforme from single brain metastasis and comparing the diagnostic performance of two region of interest placements.
To assess the value of histogram analysis, using diffusion kurtosis imaging (DKI), in differentiating glioblastoma multiforme (GBM) from single brain metastasis (SBM) and to compare the diagnostic efficiency of different region of interest (ROI) placements. Sixty-seven patients with histologically confirmed GBM (n = 35) and SBM (n = 32) were recruited. Two ROIs-the contrast-enhanced area and whole-tumor area-were delineated across all slices. Eleven histogram parameters of fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) from both ROIs were calculated. All histogram parameter values were compared between GBM and SBM, using the Mann-Whitney U test. The accuracies of different histogram parameters were compared using the McNemar test. Receiver operating characteristic (ROC) analyses were conducted to assess the diagnostic performance. In the contrast-enhanced area, FA10, FA25, FA75, FA90, FAmean, FAmedian, FAmax, MDmax, MDskewness, and MKskewness were significantly higher for GBM than for SBM. FAskewness was significantly lower for GBM than for SBM. FA25 (0.815) had the highest area under the curve (AUC). In the whole-tumor area, FA10, FA25, FA75, FA90, FASD, FAmean, FAmedian, FAmax, MDmax, MDskewness, and MKskewness were significantly higher for GBM than for SBM. FAmedian (0.805) had the highest AUC. The accuracy of FA25 in the contrast-enhanced area was significantly higher than that of the FAmedian in the whole-tumor area. GBM and SBM can be differentiated using the DKI-based histogram analysis. Placing the ROI on the contrast-enhanced area results in better discrimination.


Risk factors affecting visual outcomes following dropped nucleus after cataract surgery.
To describe the visual outcomes in eyes with dropped nucleus during phacoemulsification surgery. Singapore National Eye Centre (SNEC). Retrospective chart review of prospectively reported cases of dropped nucleus. The clinical charts of all cases of dropped nucleus (Jan 2001 to Dec 2016) were retrospectively reviewed for patient demographics, surgeon type, stage of surgery, timing of pars plana vitrectomy (PPV), and complications. Visual success was defined as best corrected visual acuity (BCVA) ≥ 20/40 at last review. Final risk factors affecting visual success were identified using multivariate logistic regression analysis. Incidence of dropped nucleus following cataract surgery was 0.17% (n = 292). Duration of follow-up was 25.5 months (mean), 18.5 months (median). There was a statistically significant difference in dropped nucleus rate between Residents (0.3%) and Faculty (0.14%) (x2 = 38.2, P < 0.001), but ensuing major complications rates were similar. PPV was performed in 251 eyes (87.2%). At final examination, 202 cases (85.2%) achieved BCVA 20/40 or better, after excluding patients with co-existing ocular pathology. Timing of vitrectomy (delayed vs same-day) did not influence the final visual success (x2 = 0.969, p = 0.51). Risk factors for poor visual outcomes included age >70 years, absence of intraocular lens (IOL) implant, and presence of major complications. Overall incidence of dropped nucleus in SNEC was 0.17%, with BCVA of 20/40 or better in 85.2% cases. Visual prognosis was influenced by patient's age, presence of IOL implant or additional major complications.


Can PK/PD be used in everyday clinical practice.
Over the last decade much insight has been gained in the relationships between dosing regimens of antimicrobials and bacterial eradication and clinical efficacy. These pharmacokinetic-pharmacodynamic (PK/PD) relationships have become available as tools in individualising antimicrobial therapy. To be able to do this, the PK parameters of the antimicrobial in the individual patient have to be known or estimated, and the MIC of the micro-organism causing the infection, known. In our hospital, we have started a programme using this approach. Preliminary results suggest that dose optimisation leads to increased efficacy and lower costs.


