Contrast-enhanced magnetic resonance imaging of central nervous system tumors: agents, mechanisms, and applications.
Brain tumors are one of the most common neoplasms in young adults and are associated with a high mortality and disability rate. Magnetic resonance imaging (MRI) is widely accepted to be the most sensitive imaging modality in the assessment of cerebral neoplasms. Because the detection, characterization, and exact delineation of brain tumors require a high lesion contrast that depends on the signal of the lesion in relation to the surrounding tissue, contrast media is given routinely. Anatomical and functional, contrast agent-based MRI techniques allow for a better differential diagnosis, grading, and especially therapy decision, planing, and follow-up. In this article, the basics of contrast enhancement of brain tumors will be reviewed. The underlying pathology of a disrupted blood-brain barrier and drug influences will be discussed. An overview of the currently available contrast media and the influences of dosage, field strength, and application on the tumor tissue contrast will be given. Challenging, contrast-enhanced, functional imaging techniques, such as perfusion MRI and dynamic contrast-enhanced MRI, are presented both from the technical side and the clinical experience in the assessment of brain tumors. The advantages over conventional, anatomical MRI techniques will be discussed as well as possible pitfalls and drawbacks.


Fear of relapse and quality of life in multiple sclerosis: The mediating role of psychological resilience.
The goal of this study was to examine the mediating role of psychological resilience in the relationship between fear of relapse and quality of life in a sample of patients with multiple sclerosis (PwMS). This cross-sectional study was developed online. A total of 240 PwMS were surveyed using the Multiple Sclerosis Quality of Life inventory, the Fear of Relapse Scale and the Connor-Davidson Resilience Scale. To perform the mediation analysis PROCESS macro was used. In our study, fear of relapse was a predictor of psychological resilience and quality of life, and psychological resilience was a predictor of quality of life. Finally, psychological resilience showed a mediating role in the relationship between fear of relapse and quality of life. Considering that resilience is a modifiable variable, the implementation of interventions aimed at enhancing resilience can have a favorable impact on the psychological well-being and quality of life of patients with multiple sclerosis.


Work-related asthma.
Work-related asthma (WRA) is highly prevalent in the adult population. WRA includes occupational asthma (OA), which is asthma caused by workplace exposures, and work-exacerbated asthma (WEA), also known as work-aggravated asthma, which is preexisting or concurrent asthma worsened by workplace conditions. In adults, the estimated prevalence of OA is 16.0%, whereas that of WEA is 21.5%. An increasing number of chemicals used in industrial production, households, and services are associated with the incidence of adult-onset asthma attributable to exposure to chemicals. This review article summarizes the different types of WRA and describes diagnostic procedures, treatment, prevention, and approaches to patient management. It is not always easy to distinguish between OA and WEA. It is important to establish a diagnosis (of sensitizer-/irritant-induced OA or WEA) in order to prevent worsening of symptoms, as well as to prevent other workers from being exposed, by providing early treatment and counseling on social security and work-related issues.


Importance of familial factors in associations between offspring birth weight and parental risk of type-2 diabetes.
It is hypothesized that associations found between birth weight and subsequent risk of type-2 diabetes are due to inherited genes affecting both fetal growth and metabolism of insulin. To study whether there is a familial (shared environmental and genetic) link between birth weight and type-2 diabetes, the authors used a sample of 11,411 Swedish like-sexed twins born from 1926 to 1958 with at least one offspring, to study the association between offspring birth weight for gestational age and parental risk of type-2 diabetes. Decreasing offspring birth weight for gestational age (with 1 SD) was associated with an increased risk of type-2 diabetes among father's [odds ratio (OR)=1.72, 95% confidence interval (CI): 1.33-2.23] and decreased risk among mothers (OR=0.43, 95% CI: 0.30-0.62), independent of grand parental and parental socio-economic status and parental smoking. In paired twin analysis, the association between offspring birth weight and mothers with risk of type-2 diabetes was similar within- and between-twin pairs, whereas father's risk was slightly smaller within than between pairs (OR(Between)=1.90, 95% CI: 1.10-3.28, and OR(Within)=1.71, 95% CI: 1.10-2.67, respectively). The well-established association between paternal type-2 diabetes and offspring birth weight seems to primarily be due to as yet unidentified non-shared environmental factors. However, familial factors shared within twin pairs may contribute to the association.


Spot the odd one out: do snake pictures capture macaques' attention more than other predators?
Detecting and identifying predators quickly is key to survival. According to the Snake Detection Theory (SDT), snakes have been a substantive threat to primates for millions of years, so that dedicated visual skills were tuned to detect snakes in early primates. Past experiments confronted the SDT by measuring how fast primate subjects detected snake pictures among non-dangerous distractors (e.g., flowers), but did not include pictures of primates' other predators, such as carnivorans, raptors, and crocodilians. Here, we examined the detection abilities of N = 19 Tonkean macaques (Macaca tonkeana) and N = 6 rhesus macaques (Macaca mulatta) to spot different predators. By implementing an oddity task protocol, we recorded success rates and reaction times to locate a deviant picture among four pictures over more than 400,000 test trials. Pictures depicted a predator, a non-predator animal, or a simple geometric shape. The first task consisted of detecting a deviant picture among identical distractor pictures (discrimination) and the second task was designed to evaluate detection abilities of a deviant picture among different distractor pictures (categorization). The macaques detected pictures of geometric shapes better and faster than pictures of animals, and were better and faster at discriminating than categorizing. The macaques did not detect snakes better or faster than other animal categories. Overall, these results suggest that pictures of snakes do not capture visual attention more than other predators, questioning previous findings in favor of the SDT.


Dual-Modal Probe Based on Polythiophene Derivative for Pre- and Intraoperative Mapping of Lymph Nodes by SPECT/Optical Imaging.
The metastatic spread of primary tumors to regional lymph nodes (LNs) is an important prognostic indicator for cancer staging and clinical therapy. Therefore, developing lymphatic mapping probes with improved accuracy and efficiency is of vital importance. Conjugated polymers (CPs) have been established as useful optical probes for sensitive biological and chemical detection. As a member of CPs family, polythiophene derivatives have drawn increasing attraction because of their superior photostability, signal amplification ability, and flexible structures for modification. In addition, these excellent properties allow the promising in vivo application to real-time LNs mapping. Here, we first reported a radiolabeled dual-modal probe based on the polythiophene derivative (99mTc-PTP) that was used for LNs mapping with high sensitivity and specificity by preoperative single-photon emission computed tomography imaging and intraoperative optical guidance. 99mTc-PTP exhibits an excellent radio-fluorescence guidance ability and a remarkable biocompatibility and holds great potential to be a powerful probe for noninvasive LNs mapping.


High-performance liquid chromatography-mass spectrometry-mass spectrometry analysis of morphine and morphine metabolites and its application to a pharmacokinetic study in male Sprague-Dawley rats.
A high-performance liquid chromatography tandem mass spectrometry-mass spectrometry (LC-MS-MS) assay was developed for the analyses of morphine, morphine glucuronides and normorphine in plasma samples from rats. The analytes were extracted by using C2 solid-phase extraction cartridges. The extraction recoveries were 100% for morphine, 84% for morphine-3-glucuronide, 64% for morphine-6-glucuronide and 88% for normorphine. Both intra- and inter-assay variabilities were below 11%. Using a plasma sample size of 100 microliters, the limits of detection were 13 nmol l-1 (3.8 ng ml-1) for morphine, 12 nmol l-1 (5.5 ng ml-1) for morphine-3-glucuronide, 26 nmol l-1 (12 ng ml-1) for morphine-6-glucuronide and 18 nmol l-1 (5.0 ng ml-1) for normorphine, at a signal-to-noise ratio of 3. The present assay was applied to a pharmacokinetic study in rats after intraperitoneal administration of morphine.


New records of three species of nematodes in Cerdocyon thous from the Brazilian Pantanal wetlands.
We report the occurrence of nematodes collected from the gut of roadkilled crab-eating foxes (two adult males and one juvenile female), Cerdocyon thous (Linnaeus, 1766), found on the BR 262 highway in Mato Grosso do Sul state, Brazil in 2011. Three helminth species were identified: Ancylostoma buckleyi, Pterygodermatites (Multipectines) pluripectinata, and Ascaridia galli. These nematodes are reported for the first time to infect C. thous from the Brazilian Pantanal wetlands, thereby expanding their geographical distribution.


Hybrid stochastic-deterministic calculation of the second-order perturbative contribution of multireference perturbation theory.
A hybrid stochastic-deterministic approach for computing the second-order perturbative contribution E(2) within multireference perturbation theory (MRPT) is presented. The idea at the heart of our hybrid scheme-based on a reformulation of E(2) as a sum of elementary contributions associated with each determinant of the MR wave function-is to split E(2) into a stochastic and a deterministic part. During the simulation, the stochastic part is gradually reduced by dynamically increasing the deterministic part until one reaches the desired accuracy. In sharp contrast with a purely stochastic Monte Carlo scheme where the error decreases indefinitely as t-1/2 (where t is the computational time), the statistical error in our hybrid algorithm displays a polynomial decay ∼t-n with n = 3-4 in the examples considered here. If desired, the calculation can be carried on until the stochastic part entirely vanishes. In that case, the exact result is obtained with no error bar and no noticeable computational overhead compared to the fully deterministic calculation. The method is illustrated on the F2 and Cr2 molecules. Even for the largest case corresponding to the Cr2 molecule treated with the cc-pVQZ basis set, very accurate results are obtained for E(2) for an active space of (28e, 176o) and a MR wave function including up to 2×107 determinants.


