Torsades de pointes ventricular tachycardia and terodiline.
We report five patients (four women, one man; mean age 74 years, range 55-87) taking terodiline who had torsades de pointes ventricular tachycardia associated with prolongation of the QT interval. The QT interval was normal before the introduction of terodiline in three patients and returned to normal after terodiline withdrawal in four. Atrioventricular conduction disturbance or bradycardia were evident in all patients. Terodiline should be prescribed with caution to elderly patients.


Two-dimensional superconductivity at the surfaces of KTaO3 gated with ionic liquid.
The recent discovery of superconductivity at the interfaces between KTaO3 and EuO (or LaAlO3) gives birth to the second generation of oxide interface superconductors. This superconductivity exhibits a strong dependence on the surface plane of KTaO3, in contrast to the seminal LaAlO3/SrTiO3 interface, and the superconducting transition temperature Tc is enhanced by one order of magnitude. For understanding its nature, a crucial issue arises: Is the formation of oxide interfaces indispensable for the occurrence of superconductivity? Exploiting ionic liquid (IL) gating, we are successful in achieving superconductivity at KTaO3(111) and KTaO3(110) surfaces with Tc up to 2.0 and 1.0 K, respectively. This oxide-IL interface superconductivity provides a clear evidence that the essential physics of KTaO3 interface superconductivity lies in the KTaO3 surfaces doped with electrons. Moreover, the controllability with IL technique paves the way for studying the intrinsic superconductivity in KTaO3.


Counterattack--medical malpractice.
This month's column introduces eight principles designed to help the gastroenterologist in his or her continuing battle for peace (of mind), justice (for both), and the un-American way (avoidance of malpractice suits).


Is Lateral Elbow Tendinopathy an Appropriate Clinical Diagnostic Term When the Condition Is Persistent?
Lateral elbow tendinopathy (LET) seems to be the most appropriate term to use in clinical practice because previous terms such as lateral epicondylitis, tennis elbow, lateral epicondylalgia, epicondylosis, enthesopathy, Father of the Bride's Elbow, lateral elbow or extensor tendonitis, lateral elbow or extensor tendinosis, and extensor tendinopathy make reference to inappropriate aetiological, anatomical, and pathophysiological terms [...].


"Assisted vaginal birth using the Paily obstetric forceps vs Ventouse - A randomized clinical trial".
Instruments used in assisted vaginal birth have seen little innovation for decades. Due to the risk of trauma and technical difficulty incurred during forceps delivery, instrumental deliveries are on a decline, and the global rate of primary cesarean birth is rising. The novel Paily Obstetric Forceps (POF) features a compact, lighter design with thinner blades, designed to increase operator comfort and minimize maternal and neonatal injuries. We aim to determine the feasibility and safety of POF in achieving vaginal birth compared to a ventouse device with a 50 mm silastic cup. We conducted a single-blinded, parallel arm, randomized clinical trial of the novel POF vs a ventouse device, in patients undergoing indicated assisted vaginal birth, at a tertiary care obstetric unit. We randomized 100 patients to be allocated on a 1:1 ratio to both intervention arms. Primary outcome was the proportion of successful instrumental deliveries. Secondary outcomes were the number of pulls required during traction and any maternal or neonatal adverse events. The POF was significantly more successful in achieving vaginal birth than the ventouse device (n = 50/50, 100 % vs n = 42/50, 84 %, p = 0.006). Operators reported requiring significantly fewer pulls during POF traction than ventouse. POF demonstrated a higher risk for maternal trauma (RR = 3.2, 95 % CI = 1.5 to 6.9, NNH = 2.7) but a lower risk for neonatal injury (RR = 0.6, 95 % CI = 0.3 to 1, NNH = 5.7). Maternal and neonatal recovery durations were comparable. There were no incidences of maternal or neonatal mortality. The POF can be used in indicated assisted vaginal birth with superior success rates and better neonatal outcomes than ventouse. Other obstetric forceps must be standardized to conduct larger superiority trials of forceps designs.


Performance and neural modeling of a compost-based biofilter treating a gas-phase mixture of benzene and xylene.
Biofilter (BF) has been regarded as a versatile gas treatment technology for removing volatile organic compounds (VOCs) from contaminated gas streams. In order for BF to be utilized in the industrial setting, it is essential to conduct research aimed at removing VOC mixtures under different inlet loading conditions, i.e. as a function of the gas flow rate and inlet VOC concentrations. The main aim of this study was to apply artificial neural networks (ANN) and determine the relationship between flow rate (FR), pressure drop (PD), inlet concentration (C), and removal efficiency (RE) in the BF treating gas-phase benzene and xylene mixtures. The ANN model was trained and tested to assess the removal efficiency of benzene (REB) and xylene (REX) under the influence of different FR, PD and C. The model's performance was assessed using a cross-validation method. The REb varied from 20% to >60%, while the REx varied from 10% to 70% during the different experimental phases of BF operation. The causal index (CI) technique was used to determine the sensitivity of the input parameters on the output variables. The ANN model with a topology of 4-4-2 performed the best in terms of predicting the RE profiles of both the pollutants. Furthermore, the effect was more pronounced for xylene because an increase in the benzene concentration reduced xylene removal (CI = -25.7170) more severely than benzene removal. An increase in the xylene concentration had a marginally positive effect on the benzene removal (CI = +0.1178).


Sediment Records of Polybrominated Diphenyl Ethers (PBDEs) from the Anhui Province Section of Yangtze River, China.
This study investigated the temporal changes of PBDEs in the sediment cores from the Anhui Province section of Yangtze River (YR), China. The dramatic increase of ∑Br3-Br9-BDEs and BDE-209 concentrations in cores in the period of ca. 1990-2008 was consistent with the booming of regional and national production and consumption of household appliances and electronics. Following declines in BDE-209 and ∑Br3-Br9-BDEs concentrations can be associated with the deceasing use of legacy commercial PBDE mixtures in recent years. Compared with the different regions around the world, sediments in the YR were moderately polluted by PBDEs. The levels and the detection rates of BDE-209 were highest among the detected PBDEs single congener. The composition analysis indicated that Deca-BDE, Octa-BDE, and Penta-BDE were the dominant forms in the YR. The increasing trends of both BDE-209 and ∑Br3-Br9-BDEs in the YR during 1990s and 2000s largely reflected the time periods for transferring PBDE sources from the developed countries to China. TOC and finer particles were strongly correlated with distributions of PBDEs in sediments.


Immune Response to LinB13, a Lutzomyia Intermedia Salivary Protein Correlates With Disease Severity in Tegumentary Leishmaniasis.
We have previously shown that seropositivity to rLinB-13, a salivary protein from Lutzomyia intermedia, predicted sand fly exposure and was associated with increased risk of developing cutaneous leishmaniasis (CL). Here, we investigated the cellular immune response to saliva from Lu. intermedia, using rLinB-13 as a surrogate antigen in naturally exposed individuals presenting positive serology to LinB-13. We also investigated the response to rLinB-13 in leishmaniasis patients, displaying active ulcers and positive PCR for Leishmania braziliensis. Peripheral blood mononuclear cells (PBMCs) stimulated in vitro with rLinB-13 secreted elevated levels of interleukin-10 (IL-10), IL-4, IL-1β, IL-1α, IL-6, and chemokines (CCL3, CCL4, CCL5, and CXCL5). CL and disseminated leishmaniasis (DL) patients displayed a significantly higher immunoglobulin G (IgG) response to rLinB-13 compared with healthy subjects, and anti-rLinB-13 IgG was positively correlated with the number of lesions in DL patients. Positive serology to rLinB-13 was also associated with chemotherapy failure. PBMCs from DL patients stimulated with rLINB-13 secreted significantly higher levels of IL-10 and IL-1β compared with CL individuals. In this study, we observed an association between humoral and cellular immune response to the sand fly salivary protein rLinB-13 and disease severity in tegumentary leishmaniasis. This study brings evidence that immunity to rLinB-13 influences disease outcome in L. braziliensis infection and results indicate that positive serology to rLinB-13 IgG can be used as a marker of DL, an emerging and severe form of disease caused by L. braziliensis.


Neonatal CD8+ T-cell differentiation is dependent on interleukin-12.
Neonatal CD8(+) T-cell activation is significantly impaired compared with that in adults. Recent studies have demonstrated that interleukin (IL)-12 is necessary as a third signal, in addition to antigen and co-stimulation, to authorize the differentiation of naive CD8(+) T cells. We examined whether human neonatal CD8(+) T cells, which possess an exclusively naive T-cell phenotype, required a third signal to authorize a productive T-cell response. IL-12 enhanced activated naive CD8(+) T-cell survival, expansion, CD25 expression, and IL-2 production. Activated CD8(+) T cells produced interferon-γ and intracellular granzyme B and were cytotoxic only in the presence of IL-12. Sustained IL-12 signaling for 72 hours was required for optimal interferon-γ production. IL-12, in concert with T cell receptor (TCR) stimulation, sustained late-stage (48-72 hours) intracellular phosphorylation and particularly total protein levels of the proximal TCR components, Lck, and CD3ξ. The requirement for a third signal for productive human neonatal CD8(+) T-cell differentiation may have implications for neonatal vaccination strategies.


Crystal structure of 1-benzyl-4-formyl-1H-pyrrole-3-carb-oxamide.
In the title compound, C13H12N2O2 (I), the mean planes of the pyrrole and benzyl rings are approximately perpendicular, forming a dihedral angle of 87.07 (4) °. There is an intra-molecular N-H⋯O hydrogen bond forming an S(7) ring motif. In the crystal, mol-ecules are linked via a pair of N-H⋯O hydrogen bonds forming inversion dimers. C-H⋯O hydrogen bonds link the dimers into chains along direction [10-1]. The chains are further linked by weak C-H⋯π inter-actions forming layers parallel to the ac plane.


Double peroxidase and histone acetyltransferase AgTip60 maintain innate immune memory in primed mosquitoes.
Immune priming in Anopheles gambiae is mediated by the systemic release of a hemocyte differentiation factor (HDF), a complex of lipoxin A4 bound to Evokin, a lipid carrier. HDF increases the proportion of circulating granulocytes and enhances mosquito cellular immunity. Here, we show that Evokin is present in hemocytes and fat-body cells, and messenger RNA (mRNA) expression increases significantly after immune priming. The double peroxidase (DBLOX) enzyme, present in insects but not in vertebrates, is essential for HDF synthesis. DBLOX is highly expressed in oenocytes in the fat-body tissue, and these cells increase in number in primed mosquitoes. We provide direct evidence that the histone acetyltransferase AgTip60 (AGAP001539) is also essential for a sustained increase in oenocyte numbers, HDF synthesis, and immune priming. We propose that oenocytes may function as a population of cells that are reprogrammed, and orchestrate and maintain a broad, systemic, and long-lasting state of enhanced immune surveillance in primed mosquitoes.