Beta-Blockers and Hypertension: Some Questions and Answers.
International guidelines have removed b-blockers from first-line treatment of hypertension, limiting their use to patients with compelling indications. The position of guidelines stems from the results of studies performed with the 1st and 2nd generation of b-blockers, which concluded that these drugs have lower cardiovascular protection, compared with other antihypertensive agents. The aim of our mini review is to answer to some questions about the effect of b-blockers on hypertension and cardiovascular protection and if these effects are different from those of other antihypertensive drugs, particularly in young and elderly patients. We evaluated the relevant systematic reviews and meta-analyses, which reported the effectiveness of b-blockers on blood pressure and cardiovascular outcomes, compared with placebo/no treatment and with other antihypertensive agents. Beta-blockers, decreased high blood pressure with no significant difference from other common antihypertensive agents. Moreover b-blockers, compared with placebo, lowered the risk of major cardiovascular outcomes, while, compared with other drug classes, the reported results are very heterogeneous. Therefore it is difficult, globally, to find a difference between b-blockers and other drug classes. Rather than looking for differences in the cardiovascular protective effect between b-blockers and other antihypertensive agents, we have to consider the different pathophysiology of hypertension in young [sympathetic hyperactivity] and elderly patients [arterial stiffness, high aortic systolic pressure]. Considering these aspects, non-vasodilating b-blockers are preferred, as first-line, in young/middle aged hypertensive subjects, while vasodilating b-blockers, are most appropriate, in elderly patients, for the favourable hemodynamic profile.


Supercritical fluid extraction of aurentiamide acetate from Patrinia villosa Juss and subsequent isolation by silica gel and high-speed counter-current chromatography.
Supercritical fluid extraction (SFE) of aurentiamide acetate from Patrinia villosa Juss was performed. The optimization of parameters was carried out using an analytical-scale supercritical fluid extraction (SFE) system. Then the extraction was scaled up by 100 times using a preparative SFE system under the optimized conditions of 55 degrees C, 35 MPa and modified CO2 with 10% methanol. Then, the crude extract I obtained by SFE was chromatographed on silica gel and the solvent system composed of petroleum ether-ethyl acetate (5:1, v/v) was used to produce the crude extract II, which was further isolated and purified by high-speed counter-current chromatography (HSCCC) with a two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (1:1.2:1.2:1, v/v/v/v). One hundred fifty-five milligrams of aurentiamide acetate was obtained from 400 mg crude extract II (contained 42% target) with a purity of 99.3% determined by HPLC and 92.3% recovery in one-step elution, and identification was performed by UV, MS, 1H NMR and 13C NMR. As far as we know, this is the first report of discovering aurentiamide acetate from the plant of Patrinia genius.


The importance of software programmable pacemakers: in vivo programming of a prototype device.
Recently, we have developed microcomputer-oriented pacemakers with true software flexibility. The first 25 devices implanted (DPG-1 type) exhibited an unexpected phenomenon caused by a microcomputer error. A safety mechanism switched off all special functions and automatically reset all parameters to standard settings. The problem was solved by noninvasive modification of the software. More than 200 units (TX-1 type), which are rate responsive pacemakers based on the QT principal, were implanted up to May 1984. These pacemakers were built using the same microelectronics as used in the DPG 1 pacemaker. Knowledge gained from clinical evaluation was directly applied not only to the patients receiving new implants but also to the preexisting implantees. This was done by software reprogramming in the implanted unit.


Pre- and post-nicotine circadian activity rhythms can be differentiated by a paired environmental cue.
Previous studies have shown that addictive drugs presented daily at fixed times produce circadian (oscillator-driven) anticipatory and evoked activity rhythms in rats. Other studies have shown that environmental cues paired with addictive drugs produce tolerance to drug effects and elicit craving behavior when presented without the drug. The present study tested these circadian entrainment and paired-cue conditioning effects together. This study compared the ability of daily nicotine and saline injections at different fixed times to entrain pre-injection (anticipatory) and post-injection (evoked) circadian activity rhythms in two groups of female Sprague-Dawley rats. One group (Paired) had an environmental cue (a tone) paired with the effects of the nicotine injection, and the second group (Unpaired) had the tone paired with the effects of the saline injection. The rats were housed singly for 56 days in chambers with attached wheels under constant dim light and rate-limited food access. During three separate injection phases, nicotine and saline were administered daily at different fixed times, and the tone was presented at the second injection time. Three multi-day test phases examined circadian activity (a) without injections or tone, (b) with the tone alone at normal and novel times, and (c) with the tone absent and with injections occurring at normal and at novel times. The results showed that nicotine entrained both pre- and post-injection circadian oscillators, and the nicotine-paired tone interfered with pre-injection anticipatory activity.