Developing a Measure to Assess Emotions Associated with Never Being Deployed.
Much research has focused on stress related to deployments; however, a substantial proportion of soldiers never deploy. In a study of 1.3 million veterans, suicide risk was higher among veterans who had never deployed. Thus, not being deployed may have an impact on soldiers' well-being; however, no measures exist to assess emotions regarding non-deployment. We aimed to develop and test an original measure of non-deployment emotions. We examined the Non-Deployment Emotions (NDE) questionnaire, a novel four-item measure of guilt, unit value, unit camaraderie, and unit connectedness in a sample of never-deployed male and female US Army Reserve/National Guard (USAR/NG) soldiers (N = 174). Data are from Operation: SAFETY (Soldiers and Families Excelling Through the Years), an ongoing survey-based study examining the health of USAR/NG soldiers and their partners. The protocol was approved by the Institutional Review Board at the State University of New York at Buffalo. The relationship between each of the items was examined by calculating correlation and alpha coefficients. Latent class analyses tested for the existence of distinct levels of negative emotions related to non-deployment. Negative binomial regression models examined the cross-sectional associations between NDE summary score and each of the following outcomes, separately: anger, anxiety, depression, and post-traumatic stress. More than half of never-deployed USAR/NG soldiers expressed negative emotions for having not been deployed. "Guilt," "value," "camaraderie," and "connectedness" were each positively correlated with each other (p < 0.001) and the internal consistency reliability was high (male soldier α = 0.90, female soldier α = 0.93). Latent class analyses revealed a superior three-class model with well-delineated class membership (entropy = 0.93): "Class 1" (low NDE; 47.6%), "Class 2" (moderate NDE; 33.8%), and "Class 3" (high NDE; 18.6%). Regression models demonstrated that greater non-deployment emotions were independently associated with more severe anger (RR = 1.02, 95% CI: 1.01, 1.03, p < 0.001), anxiety (RR = 1.06, 95% CI: 1.01, 1.11, p < 0.05), depression (RR = 1.06, 95% CI: 1.01, 1.11, p < 0.05), and PTSD (RR = 1.10, 95% CI: 1.04, 1.16, p < 0.01). Findings demonstrate that negative emotions regarding non-deployment are prevalent among never-deployed USAR/NG soldiers and that these emotions are related to a mental health. The NDE provides a measure of "guilt," "value," "camaraderie," and "connectedness" specific to non-deployed soldiers and is able to well discriminate between soldiers that have low, moderately, and highly negative non-deployment emotions. These findings suggest that all military personnel, regardless of deployment status, could be at risk for negative outcomes. As with any survey-based study, there is a potential for response bias; however, given the range of responses collected with the NDE, social desirability is unlikely. Further work is needed to confirm our findings in other components of the military and to examine soldiers in the rear detachment.


Cytotoxicity of tamoxifen in normal and tumoral cell lines and its ability to induce cellular transformation in vitro.
Tamoxifen (TAM) is a non-steroidal anti-estrogen used to treat patients with estrogen receptor-positive breast cancer and as a chemopreventive agent against breast cancer in high risk pre- and post-menopausal women. However, recent studies have shown that tamoxifen causes endometrial and hepatic cancer. In this study, we examined the effects of tamoxifen (5, 10, 25 and 50 microM) on the growth and proliferation of nine tumoral cell lines (UACC62, MCF-7, NCI-460, K-562, OVCAR-03, PC-03, HT-29, 786-0, NCI-ADR) and non-tumoral cell lines (3T3, V79, MDCK, VERO). Chinese hamster lung fibroblasts (V79) were the most sensitive lineage to tamoxifen, with 21.6% of the cells showing apoptosis at 50 microM TAM. Microscopic analysis showed that, the cellular transformation caused by TAM in V79 cells was similar to that seen with 7,12-dimethylbenz(a)anthracene, thus indicating the carcinogenicity of TAM.


3β-Acet-oxy-6-hy-droxy-imino-cholestane.
Two independent mol-ecules comprise the asymmetric unit of the title cholestane derivative, C(29)H(49)NO(3) {systematic name: (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-1,5-dimethyl-hex-yl]-6-hy-droxy-imino-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetra-deca-hydro-1H-cyclo-penta-[a]phenanthren-3-yl ace-tate}. The major differences between the mol-ecules relate to the relative orientations of the terminal acetyl [C-C-O-C torsion angles = -158.8 (3) and -81.7 (3)°] and alkyl groups [C-C-C-C = 168.9 (3) and 65.8 (4)°]. In the crystal, the independent mol-ecules associate via pairs of O-H⋯N hydrogen bonds, forming dimeric aggregates. Supra-molecular layers in the ab plane are mediated by C-H⋯O inter-actions.


On the reactivity of carboxyl groups of ribonuclease-A in anhydrous methanol.
The esterification of Ribonuclease-A in methanol/0.1 M hydrochloric acid has been studied by measuring the decrease in the number of titratable groups of the protein and estimating the amount of methanol incorporated. Esterification of nearly five of the 11 free carboxyl groups of the protein resulted in almost complete inactivation of the enzyme. The initial products of esterification have been chromatographed on Amberlite columns, and five partially active methyl ester derivatives of Ribonuclease-A have been isolated. The dimethyl ester, the initial product of esterification with reduced catalytic activity, has the carboxyl groups of Glu-49 and Asp-53 modified. Even in the non-aqueous solvent, as in the native structure of the protein in aqueous solution, these carboxyl groups are the fast reacting ones. Subsquently, the esterification reaction appears to proceed preferentially at the C-terminal region of the molecule. Comparison of the reactivities of carboxyl groups of Ribonuclease-A in acidic methanol to that known in aqueous solutions (with carbodiimides) suggests that the structure of Ribonuclease-A in the non-aqueous solvent resembles, at least in part, the structure in aqueous environment.


Applying psychiatric techniques to patients with cancer.
A patient with cancer frequently experiences significant stress in adjusting to his disease. The authors feel that cancer patients who are receiving physical care in a general hospital may benefit from psychiatric techniques used regularly by mental health professionals. They describe weekly group meetings in which newly diagnosed cancer patients talk with the hospital staff, consultants from a psychiatric institute, and more experienced cancer patients about problems in adjustment, misconceptions about cancer, reactions of family and friends, and problems in relating to their physician. To date approximately 2000 patients have attended the meetings. In most cases their anxiety has decreased as they talk with other cancer patients who have learned to live with their disease, and as they see alternative methods for dealing with their problems.


An electron microbeam cell-irradiation system at KIRAMS: performance and preliminary experiments.
An electron microbeam cell-irradiation (EMCI) system is now ready for routine operation in Korea. The system components include an electron gun operating at 1-100 keV, a beam transport chamber delivering a micron-sized beam, a cell image acquisition and positioning part and an automatic system control section. The present choice of source beam energy is 30 keV so that the radiation impact is conveyed to the targeted cells with a minimum spatial dispersion. The beam is available at 5 microm in diameter now, but can be changed in the range of 1-200 microm. The cellular dose is delivered with a standard deviation of 30% at 0.1 Gy, 10% at 1 Gy and 3% at 10 Gy. The cells are recognised by over 98% in a 1 mm x 1 mm area and the system is capable of irradiating up to 30,000 cells h(-1).


Mammalian Cell Encapsulation in Alginate Beads Using a Simple Stirred Vessel.
Cell encapsulation in alginate beads has been used for immobilized cell culture in vitro as well as for immunoisolation in vivo. Pancreatic islet encapsulation has been studied extensively as a means to increase islet survival in allogeneic or xenogeneic transplants. Alginate encapsulation is commonly achieved by nozzle extrusion and external gelation. Using this method, cell-containing alginate droplets formed at the tip of nozzles fall into a solution containing divalent cations that cause ionotropic alginate gelation as they diffuse into the droplets. The requirement for droplet formation at the nozzle tip limits the volumetric throughput and alginate concentration that can be achieved. This video describes a scalable emulsification method to encapsulate mammalian cells in 0.5% to 10% alginate with 70% to 90% cell survival. By this alternative method, alginate droplets containing cells and calcium carbonate are emulsified in mineral oil, followed by a decrease in pH leading to internal calcium release and ionotropic alginate gelation. The current method allows the production of alginate beads within 20 min of emulsification. The equipment required for the encapsulation step consists in simple stirred vessels available to most laboratories.


High-resolution melting curve analysis for rapid detection of rifampin resistance in Mycobacterium tuberculosis: a meta-analysis.
A rapid, simple, accurate, and affordable method for the detection of drug-resistant tuberculosis is very critical for the selection of antimicrobial therapy and management of patient treatment. High-resolution melting curve analysis has been used for the detection of rifampin resistance in Mycobacterium tuberculosis and has shown promise. We did a systematic review and meta-analysis of published studies to evaluate the accuracy of high-resolution melting curve analysis for the detection of rifampin resistance in clinical M. tuberculosis isolates. We searched the PubMed, BIOSIS Previews, and Web of Science databases to identify studies and included them according to predetermined criteria. We used the DerSimonian-Laird random-effects model to calculate pooled measures and applied Moses' constant for linear models to fit the summary receiver operating characteristic curve. According to the selection criteria, most of the identified studies were excluded, and only seven studies were included in the final analysis. The overall sensitivity of the high-resolution melting curve analysis was 94% (95% confidence interval [CI], 92% to 96%), and the overall specificity was very high at 99% (95% CI, 98% to 100%). The values for the pooled positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 63.39 (95% CI, 30.21 to 133.00), 0.06 (95% CI, 0.04 to 0.09), and 892.70 (95% CI, 385.50 to 2,067.24), respectively. There was no significant heterogeneity across all included studies for the measurements we evaluated. The summary receiver operating characteristic curve for the same data shows an area of 0.99 and a Q* value of 0.97. High-resolution melting curve analysis has high sensitivity and specificity for the detection of rifampin resistance in clinical M. tuberculosis isolates. This method might be a good alternative to conventional drug susceptibility tests in clinical practice.


Survey of Nursery Errors in Healthcare Centers, Isfahan, Iran.
Nurse's mistakes usually have a strong effect on the patients trust and satisfaction in the health services systems, and it can also lead to stress and moral contradicts among nurses. This study has aimed to survey the rate of nurses' mistakes, according to documents in the Isfahan Province during 2007-2012. The study was a descriptive cross-sectional study. The sample population consisted of all complaints concerning nursing services provided in hospitals, private clinics and other health service centers between 2007 and 2012, submitted to the Forensic Medicine Commission Office, in Isfahan. The data were collected by a cheklist and analyzed using SPSS version 16.0 software. Out of 708 complaints, 70 (9.8%) cases were related to nurses. Twenty-four cases led to awards. The age range of nurses was 35-40 (25.7%). Out of 70 nurses with a record, 75% (53 people) were female and the rest were male. Sixty four nurses (91.4%) were working in hospitals. Negligence was the first basis of the court rulings (16 cases out of 24). Nurses' recklessness in providing services was due to their convictions among 66.7% of the cases. Although efforts to reduce and control nurses' faults and mistakes depends on using a system for studying and removing the factors which lead to faults, human error is inevitable in every occupation and a 100% accurate operation is unreachable.