Mechanism of QSYQ on anti-apoptosis mediated by different subtypes of cyclooxygenase in AMI induced heart failure rats.
Qi-shen-yi-qi (QSYQ), one of the most well-known traditional Chinese medicine (TCM) formulas, has been shown to have cardioprotective effects in rats with heart failure (HF) induced by acute myocardial infarction (AMI). However, the mechanisms of its therapeutic effects remain unclear. In this study, we aim to explore the mechanisms of QSYQ in preventing left ventricular remodelling in rats with HF. The anti-apoptosis an anti-inflammation effects of QSYQ were investigated. Sprague-Dawley (SD) rats were randomly divided into 4 groups: sham group, model group, QSYQ treatment group and aspirin group. Heart failure model was induced by ligation of left anterior descending (LAD) coronary artery. 28 days after surgery, hemodynamics were detected. Echocardiography was adopted to evaluate heart function. TUNEL assay was applied to assess myocardial apoptosis rates. Protein expressions of cyclooxygenase1 and 2 (COX1and COX2), Fas ligand (FasL), P53 and MDM2 were measured by western-blot. RT-PCR was applied to detect expressions of our subtype receptors of PGE2 (EP1, 2, 3, and 4). Ultrasonography showed that EF and FS values decreased significantly and abnormal hemodynamic alterations were observed in model group compared to sham group. These indications illustrated that HF models were successfully induced. Levels of inflammatory cytokines (TNF-α and IL-6) in myocardial tissue were up-regulated in the model group as compared to those in sham group. Western-blot analysis showed that cyclooxygenase 2, which is highly inducible by inflammatory cytokines, increased significantly. Moreover, RT-PCR showed that expressions of EP2 and EP4, which are the receptors of PGE2, were also up-regulated. Increased expressions of apoptotic pathway factors, including P53 and FasL, might be induced by the binding of PGE2 with EP2/4. MDM2, the inhibitor of P53, decreased in model group. TUNEL results manifested that apoptosis rates of myocardial cells increased in the model group. After treatment with QSYQ, expressions of inflammatory factors, including TNF-α, IL-6 and COX2, were reduced. Expressions of EP2 and EP4 receptors also decreased, suggesting that PGE2-mediated apoptosis was inhibited by QSYQ. MDM2 was up-regulated and P53 and FasL in the apoptotic pathway were down-regulated. Apoptosis rates in myocardial tissue in the QSYQ group decreased compared with those in the model group. QSYQ exerts cardiac protective efficacy mainly through inhibiting the inflammatory response and down-regulating apoptosis. The anti-inflammatory and anti-apoptosis efficacies of QSYQ are probably achieved by inhibition of COXs-induced P53/FasL pathway. These findings provide experimental evidence for the beneficial effects of QSYQ in the clinical application for treating patients with HF.


Medical Encounters Among 94,033 Race Starters During a 16.1-km Running Event Over 3 Years in the Netherlands: SAFER XXVI.
There are limited data on the medical encounters (MEs) occurring during mass community-based running events of shorter distances (10-21.1 km). The aim of this study was to determine the incidence and nature of MEs during the largest mass participation running event in the Netherlands. We hypothesize that the incidence and nature of MEs will be similar to other running events. Descriptive epidemiological study over 3 years of a 16.1-km (10-mile) running event. Level 4. We investigated a total of 94,033 race starters at the 2017-2019 Dam tot Damloop (16.1 km), a point-to-point road race from Amsterdam to Zaandam, the Netherlands. All MEs were recorded by race medical staff on race day each year. MEs were retrospectively coded by severity, organ system, and final specific diagnosis (2019 consensus statement definition on mass community-based events). Incidence (I) per 1000 starters (95% CIs) were calculated for all MEs and serious/life-threatening MEs. The overall incidence (per 1000 starters) of all MEs was 2.75 (95% CI, 2.44-3.11), the overall incidence of serious/life-threatening MEs was 1.20 (95% CI, 1.00-1.45; 44% of MEs). Heat illnesses accounted for most MEs: hypothermia I = 0.54 (95% CI, 0.41-0.71) and hyperthermia I = 0.46 (95% CI, 0.34-0.62). Central nervous system MEs were also common (dizziness/nausea, I = 0.79; 95% CI 0.63-0.99), followed by the cardiovascular system MEs (exercise-associated postural hypotension, I = 0.36; 95% CI, 0.26-0.51). The overall incidence of MEs was low compared with longer-distance races (21.1-90 km), but the incidence and relative frequency of serious/life-threatening MEs (44% of all MEs) was much higher. Heat illness (hypothermia and exertional heat stroke) accounted for most serious/life-threatening MEs. There is a need to implement prevention strategies and interventions by specialized medical practitioners in this and similar events.


Application of atomic force microscopy to microbial surfaces: from reconstituted cell surface layers to living cells.
The application of atomic force microscopy (AFM) to probe the ultrastructure and physical properties of microbial cell surfaces is reviewed. The unique capabilities of AFM can be summarized as follows: imaging surface topography with (sub)nanometer lateral resolution; examining biological specimens under physiological conditions; measuring local properties and interaction forces. AFM is being used increasingly for: (i) visualizing the surface ultrastructure of microbial cell surface layers, including bacterial S-layers, purple membranes, porin OmpF crystals and fungal rodlet layers; (ii) monitoring conformational changes of individual membrane proteins; (iii) examining the morphology of bacterial biofilms, (iv) revealing the nanoscale structure of living microbial cells, including fungi, yeasts and bacteria, (v) mapping interaction forces at microbial surfaces, such as van der Waals and electrostatic forces, solvation forces, and steric/bridging forces; and (vi) probing the local mechanical properties of cell surface layers and of single cells.


Traveling Waves and Estimation of Minimal Wave Speed for a Diffusive Influenza Model with Multiple Strains.
Antiviral treatment remains one of the key pharmacological interventions against influenza pandemic. However, widespread use of antiviral drugs brings with it the danger of drug resistance evolution. To assess the risk of the emergence and diffusion of resistance, in this paper, we develop a diffusive influenza model where influenza infection involves both drug-sensitive and drug-resistant strains. We first analyze its corresponding reaction model, whose reproduction numbers and equilibria are derived. The results show that the sensitive strains can be eliminated by treatment. Then, we establish the existence of the three kinds of traveling waves starting from the disease-free equilibrium, i.e., semi-traveling waves, strong traveling waves and persistent traveling waves, from which we can get some useful information (such as whether influenza will spread, asymptotic speed of propagation, the final state of the wavefront). On the other hand, we discuss three situations in which semi-traveling waves do not exist. When the control reproduction number [Formula: see text] is larger than 1, the conditions for the existence and nonexistence of traveling waves are determined completely by the reproduction numbers [Formula: see text], [Formula: see text] and the wave speed c. Meanwhile, we give an interval estimation of minimal wave speed for influenza transmission, which has important guiding significance for the control of influenza in reality. Our findings demonstrate that the control of influenza depends not only on the rates of resistance emergence and transmission during treatment, but also on the diffusion rates of influenza strains, which have been overlooked in previous modeling studies. This suggests that antiviral treatment should be implemented appropriately, and infected individuals (especially with the resistant strain) should be tested and controlled effectively. Finally, we outline some future directions that deserve further investigation.


[Heart rate variability in patients with diffuse toxic goiter].
Functional state of the vegetative nervous system of 18 patients with first time diagnosed moderate thyrotoxicosis has been analyzed. Vegetative tonus, vegetative reactivity and vegetative activity during daily activity was assessed based on heart rate variability.


Velocity encoding and velocity compensation for multi-spoke RF excitation.
To investigate velocity encoded and velocity compensated variants of multi-spoke RF pulses that can be used for flip-angle homogenization at ultra-high fields (UHF). Attention is paid to the velocity encoding for each individual spoke pulse and to displacement artifacts that arise in Fourier transform imaging in the presence of flow. A gradient waveform design for multi-spoke excitation providing an algorithm for minimal TE was proposed that allows two different encodings. Such schemes were compared to an encoding approach that applies an established scheme to multi-spoke excitations. The impact on image quality and quantitative velocity maps was evaluated in phantoms using single- and two-spoke excitations. Additional validation measurements were obtained in-vivo at 7 T. Phantom experiments showed that keeping the first gradient moment constant for all k-space lines eliminates any displacements in phase-encoding and slice-selection direction for all spoke pulses but leads to artifacts for non-zero velocity components along readout direction. Introducing variable but well-defined first gradient moments in the phase-encoding direction creates displacements along the velocity vector and thus minimizes velocity-induced geometrical distortions. Phase-resolved mean volume flow in the ascending and descending aorta obtained from two-spoke excitation showed excellent agreement with single-spoke excitation over the cardiac cycle (mean difference 0.8 ± 16.2 ml/s). The use of single- and multi-spoke RF pulses for flow quantification at 7 T with controlled displacement artifacts has been successfully demonstrated. The presented techniques form the basis for correct velocity quantification and compensation not only for conventional but also for multi-spoke RF pulses allowing in-plane B1+ homogenization using parallel transmission at UHF.


Validation of ATP luminometry for rapid and accurate titration of Mycoplasma hyopneumoniae in Friis medium and a comparison with the color changing units assay.
Limited reports are available on the growth response of Mycoplasma hyopneumoniae in Friis medium and the routinely used color changing units (CCU) assay has not yet been profoundly compared with other titration methods. Firstly, growth kinetics of 7 diverse M. hyopneumoniae isolates were followed by ATP luminometry in five Friis medium batches. Secondly, results of the CCU and ATP assays were compared hereby evaluating the methods. Growth curves of all isolates had log, stationary and senescence phases, and reached similar maximal titres when cultured in the same batch of Friis medium. Doubling times (Tds) of the isolates grown in slowly shaken cultures varied between 4.8 and 7.8 h. Maximal titres, Tds, growth phase in which the phenol red indicator turned from red to yellow due to acidification by mycoplasmal metabolism, and the length of the stationary phase varied depending on the Friis medium batch. The effect of static vs. shaking culture conditions on the Td depended on the isolate. ATP and CCU assays obtained similar growth curves, but when maximal levels were reached the CCU titre dropped earlier than the ATP titre. During log phase, CCU and ATP titres were strongly linearly linked. We developed a model enabling transformation of ATP into CCU titres or vice versa. The calculated amount of ATP per CCU (1.77 amol ATP/ml) indicated that the CCU assay likely underestimates the actual cell concentration. When titres were determined as means of 3 measurements, the ATP assay was 7 times more accurate and had 11-fold lower outliers than the CCU assay. Unlike the CCU assay, luminometry only requires one measurement to obtain sufficient accuracy. It was concluded that the ATP assay constitutes a valuable robust alternative for reproducible real-time titre assessment of freshly grown M. hyopneumoniae cultures. It is faster, more accurate and time, work and cost efficient compared to the CCU assay. The assay is preferred to better standardise and describe M. hyopneumoniae cultures used in various experiments.