The association between how medical students were selected and their perceived stress levels in Year-1 of medical school.
The prevalence of medical students' mental distress is high. While schools apply various methods to select a well-performing and diverse student population, little is known about the association between different selection methods and the well-being of these students during medical school. The present retrospective multi-cohort study assessed whether students selected by high grades, assessment, or weighted lottery showed different stress perception levels in Year-1 of medical school. Of 1144 Dutch Year-1 medical students, 650 (57%) of the cohorts 2013, 2014, and 2018 who were selected by high grades, assessment, or weighted lottery completed a stress perception questionnaire (PSS-14). A multilevel regression analysis assessed the association between selection method (independent variable) and stress perception levels (dependent variable) while controlling for gender and cohort. In a post-hoc analysis, academic performance (optimal vs. non-optimal) was included in the multilevel model. Students selected by assessment (B = 2.25, p < .01, effect size (ES) = small) or weighted lottery (B = 3.95, p < .01, ES = medium) had higher stress perception levels than students selected by high grades. Extending the regression model with optimal academic performance (B=-4.38, p < .001, ES = medium), eliminated the statistically significant difference in stress perception between assessment and high grades and reduced the difference between weighted lottery and high grades from 3.95 to 2.45 (B = 2.45, p < .05, ES = small). Selection methods intended to create a diverse student population - assessment and lottery - are associated with higher stress perception levels in Year-1 of medical school. These findings offer medical schools insights into fulfilling their responsibility to take care of their students' well-being.


Paravalvular fistula in mitral valve implant. Intimation of malfunction of implant and quantification of regurgitant flow from effective area measurements.
Non-invasive ultrasound Doppler registrations and cardiac output determinations with a thermodilution catheter were performed in the presence of and after closure of a paravalvular mitral fistula in a 52-year-old patient with a 27 mm Björk-Shiley mitral valve. The data collected allowed the calculation of the regurgitant flow through the fistula. This study suggests that the method used can be of diagnostic value when mitral valve implant malfunction is suspected.


Efficient production of α-ketoglutarate in the gdh deleted Corynebacterium glutamicum by novel double-phase pH and biotin control strategy.
Production of L-glutamate using a biotin-deficient strain of Corynebacterium glutamicum has a long history. The process is achieved by controlling biotin at suboptimal dose in the initial fermentation medium, meanwhile feeding NH4OH to adjust pH so that α-ketoglutarate (α-KG) can be converted to L-glutamate. In this study, we deleted glutamate dehydrogenase (gdh1 and gdh2) of C. glutamicum GKG-047, an L-glutamate overproducing strain, to produce α-KG that is the direct precursor of L-glutamate. Based on the method of L-glutamate fermentation, we developed a novel double-phase pH and biotin control strategy for α-KG production. Specifically, NH4OH was added to adjust the pH at the bacterial growth stage and NaOH was used when the cells began to produce acid; besides adding an appropriate amount of biotin in the initial medium, certain amount of additional biotin was supplemented at the middle stage of fermentation to maintain a high cell viability and promote the carbon fixation to the flux of α-KG production. Under this control strategy, 45.6 g/L α-KG accumulated after 30-h fermentation in a 7.5-L fermentor and the productivity and yield achieved were 1.52 g/L/h and 0.42 g/g, respectively.


The ORF3 Protein of Genotype 1 Hepatitis E Virus Suppresses TLR3-induced NF-κB Signaling via TRADD and RIP1.
Hepatitis E virus (HEV) genotype 1 infection is common and can emerge as outbreaks in developing areas, thus posing a threat to public health. However, due to the absence of feasible animal models, the mechanism of HE pathogenesis remains obscure. The HEV pathogenic mechanism has been suggested to be mediated by the immune system and not by direct viral duplication. We firstly discovered that the open reading frame 3 (ORF3) protein of genotype 1 HEV downregulates TLR3-mediated NF-κB signaling in Human A549 Lung Epithelial Cells (A549 cells) which were exposed to different TLR agonists associated with viral nucleic acids. Additionally, we identified the P2 domain of ORF3 as being responsible for this inhibition. Intriguingly, tumor necrosis factor receptor 1-associated death domain protein (TRADD) expression and receptor-interacting protein kinase 1 (RIP1) K63-ubiquitination were reduced in the presence of both ORF3 and Poly(I:C). Furthermore, we found that Lys377 of RIP1 acts as the functional ubiquitination site for ORF3-associated inhibition. Overall, we found that ORF3 protein downregulates TLR3-mediated NF-κB signaling via TRADD and RIP1. Our findings provide a new perspective on the cellular response in HEV infection and expand our understanding of the molecular mechanisms of HEV pathogenesis in innate immunity.