Computer-Aided Brain Tumor Diagnosis: Performance Evaluation of Deep Learner CNN Using Augmented Brain MRI.
Brain tumor is a deadly neurological disease caused by an abnormal and uncontrollable growth of cells inside the brain or skull. The mortality ratio of patients suffering from this disease is growing gradually. Analysing Magnetic Resonance Images (MRIs) manually is inadequate for efficient and accurate brain tumor diagnosis. An early diagnosis of the disease can activate a timely treatment consequently elevating the survival ratio of the patients. Modern brain imaging methodologies have augmented the detection ratio of brain tumor. In the past few years, a lot of research has been carried out for computer-aided diagnosis of human brain tumor to achieve 100% diagnosis accuracy. The focus of this research is on early diagnosis of brain tumor via Convolution Neural Network (CNN) to enhance state-of-the-art diagnosis accuracy. The proposed CNN is trained on a benchmark dataset, BR35H, containing brain tumor MRIs. The performance and sustainability of the model is evaluated on six different datasets, i.e., BMI-I, BTI, BMI-II, BTS, BMI-III, and BD-BT. To improve the performance of the model and to make it sustainable for totally unseen data, different geometric data augmentation techniques, along with statistical standardization, are employed. The proposed CNN-based CAD system for brain tumor diagnosis performs better than other systems by achieving an average accuracy of around 98.8% and a specificity of around 0.99. It also reveals 100% correct diagnosis for two brain MRI datasets, i.e., BTS and BD-BT. The performance of the proposed system is also compared with the other existing systems, and the analysis reveals that the proposed system outperforms all of them.


Fractal Nature of Food Materials.
Through the concept of fractals, the new non-integer dimensional world is introduced. Experimental results to show this new world are taken from the author and his colleagues' own works. A few words are given also to the scaling law in the "Critical phenomena" in relation to sol-gel transition, and Chaos, both of which are closely related to the fractal.


Major role of the CYP2C isozymes in deamination of amphetamine and benzphetamine: evidence for the quinidine-specific inhibition of the reactions catalysed by rabbit enzyme.
1. The cytochrome P450 isozymes involved in the deamination of amphetamine (AP) and benzphetamine (BZP) have been studied in liver microsomes from rabbit and rat using isozyme-specific inhibitors. 2. Metabolism of BZP in rat yielding phenylacetone and formaldehyde was moderately inhibited by testosterone and chloramphenicol. N-Debenzylation was thought to be P450-dependent, but all inhibitors except for a non-specific inhibitor, SKF-525A, failed to inhibit this reaction. 3. In rabbit, quinidine and testosterone were potent inhibitors of both BZP deamination and dealkylation. Deamination of AP in rabbit was extensively inhibited only with quinidine. 4. AP deamination with purified rabbit CYP2C3, which was previously identified as the major isozyme responsible for this metabolism, was extensively inhibited with quinidine, previously thought to be a specific inhibitor of CYP2D. 5. These results strongly support the notion that the CYP2C isozymes play a major role in the deamination of both AP and BZP, but not for N-debenzylation of BZP in rat. However, on the basis of different sensitivities toward inhibitors, multiple isozymes seem to be involved in BZP deaminations in both species.


Effect of anti-spectrin antibody and ATP on deformability of resealed erythrocyte membranes.
Deformability of resealed erythrocyte membranes was measured by using an ektacytometer. Divalent anti-spectrin antibody, but not monovalent anti-spectrin Fab fragments, decreased membrane deformability. Membranes resealed with MgATP were more deformable than those without MgATP. Exogenous alkaline phosphatase, which dephosphorylates spectrin, decreased membrane deformability. These results suggest that spectrin is an essential component of the system that determines erythrocyte deformability. They are consistent with the view that the role of ATP in membrane deformability is mediated through phosphorylation of the spectrin.


EXPERIMENTAL EVOLUTION OF RESISTANCE IN BRASSICA RAPA: CORRELATED RESPONSE OF TOLERANCE IN LINES SELECTED FOR GLUCOSINOLATE CONTENT.
The evolutionary response of plant populations to selection for increased defense may be constrained by costs of defense. The purpose of this study was to investigate such constraints on the evolution of defense due to a cost of defense manifested as a trade-off between defense and tolerance. Variation in the response to artificial damage (tolerance) among lines of Brassica rapa that had been artificially selected for foliar glucosinolate content (defense) was examined. Leaf area was removed from replicates of three selection lines (high glucosinolates, control, and low glucosinolates) at three damage levels (0%, 20%, and 60% damage). An external cost of defense would result in a statistically significant selection line by damage treatment interaction, with those selected for high defense expressing less tolerance than those selected for low defense. Damage treatment had a significant overall effect on estimated total fitness, with fitness declining with increasing damage level. Further, selection line also had a significant overall effect on estimated total fitness, with low-defense selection lines having higher fitness compared to both control and high-defense selection lines. More importantly, a cost of defense in terms of tolerance was demonstrated by a significant selection line-by-damage treatment interaction. This interaction was in the direction to demonstrate a genetic trade-off between defense and tolerance, with low-defense selection lines decreasing estimated total fitness in response to damage less than both control and high-defense selection lines. Variation in tolerance among selection lines was due to the greater ability of low-defense lines to maintain fruit and seed production despite the presence of damage. In terms of tolerance, this cost of glucosinolate production in B. rapa could constrain the evolution of increased defense and, in so doing, maintain individuals within the population that are poorly defended yet tolerant.


Antisickling activity of amino acid benzyl esters.
The sickling of homozygous sickel cells upon deoxygenation is inhibited in the presence of 3 mM L-phenylalanine benzyl ester (Phe-OBzl) or benzyl esters of other aromatic or hydrophobic amino acids. Phe-OBzl was found to permeate into erythrocytes rapidly, and the deoxygenated cells maintained considerable flexibility as measured by their ability to pass through 3-micron pores. The osmotic fragility of the cells was unchanged and the oxygen dissociation curve was shifted slightly from a 50% saturation values of 28.5 mm Hg to 31.0 mm Hg. At lower concentrations of Phe-OBzl some antisickling activity was seen. The Phe-OBzl antisickling activity may involve both binding to deoxyhemoglobin S and modification of the erythrocyte membrane. This class of compounds has considerable potential as therapeutic agents for the treatment of sickle cell disease.


Amyloid Assembly Endows Gad m 1 with Biomineralization Properties.
Acid proteins capable of nucleating Ca2+ and displaying aggregation capacity play key roles in the formation of calcium carbonate biominerals. The helix-loop helix EF-hands are the most common Ca2+-binding motifs in proteins. Calcium is bound by the loop region. These motifs are found in many proteins that are regulated by calcium. Gad m 1, an Atlantic cod β-parvalbumin isoform, is a monomeric EF-hand protein that acts as a Ca2+ buffer in fish muscle; the neutral and acid apo-forms of this protein can form amyloids. Since Ca2+-nucleating proteins have a propensity to form extended β-strand structures, we wondered whether amyloid assemblies of an EF-hand protein were able to influence calcium carbonate crystallization in vitro. Here, we used the Gad m 1 chain as a model to generate monomeric and amyloid assemblies and to analyze their effect on calcite formation in vitro. We found that only amyloid assemblies alter calcite morphology.


The Neutrophil-Lymphocyte Ratio Is Associated with Coronary Artery Calcification in Asymptomatic Korean Males: A Cross-Sectional Study.
Introduction. The neutrophil-lymphocyte ratio (NLR) is a significant systemic predictor of cardiovascular disease (CVD). The coronary artery calcium score (CACS) reflects coronary artery calcification and is an independent risk factor for coronary artery stenosis. In the present study, we explored the relationship between the NLR and CACS in terms of subclinical inflammation and coronary artery calcification. Materials and Methods. We evaluated males and females who did not have CVD, diabetes, high blood pressure, or high fasting blood sugar levels. We measured white blood cell, neutrophil, lymphocyte counts, fasting blood sugar, total cholesterol, high-density lipoprotein cholesterol, triglycerides (TG), and high-sensitivity C-reactive protein levels in blood samples. We also obtained CACSs using coronary multidetector computed tomography. Results. Multivariate logistic regression showed that older age was significantly associated with a higher CACS (P < 0.001); males had higher CACSs than females (P < 0.001); and the higher the TG level, the higher the CACS (P = 0.019). The NLR of males, but not females, was significantly associated with the CACS. Conclusion. An independent association between the NLR and CACS was thus evident in healthy adult males after adjusting for other CVD risk factors. Therefore, the NLR is a significant predictor of potential CVD in male subjects with subclinical atherosclerosis.


Effect of different pulses of nitric oxide on venous admixture in the anaesthetized horse.
Dependent atelectatic lung areas open towards the end of inspiration when the lung opening pressure increases, and recollapse during expiration. We hypothesized that inhaled nitric oxide (NO) counteracts hypoxic vasoconstriction in these collapsing lung areas, resulting in increased pulmonary shunt perfusion. We administered NO as a pulse and varied the pulse timing during inspiration in equine anaesthesia, where atelectasis develops regularly. Six spontaneously breathing standard breed trotters were studied under isoflurane anaesthesia in lateral recumbency. NO pulsed into the first 30% of inspiration (group NOp1) was assumed to affect open lung areas. To cover more open lung areas NO was then pulsed into the first 60% of inspiration (group NOp2). In a third group, administration between 50 and 80% of inspiration was aimed at the intermittently opening lung areas (group NOp3). With NOp1, venous admixture decreased by 8 (2)% (mean (SEM), P=0.045) and with NOp2 by 10 (1)% (P=0.01). With NOp3, venous admixture reduction was insignificant. Pulsed administration of NO in early inspiration is optimal in reducing right to left vascular shunt in atelectatic equine lung. This reduction is positively correlated with the magnitude of the initial shunt. With administration in early inspiration, NO is mostly taken up by the lung. This prevents NO accumulation and NO2 formation in rebreathing circuits. These findings may be important in humans when atelectasis occurs increasingly with overweight and age during anaesthesia, but also in postoperative intensive care and in ARDS.