Multifunctional High Entropy Alloys Enabled by Severe Lattice Distortion.
Since 2004, the design of high entropy alloys (HEAs) has generated significant interest within the materials science community due to their exceptional structural and functional properties. By incorporating multiple principal elements into a common lattice, it is possible to create a single-phase crystal with a highly distorted lattice. This unique feature enables HEAs to offer a promising combination of mechanical and physical properties that are not typically observed in conventional alloys. In this article, an extensive overview of multifunctional HEAs that exhibit severe lattice distortion is provided, covering the theoretical models that are developed to understand lattice distortion, the experimental and computational methods employ to characterize lattice distortion, and most importantly, the impact of severe lattice distortion on the mechanical, physical and electrochemical properties of HEAs. Through this review, it is hoped to stimulate further research into the study of distorted lattices in crystalline solids.


THE NEOLIBERAL TURN IN AMERICAN HEALTH CARE.
Leaving millions both uninsured and underinsured, the Affordable Care Act does not create a system of universal health care in the United States. To understand its shortcomings, we have to understand it as part of a historic shift in the political economy of American health care. This "neoliberal turn" began as a reaction against the welfare state as it expanded during the New Deal and post-World War II period. What began as a movement associated with philosophers like Friedrich Hayek ultimately had a powerful impact via the attraction of powerful corporate sponsors and political supporters, and it was to historically transform American health care thought and organization. In health policy circles, for example, it can be seen in a rising emphasis on "moral hazard," overuse, and cost sharing above a concern with universalism and equity. It was likewise manifested by the corporatization of the health maintenance organization and the rise of the "consumer-driven" health care movement. By the time of the health care reform debate, the influence of corporate "stakeholders" was to prove predominant. These developments, however, must be construed as connected parts of a much larger political transformation, reflected in rising inequality and privatization, occurring both domestically and internationally.


Analytical performances of the Diazyme ADA assay on the Cobas® 6000 system.
To evaluate the analytical performance of the Diazyme ADA assay on the Cobas® 6000 system for pleural fluid samples analysis. Imprecision, linearity, calibration curve stability, interference, and correlation studies were completed. The Diazyme ADA assay demonstrated excellent precision (CV<4%) over the analytical measurement range (0.5-117 U/L). Bilirubin above 50 μmol/L and haemoglobin above 177 μmol/L interfered with the test, inducing a negative and a positive interference respectively. The Diazyme ADA assay correlated well with the Giusti method (r(2)=0.93) but exhibited a negative bias (~ -30%). The Diazyme ADA assay on the Cobas® 6000 system represents a rapid, accurate, precise and reliable method for determination of ADA activity in pleural fluid samples.


Complete Genome Sequence of Cyanobacterium Geminocystis sp. Strain NIES-3709, Which Harbors a Phycoerythrin-Rich Phycobilisome.
The cyanobacterium Geminocystis sp. strain NIES-3709 accumulates a larger amount of phycoerythrin than the related NIES-3708 strain does. Here, we determined the complete genome sequence of the NIES-3709 strain. Our genome data suggest that the different copy number of rod linker genes for phycoerythrin leads to the different phycoerythrin contents between the two strains.


Evaluation of mebendazole for the treatment of trichuriasis.
Trichuris trichiura was found to cause severe refractory clinical illness in 25 child patients admitted to a rural hospital in northeast Queensland over a six-month period. Mebendazole produced significant alleviation of symptoms. Symptomless carrier states in 70 patients admitted to hospital for other complaints were also studied. Thirty-five of these were treated with mebendazole with a notable reduction in worm loads (as measured by Stoll egg counts) when compared with the control group. The effects of three-day and four-day courses of mebendazole on symptomless carriers are compared.


Regulation of nuclear transcription factors by stress signals.
1. A diverse array of stressful stimuli induces changes in gene expression via post-translational modification of transcription factors. 2. Study of activator protein (AP-1) transcription factor regulation has revealed a novel family of protein-serine kinases. Molecular cloning and expression of these proteins have demonstrated their specific activation by stress stimuli such as UV irradiation, heat, ischaemia/reperfusion and metabolic toxins. 3. Dissection of the regulation of the stress-activated protein kinases has revealed a similar but distinct mechanism to mitogen-activated protein kinases suggesting that cellular responses to stress may partially overlap with normal growth responses and have common nuclear targets.


Hepatic pseudo-anisotropy: a specific artifact in hepatic diffusion-weighted images obtained with respiratory triggering.
Hepatic pseudo-anisotropy is an artifact observed in hepatic diffusion-weighted imaging under respiratory triggering (RT-DWI). To determine the clinical significance of this phenomenon, hepatic RT-DW images were reviewed. One hundred and five MR examinations, including RT-DWI, were assessed. The patient group included 62 non-cirrhotic and 43 cirrhotic individuals. All images were evaluated by mutual agreement of two radiologists from the viewpoints of incidence of pseudo-anisotropy and correlation between pseudo-anisotropy and the quality of trace images. The ADC of normal hepatic parenchyma of non-cirrhotic livers were measured in both areas with and without pseudo-anisotropy. Pseudo-anisotropy was observed in 60% of non-cirrhotic (37/62) and 30% of cirrhotic (13/43) images. The difference between the two groups was statistically significant (P < 0.001). The quality of trace images showed a tendency to worsen as pseudo-anisotropy became significant. However, the quality of trace images was generally satisfactory, with only two patients whose trace images were difficult to interpret due to pseudo-anisotropy. The areas with pseudo-anisotropy showed higher ADC than those without pseudo-anisotropy (P < 0.001). Pseudo-anisotropy is a type of artifact that originates from respiratory movement. Even though respiratory triggering is employed, ADC measurement of the liver is inaccurate because of pseudo-anisotropy, especially in non-cirrhotic patients.


New cytotoxic and anti-inflammatory steroids from the soft coral Klyxum flaccidum.
Four new steroids, namely klyflaccisteroids G-J (1-4) were isolated from the Formosan soft coral Klyxum flaccidum. The structures of compounds 1-4 were established by spectral data analysis (IR, MS, 1D and 2D NMR) and comparison of spectral data with those of the related known compounds. Cytotoxicity assay revealed that 4 exhibited inhibition activity against the growth of HT-29, P388 and K562 cancer cell lines, whereas 2 showed selective cytotoxicity toward P388 cells. Compound 4 was also found to display significant anti-inflammatory activity for suppressing superoxide anion generation (O2(-)) and elastase release.


Ultrastructural demonstration of exocytosis of neurosecretory granules in the neurohypophysis of the frog Rana temporalia.
The release of neurosecretory granules by exocytosis was ultrastructurally observed in the neurohypophysis pars nervosa (posterior lobe) of the frog Rana temporalia with the tannic acid-Ringer fixation method. Electron microscopic analysis with the immunogold method revealed that many of putative neurosecretory granules displayed oxytocin-like immunoreactivity.


Congenital sinuses of the lower lip: reappraisal of Van der Woude syndrome on the basis of nine patients.
Congenital sinuses on the lower lip in association with cleft lip, cleft palate, or both are rare and occur in four syndromes, namely Van der Woude syndrome, popliteal pterygium syndrome, orofacial digital syndrome, and the ankyloblepharon filiform adnatum. The most common and best studied among these--the Van der Woude syndrome--is believed to be due to an autosomally dominant gene with 80 to 100% penetrance and a variable expressivity. We present our study of 9 patients with congenital lower lip sinuses and the penetrance in their families. On the basis of our observations we conclude that this syndrome may have low penetrance among the populations studied.


Development of the VBLaST: a virtual basic laparoscopic skill trainer.
The FLS training tool box has now been adopted by the Society of Gastrointestinal Endoscopic Surgeons (SAGES) as an official training tool for minimally invasive procedures. To overcome the limitations of the physical FLS training tool box, we have developed a Virtual Basic Laparoscopic Skill Trainer (VBLaSTTM) system, which is a 3D simulator that will allow trainees to acquire basic laparoscopic skill. The outcome of this work is the development of an integrated visio-haptic workstation environment including force feedback devices and a stereo display interface whereby trainees can practice on virtual versions of the FLS. Realistic graphical rendering and high fidelity haptic interactions are achieved. Surgical skill training is a long and tedious process of acquiring fine motor skills. It is expected that residents would start on trainers such as VBLaSTTM and after reaching a certain level of competence would progress to the more complex trainers for training on specific surgical procedures.


Compression of the common hepatic duct by the right hepatic artery.
Magnetic resonance (MR) cholangiography has been used wildly as preoperative examination before laparoscopic cholecystectomy (LSC). However, cases that suggested the stenotic lesion of extrahepatic bile duct are not so rare in MR cholangiography. When stenosis is found, further examination is needed to avoid the possibility of bile duct cancer. We reported a case in which the stenotic lesion was diagnosed compression of the common hepatic duct by the right hepatic artery by multislice CT (MCT) cholangiography.


The role of HPV in head and neck cancer and review of the HPV vaccine.
Recent data demonstrate that human papillomavirus also plays a role in cancers other than ano-genital cancers, specifically head and neck cancers, and non-cancerous conditions such as recurrent respiratory papillomatosis. As more and more information about the role of infection in non-cervical diseases is amassed, additional questions about whether prophylactic human papillomavirus vaccines will effectively prevent these conditions are raised. This article reviews the epidemiology of oral human papillomavirus infection and the role of human papillomavirus in head and neck cancers. In addition, it will review the known clinical indications for human papillomavirus vaccination, and highlight other potential clinical targets for the vaccine that have not yet been demonstrated in clinical trials but for which there is biologic plausibility.


Do patient preferences influence decisions on treatment for patients with steroid-refractory ulcerative colitis?
Patients with steroid-refractory ulcerative colitis face a difficult treatment decision between colectomy and therapy with infliximab or cyclosporine. The aim of this study was to understand how individual patient preferences for the various treatment outcomes influence the optimal treatment decision for a given patient. A Markov model was used to simulate treatment with total colectomy with an ileo pouch-anal anastomosis (TC/IPAA), cyclosporine (CSA), infliximab (INFLX), and infliximab followed by cyclosporine for treatment failures (INFLX-->CSA). Utility weights for treatment outcomes were elicited from 48 patients using both time trade-off and visual rating scale methods. Preference sets were applied to the model to identify the therapy that maximized quality-adjusted life years (QALYs) for each patient. Sensitivity analyses were performed to assess model robustness. Optimal treatment was highly variable among patients (INFLX-->CSA = 42%, 20/48; TC/IPAA = 37%, 18/48; CSA = 21%, 10/48; INFLX = 0%, 0/48). However, when average preference weights from our sample were applied to the model, medical treatments were superior to TC (CSA = .26 QALYs gained vs TC/IPAA; INFLX-->CSA = .25 QALYs gained vs TC/IPAA). Patient preferences have a clear impact on the optimal treatment for steroid-refractory ulcerative colitis. Although averaged preferences support the use of medical interventions, a third of individual patients may benefit most from proceeding directly to colectomy. Failure to fully assess individual preferences may result in suboptimal treatment for these patients.


