3D Acoustic Wave Sparsely Activated Localization Microscopy With Phase Change Contrast Agents.
The aim of this study is to demonstrate 3-dimensional (3D) acoustic wave sparsely activated localization microscopy (AWSALM) of microvascular flow in vivo using phase change contrast agents (PCCAs). Three-dimensional AWSALM using acoustically activable PCCAs was evaluated on a crossed tube microflow phantom, the kidney of New Zealand White rabbits, and the brain of C57BL/6J mice through intact skull. A mixture of C 3 F 8 and C 4 F 10 low-boiling-point fluorocarbon gas was used to generate PCCAs with an appropriate activation pressure. A multiplexed 8-MHz matrix array connected to a 256-channel ultrasound research platform was used for transmitting activation and imaging ultrasound pulses and recording echoes. The in vitro and in vivo echo data were subsequently beamformed and processed using a set of customized algorithms for generating 3D super-resolution ultrasound images through localizing and tracking activated contrast agents. With 3D AWSALM, the acoustic activation of PCCAs can be controlled both spatially and temporally, enabling contrast on demand and capable of revealing 3D microvascular connectivity. The spatial resolution of the 3D AWSALM images measured using Fourier shell correlation is 64 μm, presenting a 9-time improvement compared with the point spread function and 1.5 times compared with half the wavelength. Compared with the microbubble-based approach, more signals were localized in the microvasculature at similar concentrations while retaining sparsity and longer tracks in larger vessels. Transcranial imaging was demonstrated as a proof of principle of PCCA activation in the mouse brain with 3D AWSALM. Three-dimensional AWSALM generates volumetric ultrasound super-resolution microvascular images in vivo with spatiotemporal selectivity and enhanced microvascular penetration.


Activation of a peroxisome-proliferating catabolite of cholic acid to its CoA ester.
We have shown that a microbial cholic acid catabolite (4R)-4-(2,3,4,6,6a beta,7,8,9,9a alpha,9b beta-decahydro-6a beta-methyl-3-oxo- 1H-cyclopenta[f]quinolin-7 beta-yl)valeric acid (DCQVA), is a potent peroxisome proliferator. In this paper a possible key stage in DCQVA metabolism, the activation of DCQVA to its CoA ester, has been investigated in rat liver microsomes and particulate fractions. The microsomal reaction was dependent on CoA, ATP, DCQVA (0.2-1 mM) and protein content. The reaction was decreased by storage at 4 degrees C, preincubation of microsomes at 37 degrees C for 5 min, or inclusion of Triton X-100 in the reaction mixture. Such treatments also enhanced generation of long-chain fatty acyl-CoAs, as determined by h.p.l.c. analysis. The same effect was caused by exposing the microsomes to phospholipase A2, suggesting that endogenous fatty acids may compete with DCQVA for esterification with CoA. Subcellular fractionation of rat liver demonstrated that the activity of DCQVA-CoA synthesis was localized predominantly in the microsomal fraction, in contrast to long-chain fatty acyl-CoA synthetase, which was distributed among all particulate fractions. Administration of clofibrate of rats did not affect the distribution of DCQVA-CoA synthesis activity. In contrast to a 2-fold induction of long-chain fatty acyl-CoA synthetase by clofibrate treatment, the activity of DCQVA-CoA synthesis in the microsomal fraction decreased by 80%. These results suggest that DCQVA is activated by an enzyme distinct from long-chain fatty acyl-CoA synthetase. The resulting perturbation of fatty acid metabolism may be involved in the mechanism whereby DCQVA causes peroxisome proliferation.


Anti-biofouling therapeutic nanoparticles with removable shell and highly efficient internalization by cancer cells.
Cationic gelatin nanoparticles ((+)nGNPs) were prepared by in situ polymerization upon the surfaces of monodispersed gelatin nanoparticles (GNPs) using N-(3-Aminopropyl)methacrylamide (APm) as monomer, which were then decorated with doxorubicin terminated poly(2-methylacryloyloxyethyl phosphorylcholine) (DOX-pMPC) via EDC/NHS conjugation to obtain core-shell nanoparticles ((+)nGNPs@DOX-pMPC) for cancer therapy. The non-fouling pMPC shell could effectively shield the positively charged surface of inner nanoparticle and prevent non-specific protein adsorption, thus endowing the materials with potential for long-acting cancer treatment. Furthermore, the acyl hydrazone bond connecting DOX and pMPC chain could be easily hydrolyzed in the weakly acidic tumor microenvironment. After decladding of the pMPC shell, electropositive (+)nGNPs carrying the drugs can be effectively internalized by cancer cells to induce apoptosis, avoiding undesirable hindrance caused by the superhydrophilic outer layer. On combining the above properties, this drug delivery system can be a promising candidate for long-acting, low-toxicity and high-efficiency cancer therapy.