Whole-heart dipyridamole stress first-pass myocardial perfusion MRI for the detection of coronary artery disease.
A whole-heart coverage MRI sequence, which employes a hybrid of fast gradient echo and echo planar acquisition imaging (FastCard EchoTrain), has recently been developed. Using this sequence, a first-pass myocardial perfusion MRI was shown to be a good noninvasive modality for detecting coronary artery disease (CAD) in a clinical setting. In addition, the clinical usefulness of delayed enhanced MRI has recently been reported. The objectives of this study were (1) to investigate the accuracy of dipyridamole stress first-pass myocardial perfusion MRI for diagnosing CAD (> 50% stenosis) and (2) to clarify whether additional delayed enhancement MRI has any clinical significance. We performed first-pass myocardial perfusion MRI in 102 consecutive patients (66 +/- 9 years old) suspected to have CAD or new lesions in patients with well-documented prior myocardial infarction (MI). Using a 1.5 T cardiac MR imager (GE CV/i), eight short axis MR images of the left ventricle were acquired by injecting gadolinium (0.1 mmol/kg) under dipyridamole infusion stress (0.56 mg/kg). Fifteen minutes later, aminophylline (250 mg) was injected and first-pass perfusion MRI was repeated in the resting state in order to evaluate both the presence of perfusion defect and delayed enhancement. The presence of perfusion defect and delayed enhancement was determined based on a visual qualitative analysis by the agreement of two separate readers who were blinded to any clinical information. Based on the stress and rest findings, no defect, reversible defect, or fixed defect with or without delayed enhancement was recorded in any patient. The MR findings revealed 76 CAD patients, including 24 MI patients with new lesions and 26 patients without CAD on coronary angiography. The presence of stress perfusion defect had a 93% sensitivity and an 85% specificity for diagnosing CAD. A fixed defect showed an 86% sensitivity and a 66% specificity for diagnosing a prior MI. Patients with a fixed defect with delayed enhancement had more significant stenosis in the infarct related artery than in those without any enhancement (11/26 vs 15/20, P < 0.05). Dipyridamole stress first-pass myocardial perfusion MRI using the FastCard EchoTrain was found to be a clinically useful and accurate modality for diagnosing CAD.


[Adhesion molecules in type 2 diabetes].
Abnormal levels some of serum soluble adhesion molecules (ICAM-1, VICAM-1, E-selectin, P-selectin, L-selectin) have been detected in type 2 diabetic patients. There is some evidence that levels of soluble adhesion molecules depend on glycemic control, disturbances of lipid metabolism, obesity and insulin resistance. There is a few of clinical data till now, which have been suggested the significance role of adhesion molecules in pathogenesis of microangiopathy and macroangiopathy in type 2 diabetics. It is possible that in some cases measurement of serum adhesion molecules may be useful for predicting, early diagnosing prophylactic and monitoring of treatment of diabetic type 2 complications. We can modify serum levels of soluble adhesion molecules by nonpharmacologic and pharmacologic treatment.


Cholesterol modulates the interaction of the islet amyloid polypeptide with membranes.
The deposition of insoluble amyloid fibrils resulting from the aggregation of the human islet amyloid polypeptide (hIAPP) within the islet of Langerhans is a pathological feature of type 2 diabetes mellitus (T2DM). Increasing evidence indicates that biological membranes play a key role in amyloid aggregation, modulating among others the kinetics of amyloid formation, and being the target of toxic species generated during amyloid formation. In T2DM patients, elevated levels of cholesterol, an important determinant of the physical state of biological membranes, are observed in β-cells and are thought to directly impair β-cell function and insulin secretion. However, it is not known whether cholesterol enhances membrane-interaction or membrane-insertion of hIAPP. In this study, we investigated the effect of cholesterol incorporated in zwitterionic and anionic membranes. Our circular dichroism and liquid state NMR data reveal that 10-30% of cholesterol slightly affects the aggregational and conformational behaviour of hIAPP. Additional fluorescence results indicate that 10 and 20% of cholesterol slightly slow down the kinetics of oligomer and fibril formation while anionic lipids accelerate this kinetics. This behavior might be caused by differences in membrane insertion and therefore in membrane binding of hIAPP. The membrane binding affinity was evaluated using (1)H NMR experiments and our results show that the affinity of hIAPP for membranes containing cholesterol is significantly smaller than that for membranes containing anionic lipids. Furthermore, we found that hIAPP-induced membrane damage is synchronized to fibril formation in the absence and in the presence of cholesterol.


Suppurative complications of frontal sinusitis in children.
A retrospective review of children diagnosed and treated for suppurative complications of paranasal sinusitis was undertaken to describe clinical presentation, microbiology, and treatment. This review includes children with subgaleal abscess and osteomyelitis of the frontal bone, subdural empyema, frontal lobe abscess, meningitis, and encephalitis. Staphylococcus aureus and group C beta-hemolytic Streptococcus were isolated agents. All children were treated with intravenous antibiotics with drainage of both the sinus and extracranial and intracranial suppurations. Results of treatment in the series support the opinion that combined aggressive surgical and antibiotic treatment is a preferred method in complicated sinusitis in children.


Concomitant carotid endarterectomy and coronary bypass surgery: outcome of on-pump and off-pump techniques.
There continues to be a dilemma regarding the best means of surgical management of significant carotid artery disease in patients requiring coronary artery bypass surgery. A combined approach of coronary artery bypass and carotid endarterectomy has shown good results in patients with concomitant carotid and coronary artery disease. We reviewed our results of coronary artery surgery using conventional cardiopulmonary bypass or off-pump techniques and carotid endarterectomy done as a combined procedure. Between January 1996 and June 2002, 358 patients underwent concomitant coronary artery bypass and carotid endarterectomy. There were 140 males (84.3%) and 26 females (15.7%) in group I. Group II consisted of 158 males (82.3%) and 34 females (17.7%). One hundred sixty-six patients (group I) were done off pump whereas in 192 patients (group II), the procedure was done using conventional cardiopulmonary bypass. Carotid endarterectomy was performed before coronary artery bypass surgery in both groups. The average number of grafts were 3.4 +/- 0.8 with average operative time of 4.2 +/- 0.4 hours in group I, and 3.3 +/- 0.8 graft with operative time of 5.3 +/- 1.2 hours in group II (p = 0.239 and p < 0.001, respectively). There were 2 deaths (1.2%) in group I and 3 deaths (1.6%) in group II (p = 0.870). No patient from group I and 1 patient (0.5%) from group II had postoperative stroke (p = 0.941). Mean hospital stay was 9.0 +/- 1.2 days in group I and 11.2 +/- 1.7 days in group II (p < 0.001). At mean follow-up of 2.8 +/- 0.9 years in group I, 2 patients (1.2%) had late death due to cardiac failure and contralateral carotid endarterectomy was done in 2 patients (1.2%). Group II had mean follow-up of 2.4 +/- 0.6 years, during which 4 patients (2.1%) had late death and contralateral carotid endarterectomy was done in 3 patients (1.6%). Late stroke was seen in 1 patient (0.6%) from group I and 2 patients (1.0%) from group II. Concomitant carotid endarterectomy and coronary artery bypass is a safe and effective procedure in patients with significant coronary and carotid artery disease. Equally good results can be reproduced using cardiopulmonary bypass or off-pump techniques for coronary artery surgery, with low morbidity, mortality, and good long-term results.


[Development and pharmaceutical evaluation of hydrophobic cyclodextrin derivatives as modified-release drug carriers].
Hydrophobic cyclodextrin (CyD) derivatives, such as 2,6-di-O-ethyl-beta-CyD (DE-beta-CyD), 2,3,6-tri-O-ethyl-beta-CyD (TE-beta-CyD), carboxymethylethyl-beta-CyDs (CME-beta-CyDs) with different degrees of substitution, 2,3,6-tri-O-acyl-beta-CyDs with different alkyl chains (C1-C12) were prepared and their chemical structures and physicochemical properties were elucidated. Furthermore, possible utilities of hydrophilic and hydrophobic CyD derivatives as modified-release drug carriers were evaluated on the basis of in vitro/in vivo correlations. The results obtained in this study are as follows: (1) Hydrophilic CyDs such as 2-hydroxypropyl-beta-CyD are useful as immediate-release type carriers for poorly water-soluble drugs such as nifedipine. (2) Hydrophobic CyDs such as ethylated and acylated beta-CyDs can be used as prolonged-release type carriers for water-soluble drugs such as diltiazem hydrochloride, buserelin acetate and molsidomine. (3) Enteric CME-beta-CyD derivatives are useful as delayed-release type carriers, and also as stabilizers for prostaglandin E and carmofur which are labile under alkaline conditions. (4) Various release rates can be obtained by combining hydrophilic and hydrophobic CyD derivatives in appropriate mixing ratios, e.g., double-layer tablets consisting of beta-CyD complex and DE-beta-CyD/CME-beta-CyD complexes released drugs rapidly at an initial stage, followed by slow release. The combination of CyD derivatives and pharmaceutical additives was also useful to modify the release rate of various drug molecules.


Photonic band-gap inhibition of modulational instabilities.
Spatial structures as a result of a modulational instability are studied in a nonlinear cavity with a photonic crystal. The interaction of the modulated refractive index with the nonlinearity inhibits the instability via the creation of a photonic band gap. A novel mechanism of light localization due to defects and pattern inhibition is also described.


[LH and gamete quality].
Potential contribution of LH to controlled ovarian stimulation in the final maturation of the oocyte and in preparation of the endometrium. LH and oocyte maturation LH and implantation Implantation rate variable but increased with LH/hCG, probably due to fewer abortions. Is LH/hCG is an immunomodulator but it may have a positive impact on the quality of the gametes through cytoplasmic improvement.


[Recent advances in the application of nanobody technology: a review].
As a malleable and novel tool for antigen recognition and modulation, nanobodies have the advantages of small size, easiness of expression, screening and modification, as well as high affinity and stability. Nanobodies are capable of recognizing more cryptic antigenic epitopes that are difficult to be recognized by traditional antibodies, making them increasingly used in the diagnosis and treatment of various diseases and assays. Nanobodies are also playing an irreplaceable role in the basic research. This review summarized the recent development of nanobodies and their derivatives in the detection of small molecules, pathogenic microorganisms and diagnosis of diseases, as well as in the fields of targeted therapies, cellular and molecular imaging. Broad prospects of nanobodies in the field of protein conformation studies were also reviewed.


Five-Year Outcome of Self-Expanding Covered Stents for Superficial Femoral Artery Occlusive Disease and an Analysis of Factors Predicting Failure.
To investigate the 5-year outcome of patients treated with self-expanding covered stents for superficial femoral artery (SFA) occlusive disease and identify parameters that could predict loss of primary patency. In a dual-center study, 315 consecutive patients (mean age 69.0±10.1 years; 232 men) treated for SFA occlusive disease in 334 limbs with Viabahn self-expanding covered stents between 2001 and 2014 were retrospectively analyzed. Mean lesion length was 11.7±8.8 cm, and half of the lesions were classified as TASC II C/D. Five-year patency rates were calculated, and Cox regression analyses were performed to assess potential factors affecting patency. All-cause mortality at 5 years was 14.1%. Primary patency rates at 1, 3, and 5 years were 72.2%, 51.8%, and 47.6%, respectively, with secondary patency rates of 86.2%, 78.7%, and 77.5%. Parameters predicting loss of primary patency in a univariate analysis were covered stent diameter (p=0.001), the number of covered stents per lesion (p=0.015), and TASC II D classification (p=0.007). Covered stent diameter was the only parameter predicting loss of primary patency in the multivariate regression analysis (p=0.001), with 7-mm covered stents having superior performance. Five-year patency rates of self-expanding covered stents inserted for SFA occlusive disease are within an acceptable range. Covered stent diameter is the most relevant factor in predicting loss of primary patency, and thus, an adequate diameter of the distal landing site seems to be among the most important factors in the decision-making process. In smaller vessels, one should not use covered stents but venous conduits, as oversizing may be detrimental.