Happy Moms, Happier Dads: Gendered Caregiving and Parents' Affect.
Parenting is emotionally demanding and highly gendered. We use data from the American Time Use Survey to examine mothers' and fathers' momentary affect during childcare activities. We observe a gender imbalance in the emotional rewards of childcare: fathers report more happiness, less stress, and less tiredness than mothers. We introduce the "care context"-defined as the type of childcare activity, when and where it takes place, who is present, and how much care is involved-as an explanation for these gender differences in parents' affect. The analysis reveals that most dimensions of the care context vary between mothers and fathers. We also find that the care context fully accounts for differences in mothers' and fathers' happiness, partially explains differences in stress, and does little to explain differences in tiredness. Thus, the gender imbalance in the emotional rewards of childcare is partially due to parents' highly gendered engagement with their children.


[Severe bilateral keratomalacia].
In contrast to developing countries, xerophthalmia is rather rare in developed countries. Malnutrition (e.g. in mentally deficient or psychiatric patients), chronic liver diseases (e.g. due to alcoholism), or bowel surgery can be reasons for vitamin A deficiency in developed countries. The prodromal stage of hypovitaminosis A is characterized by nyctalopia, which often manifests subclinically. Longer lasting and severe cases of vitamin A deficiency may be complicated by the occurrence of keratinizing metaplasia in the cornea and conjunctiva, xerosis, keratomalacia or blindness.


PARP-dependent and NAT10-independent acetylation of N4-cytidine in RNA appears in UV-damaged chromatin.
RNA modifications have been known for many years, but their function has not been fully elucidated yet. For instance, the regulatory role of acetylation on N4-cytidine (ac4C) in RNA can be explored not only in terms of RNA stability and mRNA translation but also in DNA repair. Here, we observe a high level of ac4C RNA at DNA lesions in interphase cells and irradiated cells in telophase. Ac4C RNA appears in the damaged genome from 2 to 45 min after microirradiation. However, RNA cytidine acetyltransferase NAT10 did not accumulate to damaged sites, and NAT10 depletion did not affect the pronounced recruitment of ac4C RNA to DNA lesions. This process was not dependent on the G1, S, and G2 cell cycle phases. In addition, we observed that the PARP inhibitor, olaparib, prevents the recruitment of ac4C RNA to damaged chromatin. Our data imply that the acetylation of N4-cytidine, especially in small RNAs, has an important role in mediating DNA damage repair. Ac4C RNA likely causes de-condensation of chromatin in the vicinity of DNA lesions, making it accessible for other DNA repair factors involved in the DNA damage response. Alternatively, RNA modifications, including ac4C, could be direct markers of damaged RNAs.


Multidisciplinary Lupus Nephritis Clinic Reduces Time to Renal Biopsy and Improves Care Quality.
Patients with lupus nephritis (LN) have a 26-fold higher mortality rate compared with their peers. Kidney biopsy, the gold standard diagnostic method for LN, may have an average wait time of more than 50 days. Other gaps in quality process measures during LN visits have also been reported. A subspecialty multidisciplinary clinic (MDC) can provide better care and quality in LN; therefore, we aimed to examine how an LN MDC impacted time to biopsy, time to treatment, and other quality measures. We included all validated patients with LN who underwent diagnostic kidney biopsies between the 2011 to 2017 pre-MDC period and the 2018 to 2020 post-MDC period. We compared time to biopsy and treatment and quality measures between the two periods and examined factors associated with timely LN diagnosis, defined as a biopsy within 21 days. During the pre- and post-MDC periods, 53 and 21 patients with LN underwent a diagnostic biopsy, respectively. We found a decrease in the median time to biopsy from 26 days to 16 days after starting the LN clinic (P = 0.014). Beyond clinical factors, the presence of social factors, such as being of a non-White race and having food insecurity, were associated with 54% lower odds of timely diagnosis (adjusted Hazards Ratio [aHR] = 0.46; 95% confidence interval: 0.22-0.93; P = 0.031). We found higher odds of quality measure performance during the post- versus pre-MDC period. Wait times to diagnose LN decreased by 40% and higher quality measure performance was noted after establishing an LN MDC. Systemic and social barriers predicted delays in diagnosis that may be addressed by MDCs.


Activation of the PERK-eIF2α Pathway Is Associated with Tumor-infiltrating Lymphocytes in HER2-Positive Breast Cancer.
We evaluated endoplasmic reticulum stress and unfolded protein response (UPR) activation, as possible mechanisms for influx of tumor infiltrating lymphocytes (TILs), and the correlation between UPR activation and mammalian target of rapamycin (mTOR) pathway activation. TILs and the immunohistochemical expression of protein kinase RNA-like endoplasmic reticulum kinase (PERK), phospho-eukaryotic translation initiation factor 2α (p-eIF2α) and phosphorylated S6 (pS6) were evaluated in 447 human epidermal growth factor receptor 2 (HER2)-positive breast cancer tissues. High expression of PERK, p-eIF2α and pS6 was observed in 270 (60.4%), 259 (57.9%), and 187 (41.8%) cases, respectively, and was significantly associated with a high histological grade, high numbers of TILs, peritumoral lymphocytic infiltration, and tertiary lymphoid structures in HER2-positive breast cancer tissues. The results suggest endoplasmic reticulum stress and UPR activation as possible mechanisms for the influx of TILs in HER2-positive breast cancer. Evaluation of PERK and p-eIF2α expression might be important in identifying targets for cancer therapies in modulating endoplasmic reticulum stress.


Sequential treatment with vindesine-ifosfamide-platinum (VIP) chemotherapy followed by platinum sensitized radiotherapy in stage IIIB non-small cell lung cancer: a phase II trial.
Daily administration of cisplatin concomitant with radiotherapy improved the overall survival in inoperable non-small cell lung cancer (NSCLC) in one EORTC study. In this study, we prospectively investigated the efficacy and toxicity of a sequential treatment with three cycles of vindesine-ifosfamide-platinum (VIP) induction chemotherapy, followed by daily cisplatin-sensitized radiotherapy. Between June 1993 and June 1995, 23 previously untreated patients with stage IIIB NSCLC with World Health Organization performance status 0 or 1 were included. Chemotherapy consisted of platinum 30 mg/m2 and ifosfamide 1200 mg/m2 i.v. on days 1, 2 and 3, and vindesine 3 mg/m2 i.v. on days 1 and 8, every 4 weeks. After three cycles and at least stable disease, radiotherapy was started (30 Gy in 10 fractions, followed by a boost of 22 Gy in 10 fractions). Each fraction was preceded by Platinum 6 mg/m2 i.v. Nineteen patients completed the sequential therapy. One patient died from neutropenic sepsis during the first cycle of chemotherapy, and three patients had progressive disease after chemotherapy. The overall response rate after sequential therapy was 47% (95% confidence interval 24-80), median survival was 10.6 months, 1- and 2-year survival rates were 47 and 16%, respectively. Major toxicity consisted of neurotoxicity grade III-IV in 18% and of leukopenia grade III-IV in 22% of the patients. Acute radiation pneumonitis grade III occurred in 11% of the patients. Three-drug VIP induction chemotherapy followed by cisplatin-sensitized radiotherapy is feasible, with acceptable, albeit substantial, toxicity. In spite of the theoretically promising sequence of therapies, survival results remain disappointingly low.


Value of serum levels of carcinoembryonic antigen, CEA, and gastrointestinal cancer antigen, GICA or CA 19-9, for preoperative staging and postoperative monitoring of patients with colorectal carcinoma.
Serum levels of gastrointestinal cancer antigen (GICA) and carcinoembryonic antigen (CEA) were determined in 167 patients with colorectal carcinoma. Eighty-eight patients were studied preoperatively, and 79 postoperatively, before, at the time of, and after the diagnosis of relapse. The authors aimed to assess how often the GICA test failed, i.e., was false-negative in patients in whom the CEA test was true-positive and, more importantly, whether it could give diagnostic information in patients in whom the CEA test failed. Before surgery, serum GICA gave similar information to serum CEA in 56 percent of the patients: true-positive in 18 percent and false-negative in 38 percent; less information in 42 percent; and more information in only 2 percent. During the postoperative follow-up, serum GICA gave similar information to serum CEA in 55 percent of the patients: true-positive (i.e., rising persistently from a postoperative nadir) in 27 percent and false-negative in 28 percent; less information in 44 percent; and more information in only 1 percent. Therefore, this test in its present version, where both the catcher and the tracer antibody are the same, NS 19-9, is redundant.


Color from invisible flicker: a failure of the Talbot-Plateau law caused by an early 'hard' saturating nonlinearity used to partition the human short-wave cone pathway.
The Talbot-Plateau law fails for flicker detected by the short-wavelength-sensitive (S) cones: a 30-40 Hz target, flickering too fast for the flicker to be resolved, looks more yellow than a steady target of the same average intensity. The color change, which is produced by distortion at an early compressive nonlinearity, was used to reveal a slightly bandpass S-cone temporal response before the distortion site and a lowpass response after it. The nonlinearity is probably a 'hard' nonlinearity that arises because the S-cone signal is limited by a response ceiling, which the mean signal level approaches and exceeds as the S-cone adaptation level increases. The nonlinearity precedes the combination of flicker signals from all three cone types.


Biodegradation of Azo Dye Disperse Orange S-RL by a Newly Isolated Strain Acinetobacter sp. SRL8.
The strain SRL8, which could decolorize the azo dye disperse orange S-RL (S-RL), was first isolated from sludge and identified as Acinetobacter sp. through physiobiochemical identification and 16S rRNA gene sequences. The effects of temperature, pH, dye concentration, O2, and glucose concentration on S-RL decolorization by the strain SRL8 were studied. The optimal conditions were 30 °C, pH 7.0, 4g·L(-1) of inoculation (wet cells), and microaerophilic incubation. The decolorization percentage for S-RL by the strain SRL8 could reach 90.2% under optimal conditions. The strain SRL8 was highly tolerant to the azo dye SRL up to 300 mg·L(-1) and it had a broad decolorizing spectrum. According to the Monod equation, kinetic parameters of decolorization by SRL8 were calculated. The vmax and Km were 5.57×10(-3) h(-1) and 14.53 mg·L(-1), respectively.


Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying.
Methods for detection of anxiolytic-like behavioral effects of serotonin uptake inhibitors are limited. The present study introduces a new quantitative method that permits dose-effect analysis of these compounds. Male NIH Swiss mice were given 60-min access to a piece of cotton gauze and the amount of material not torn into nesting material was weighed. Other groups of mice were individually placed in containers with 20 marbles resting on top of sawdust bedding. The number of marbles buried (2/3) by sawdust after 30 min was counted. Mice were first placed on a 6-rpm rotorod and the number of mice falling off twice in 2 min was measured. Serotonin uptake inhibitors (clomipramine, citalopram, fluoxetine, and venlafaxine) dose-dependently suppressed nestlet shredding and marble burying at doses that were generally without effect on rotorod performance. The amine-based antidepressant agents imipramine and desipramine as well as the selective norepinephrine transport inhibitor nisoxetine produced similar qualitative effects on these behaviors. Anxiolytics (chlordiazepoxide, bretazenil, buspirone, and pentobarbital) produced effects in the nestlet assay that were similar to those reported using another anxiolytic assay in mice (punished responding), whereas these compounds were not active at non-motor-impairing doses in the marble burying assay. The antipsychotic agents chlorpromazine and risperidone generally demonstrated suppression of nestlet shredding and marble burying at doses that impaired rotorod performance. Although d-amphetamine suppressed nestlet shredding and marble burying at doses without effect on the rotorod, d-amphetamine but not fluoxetine stimulated locomotor activity. Both nestlet shredding and marble burying behaviors were generally consistent across five consecutive experimental sessions and fluoxetine did not produce any systematic trends over repeated testing. The methods should have utility in defining pharmacological effects of these compounds in vivo. Moreover, these data may be useful in the context of other behavioral effects when assessing the relevance of a compound for its potential therapeutic potential as an anxiolytic (nestlet shredding) or as an anti-obsessive-compulsive disorder agent (marble burying).


Identifying high risk clinical phenogroups of pulmonary hypertension through a clustering analysis.
The classification and management of pulmonary hypertension (PH) is challenging due to clinical heterogeneity of patients. We sought to identify distinct multimorbid phenogroups of patients with PH that are at particularly high-risk for adverse events. A hospital-based cohort of patients referred for right heart catheterization between 2005-2016 with PH were included. Key exclusion criteria were shock, cardiac arrest, cardiac transplant, or valvular surgery. K-prototypes was used to cluster patients into phenogroups based on 12 clinical covariates. Among 5208 patients with mean age 64±12 years, 39% women, we identified 5 distinct multimorbid PH phenogroups with similar hemodynamic measures yet differing clinical outcomes: (1) "young men with obesity", (2) "women with hypertension", (3) "men with overweight", (4) "men with cardiometabolic and cardiovascular disease", and (5) "men with structural heart disease and atrial fibrillation." Over a median follow-up of 6.3 years, we observed 2182 deaths and 2002 major cardiovascular events (MACE). In age- and sex-adjusted analyses, phenogroups 4 and 5 had higher risk of MACE (HR 1.68, 95% CI 1.41-2.00 and HR 1.52, 95% CI 1.24-1.87, respectively, compared to the lowest risk phenogroup 1). Phenogroup 4 had the highest risk of mortality (HR 1.26, 95% CI 1.04-1.52, relative to phenogroup 1). Cluster-based analyses identify patients with PH and specific comorbid cardiometabolic and cardiovascular disease burden that are at highest risk for adverse clinical outcomes. Interestingly, cardiopulmonary hemodynamics were similar across phenogroups, highlighting the importance of multimorbidity on clinical trajectory. Further studies are needed to better understand comorbid heterogeneity among patients with PH.


Pathogens and antibiotic resistance genes during the landfill leachate treatment process: Occurrence, fate, and impact on groundwater.
Landfill leachate is an essential source of pathogens and antibiotic resistance genes (ARGs) in the environment. However, information on the removal behavior of pathogens and ARGs during the leachate treatment and the impact on surrounding groundwater is limited. In this study, we investigated the effects of leachate treatment on the removal of pathogens and ARGs with metagenomic sequencing, as well as the impact of landfill effluent on groundwater. It is shown that the leachate treatment could not completely remove pathogens and ARGs. Twenty-nine additional pathogens and twenty-nine ARGs were newly identified in the landfill effluent. The relative abundance of pathogens and multiple antibiotic resistance genes decreased after ultrafiltration but relative abundance increased after reverse osmosis. In addition, the relative abundances of Acinetobacter baumannii, Erwinia amylovora, Escherichia coli, Fusarium graminearum, Klebsiella pneumoniae, and Magnaporthe oryzae, as well as mdtH, VanZ, and blaOXA-53 increased significantly in the landfill effluent compared to the untreated leachate. The relative abundance of some mobile genetic elements (tniA, tniB, tnpA, istA, IS91) in leachate also increased after ultrafiltration and reverse osmosis. The size of pathogens, the size and properties of ARGs and mobile genetic elements, and the materials of ultrafiltration and reverse osmosis membranes may affect the removal effect of pathogens, ARGs and mobile genetic elements in leachate treatment process. Interestingly, the pathogens and ARGs in landfill effluent were transferred to groundwater according to SourceTracker. The ARGs, mobile genetic elements, and pathogens that are difficult to remove in the leachate treatment process, provide a reference for optimizing the leachate treatment process and improving the control of pathogens and ARGs. Furthermore, this study clarifies the effect of landfill leachate sources of pathogens and ARGs in groundwater.


Effect of slotted wing tips on yawing moment characteristics.
The aerodynamic yawing moment characteristics of bird wings with slotted tips are dealt with. Emphasis is placed on the effect of sweep which the separated feathers constituting the wing tips show and which can reach significant values. Reference is made to basic aerodynamic characteristics of wings with sweep which yields a stabilizing yawing moment significantly larger than that of unswept wings. Then, the yawing moment characteristics are determined for a wing, the features of which are considered as representative of bird wings with sweep in their slotted tips. A sophisticated aerodynamic procedure is used for obtaining results of high precision. It is shown that the sweep in the slotted wing tips yields a stabilizing yawing moment of significant magnitude, considerably increasing with the lift coefficient. To make the significance of wing tip sweep for the ability to generate yawing moments more perspicuous, a wing modification the slotted tips of which are unswept is considered for comparison. It turns out that this wing shows yawing moments which are substantially smaller. A physical insight into the effect of slotted wing tip sweep on the aerodynamic yawing moment characteristics is provided by showing the underlying mechanism. From the results presented in this paper it follows that the sweep in slotted wing tips provides a substantial contribution to the aerodynamic yawing moment and, thus, to yaw stability. It may be concluded that this is an essential reason why there is sweep in the slotted tips of bird wings.


Tuning Polymer Hydrophilicity to Regulate Gel Mechanics and Encapsulated Cell Morphology.
Mechanically tunable hydrogels are attractive platforms for 3D cell culture, as hydrogel stiffness plays an important role in cell behavior. Traditionally, hydrogel stiffness has been controlled through altering either the polymer concentration or the stoichiometry between crosslinker reactive groups. Here, an alternative strategy based upon tuning the hydrophilicity of an elastin-like protein (ELP) is presented. ELPs undergo a phase transition that leads to protein aggregation at increasing temperatures. It is hypothesized that increasing this transition temperature through bioconjugation with azide-containing molecules of increasing hydrophilicity will allow direct control of the resulting gel stiffness by making the crosslinking groups more accessible. These azide-modified ELPs are crosslinked into hydrogels with bicyclononyne-modified hyaluronic acid (HA-BCN) using bioorthogonal, click chemistry, resulting in hydrogels with tunable storage moduli (100-1000 Pa). Human mesenchymal stromal cells (hMSCs), human umbilical vein endothelial cells (HUVECs), and human neural progenitor cells (hNPCs) are all observed to alter their cell morphology when encapsulated within hydrogels of varying stiffness. Taken together, the use of protein hydrophilicity as a lever to tune hydrogel mechanical properties is demonstrated. These hydrogels have tunable moduli over a stiffness range relevant to soft tissues, support the viability of encapsulated cells, and modify cell spreading as a consequence of gel stiffness.


Neurocytoma arising from a mature ovary teratoma: a case report.
Central neurocytoma/extraventricular neurocytoma is a central nervous system (CNS) tumor composed of uniform round cells with neuronal differentiation. The typical lesions of central neurocytoma/extraventricular neurocytoma are at the interventricular foramen of the lateral ventricles (central neurocytoma) or brain parenchyma (extraventricular neurocytoma). Mature teratoma is a benign germ cell tumor commonly found in young women. Herein, we report a 24-year-old female with neurocytoma in a mature teratoma of the right ovary. The histological examinations showed mature epidermis, skin appendages, adipose and bone tissues in the tumor; microscopic foci of immature cartilage tissues were also found in some parts. In addition, massive solid sheets and uniform round tumor cells were found in the neuroectodermal tissues, with the formation of neuropil-like islands. Immunohistochemical examinations showed that the tumor cells were synaptophysin- and NeuN-positive but GFAP-negative. Based on these findings, the woman was diagnosed with neurocytoma arising from mature ovary teratoma, with microscopic foci of immature cartilage tissues. This is the fourth case report of neurocytoma outside the CNS to date.


In vitro strength comparison of hydroxyapatite cement and polymethylmethacrylate in subchondral defects in caprine femora.
Hydroxyapatite cement was investigated in situ for the reconstruction of juxta-articular defects. Polymethylmethacrylate is currently the most commonly used material for the reconstruction of bone defects following the exteriorization and curettage of aggressive benign tumors. In vitro, we compared the effects of hydroxyapatite cement and polymethylmethacrylate in restoring the stiffness of the subchondral plate in a caprine femoral defect model. Ten matched pairs of caprine femora underwent nondestructive compression testing normal to the load-bearing surface. A standardized subchondral defect 12 mm in diameter was created in the medial femoral condyle. Compression testing was repeated to determine the reduction in stiffness caused by the defect. Each femur from each pair was randomly assigned to one of two groups (n=9), and the defects were augmented with either polymethylmethacrylate or hydroxyapatite cement. After 12 hours, compression testing was repeated to determine the subchondral stiffness after augmentation. Compared with intact femora, the defect specimens that were later treated with either polymethylmethacrylate or hydroxyapatite cement exhibited stiffness values of 70 (386+/-107 N/mm) and 59% (343+/-94 N/mm) respectively, which represented a significant reduction in stiffness (p=0.05). Augmentation with polymethylmethacrylate or hydroxyapatite cement restored stiffness by 81 (450+/-111 N/mm) and 71% (413+/-115 N/mm), respectively, of the values of intact specimens. Hydroxyapatite cement restored stiffness significantly (p=0.05) over the stiffness of the nonaugmented defect compared with the stiffness after augmentation with polymethylmethacrylate (p=0.12). Neither polymethylmethacrylate nor hydroxyapatite cement restored stiffness to that of intact femora (p=0.05). In the current detect model, hydroxyapatite cement was comparable with polymethylmethacrylate in restoring subchondral stiffness. Unlike polymethylmethacrylate, however, hydroxyapatite cement has the following advantages: it is osteoconductive, is replaced by host bone, and avoids the potential for thermal necrosis. Hydroxyapatite cement may therefore provide a viable alternative to polymethylmethacrylate for augmentation of juxta-articular and other bone defects.