Site-specific modification of calmodulin Ca²(+) affinity tunes the skeletal muscle ryanodine receptor activation profile.
The skeletal muscle isoform of the ryanodine receptor Ca²(+)-release channel (RyR1) is regulated by Ca²(+) and CaM (calmodulin). CaM shifts the biphasic Ca²(+)-dependence of RyR1 activation leftward, effectively increasing channel opening at low Ca²(+) and decreasing channel opening at high Ca²(+). The conversion of CaM from a RyR1 activator into an inhibitor is due to the binding of Ca²(+) to CaM; however, which of CaM's four Ca²(+)-binding sites serves as the switch for this conversion is unclear. We engineered a series of mutant CaMs designed to individually increase the Ca²(+) affinity of each of CaM's EF-hands by increasing the number of acidic residues in Ca²(+)-chelating positions. Domain-specific Ca²(+) affinities of each CaM variant were determined by equilibrium fluorescence titration. Mutations in sites I (T26D) or II (N60D) in CaM's N-terminal domain had little effect on CaM Ca²(+) affinity and regulation of RyR1. However, the site III mutation N97D increased the Ca²(+)-binding affinity of CaM's C-terminal domain and caused CaM to inhibit RyR1 at a lower Ca²(+) concentration than wild-type CaM. Conversely, the site IV mutation Q135D decreased the Ca²(+)-binding affinity of CaM's C-terminal domain and caused CaM to inhibit RyR1 at higher Ca²(+) concentrations. These results support the hypothesis that Ca²(+) binding to CaM's C-terminal acts as the switch converting CaM from a RyR1 activator into a channel inhibitor. These results indicate further that targeting CaM's Ca²(+) affinity may be a valid strategy to tune the activation profile of CaM-regulated ion channels.


The moral affiliations of disgust: a functional MRI study.
Recent investigations in cognitive neuroscience have shown that ordinary human behavior is guided by emotions that are uniquely human in their experiential and interpersonal aspects. These "moral emotions" contribute importantly to human social behavior and derive from the neurobehavioral reorganization of the basic plan of emotions that pervade mammalian life. Disgust is one prototypic emotion with multiple domains that include viscerosomatic reaction patterns and subjective experiences linked to (a) the sensory properties of a class of natural stimuli, (b) a set of aversive experiences and (c) a unique mode of experiencing morality. In the current investigation, we tested the hypotheses that (a) the experience of disgust devoid of moral connotations ("pure disgust") can be subjectively and behaviorally differentiated from the experience of disgust disguised in the moral emotion of "indignation" and that (b) pure disgust and indignation may have partially overlapping neural substrates. Thirteen normal adult volunteers were investigated with functional magnetic resonance imaging as they read a series of statements depicting scenarios of pure disgust, indignation, and neutral emotion. After the scanning procedure, they assigned one basic and one moral emotion to each stimulus from an array of six basic and seven moral emotions. Results indicated that (a) emotional stimuli may evoke pure disgust with or without indignation, (b) these different aspects of the experience of disgust could be elicited by a set of written statements, and (c) pure disgust and indignation recruited both overlapping and distinct brain regions, mainly in the frontal and temporal lobes. This work underscores the importance of the prefrontal and orbitofrontal cortices in moral judgment and in the automatic attribution of morality to social events. Human disgust encompasses a variety of emotional experiences that are ingrained in frontal, temporal, and limbic networks.


Using simulation to evaluate clinical competence after impairment.
It is important for individual dentists and the profession to have access to a process for evaluating the clinical competence of practitioners who are professionally impaired as a result of an accident or a medical disability. No common standards for such evaluations currently exist, however, as demand for this type of assessment is still rare. This article reviews the evaluative approach taken by a team of experienced dental educators in examining three dentists who suffered from medical disabilities. An attempt was made to standardize the evaluation process by using clinical simulation to create an environment that would be comfortable for the dentists and acceptable to the lawyers and the insurance companies. Following evaluation, recommendations on individual competence were made, contributing to a faster resolution of legal and insurance issues.