Hypoxia‑induced mitophagy regulates proliferation, migration and odontoblastic differentiation of human dental pulp cells through FUN14 domain‑containing 1.
FUN14 domain‑containing 1 (FUNDC1) is a receptor that has been previously reported to activate hypoxia‑induced mitophagy. However, the potential role of FUNDC1 in the pathophysiology of dental pulp diseases remains unknown. Therefore, present study first collected tissue specimens from patients with pulpitis and from healthy individuals. The results of reverse transcription‑quantitative PCR and immunohistochemical staining revealed markedly increased FUNDC1 and hypoxia‑inducible factor‑1α expression in pulpitis tissue specimens compared with those from healthy individuals. To provide a theoretical basis for the study of the occurrence, development and reparative mechanisms in the dental pulp after tissue injury, the present study then investigated the role of hypoxia‑induced mitophagy in the regulation of proliferation, migration and odontoblastic differentiation in human dental pulp cells (HDPCs), in addition, to the possible involvement of FUNDC1. The surface markers and multipotent differentiation capabilities of HDPCs were performed by flow cytometry (surface markers), alizarin red (osteogenic capabilities), alcian blue (chondrogenic capabilities) and oil red O (adipogenic capabilities). Following culture under hypoxia conditions (1% O2) for varying time periods, the proliferation, migration and odontoblastic differentiation of HDPCs were measured using Cell Counting Kit‑8, wound healing and Transwell migration assays, alkaline phosphatase staining and activity tests and western blotting (runt‑related transcription factor 2, collagen I, osterix and osteopontin), respectively. Immunofluorescence and western blotting were performed to measure the expression levels of hypoxia‑inducible factor‑1α, pro‑fission dynamin‑related protein 1, mitochondria‑related proteins translocase of inner mitochondrial membrane 23 and translocase of outer mitochondrial membrane 20, in addition to those of autophagy markers (p62, LC3II, Beclin‑1 and autophagy‑related 5). Transmission electron microscopy was also used to image the autophagosomes and mitochondrial morphology. In addition, to study the functional role of FUNDC1, its expression was silenced by liposome‑mediated transfection with small interfering RNA into HDPCs. Compared with those in HDPCs cultured under normoxic conditions (21% O2), the ability of autophagy in HDPCs cultured under hypoxic conditions for 18 h was markedly increased, whilst the proliferation, migration and odontoblastic differentiation were also enhanced. Increased numbers of autophagosomes could also be observed in the hypoxic group. However, FUNDC1 knockdown in HDPCs reversed the aforementioned effects. Overall, data from the present study suggest that hypoxia can promote the proliferation, migration and odontoblastic differentiation of HDPCs, where the underlying mechanism may be associated with the activation of mitophagy downstream of FUNDC1.


Sex difference in mouse metabolic response to erythropoietin.
Erythropoietin (EPO) is the cytokine that regulates red blood cell production. Less understood is the nonerythroid action of EPO, including metabolic regulation of fat accumulation and glucose homeostasis. Although EPO treatment increased hematocrit and improved glucose tolerance in male and female mice, we observed a gender difference in EPO effects in weight control. EPO treatment reduced diet-induced weight gain from 9.6 ± 1.5 to 4.2 ± 1.4 g in male mice (P < 0.001), while the weight gain in female mice was similar (4.7 ± 2.0 g with PBS treatment and 3.3 ± 2.1 g with EPO treatment). EPO treatment also reduced weight gain in ovariectomized female mice, while the effect was abrogated with estradiol supplementation, suggesting that the sex-differential response to EPO was associated with estrogen. Furthermore, mice with targeted deletion of EPO receptor in white adipose tissue exhibited sex-differential phenotype in weight control and glucose sensitivity, and EPO receptor gene expression was reduced in wild-type female mice, suggesting that white adipose tissue plays an integral role in mediating the metabolic effects of EPO. Our data provide evidence for a sex-differential response to EPO in weight control in mice and underscore the potential for gender specific EPO action beyond erythropoiesis.-Zhang, Y., Rogers, H. M., Zhang, X., Noguchi, C. T. Sex difference in mouse metabolic response to erythropoietin.


Antimicrobial activity of antibiotics in combination with natural flavonoids against clinical extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae.
Extended-spectrum beta-lactamases (ESBLs) are plasmid-mediated class A enzymes commonly found in the family Enterobacteriaceae, mainly in Klebsiella pneumoniae. Flavonoids have also been reported to possess antimicrobial activity. In this study, the in vitro activities of 18 antibiotics and 12 flavonoids against 20 ESBL-producing K. pneumoniae isolates were evaluated. All of these isolates were susceptible to imipenem and cefmetazole, but were resistant to ampicillin, ampicillin/sulbactam, aztreonam, cefazolin, cefoperazone, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, piperacillin and ticarcillin. Susceptibilities to amikacin, amoxicillin/clavulanate, cefoxitin, ciprofloxacin and gentamicin were variable. Myricetin, a flavonol, inhibited ESBL-producing K. pneumoniae isolates at a high minimum inhibitory concentration (MIC) (MIC(90) value 256 mg/mL), but exhibited significant synergic activity against ESBL-producing K. pneumoniae in separate combination with amoxicillin/clavulanate, ampicillin/sulbactam and cefoxitin. Because of the low-toxic nature of flavonoids, the combination of antibiotics and flavonoids is a potential new strategy for developing therapies for infections caused by ESBL-producing bacteria in the future.


A review of problems in clinical acupuncture research.
Although laboratory studies indicate that acupuncture can have physiological effects, clinical studies of acupuncture are frequently inconclusive. Randomized controlled trials are the best way to test for the specific effectiveness of a therapy. Problems in clinical acupuncture research include the diversity of forms of therapy, individualised treatments, binding, choosing a credible control procedure, selecting suitable endpoints and traditional diagnosis. The enthusiasm of proponents of acupuncture may bias the research they are performing. None of these difficulties is insurmountable. Examples of rigorous trials are listed and some suggestions are offered on ways of improving research.


Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) - What We Have Learned after 40 Years of the Diagnosis of This Clinical Entity.
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) was initially recognized as a clinical entity by Fontaine and Marcus, who evaluated a group of patients with ventricular tachyarrhythmia from a structurally impaired right ventricle (RV). Since then, there have been significant advances in the understanding of the pathophysiology, manifestation and clinical progression, and prognosis of the pathology. The identification of genetic mutations impairing cardiac desmosomes led to the inclusion of this entity in the classification of cardiomyopathies. Classically, ARVC/D is an inherited disease characterized by ventricular arrhythmias, right and / or left ventricular dysfunction; and fibro-fatty substitution of cardiomyocytes; its identification can often be challenging, due to heterogeneous clinical presentation, highly variable intra- and inter-family expressiveness, and incomplete penetrance. In the absence of a gold standard that allows the diagnosis of ARVC/D, several diagnostic categories were combined and recently reviewed for a higher diagnostic sensitivity, without compromising the specificity. The finding that electrical abnormalities, particularly ventricular arrhythmias, usually precede structural abnormalities is extremely important for risk stratification in positive genetic members. Among the complementary exams, cardiac magnetic resonance imaging (CMR) allows the early diagnosis of left ventricular impairment, even before morpho-functional abnormalities. Risk stratification remains a major clinical challenge, and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. The disqualification of the sport prevents cases of sudden death because the effort can trigger not only the electrical instability, but also the onset and progression of the disease.


Establishment and characterization of patient-derived organoids from a young patient with cervical clear cell carcinoma.
Cervical clear cell carcinoma (cCCC) constitutes an extremely rare subtype of cervical cancer. Consequently, its pathogenesis remains largely unknown, with no cell lines established from primary tumors. Here, we report the first establishment of cCCC organoids, from biopsy samples of a 23-year-old patient diagnosed with cCCC. By applying a protocol that we recently optimized for gynecological tumors, we were able to propagate a patient-derived cell line (PDC) for more than 6 months as organoids. This PDC tolerated cryopreservation and proliferated either as spheroids or adherent cells, and developed xenografts in immunodeficient mice, ensuring robust utility as a cell line. Intriguingly, the resected tumor focally contained serous carcinoma (SC) in a tiny protruding lesion. Both organoids and derivative xenografts resembled the CCC component of the original tumor in histology, immunostaining profile, and genome-wide copy number changes, including focal gain of MET. Genomic analysis revealed that both organoids and the CCC component harbored only a few mutations, of which 2 mutations were shared in common. In contrast, the SC component showed a mutator-phenotype and prominent genome instability along with biallelic inactivation of TP53, but none of them were found in organoids or the CCC component. The PDC proved sensitive to major chemotherapeutic agents and MET inhibitors. These observations clearly indicated that the PDC, designated as YMC7, can be used as a novel cCCC cell line and provide novel insights into the pathogenesis of mixed cervical adenocarcinoma. As a valuable resource for rare cancer, it will likely contribute to investigations in many fields.


A Self-Organizing Approach to Subject-Verb Number Agreement.
We present a self-organizing approach to sentence processing that sheds new light on notional plurality effects in agreement attraction, using pseudopartitive subject noun phrases (e.g., a bottle of pills). We first show that notional plurality ratings (numerosity judgments for subject noun phrases) predict verb agreement choices in pseudopartitives, in line with the "Marking" component of the Marking and Morphing theory of agreement processing. However, no account to date has derived notional plurality values from independently needed principles of language processing. We argue on the basis of new experimental evidence and a dynamical systems model that the theoretical black box of notional plurality can be unpacked into objectively measurable semantic features. With these semantic features driving structure formation (and hence agreement choice), our model reproduces the human verb production patterns as a byproduct of normal processing. Finally, we discuss how the self-organizing approach might be extended to other agreement attraction phenomena.