Tongyang Huoxue decoction (TYHX) ameliorating hypoxia/reoxygenation-induced disequilibrium of calcium homeostasis via regulating β-tubulin in rabbit sinoatrial node cells.
β-tubulin is a skeletal protein of sinoatrial node cells (SANCs) that maintains the physiological structure of SANCs and inhibits calcium overload. Tongyang Huoxue decoction (TYHX) is widely used to treat sick sinus syndrome (SSS) owing to its effects on calcium channels regulation and SANCs protection. This study focuses on the mechanism of TYHX in improving the hypoxia/reoxygenation (H/R)-induced disequilibrium of calcium homeostasis in SANCs via regulating β-tubulin. Real-Time PCR (RT-PCR) and Western Blot were adopted to detect the mRNA and protein expression levels of calcium channel regulatory molecules. Laser confocal method was employed to examine β-tubulin structure and fluorescence expression levels in SANCs, as well as calcium wave and calcium release levels. It was found that the fluorescence expression level decreased and the β-tubulin structure of SANCs was damaged after H/R treatment. The mRNA and protein expression levels of SERCA2a/CaV1.3/NCX and β-tubulin decreased, while the mRNA and protein expression of RyR2 increased. The results of calcium wave and calcium transient experiments showed that the fluorescence expression level of Ca2+ increased and calcium overload occurred in SANCs. After treatment with TYHX, the mRNA and protein expression levels of SERCA2a/CaV1.3/NCX and β-tubulin increased, while the mRNA and protein expression levels of RyR2 decreased and the cell structure was restored. Interestingly, the regulation of TYHX on calcium homeostasis was further enhanced after Ad-β-tubulin treatment and counteracted after siRNA-β-tubulin treatment. These results suggest that TYHX could maintain calcium homeostasis via regulating β-tubulin, thus protecting against H/R-induced SANCs injury, which may be a new target for SSS treatment.


Hydroxycinnamic acids do not prevent aortic atherosclerosis in hypercholesterolemic golden Syrian hamsters.
The protective effect of hydroxycinnamic acids, i.e. caffeic acid (CA) and sinapic acid (SA) present in wine, and chlorogenic acid (CHA) present in apple, compared to a red wine phenolic extract (RWPE) was investigated in hamsters fed an atherogenic diet for 12 weeks. Five groups of 8 hamsters fed such a diet received by force-feeding RWPE, CA or SA in water, mimicking a moderate consumption of alcohol-free red wine. Controls received water and CHA force-feeding was extrapolated from apple consumption. Plasma cholesterol concentration was lower in group that received RWPE (-22%) and hydroxycinnamic acids had no effect. Plasma apolipoprotein Apo-A1 concentration was not affected; consumption of RWPE only decreased Apo-B concentration (-46%). Liver superoxide dismutase activity was 33% lower and glutathione peroxidase activity was 67% greater in the group receiving RWPE compared to controls; there was no effect when CA, SA or CHA were given. All the phenolic compounds significantly increased plasma antioxidant capacity (about 28% on average) compared with controls. Aortic fatty streak area was significantly reduced in the group receiving RWPE (-30%) in comparison with controls and hydroxycinnamic acids. Our findings demonstrate that chronic ingestion of the nonalcoholic components of red wine, mainly polyphenols, prevent the development of atherosclerosis in hamster and that wine hydroxycinnamic acids are not the phenolic compounds involved in such a beneficial effect.


Fully validated UPLC-MS/MS method for quantifying Favipiravir in human plasma boosted lean six sigma: An application for a bioequivalence study.
This research developed and validated a highly sensitive and selective UPLC-MS/MS approach using a triple quadrupole mass spectrometer for quantifying favipiravir. Moreover, we introduced a study evaluating bioequivalence using two drugs, Favibrivix and Avigan, containing favipiravir. Lean Six Sigma verified the capacity and performance of the process. Protein precipitation extraction was utilized to extract favipiravir from the collected human matrices. We used an Acquity UPLCr BEH HILIC column and valproic acid as an internal standard. Furthermore, we conducted the procedure using an isocratic elution comprising acetonitrile and 0.005% ammonia in water (75:25, v/v), a flow rate of 0.25 ml/min, a temperature controlled at 10°C and an injection volume of 1.0 μl. Our UPLC-MS/MS process has a broad range (50-10,000 ng/ml) with a determination coefficient of 0.9980. We validated the method in line with the US Food and Drug Administration. The findings revealed that the test, Favibrivix 200 mg/tablet, and the reference, Avigan® 200 mg/tablet, were statistically bioequivalent in healthy Egyptian participants.


Annual exposure to PM10 is related to cerebral small vessel disease in general adult population.
Ambient air pollution is one of the most important global health issues. Although several studies have been reported the associations between air pollution and brain function or structure, impact of the air pollution on cerebral small vessel disease (cSVD) have rarely been explored in Asian adult population. We evaluated the association between exposure to air pollutants and cSVD in Korean asymptomatic adults. This cross-sectional study included 3257 participants of a health screening program from January 2006 to December 2013. All participants performed brain magnetic resonance imaging. To assess the cSVD, we considered three features such as white matter hyperintensities (WMH), silent lacunar infarction (SLI), and cerebral microbleeds (CMBs). The annual average exposure to air pollutants [particulate matter ≤ 10 μm in aerodynamic diameter (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO)] was generated. The mean [standard deviation (SD)] age of the total 3257 participants was 56.5 (9.5) years, and 54.0% of them were male. Among all the included participants, 273 (8.4%) had SLI and 135 (4.1%) had CMBs. The mean volume (± SD) of WMH was 2.72 ± 6.57 mL. In result of linear regression analysis, the volume of WMH was associated with various potential factors including age, height, weight, smoking and alcohol consumption status, blood pressure (BP), hypertension, and diabetes mellitus. SLI-positive group, compared to the SLI-negative group, was older, shorter, and had higher BP as well as higher frequency of hypertension and diabetes mellitus. After adjusting for covariates, the annual average concentration of PM10 was significantly associated with the volume of WMH [β (95% CI) for Model 1 = 0.082 (0.038- 0.125), p < 0.001; β (95% CI) for Model 2 = 0.060 (0.013, 0.107), p = 0.013]. CMBs were not associated with the annual average concentration of PM10. No significant associations of NO2, SO2, and CO with cSVD were observed. In conclusion, PM10 exposure is associated with significant increases in brain WMH' volume and silent lacunar infarcts in asymptomatic adults.


Release of eicosanoids and endothelin in an experimental model of adult respiratory distress syndrome.
In an experimental model of adult respiratory distress syndrome (ARDS) we have investigated the release of several vasoactive mediators since the rapid and severe increase in pulmonary arterial pressure is known to be a key feature in this condition. Intravenous injection of oleic acid (OA) into rats resulted in the development of a syndrome similar to ARDS characterized by severe hypoxia. As early as 15 min after OA injection elevated levels of 11-deoxy-15-keto-13,14-dihydro-11,16-cyclo-prostaglandin (PG) E2 (DKH2-cyclo-PGE2) as an indicator of endogenous PGE2 formation could be observed. Similarly, elevated levels of cysteinyl-leukotrienes (LT), determined as immunoreactive (ir) LTE4, and ir-endothelin (ET) could be detected. These mediators were found to be elevated in plasma samples for at least 3 h. In addition, rather large amounts of ir-ET could be detected in bronchoalveolar lavage (BAL) fluid samples between 1 h and 3 h. Thus, it seems possible that cysteinyl-LT and peptides of the ET family, both known for their vasoactivity, might be involved in the pathophysiological process of ARDS.


Contraceptive use and family planning after labor in the European part of the Russian Federation: 2-year monitoring.
To explore the main determinants of the reproductive behavior of nursing mothers, all inhabitants of the central part of the European region of the Russian Federation, their use of modern contraceptive methods and their attitude to future family planning. Open cohort multicenter study of 1200 nursing mothers aged 16-42 years interviewed at 3-5 days' postpartum, with subsequent longitudinal monitoring ofthe majority in the local family planning centers during the 2 years after labor. The main determinants of the reproductive behavior of this cohort of women are an early debut of sexual activity, several partners in their reproductive history, relatively early marriage with a motivation to have one child in their family and the tendency to use induced abortion as one of the methods of birth regulation. Our experience of postpartum counselling demonstrated positive changes in the women's attitudes to modern contraceptive methods. The data reveal that the induced abortion rate among 639 mothers regularly followed-up during the first year postpartum was 4.4%, and among 606 during the second year was 5.1%. The corresponding rates among 129 women who did not visit the family planning centers and who were only interviewed 2 years after labor were 9.3% and 8.5%, respectively. Our data show that the unmet needs are remarkably concentrated among women who have given birth within the last year or two, and who need augmented attention from the family planning and reproductive health services.


[A foreign body in the knee joint--a very rare injury in children].
Cause of uncertain knee-complaints in children can be foreign bodies which penetrated unnoticed the joint cavity. Here we report an unusual injury of this kind. A glass-foreign body intruded the knee joint in childhood. Complaints occurred for the first time in adult age. The diagnostic and therapeutic measures in such injuries are shown. At removal of the foreign body tetanus immunisation is necessary.


[Rupture of the spleen in a patient with infectious mononucleosis].
A case of rupture of the spleen in connection with infectious mononucleosis is described. Simultaneously the frequency and findings of this serious complication are mentioned.


The Role of Simulation in Microsurgical Training.
Simulation has been established as an integral part of microsurgical training. The aim of this study was to assess and categorize the various simulation models in relation to the complexity of the microsurgical skill being taught and analyze the assessment methods commonly employed in microsurgical simulation training. Numerous courses have been established using simulation models. These models can be categorized, according to the level of complexity of the skill being taught, into basic, intermediate, and advanced. Microsurgical simulation training should be assessed using validated assessment methods. Assessment methods vary significantly from subjective expert opinions to self-assessment questionnaires and validated global rating scales. The appropriate assessment method should carefully be chosen based on the simulation modality. Simulation models should be validated, and a model with appropriate fidelity should be chosen according to the microsurgical skill being taught. Assessment should move from traditional simple subjective evaluations of trainee performance to validated tools. Future studies should assess the transferability of skills gained during simulation training to the real-life setting.