Chitosan-olive oil microparticles for phenylethyl isothiocyanate delivery: Optimal formulation.
Phenylethyl isothiocyanate (PEITC), a chemopreventive compound, is highly reactive due to its considerably electrophilic nature. Furthermore, it is hydrophobic and has low stability, bioavailability and bioaccessibility. This restricts its use in biomedical and nutraceutical or food applications. Thus, the encapsulation of this agent has the function of overcoming these limitations, promoting its solubility in water, and stabilizing it, preserving its bioactivity. So, polymeric microparticles were developed using chitosan-olive oil-PEITC systems. For this, an optimisation process (factors: olive oil: chitosan ratio and PEITC: chitosan ratio) was implemented through a 3-level factorial experimental design. The responses were: the particle size, zeta-potential, polydisperse index, and entrapment efficiency. The optimal formulation was further characterised by FTIR and biocompatibility in Caco-2 cells. Optimal conditions were olive oil: chitosan and PEITC: chitosan ratios of 1.46 and 0.25, respectively. These microparticles had a size of 629 nm, a zeta-potential of 32.3 mV, a polydispersity index of 0.329, and entrapment efficiency of 98.49%. We found that the inclusion process affected the optical behaviour of the PEITC, as well as the microparticles themselves and their interaction with the medium. Furthermore, the microparticles did not show cytotoxicity within the therapeutic values of PEITC. Thus, PEITC was microencapsulated with characteristics suitable for potential biomedical, nutraceutical and food applications.


Lysophosphatidic acid enhances stromal cell-directed angiogenesis.
Ischemic diseases such as peripheral vascular disease (PVD) affect more than 15% of the general population and in severe cases result in ulcers, necrosis, and limb loss. While the therapeutic delivery of growth factors to promote angiogenesis has been widely investigated, large-scale implementation is limited by strategies to effectively deliver costly recombinant proteins. Multipotent adipose-derived stromal cells (ASC) and progenitor cells from other tissue compartments secrete bioactive concentrations of angiogenic molecules, making cell-based strategies for in situ delivery of angiogenic cytokines an exciting alternative to the use of recombinant proteins. Here, we show that the phospholipid lysophosphatidic acid (LPA) synergistically improves the proangiogenic effects of ASC in ischemia. We found that LPA upregulates angiogenic growth factor production by ASC under two- and three-dimensional in vitro models of serum deprivation and hypoxia (SD/H), and that these factors significantly enhance endothelial cell migration. The concurrent delivery of LPA and ASC in fibrin gels significantly improves vascularization in a murine critical hindlimb ischemia model compared to LPA or ASC alone, thus exhibiting the translational potential of this method. Furthermore, these results are achieved using an inexpensive lipid molecule, which is orders-of-magnitude less costly than recombinant growth factors that are under investigation for similar use. Our results demonstrate a novel strategy for enhancing cell-based strategies for therapeutic angiogenesis, with significant applications for treating ischemic diseases.


Multi-fidelity machine-learning with uncertainty quantification and Bayesian optimization for materials design: Application to ternary random alloys.
We present a scale-bridging approach based on a multi-fidelity (MF) machine-learning (ML) framework leveraging Gaussian processes (GP) to fuse atomistic computational model predictions across multiple levels of fidelity. Through the posterior variance of the MFGP, our framework naturally enables uncertainty quantification, providing estimates of confidence in the predictions. We used density functional theory as high-fidelity prediction, while a ML interatomic potential is used as low-fidelity prediction. Practical materials' design efficiency is demonstrated by reproducing the ternary composition dependence of a quantity of interest (bulk modulus) across the full aluminum-niobium-titanium ternary random alloy composition space. The MFGP is then coupled to a Bayesian optimization procedure, and the computational efficiency of this approach is demonstrated by performing an on-the-fly search for the global optimum of bulk modulus in the ternary composition space. The framework presented in this manuscript is the first application of MFGP to atomistic materials simulations fusing predictions between density functional theory and classical interatomic potential calculations.