Analysis of Rayleigh match data with psychometric functions.
Color matches have been used for a variety of purposes, yet the psychometric properties of color-matching data have not been thoroughly investigated. A method is given for generating psychometric functions for the two ends of the color-matching range by use of a perceptual dimension for stimulus magnitude based on ratios of cone quantal catches. The analysis was applied to Rayleigh match data gathered from 250 naïve observers with an automated protocol. Slopes of the psychometric functions were significantly shallower for anomalous trichromats than for normal trichromats, consistent with the assumption that stimulus magnitude is based on ratios of cone quantal catches. These results indicate that the tester's criterion for response consistency can strongly affect Rayleigh match widths. The analysis may also be useful for other perceptual tasks, such as contrast matching and spatial alignment.


Clinical instruments and methods for assessing physical oral health: A systematic review.
This study aimed at exploring available clinical instruments and methods for assessing physical oral health, and at identifying those with sufficient diagnostic performance. A systematic literature search was conducted in Embase and MEDLINE. Identified instruments and methods were critically appraised, and quality of diagnostic performance was rated by two independent reviewers as A (sufficient diagnostic performance), B (either sufficient reliability or validity) or C (insufficient quality, or empirical results unsatisfactory and/or inconsistent). For all A-rated instruments and methods, an in-depth literature search was conducted to supplement and verify their effectiveness and accuracy. A total of 141 instruments and methods were identified. Only 12 methods with sufficient diagnostic performance could be rated as A, 72 were rated as B, and 34 received a C-rating. Further 23 instruments and methods could not be rated due to lack of available information on diagnostic performance. Of all A-rated instruments, six were designed for tooth structure, two for periodontium, one for endodontium and three for temporomandibular joints and muscles. Even though some instruments and methods exhibited good to excellent reliability and validity and can be recommended for research and clinical practice, they do not allow assessing all components of physical oral health. There is a need to identify and define standard instruments, and for components of physical oral health where methods with sufficient diagnostic performance are lacking, further research is required.


Aspirin attenuates cerebral ischemic injury in diabetic rats.
Diabetes is an independent risk factor for ischemic stroke. Large randomized trials have shown that aspirin reduces stroke risks in patients with diabetes. However, there was no study that reported whether aspirin could attenuate the cerebral ischemic injury when administered prior to cerebral ischemia in diabetes. The objective of the present study was to evaluate the effects of aspirin on focal cerebral ischemia in diabetic rats. Diabetic rats received an oral administration of aspirin for 7 d prior to be subjected to a permanent middle cerebral artery occlusion (MCAO). The infarct volume of the brain was assessed in brain slices stained with 2% solution of triphenyltetrazolium chloride. Behavioral tests were used to evaluate the damage to the central nervous system. Platelet aggregation induced by adenosine diphosphate was measured. The results showed that aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume and decreased neurological deficit scores compared with vehicle treatment. Aspirin (30 mg/kg) treatment also reduced platelet aggregation. Administration of aspirin did not alter the levels of blood glucose and insulin in diabetic rats. The findings suggest that pretreatment with aspirin may be effective to attenuate cerebral ischemic injury in diabetic patients.


Comparison of dental caries experience and salivary parameters among children with Down syndrome and healthy controls in Chennai, Tamil Nadu.
Although there have been numerous studies on dental caries in children with Down syndrome, the reports are conflicting. Studies on salivary chemical composition of children with Down syndrome are limited. The study aims to evaluate and compare the dental caries experience, salivary flow rate, pH, buffering capacity, and concentration of sodium, potassium, calcium, phosphorus, total proteins, and sialic acid in children with Down syndrome and healthy controls. This was a cross-sectional study. Forty subjects with Down syndrome aged 5-18 years fulfilling the eligibility criteria from six special schools were selected by snowball sampling. Sixty healthy controls from six neighborhood schools fulfilling the eligibility criteria were selected by simple random sampling by matching the age, gender, and socioeconomic status. Sociodemographic data, oral hygiene practices, diet history and dental caries experience were recorded. About 6 mL of stimulated whole saliva was collected. Salivary flow rate, salivary pH, buffering capacity, and the concentration of sodium, potassium, calcium, phosphorus, total proteins, and sialic acid were determined. There was no significant difference in the mean proportional caries rate between the study and control group (P = 0.90). Salivary pH (P = 0.00) and salivary sodium concentration (P = 0.02) were significantly low in the study group than the control group. Salivary buffering capacity was significantly higher in the study group than the control group (P = 0.001). Dental caries experience of children with Down syndrome was similar to the healthy controls. School health programs could be implemented in special schools to improve oral and general health of special children.


Stationary entangled radiation from micromechanical motion.
Mechanical systems facilitate the development of a hybrid quantum technology comprising electrical, optical, atomic and acoustic degrees of freedom1, and entanglement is essential to realize quantum-enabled devices. Continuous-variable entangled fields-known as Einstein-Podolsky-Rosen (EPR) states-are spatially separated two-mode squeezed states that can be used for quantum teleportation and quantum communication2. In the optical domain, EPR states are typically generated using nondegenerate optical amplifiers3, and at microwave frequencies Josephson circuits can serve as a nonlinear medium4-6. An outstanding goal is to deterministically generate and distribute entangled states with a mechanical oscillator, which requires a carefully arranged balance between excitation, cooling and dissipation in an ultralow noise environment. Here we observe stationary emission of path-entangled microwave radiation from a parametrically driven 30-micrometre-long silicon nanostring oscillator, squeezing the joint field operators of two thermal modes by 3.40 decibels below the vacuum level. The motion of this micromechanical system correlates up to 50 photons per second per hertz, giving rise to a quantum discord that is robust with respect to microwave noise7. Such generalized quantum correlations of separable states are important for quantum-enhanced detection8 and provide direct evidence of the non-classical nature of the mechanical oscillator without directly measuring its state9. This noninvasive measurement scheme allows to infer information about otherwise inaccessible objects, with potential implications for sensing, open-system dynamics and fundamental tests of quantum gravity. In the future, similar on-chip devices could be used to entangle subsystems on very different energy scales, such as microwave and optical photons.


Polyarticular Form of Pigmented Villonodular Synovitis. Radiation and Surgical Therapy: Long Term Follow-up.
We describe a case of 30-year old male followed-up since the age of 6 for severe type of rare combination of polyarticular form of pigmented villonodular synovitis with hereditary malformation constellation consistent with Noonan-like syndrome. Within 20 years, the patient underwent repeated synovectomies of large joints with temporary effect only. Radiation therapy with the dose of 30 Gy in 15 sessions has been applied for active aggressive synovitis of both knees associated with pain and progressive joint destruction. Favorable effect lasted for 3 years. Progressive destruction with range-of-motion limitation required successive total joint replacement of both knee joints. Left knee prosthesis has been revised for aseptic loosening after 3.5 years. It is now 5 years since the right knee primoimplantation and 3 years since the left knee reimplantation without signs of component loosening or recurrence, with satisfactory clinical and functional outcome.


Acceptance of a structured diagnostic interview in children, parents, and interviewers.
The objective of this study was to investigate the satisfaction and acceptance of a structured diagnostic interview in clinical practice and in a research setting. Using the Structured Diagnostic Interview for Mental Disorders in Children and Adolescents (Kinder-DIPS), 28 certified interviewers conducted 202 interviews (115 with parents, 87 with children). After each interview, children, parents, and interviewers completed a questionnaire assessing the overall satisfaction (0 = not at all satisfied to 100 = totally satisfied) and acceptance (0 = completely disagree to 3 = completely agree) with the interview. Satisfaction ratings were highly positive, all means >82. The mean of the overall acceptance for children was 2.43 (standard deviation [SD] = 0.41), 2.54 (SD = 0.33) of the parents, 2.30 (SD = 0.43) of the children's interviewers, and 2.46 (SD = 0.32) of the parents' interviewers. Using separate univariate regression models, significant predictors for higher satisfaction and acceptance with the interview are higher children's Global Assessment of Functioning, fewer number of children's diagnoses, shorter duration of the interview, a research setting, female sex of the interviewer, and older age of the interviewer. Results indicate that structured diagnostic interviews are highly accepted by children, parents, and interviewers. Importantly, this is true for different treatment settings.


Nomenclature and synonymic remarks on two species of Eupterotidae (Lepidoptera) described by Johan Christian Fabricius, and notes on related species.
Types of two species of monkey moths (Eupterotidae, Lepidoptera) described by Johan Christian Fabricius were located and are here figured for the first time, and lectotypes are designated for both species. The lectotype of Bombyx hibisci Fabricius 1775 is a male from the Hunterian Museum (Glasgow). The lectotype of Bombyx orientalis Fabricius 1793, originally listed from "Dom. Lund" was found in the Zoological Museum-University of Copenhagen (as temporarily loan from the Zoological Museum of Kiel University) with an old incorrect identification label. Both species are members of the genus Eupterote Hübner, 1820 (so-called Brachytera-lineage). The following new synonymy can thus be established: Eupterote orientalis (Fabricius, 1793), comb. nov. (= Dreata geminata Walker 1855, syn. nov., syn. corr.; = Eupterote geminata var. hebes Grünberg 1914, syn. nov.; = Dreata anada Moore 1860, syn. nov., = Brachytera phalaenaria C. R. Felder, 1874, syn. nov., = Eupterote auriflua Moore, 1884, syn. nov.). The type locality for orientalis originally given as "India orientali" is likely to be Sri Lanka. The related taxon, Eupterote gardneri Bryk, 1950, stat. nov. is established as valid species (bona species) with the a new synonym, Eupterote bifasciata Kishida, 1994, syn. nov. Eupterote primularis Moore, 1884 is considered a distinct species native to Central and Southern India.


A plea for pragmatism in clinical research ethics.
Pragmatism is a distinctive approach to clinical research ethics that can guide bioethicists and members of institutional review boards (IRBs) as they struggle to balance the competing values of promoting medical research and protecting human subjects participating in it. After defining our understanding of pragmatism in the setting of clinical research ethics, we show how a pragmatic approach can provide guidance not only for the day-to-day functioning of the IRB, but also for evaluation of policy standards, such as the one that addresses acceptable risks for healthy children in clinical research trials. We also show how pragmatic considerations might influence the debate about the use of deception in clinical research. Finally, we show how a pragmatic approach, by regarding the promotion of human research and the protection of human subjects as equally important values, helps to break down the false dichotomy between science and ethics in clinical research.