Interval gastric cancer: A call to attentiveness and action.
Endoscopy is the most effective method for identifying gastric adenocarcinoma (GAC). Interval gastric cancer (IGC) is GAC that is diagnosed 2-3 years after a normal endoscopy. Its characteristics are unknown in the Colombian environment. The clinical, histopathologic, and endoscopic characteristics were evaluated, along with the presentation rate, proton pump inhibitor (PPI) use, and IGC survival rate, and compared with other types of GAC. A retrospective, analytic study was conducted on a prospective cohort. It evaluated 513 patients with GAC treated at our institution, within the time frame of January 2012 and June 2018. The patients had endoscopic diagnosis of GAC and endoscopy within the past three years that was negative for tumor. A total of 513 patients diagnosed with GAC were evaluated. Forty-two of the patients had IGC (8.2%): 9 early lesions and 33 advanced lesions (79%). The IGCs were smaller (31 vs. 41 mm; P < .01), as well as flatter and more depressed (P < .01). There was no association with PPI use, but there was an association with a history of gastrectomy and anastomosis (P = .02), as well as the absence of red flags (P < .003). The most frequent locations were the gastric body (52%) and the antrum (26%). Overall two-year survival was similar between IGC and GAC (37.1 vs. 39.3%, P = .72). A total of 8.2% of recently diagnosed GAC were cases of IGC. The presence of anastomosis and the absence of red flags were related to IGC. Overall survival was poor and there were no differences from the other types of GAC detected.


Extending the indication for robot-assisted retroperitoneal partial nephrectomy to antero-lateral renal tumors.
Robot-assisted retroperitoneal partial nephrectomy (RARPN) is typically employed for posterior renal tumors. This work aimed to extend the indication of RARPN to patients with selected antero-lateral renal tumor. Patients who underwent RARPN between December 2013 and September 2015 at the authors' institution were enrolled. Two intersecting lines were drawn on an axial CT image to define the medial/lateral nature of anterior renal tumors. Patients with antero-lateral tumor and posterior tumor were compared. Antero-lateral tumors constituted 56.1% (32/57) of the total cases. The perioperative outcomes between the two groups were comparable. Although the operation time was longer for the antero-lateral tumor group, it did not show statistical significance. No cases had positive margins. There was one case of Clavien-Dindo grade IIIa complication in the antero-lateral tumor group. RARPN is a safe and effective procedure not only for posterior renal tumors but also for carefully selected antero-lateral renal tumors. Copyright © 2016 John Wiley & Sons, Ltd.


Modulation of cellular thiol status affects FoxO activity and life span.
Diethyl maleate (DEM) is a thiol-depleting agent frequently employed in cell culture analyses. Here, we investigated the effect of DEM exposure on insulin signaling at the level of FoxO transcription factor activity and its potential consequences for stress resistance and life span. Exposure of HepG2 human hepatoma cells to subcytotoxic concentrations of DEM resulted in nuclear accumulation of overexpressed EGFP-tagged FoxO1a. DEM-induced nuclear accumulation overrode insulin-induced nuclear exclusion of FoxO1a. Despite a slightly enhanced FoxO DNA binding activity in DEM-exposed cells, expression of FoxO-regulated genes (glucose 6-phosphatase, selenoprotein P) was downregulated, indicating that nuclear accumulation does not necessarily coincide with enhanced transcription factor activity. To test for an effect of DEM on organismal stress resistance, we exposed C. elegans roundworms to the thiol depletor. Survival in the presence of the redox cycler paraquat was significantly increased following exposure to DEM, implying that DEM pre-exposure induced cellular resistance against oxidative stress. Furthermore, in DEM-exposed C. elegans populations expressing a GFP-tagged version of the C. elegans FoxO ortholog, DAF-16, numbers of worms with predominantly nuclear DAF-16 increased - in line with the findings from HepG2 cells. In keeping with the known function of DAF-16 in stress resistance, C. elegans life span was elevated upon exposure to DEM in a concentration-dependent manner. A maximum extension of life span and deceleration of aging was achieved at 100 µ? of DEM. In summary, exposure to DEM caused a modulation of FoxO subcellular localization in both HepG2 cells and C. elegans roundworms, followed by a modulation of life span and stress resistance in C. elegans.