Association between human leukocyte antigen gene polymorphisms and multiple EPIYA-C repeats in gastrointestinal disorders.
Polymorphisms of human leukocyte antigen (HLA) genes are suggested to increase the risk of gastric cancer (GC). To investigate the HLA allele frequencies of patients with GC relative to a control group in terms of CagA+ multiple (≥ 2) EPIYA-C repeats. The patient group comprised 94 patients [44 GC and 50 duodenal ulcer (DU) patients], and the control group comprised 86 individuals [(50 non-ulcer dyspepsia patients and 36 people with asymptomatic Helicobacter pylori (H. pylori)]. Polymerase chain reaction was performed for the amplification of the H. pylori cagA gene and typing of EPIYA motifs. HLA sequence-specific oligonucleotide (SSO) typing was performed using Lifecodes SSO typing kits (HLA-A, HLA-B HLA-C, HLA-DRB1, and HLA-DQA1-B1 kits). The comparison of GC cases in terms of CagA+ multiple (≥ 2) EPIYA-C repeats showed that only the HLA-DQB1*06 allele [odds ratio (OR): 0.37, P = 0.036] was significantly lower, but significance was lost after correction (Pc = 0.1845). The HLA-DQA1*01 allele had a high ratio in GC cases with multiple EPIYA-C repeats, but this was not significant in the univariate analysis. We compared allele frequencies in the DU cases alone and in GC and DU cases together using the same criterion, and none of the HLA alleles were significantly associated with GC or DU. Also, none of the alleles were detected as independent risk factors after the multivariate analysis. On the other hand, in a multivariate logistic regression with no discriminative criterion, HLA-DQA1*01 (OR = 1.848), HLA-DQB1*06 (OR = 1.821) and HLA-A*02 (OR = 1.579) alleles were detected as independent risk factors for GC and DU. None of the HLA alleles were detected as independent risk factors in terms of CagA+ multiple EPIYA-C repeats. However, HLA-DQA1*01, HLA-DQB1*0601, and HLA-A*2 were independent risk factors with no criterion in the multivariate analysis. We suggest that the association of these alleles with gastric malignancies is not specifically related to cagA and multiple EPIYA C repeats.


Bone mineral density in children with myelomeningocele: effect of hydrochlorothiazide.
Children with myelomeningocele experience difficulty with ambulation, which leads to immobilization and secondary loss of bone mineral density (BMD). In addition, non-ambulatory myelomeningocele patients have higher urinary calcium losses than their ambulatory counterparts. Hydrochlorothiazide (HCTZ) is known to reduce urinary calcium loss and increase BMD in non-myelomeningocele patients with hypercalciuria. This study examines the effect of HCTZ on urinary calcium and BMD in non-ambulatory children with myelomeningocele. Thirteen of 20 non-ambulatory patients with myelomeningocele completed the year-long randomized double-blinded study (placebo = 7 and HCTZ = 6). Evaluation included electrolytes, PTH, osteocalcin, 1, 25-OH vitamin D, urinary pyridinolines/deoxypyridinolines (U(pyr/dpyr)), urinary calcium/creatinine (U(Ca/Cr)), and forearm BMD (dual X-ray absorptiometry). Follow-up electrolytes were obtained at 1-2, 6, and 12 months and U(Ca/Cr) and BMD was obtained again at 12 months. There were no initial differences between the placebo and HCTZ groups. U(Ca/Cr) decreased in the HCTZ group after treatment (0.20+/-0.09 vs. 0.04+/-0.02, p<0.05). However, forearm BMD ( z-scores) after 1 year remained unchanged in both the HCTZ (-5.95+/-0.98 to -5.86+/-0.92) and placebo (-7.19+/-0.69 to -6.67+/-0.63) groups. While use of HCTZ for 1 year did not affect BMD, it reduced urinary calcium excretion in non-ambulatory children with myelomeningocele.


Color Doppler twinkling artifacts in small-bowel bezoars.
Small-bowel bezoars usually form in the stomach and may subsequently cause small-bowel obstruction. Bezoars associated with small-bowel obstruction have been accurately diagnosed by computed tomography, although some case reports have described the specific sonographic findings of small-bowel bezoars. Bezoars can be overlooked by sonographic examination if a dilated small-bowel loop contains a large amount of air. Twinkling artifacts on color Doppler images appear as rapidly fluctuating red and blue signals behind certain strongly reflecting structures. In this series, we hypothesize that twinkling artifacts might appear in small-bowel bezoars, and we describe the presence of twinkling artifacts in 3 cases of small-bowel bezoars presenting as small-bowel obstruction.


Gastrointestinal scintiscanning: dosimetry.
Calculations of the dosimetry associated with orally administered 99mTc labeled cellulose fibres and 111In labeled plastic particles were performed for adult standard man using MIRD methodology. The applied gastrointestinal transit parameters of these radiopharmaceuticals probably reflect the ranges of these parameters, regarding nondigestible components used for gastrointestinal transit studies. However, the critical organ for both radiopharmaceuticals was the large intestine.


Design of a H2 O2 -generating P450SPα fusion protein for high yield fatty acid conversion.
Sphingomonas paucimobilis' P450SPα (CYP152B1) is a good candidate as industrial biocatalyst. This enzyme is able to use hydrogen peroxide as unique cofactor to catalyze the fatty acids conversion to α-hydroxy fatty acids, thus avoiding the use of expensive electron-donor(s) and redox partner(s). Nevertheless, the toxicity of exogenous H2 O2 toward proteins and cells often results in the failure of the reaction scale-up when it is directly added as co-substrate. In order to bypass this problem, we designed a H2 O2 self-producing enzyme by fusing the P450SPα to the monomeric sarcosine oxidase (MSOX), as H2 O2 donor system, in a unique polypeptide chain, obtaining the P450SPα -polyG-MSOX fusion protein. The purified P450SPα -polyG-MSOX protein displayed high purity (A417 /A280 = 0.6) and H2 O2 -tolerance (kdecay = 0.0021 ± 0.000055 min-1 ; ΔA417 = 0.018 ± 0.001) as well as good thermal stability (Tm : 59.3 ± 0.3°C and 63.2 ± 0.02°C for P450SPα and MSOX domains, respectively). The data show how the catalytic interplay between the two domains can be finely regulated by using 500 mM sarcosine as sacrificial substrate to generate H2 O2 . Indeed, the fusion protein resulted in a high conversion yield toward fat waste biomass-representative fatty acids, that is, lauric acid (TON = 6,800 compared to the isolated P450SPα TON = 2,307); myristic acid (TON = 6,750); and palmitic acid (TON = 1,962).


Hypophosphatasia.
Hypophosphatasia is a rare inherited disorder characterized by defective bone and tooth mineralization, and deficiency of serum and bone alkaline phosphatase activity. The frequency of the disease has been estimated to be one in 100 000 for severe forms, but mild forms of hypophosphatasia may be more common. The symptoms are highly variable in their clinical expression, which ranges from stillbirth without mineralized bone to early tooth loss without bone symptoms. The transmission of severe forms is autosomal recessive, while milder forms may be transmitted as dominant or recessive autosomal traits. The diagnosis is based on serum alkaline phosphatase assay and molecular analysis of the liver/bone/kidney alkaline phosphatase gene (ALPL). Currently, there is no treatment for the disease. Over the past 10 years, great progress has been made in understanding the structure of tissue non-specific alkaline phosphatase, its function in bone mineralization, and the effect of ALPL mutations responsible for hypophosphatasia.


Adherence to antidiabetic treatment among patients managed in primary care centres in Spain: the INTENSE study.
To determine the degree and factors related to non-insulin antidiabetic drug (NIAD) adherence in people with type 2 diabetes mellitus (DM2) treated in primary carecentres in Spain. We did a cross-sectional study. During the study visit, variables related todifferent clinical characteristics, Adherence to Refills and Medications Scale Spanishversion (ARMS-e) and usage of NIAD were collected. We estimated the adherence toNIADs using the proportion of days covered (PDC) equation. In total, 515 participants were included in the study. The mean PDC ratio was70.6 ( ± 28.9), and 50.5% (260) were classified as good adherent (PDC ≥80). Good adherence was highest among users of metformin (67.3%) and lowest among the participants using thiazolidinedione (0.8%). The score for ARMS-e was higher in the poor adherence group. In the multivariable analysis, HbA1c and the use of GLP1-RA or SGLT-2i were negatively associated with good adherence (odds ratio [OR]: 0.67, 95% confidence interval [CI]: 0.54, 0.82, OR: 0.20, 95%CI: 0.08, 0.46; OR: 0.56, 95%CI: 0.35, 0.89, respectively). Adherence to NIADs observed in our study is far from optimal. HbA1c and ARMS-e items could be used as adherence indicators to encourage treatment changes to improve T2DM control.


Caution: the differences between CT and ACT may be larger (and smaller) than they appear.
Hofmann, Asmundson, & Beck (2013--this issue) offer an overview of cognitive-behavior therapy (CBT) as well as its similarities and differences from so-called "third-generation" behavior therapies, particularly Acceptance and Commitment Therapy (ACT). In this commentary we suggest that CBT is most accurately viewed as a broad family of distinct psychotherapy models that includes the traditional Beckian approach of cognitive therapy as well as newer acceptance-based approaches such as ACT. We argue that Hofmann, Asmundson, & Beck's discussion of the differences in CT and ACT's view of the causal role of cognition lacks clarity. For instance, the behavior analytic framework of ACT does not categorically deny any causal role of cognitions in behavioral and emotional responses. Similarly, we disagree with the authors' contention that CT utilizes primarily antecedent-focused and ACT employs response-focused emotion regulation strategies. In addition, we take the view that the empirical evidence for CT, although very impressive, does not reduce the impetus to innovate. We object to some of Hofmann, Asmundson, & Beck's interpretation of component and mediational analyses and argue that the field does, in fact, need to question CT's postulated mechanism of action (i.e., cognitive change), both on theoretical and pragmatic grounds. At the same time, although preliminary research on ACT is promising, we suggest that its proponents need to be appropriately humble in their claims. In particular, like CT, ACT cannot yet make strong claims that its unique and theory-driven intervention components are active ingredients in its effects. We conclude that the fundamental differences between CT and ACT are philosophical and theoretical rather than technological.