Responses of renal, coronary and vertebral vasculatures to MC-838 and captopril in anesthetized dogs.
The regional hemodynamic effects of MC-838, a new angiotensin-converting enzyme inhibitor, and captopril at equidepressor doses were examined in the anesthetized dog by simultaneously measuring renal (RBF), coronary (CBF), vertebral (VBF) arterial and aortic blood flow (AoF). Hemodynamic responses to angiotensin I (AI), AII and noradrenaline were compared before and after the administration of each inhibitor. MC-838 (3 mg/kg i.v.) lowered gradually aortic pressure (AoP) and increased moderately AoF and RBF up to 60 min after the administration. Captopril (0.1 mg/kg i.v.) lowered AoP immediately after the administration and increased AoF and RBF more shortly than MC-838. Neither inhibitor produced a marked change in VBF or CBF. The effects of the inhibitors in the renal vascular bed was much greater than that in vertebral and coronary vascular beds, although vascular resistance in all of them was significantly reduced. Each of the drugs inhibited the pressor and renal vasoconstrictor responses to AI. These results indicate that the renal vasculature is more sensitive to both MC-838 and captopril than vertebral and coronary vasculature, but MC-838 has a slower and longer-lasting action than does captopril.


Going round in circles: shape effects in the Ebbinghaus illusion.
The Ebbinghaus illusion has traditionally been considered as either a sensory or a cognitive illusion, or some combination of these two. Cognitive contrast explanations take support from the way the illusion varies with the degree of shape similarity between the test and inducing elements; we show, however, that contour interaction explanations may account for this result too. We therefore tested these alternative theories by measuring the illusion with different test shapes as well as different inducer shapes, in all combinations. We found that for angular or hexagonal test shapes there is no similarity effect, and for some shape combinations there is no significant illusion, in contradiction to both of the traditional hypotheses. Instead, we suggest that an integrated model of visual processing is needed to account for the illusion.


Bovine viral diarrhea virus strain Oregon: a novel mechanism for processing of NS2-3 based on point mutations.
Bovine viral diarrhea virus (BVDV) isolates can either be cytopathogenic (cp) or noncytopathogenic (noncp). While both biotypes express the nonstructural protein NS2-3, generation of NS3 strictly correlates with the cp phenotype. The production of NS3 is usually caused by cp specific genome alterations, which were found to be due to RNA recombination. Molecular analyses of the cp BVDV strain Oregon revealed that it does not possess such genome alterations but nevertheless is able to generate NS3 via processing of NS2-3. The NS3 serine protease is not involved in this cleavage, which, according to protein sequencing, occurs between amino acids 1589 and 1590 of the BVDV Oregon polyprotein. Transient-expression studies indicated that important information for the cleavage of NS2-3 is located within NS2. This was verified by expression of chimeric constructs containing cDNA fragments derived from BVDV Oregon and a noncp BVDV. It could be shown that the C-terminal part of NS2 plays a crucial role in NS2-3 cleavage. These data, together with results obtained by site-specific exchanges in this region, revealed a new mechanism for NS2-3 processing which is based on point mutations within NS2.


Carcinoembryonic antigen (CEA) testing in colorectal cancer follow up: what do patients think?
The carcinoembryonic antigen (CEA) blood test is included in most colorectal cancer follow up protocols, despite little clear evidence for its cost-effectiveness and survival benefit. In this study, patients' views were sought on the use of the CEA blood test in their follow up. Strong associations were found between the age of a patient's children and their concern about cancer recurrence and between concern about recurrence and anxiety about CEA test results (p<0.0001). Many patients expressed a desire for prognostic information, however uncertain or poor. Patients' views should be sought when designing colorectal cancer follow up protocols to ensure their needs are adequately addressed.


CD4+ CD45R- suppressor-inducer T-cell clones: requirements for cellular interaction, proliferation and lymphokines for the induction of suppression in peripheral blood mononuclear cells.
Regulation of the induction of suppressive activity in peripheral blood mononuclear cells (PBMC) by human major histocompatibility complex (MHC) class II+ CD4+ CD45R+ suppressor-inducer T-cell clones has been investigated. Previously, it was shown that in this system, cyclosporin A-sensitive precursors gave rise to allo-indifferent MHC-unrestricted CD4+ suppressive cells. Their induction could be blocked by monoclonal antibodies (mAb) to multilocus MHC class II gene products (TU 39) but not by mAb preferentially reacting with HLA-DR, -DQ or -DP molecules. This product, functionally defined, was termed 'DY'. It is shown here that induction of suppression by DY follows established activation pathways: (i) cell adhesion was required because CD11a (LFA-1) mAb blocked suppressor-induction; (ii) CD4 mAb also blocked, consistent with the involvement of class II products in suppressor-induction; (iii) cell proliferation was required because mAb to transferrin receptors, or irradiation, inhibited induction; and (iv) such proliferation appeared to be interleukin (IL)-2-dependent because it was blocked by mAb to IL-2 receptor, and enhanced by exogenous IL-2 but not IL-4. It was also enhanced by exogenous IL-1 and IL-6, but not by IL-3, tumour necrosis factor-alpha (TNF alpha) or interferon-gamma (IFN-gamma). It therefore seems that the requirements for activation of suppression by CD4+ DY+ T-cell clones in this in vitro model bear many similarities to those for CD4+ helper T cells, namely, mediation by MHC class II with CD4 involvement, dependency on LFA-1-influenced cell interactions, and reliance on clonal expansion caused by IL-2 and possibly amplified by IL-1 and/or IL-6.


Relationship between Physical Activity and Physical Fitness in Preschool Children: A Cross-Sectional Study.
To evaluate the relationships between objectively measured physical activity and physical fitness among preschool children. A total of 346 participants (201 boys and 145 girls) aged 3.5-5.5 years (M = 4.5 yr, SD = 0.47) from Shanghai, China, completed physical fitness assessments, including triceps skinfold thickness (TSFT), grip strength, tennis throwing, sit and reach test, standing long jump, balance beam, 10mSRT, and 20mSRT. Physical activity was objectively measured by ActiGraphGT3X+ accelerometer. Multiple linear regression models were used to explore the cross-sectional associations between PA and physical fitness after adjusting for age, gender, BMI, and valid wearing time. Positive associations were observed between stand long jump (p < .01), tennis throwing (p < .01), laps in 20mSRT (p < .01), and MVPA. However, TSFT (p < .05), time in 10mSRT (p < .01), and balance beam (p < .05) were negatively associated with MVPA. Furthermore, positive associations were found between stand long jump (p < .01), tennis throwing (p < .01), and MVPA only in boys. Negative associations were found between time on balance beam (p < .01) and MVPA only in girls. MVPA appears to be an effective and reliable predictor of preschoolers' physical fitness. Boys' body composition, muscular strength, explosive strength, agility, aerobic fitness, girls' agility, aerobic fitness, and balance could improve as MVPA increases.


A Sense of Belonging: Perceptions of the Medical School Learning Environment among URM and Non-URM Students.
Phenomenon: Improving the learning environment (LE), particularly for students underrepresented in medicine (URM), has become an important goal for institutions that provide undergraduate and graduate medical education. Until recently, research and intervention development have been limited by the lack of comprehensive theoretical frameworks. A multi-dimensional conceptual model of the medical school environment, developed by Gruppen and colleagues in 2019, provides a useful framework for guiding research and interventions in this area.Approach: Using Gruppen et al's model, this study investigated experiences of the LE from the perspectives of both URM and non-URM students at a medical school in New York City. In examining experiences of the organizational, social, and physical domains of the LE, we sought to explore the symbolic and experiential links across domains and identify concrete needs for improvement.Findings: Institutional structures and policies, features of the built environment, and social relationships that put learning first and generated a sense of community were highly valued. Although both URM and non-URM students shared many perceptions and experiences, URM students expressed heightened vulnerability to the experiences of devaluation and exclusion.Insights: All participants in the study greatly appreciated aspects of the LE that made them feel like valued members of the community. Medical schools should approach the task of improving the LE for URM students using a comprehensive, multi-dimensional approach.


LRRK2 Kinase Inhibition Attenuates Neuroinflammation and Cytotoxicity in Animal Models of Alzheimer's and Parkinson's Disease-Related Neuroinflammation.
Chronic neuroinflammation plays a crucial role in the progression of several neurodegenerative diseases (NDDs), including Parkinson's disease (PD) and Alzheimer's disease (AD). Intriguingly, in the last decade, leucine-rich repeat kinase-2 (LRRK2), a gene mutated in familial and sporadic PD, was revealed as a key mediator of neuroinflammation. Therefore, the anti-inflammatory properties of LRRK2 inhibitors have started to be considered as a disease-modifying treatment for PD; however, to date, there is little evidence on the beneficial effects of targeting LRRK2-related neuroinflammation in preclinical models. In this study, we further validated LRRK2 kinase modulation as a pharmacological intervention in preclinical models of AD- and PD-related neuroinflammation. Specifically, we reported that LRRK2 kinase inhibition with MLi2 and PF-06447475 (PF) molecules attenuated neuroinflammation, gliosis and cytotoxicity in mice with intracerebral injection of Aβ1-42 fibrils or α-syn preformed fibrils (pffs). Moreover, for the first time in vivo, we showed that LRRK2 kinase activity participates in AD-related neuroinflammation and therefore might contribute to AD pathogenesis. Overall, our findings added evidence on the anti-inflammatory effects of LRRK2 kinase inhibition in preclinical models and indicate that targeting LRRK2 activity could be a disease-modifying treatment for NDDs with an inflammatory component.


Differential requirements of Hsp90 and DNA for the formation of estrogen receptor homodimers and heterodimers.
The two estrogen receptor (ER) subforms, ERalpha and ERbeta, are capable of forming DNA-binding homodimers and heterodimers. Although binding to DNA is thought to stabilize ER dimers, how ERalpha/alpha, ERbeta/beta, and ERalpha/beta dimerization is regulated by DNA and the chaperone protein Hsp90 is poorly understood. Using our highly optimized bioluminescence resonance energy transfer assays in conjunction with assays for transcriptional activation of ERs, we determined that DNA binding appears to play a minor role in the stabilization of ER dimers, especially in the case of ERbeta/beta homodimers. These findings suggest that ER dimers form before they associate with chromatin and that DNA binding plays a minor role in stabilizing ER dimers. Additionally, although Hsp90 is essential for the proper dimerization of ERalpha/alpha and ERalpha/beta, it is not required for the proper dimerization of ERbeta/beta. Despite this, Hsp90 is critical for the estrogen-dependent transcriptional activity of the ERbeta/beta homodimer. Thus, Hsp90 is implicated as an important regulator of distinct aspects of ERalpha and ERbeta action.