Percutaneous computer-assisted translaminar facet screw: an initial human cadaveric study.
Translaminar facet screws are a minimally invasive technique for posterior lumbar fixation with good success rates. Computer-assisted image navigation using virtual fluoroscopy allows multiple simultaneous screens in various planes to plan and drive spinal instrumentation. This study evaluates the percutaneous placement of translaminar facet screws with the use of virtual fluoroscopy as an image guidance technique. A human cadaveric study was performed with a percutaneous reference frame applied to the iliac crest. Ten translaminar facet screws were placed bilaterally at five levels. Anteroposterior and lateral images were used to navigate 4.0-mm screws through a percutaneous portal under virtual fluoroscopy. An axial computed tomographic scan through the instrumented levels was obtained after the screws were placed. Screws were graded on entry, course through the lamina, and terminus. A grading system was devised to grade the course through the lamina. All 10 screw-entry points were judged optimal at the spinous process laminar junction. There were five Grade I breeches with less than 1/2 the screw through the lamina, and five Grade 0 screw placements with the screw contained completely within the lamina. The termination point was acceptable in five screws. The screws that began on the right and terminated on the left were all found to have grade II breakouts. No screws placed the spinal canal or exiting nerve root at risk. Virtual fluoroscopy provides significant assistance in percutaneous placement of translaminar facet screws and results in safe position of entry, lamina course, and terminus.


Increased hepatic androgen receptor expression in female rats during diethylnitrosamine liver carcinogenesis. A possible correlation with liver tumor development.
This study investigated the relationship between liver tumor development and androgen-receptor expression in diethylnitrosamine hepatocarcinogenesis in Wistar rats (SUAH substrain). Random liver samples were assayed by an isoelectric focusing method, with [3H]mibolerone as androgenic radioligand. After 16 wk of oral diethylnitrosamine treatment there was a greater than 20-fold increase in hepatic androgen receptor concentration in female rats (control group 0.3 +/- 0.07 fmol/mg cytosol protein; test group 8.36 +/- 0.96 fmol/mg cytosol protein; p less than 0.001, unpaired Student's t-test). This coincided with, and may be related to, an accelerated development of neoplastic nodules or hepatocellular carcinoma, or both. Male rats showed slower tumor development and no change in androgen receptor concentrations. This model is the first to demonstrate significantly increased androgen sensitivity in experimental hepatic carcinogenesis analogous to increased androgen receptor expression in human hepatocellular carcinoma. It may provide insight into steroid hormone sensitivity in developing tumors, and a means of testing potential therapeutic use of hormonal manipulation in human liver cancer.


Enhanced germicidal effects of pulsed UV-LED irradiation on biofilms.
The major objective of the study was to evaluate the enhanced germicidal effects of low-frequency pulsed ultraviolet A (UVA)-light-emitting diode (LED) on biofilms. The germicidal effects of UVA-LED irradiation (365 nm, 0·28 mW cm(-2) , in pulsed or continuous mode) on Candida albicans or Escherichia coli biofilms were evaluated by determining colony-forming units. The morphological change of microbial cells in biofilms was observed using scanning electron microscopy. After 5-min irradiation, over 90% of viable micro-organisms in biofilms had been killed, and pulsed irradiation (1-1000 Hz) had significantly greater germicidal ability than continuous irradiation. Pulsed irradiation (100 Hz, 60 min) almost completely killed micro-organisms in biofilm (>99·9%), and 20-min irradiation greatly damaged both microbial species. Interestingly, few hyphae were found in irradiated Candida biofilms. Moreover, mannitol treatment, a scavenger of hydroxyl radicals (OH(•) ), significantly protected viable micro-organisms in biofilms from UVA-LED irradiation. The study demonstrated that pulsed UVA-LED irradiation has a strong germicidal effect (maximum at 100 Hz, over 5-min irradiation) and causes the disappearance of hyphal forms of Candida. This study can assist in developing a low-frequency pulsed UVA-LED system to be applied to pathogenic biofilms for disinfection.


R411C mutation of the ALAS2 gene encodes a pyridoxine-responsive enzyme with low activity.
A R411C missense mutation of the erythroid-specific delta-aminolaevulinate synthase (ALAS2) gene was identified in a pedigree with X-linked pyridoxine-responsive sideroblastic anaemia (XLSA). The normal and the mutant cDNAs were expressed in E. coli, and the enzyme protein was purified. ALAS activity of the mutant enzyme was 12% and 25%, when incubated in the absence and the presence of pyridoxal 5'-phosphate, respectively, compared with that of the wild-type enzyme. These findings suggest that the R411C mutation accounts for low ALAS activity and a partial pyridoxine-responsiveness of the disease in the patient.