Calcium metabolism in pregnancy and the perinatal period: a review.
Calcium homeostasis is a complex process involving calcium, other involved ions, and three calcitropic hormones, parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D3. The principal maternal adjustment during pregnancy is an increasing parathyroid hormone secretion which maintains the serum calcium concentration in the face of a falling albumin level, an expanding extracellular fluid volume, an increasing renal excretion, and placental calcium transfer. The placenta transports calcium ions actively, making the fetus hypercalcemic relative to its mother, which in turn stimulates calcitonin release and perhaps suppresses parathyroid hormone secretion by the fetus. A unique extrarenal system for 1 alpha-hydroxylation of 25-hydroxyvitamin D3 exists in the placenta and/or decidua, providing a source of 1,25-dihydroxyvitamin D3 for the fetus. With the abrupt cessation of the placental source of calcium at birth, the neonate's serum calcium level falls for 24 to 48 hours, then stabilizes and rises slightly. Hyperparathyroidism during pregnancy causes complications in both mother and infant and should usually be treated surgically as soon as diagnosed. Maternal hypoparathyroidism can be treated satisfactorily with high doses of supplemental calcium and vitamin D. Osteopenia accompanying long-term heparin administration may respond to 1,25-dihydroxyvitamin D3 (calcitriol) therapy. Diabetes in pregnancy is associated with disturbed neonatal calcium homeostasis, perhaps due to chronic hypomagnesemia. A possible etiologic role of calcium deficiency in pregnancy-related hypertension has been suggested. Dietary deficiency of calcium and/or vitamin D during gestation may lead to several adverse effects in the newborn infant.


Association Between Dispatch Complaint and Critical Prehospital Time Intervals in Suspected Stroke 911 Activations in the National Emergency Medical Services Information System, 2012-2016.
Emergency Medical Services can help improve stroke outcomes by recognizing stroke symptoms, establishing response priority for 911 calls, and minimizing prehospital delays. This study examines 911 stroke events and evaluates associations between events dispatched as stroke and critical EMS time intervals. Data from the National Emergency Medical Services Information System, 2012 to 2016, were analyzed. Activations from 911 calls with a primary or secondary provider impression of stroke were included for adult patients transported to a hospital destination. Three prehospital time intervals were evaluated: (1) response time (RT) ≤8 min, (2) on-scene time (OST) ≤15 min, and (3) transport time (TT) ≤12 min. Associations between stroke dispatch complaint and prehospital time intervals were assessed using multivariate regression to estimate adjusted risk ratios (ARR) and 95% confidence intervals (CIs). Approximately 37% of stroke dispatch complaints were identified by EMS as a suspected stroke. Compared to stroke events without a stroke dispatch complaint, median OST was shorter for events with a stroke dispatch (16 min vs. 14 min, respectively). In adjusted analyses, events dispatched as stroke were more likely to meet the EMS time benchmark for OST ≤15 min (OST, 1.20 [1.20-1.21]), but not RT or TT (RT, [1.00-1.01]; TT, 0.95 [0.94-0.95]). Our results indicate that dispatcher recognition of stroke symptoms reduces the time spent on-scene by EMS personnel. These findings can inform future EMS stroke education and quality improvement efforts to emphasize dispatcher recognition of stroke signs and symptoms, as EMS dispatchers play a crucial role in optimizing the prehospital response.


Diverse cellular transformation capability of overexpressed genes in human hepatocellular carcinoma.
For isolation of novel cellular transforming genes that potentially participated in hepatocarcinogenesis, we conducted anchorage-independent growth (AIG) assays on 10 human liver cancer cell lines and observed strong AIG capabilities in PLC5 and Huh7 but negligible in Tong cells. After cloning of genes by differential subtractive chain reactions (DSC) from strong AIG to AIG negative cells, we sequenced 2304 clones and identified 245 genes. After four stringent criteria for selection of transforming genes among DSC clones, our results of quantitative RT-PCR analysis indicated that six genes, DDX3, EIF3S2, CLIC1, HDGF, GPC3, and HSPCA were overexpressed in 64%, 62%, 60%, 58%, 49%, and 47%, respectively, of 45 hepatocellular carcinoma (HCC) tissues. The results of cellular transformation capability by AIG assays indicated that the transfectants of EIF3S2 showed the strongest (> 100-fold), DDX3 and CLIC1 were moderate, GPC3 and HSPCA were weak, and HDGF was none in forming colonies in soft agar. Together, our results suggested that Tong is a suitable human cell line for screening of overexpressed and/or cellular transforming genes. In addition, our results suggested that diverse functions of cellular transforming genes in various biological pathways could transform human Tong cells and potentially reveal new targets for drug development of HCC.


Calculation of received dose intensity for combinations of drugs using small-cell lung carcinoma treatment regimens as examples.
Programs are presented for the calculation of received dose intensity in combination chemotherapy regimens. These provide methods for determining the final dose intensity, the mean cumulative dose intensity together with its standard error, and other tabular and graphic summaries. Two ways of dividing patients into high and low received-dose-intensity groups are proposed. Methods are illustrated using data from Mid-Atlantic Oncology Program (MAOP) 2183, a phase III evaluation of a six-drug alternating combination vs a three-drug "standard" combination treatment for extensive small-cell lung cancer. Comparisons of received dose intensity with demographic and outcome variables are presented.


Immunological unresponsiveness induced by recipient cells transfected with donor MHC genes.
Immunological unresponsiveness to allografts can be achieved by pretreating recipients with cells (whole blood, erythrocytes, lymphocytes) expressing donor-specific histocompatibility antigens. Attempts to determine the relative contribution of class I or class II major histocompatibility antigens and/or minor histocompatibility (miH) antigens towards the induction of an unresponsive state have yielded conflicting results. We have addressed this issue using DNA-mediated gene transfer to introduce murine class I or class II major histocompatibility complex (MHC) genes from the organ donor into cells of recipient origin. This allowed murine recipients of cardiac allografts to be pretreated with either donor cells sharing only an isolated class I or class II MHC locus product with the donor organ. We show that pretreatment with either donor class I or class II antigens prolongs survival of cardiac allografts, and that the capacity of a particular donor MHC antigen to induce unresponsiveness is the product of its intrinsic immunogenicity and the antigen load delivered during pretreatment. These results explain discrepancies in earlier studies of antigen-induced unresponsiveness and suggest a novel approach to specific immunosuppression in clinical transplantation.


Implementation of game-based training in oral rehabilitation of edentulous patients in an undergraduate dental course.
Coronavirus disease-19 dramatically changed the learning conditions of dental students, with restricted access to training sessions and clinical practice. The "Playdent" project proposed the integration of serious games (SGs) in the third-year curriculum, based on tailor-made scenarios questioning the first dental visit of edentulous patients, and examined whether training with the games would advance students' learning outcomes. Test scores of 89 students, allocated either to a "test" group that accessed SGs during a 4-week test period in addition to conventional lectures or to a "control" group that benefited solely from conventional lectures, were measured before and immediately after the test period. The subsequent satisfaction of students was assessed in the "test" group. Scores obtained after the 4-week period significantly increased within the "test" group (11.1% ± 24.9%, p = 0.04, degree of freedom [df] = 30) while they did not change within the "control" group (p = 0.21, df = 57). Qualitative feedback expressed by students who played SGs during the 4-week period demonstrated that 71% of them rated the SGs as satisfactory and 91% of them judged the consistency of SGs content with lectures to be satisfactory. Game-based learning showed a positive impact on the learning outcomes of third-year students. Qualitative assessments provide insights into the pertinence of SGs offered in addition to traditional lectures of third-year complete denture courses. SGs may consolidate skills in oral rehabilitation acquired through traditional passive learning formats proposed in preclinical courses.


A hierarchical Bayesian birth cohort analysis from incomplete registry data: evaluating the trends in the age of onset of insulin-dependent diabetes mellitus (T1DM).
Childhood diabetes is one of the major non-communicable diseases in children under 15 years of age. It requires a life-long insulin treatment and may lead to serious complications. Along with the worldwide increase in the incidence several countries have recently reported a decreasing trend in the age of onset of the disease. The aim of this study is to analyse long-term data on the incidence of the childhood diabetes in Finland from the birth cohorts perspective. The annual incidence data were available for the period 1965--1996 which translates into 1951--1996 birth cohorts. Hence the data consist of completely and partially observed cohorts. Bayesian modelling was employed in the analysis. Several different priors and cohort combinations were tried in order to determine the sensitivity of the results. The cumulative birth cohort incidence of diabetes was determined to have an increasing average annual trend of 2.5 per cent. Although the average birth cohort-specific age of onset was estimated to have decreased slightly over the years of observation, the trend could be a result of random variation.


5-N-ethyl Carboxamidoadenosine Stimulates Adenosine-2b Receptor-Mediated Mitogen-Activated Protein Kinase Pathway to Improve Brain Mitochondrial Function in Amyloid Beta-Induced Cognitive Deficit Mice.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss in memory as one of the cardinal features. 5-N-ethyl carboxamidoadenosine (NECA), an agonist of adenosine-2b receptor, exerts neuroprotective activity against several experimental conditions. Further, NECA activates mitogen-activated protein kinase (MAPK) and also attenuates mitochondrial toxicity in mammalian tissues other than brain. Moreover, there is no report on the role of A2b/MAPK-mediated signaling pathway in Aβ-induced mitochondrial toxicity in the brain of the experimental animals. Therefore, the present study evaluated the neuroprotective activity of NECA with or without MAPK inhibitor against Aβ-induced cognitive deficit and mitochondrial toxicity in the experimental rodents. Further, the effect of NECA with or without MAPK inhibitor was evaluated on Aβ-induced mitochondrial toxicity in the memory-sensitive mice brain regions. Intracerebroventricular (ICV) injection of Aβ 1-42 was injected to healthy male mice through Hamilton syringe via polyethylene tube to induce AD-like behavioral manifestations. NECA attenuated Aβ-induced cognitive impairments in the rodents. In addition, NECA ameliorated Aβ-induced Aβ accumulation and cholinergic dysfunction in the selected memory-sensitive mouse HIP, PFC, and AMY. Further, NECA significantly attenuated Aβ-induced mitochondrial toxicity in terms of decrease in the mitochondrial function, integrity, and bioenergetics in the brain regions of these animals. However, MAPKI diminished the therapeutic effects of NECA on behavioral, biochemical, and molecular observations in AD-like animals. Therefore, it can be speculated that NECA exhibits neuroprotective activity perhaps through MAPK activation in AD-like rodents. Moreover, A2b-mediated MAPK activation could be a promising target in the management of AD.


Three-dimensional description of ligamentous attachments around the lunate.
To detail the location and area of specific ligament attachments on the 3-dimensional (3-D) surface morphology of the individual carpal bones. We describe the attachment regions of both extrinsic and intrinsic intercarpal ligaments by using a combination of detailed dissection, computed tomography imaging, and a 3-D digitization technique and provide detailed information about ligament attachments around the lunate. The length, width, and thickness of each ligament are described in millimeters and its area of attachment is given in square millimeters and as a percentage of the bone surface and/or total ligament attachment area. The attachment sites of the ligaments also are shown visually on 3-D images of the bones. This study improves the knowledge and understanding of carpal ligament anatomy, which can result in better intraoperative assessment of ligament integrity/disruption and allow more accurate and anatomic repair, reattachment, and/or reconstruction of carpal ligaments for the treatment of carpal instability.