Five-year outcome of clinical recovery and subjective well-being in older Dutch patients with schizophrenia.
Outcome of schizophrenia in later life can be evaluated from different perspectives. The recovery concept has moved forward this evaluation, discerning clinical-based and patient-based definitions. Longitudinal data on measures of recovery in older individuals with schizophrenia are scant. This study evaluated the five-year outcome of clinical recovery and subjective well-being in a sample of 73 older Dutch schizophrenia patients (mean age 65.9 years; SD 5.4), employing a catchment-area based design that included both community living and institutionalized patients regardless of the age of onset of their disorder. At baseline (T1), 5.5% of participants qualified for clinical recovery, while at five-year follow-up (T2), this rate was 12.3% (p = 0.18; exact McNemar's test). Subjective well-being was reported by 20.5% of participants at T1 and by 27.4% at T2 (p = 0.27; exact McNemar's test). Concurrence of clinical recovery and subjective well-being was exceptional, being present in only one participant (1.4%) at T1 and in two participants (2.7%) at T2. Clinical recovery and subjective well-being were not correlated neither at T1 (p = 0.82; phi = 0.027) nor at T2 (p = 0.71; phi = -0.044). There was no significant correlation over time between clinical recovery at T1 and subjective well-being at T2 (p = 0.30; phi = 0.122) nor between subjective well-being at T1 and clinical recovery at T2 (p = 0.45; phi = -0.088). These results indicate that while reaching clinical recovery is relatively rare in older individuals with schizophrenia, it is not a prerequisite to experience subjective well-being.


Epidermal growth factor activates the Rho GTPase-activating protein (GAP) Deleted in Liver Cancer 1 via focal adhesion kinase and protein phosphatase 2A.
Deleted in Liver Cancer 1 (DLC1) is a RHO GTPase-activating protein (GAP) that negatively regulates RHO. Through its GAP activity, it modulates the actin cytoskeleton network and focal adhesion dynamics, ultimately leading to suppression of cell invasion and metastasis. Despite its presence in various structural and signaling components, little is known about how the activity of DLC1 is regulated at focal adhesions. Here we show that EGF stimulation activates the GAP activity of DLC1 through a concerted mechanism involving DLC1 phosphorylation by MEK/ERK and its subsequent dephosphorylation by protein phosphatase 2A (PP2A) and inhibition of focal adhesion kinase by MEK/ERK to allow the binding between DLC1 and PP2A. Phosphoproteomics and mutation studies revealed that threonine 301 and serine 308 on DLC1, known previously to be mutated in certain cancers, are required for DLC1-PP2A interaction and the subsequent activation of DLC1 upon their dephosphorylation. The intricate interplay of this "MEK/ERK-focal adhesion kinase-DLC1-PP2A" quartet provides a novel checkpoint in the spatiotemporal control of cell spreading and cell motility.


Automatic Annotation Tool to Support Supervised Machine Learning for Scaphoid Fracture Detection.
The aim of this work is to develop and validate an automatic annotation tool for the detection and bone localization of scaphoid fractures in radiology reports. To achieve this goal, a rule-based method using a Natural Language Processing (NLP) tool was applied. Finite state automata were constructed to detect, classify and annotate reports. An evaluation of the method on a manually annotated dataset has shown 96,8% of total match.


Dyspareunia in HIV-positive and HIV-negative middle-aged women: a cross-sectional study.
To evaluate whether dyspareunia is associated with HIV status in menopausal women and also to assess which factors are associated with dyspareunia in a group of HIV-positive menopausal women. A cross-sectional study was conducted with 178 HIV-negative and 128 HIV-positive women aged 40-60 years. The Short Personal Experiences Questionnaire (SPEQ) was used to collect data. Sociodemographic, clinical, behavioural and reproductive factors were evaluated, as well as factors related to the HIV infection. Dyspareunia was defined as pain during intercourse. A bivariate analysis and Poisson multiple regression analysis were performed. Overall, 41.4% of the HIV-positive women reported dyspareunia compared with 34.8% of the HIV-negative women (p=0.242). In the HIV-positive women, bivariate analysis revealed an association between dyspareunia and having a steady partner (p=0.047); the woman's partner having undergone HIV testing (p=0.020); vaginal dryness (p<0.001); muscle/joint pain (p=0.021); physical/emotional violence (p=0.049); urinary incontinence (p=0.004); and the use of lamivudine/zidovudine (p=0.048). The Poisson multiple regression analysis found an association between dyspareunia and vaginal dryness (prevalence ratio (PR)=1.96, 95% CI 1.10 to 3.50, p=0.023) and urinary incontinence (PR=1.86, 95% CI 1.06 to 3.27, p=0.031). Dyspareunia was common in this group of HIV-positive women and was associated principally with vaginal dryness and urinary incontinence. The importance of treating dyspareunia within the context of sexual health in this group of women should be emphasised and appropriate management of this issue may reduce the likelihood of lesions on the vaginal wall, which may act as a portal of entry for other infections.


Sentinel hospital surveillance of HIV infection in Quebec. Quebec Sentinel Hospital HIV-Seroprevalence Study Group.
To measure the HIV seroprevalence rate in a surrogate sample of the general population in the province of Quebec, using a network of sentinel hospitals. Anonymous unlinked sentinel surveillance study. Outpatient surgery units in 19 acute care hospitals throughout Quebec. All patients attending the outpatient surgery units from November 1990 to October 1992. A total of 61,547 plasma samples were obtained from leftover blood samples collected for cell counts. Fifty samples were excluded because of an insufficient amount of plasma and one because of an indeterminate result. HIV antibody testing with enzyme-linked immunosorbent assay; positive results confirmed with radioimmunoprecipitation assay. HIV antibody status, sex, year of birth and area of residence. The crude seroprevalence rate among the subjects aged 15 years or more was 0.4 per 1000 population (95% confidence interval [CI] 0.2 to 0.7) among the women and 3.6 per 1000 population (95% CI 2.8 to 4.4) among the men (p < 0.001). The rate after adjustment for age, sex and geographic distribution of the study population was 2.3 per 1000 population (95% CI 1.9 to 2.7). The seroprevalence rate among the male patients in the City of Montreal was much higher than the rates elsewhere in the province. It increased progressively during each of the four 6-month intervals of the study: 8.1, 8.7, 13.9 and 18.3 per 1000 respectively (chi 2 linear trend = 4.76; p = 0.029). No similar trends were observed outside Montreal for the male patients. There were too few seropositive female patients to draw any solid conclusion. Despite the possible drawbacks of a nonrandomized sampling scheme, this study suggests that in the male population the HIV seroprevalence rate is increasing in Montreal and is stable in all other areas of the province. The continued surveillance of HIV infection through anonymous unlinked studies is useful to monitor trends.


The zoonotic poxviruses.
Animal poxviruses occasionally produce human skin disease often associated with systemic illness. Lesions are painful blisters and crusted eschars and are usually self-limiting and rarely fatal. Treatment is generally supportive.


[Virtual paediatric medicine].
Health information technology (eHealth) can be cost-effective if it replaces existing care services. The introduction of eHealth has provided the opportunity to directly support and improve care for children with chronic diseases. We show an example of this in children with diabetes mellitus. Giving patients direct feedback on their glucose levels results in better outcomes of patient care. Accessing data from electronic patient files and using them effectively, however, is not yet possible in a number of health care institutions.


Virtual visits in home health care for older adults.
This review identifies the content of virtual visits in community nursing services to older adults and explores the manner in which service users and the nurses use virtual visits. An integrative literature review. Data collection comprised a literature search in three databases: Cinahl, Medline, and PubMed. In addition, a manual search of reference lists and expert consultation were performed. A total of 12 articles met the inclusion criteria. The articles were reviewed in terms of study characteristics, service content and utilization, and patient and health care provider experience. Our review shows that in most studies the service is delivered on a daily basis and in combination with in-person visits. The findings suggest that older home-dwelling patients can benefit from virtual visits in terms of enhanced social inclusion and medication compliance. Service users and their nurses found virtual visits satisfactory and suitable for care delivery in home care to the elderly. Evidence for cost-saving benefits of virtual visits was not found. The findings can inform the planning of virtual visits in home health care as a complementary service to in-person visits, in order to meet the increasingly complex needs of older adults living at home.


Impact of COVID-19 vaccination on mortality after acute myocardial infarction.
COVID-19 vaccines are highly immunogenic but cardiovascular effects of these vaccines have not been properly elucidated. To determine impact of COVID-19 vaccination on mortality following acute myocardial infarction (AMI). This was a single center retrospective observation study among patients with AMI enrolled in the the North India ST-Elevation Myocardial Infarction (NORIN-STEMI) registry. In all the enrolled patients, data regarding patient's vaccination status including details on type of vaccine, date of vaccination and adverse effects were obtained. All enrolled subjects were followed up for a period of six months. The primary outcome of the study was all-cause mortality both at one month and at six months of follow-up. Propensity-weighted score logistic regression model using inverse probability of treatment weighting was used to determine the impact of vaccination status on all-cause mortality. A total of 1578 subjects were enrolled in the study of whom 1086(68.8%) were vaccinated against COVID-19 while 492(31.2%) were unvaccinated. Analysis of the temporal trends of occurrence of AMI post vaccination did not show a specific clustering of AMI at any particular time. On 30-day follow-up, all-cause mortality occurred in 201(12.7%) patients with adjusted odds of mortality being significantly lower in vaccinated group (adjusted odds ratio[aOR]: 0.58, 95% CI: 0.47-0.71). Similarly, at six months of follow-up, vaccinated AMI group had lower odds of mortality(aOR: 0.54, 95% CI: 0.44 to 0.65) as compared to non-vaccinated group. COVID-19 vaccines have shown to decrease all-cause mortality at 30 days and six months following AMI.


The eosinophilia-myalgia syndrome: the Los Alamos Conference.
On June 12 and 13, 1990 the Los Alamos National Laboratory in cooperation with the New Mexico Department of Health and Environment, the Centers for Disease Control (CDC), the Food and Drug Administration (FDA), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) hosted a conference on the eosinophilia-myalgia syndrome. Fifty presentations covered a variety of important issues which are summarized herein.


Evoked potentials in clinical trials for multiple sclerosis.
Multiple sclerosis produces disruption of conduction in the central nervous system by a variety of mechanisms, relating, in part, to loss of the myelin sheath. Although often not well correlated with the clinical course of the disease in individual patients, the resulting evoked potential (EP) disturbances can serve as measures of an accumulating disease burden, particularly in longitudinal population studies. Accordingly, EPs can serve as useful instruments for assessing the effectiveness of therapeutic agents which may alter the course of the multiple sclerosis. Furthermore, since EPs measure conduction within the central nervous system, they provide a means of directly assessing symptomatic treatments designed to improve central conduction.