Oblique impact: a process for obtaining meteorite samples from other planets.
Cratering flow calculations for a series of oblique to normal (10 degrees to 90 degrees ) impacts of silicate projectiles onto a silicate halfspace were carried out to determine whether or not the gas produced upon shock-vaporizing both projectile and target material would form a downstream jet that could entrain and propel SNC meteorites from the Martian surface. The difficult constraints that the impact origin hypothesis for SNC meteorites has to satisfy are that these meteorites are lightly to moderately shocked and yet have been accelerated to speeds in excess of the Martian escape velocity (more than 5 kilometers per second). Two-dimensional finite difference calculations were performed that show that at highly probable impact velocities (7.5 kilometers per second), vapor plume jets are produced at oblique impact angles of 25 degrees to 60 degrees and have speeds as great as 20 kilometers per second. These plumes flow nearly parallel to the planetary surface. It is shown that upon impact of projectiles having radii of 0.1 to 1 kilometer, the resulting vapor jets have densities of 0.1 to 1 gram per cubic centimeter. These jets can entrain Martian surface rocks and accelerate them to velocities greater than 5 kilometers per second. This mechanism may launch SNC meteorites to earth.


Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging.
To determine if repeated intravenous exposures to gadolinium-based contrast agents (GBCAs) are associated with neuronal tissue deposition. In this institutional review board-approved single-center study, signal intensities from T1-weighted magnetic resonance (MR) images and postmortem neuronal tissue samples from 13 patients who underwent at least four GBCA-enhanced brain MR examinations between 2000 and 2014 (contrast group) were compared with those from 10 patients who did not receive GBCA (control group). Antemortem consent was obtained from all study participants. Neuronal tissues from the dentate nuclei, pons, globus pallidus, and thalamus of these 23 deceased patients were harvested and analyzed with inductively coupled plasma mass spectrometry (ICP-MS), transmission electron microscopy, and light microscopy to quantify, localize, and assess the effects of gadolinium deposition. Associations between cumulative gadolinium dose, changes in T1-weighted MR signal intensity, and ICP-MS-derived tissue gadolinium concentrations were examined by using the Spearman rank correlation coefficient (ρ). Compared with neuronal tissues of control patients, all of which demonstrated undetectable levels of gadolinium, neuronal tissues of patients from the contrast group contained 0.1-58.8 μg gadolinium per gram of tissue, in a significant dose-dependent relationship that correlated with signal intensity changes on precontrast T1-weighted MR images (ρ = 0.49-0.93). All patients in the contrast group had relatively normal renal function at the time of MR examination. Gadolinium deposition in the capillary endothelium and neural interstitium was observed only in the contrast group. Intravenous GBCA exposure is associated with neuronal tissue deposition in the setting of relatively normal renal function. Additional studies are needed to investigate the clinical significance of these findings and the generalizability to other GBCAs. Online supplemental material is available for this article.


A torrid zone on mouse chromosome 1 containing a cluster of recombinational hotspots.
Within the 2.38-Mb Ath1 region of mouse chromosome 1, 42 of 45 genetic crossovers from crosses between C57BL/6J (B6) and either C3H/HeJ (H) or Mus spretus (SPRET) occurred in four zones (A-D); zone A, 100 kb long, contained a cluster of at least four recombination hotspots. F1 sperm assays indicate that within this "torrid zone" the most active hotspot (A3) can initiate recombination on H and SPRET but not B6 chromosomes. The A3 DNA sequence contains a (G/C)TTT repeat, long stretches of A or T, and a cyclic variation in AT content. Recombination was drastically reduced in a cross between B6 and a B6.SPRET Ath1 congenic strain, but was unaffected in a B6 x B6.H Ath1 congenic cross. Similar nonrandom clustering of hotspots has been observed in yeast and the major histocompatibility complexes of human and mouse. To the extent that torrid zones are a general feature of mammalian genomes, they have considerable implications for genetic mapping strategies in both human populations and mouse crosses.


[Effect of the combined action of hydrogen fluoride and phosphine on the structural and functional properties of the sarcoplasmic reticulum membranes of the myocardium with nutrition of varying character].
A study was made of the activity of transport ATPases of rat myocardial sarcoplasmic reticulum membranes under the conditions of different-character nutrition and under the action of hydrogen fluoride and phosphine. The combined effect of the gases under study was accompanied by activation of Ca2+ ATPase and total ATPase. The character of nutrition, the degree of its adequacy according to retinol, tocopherol, ascorbic acid and essential amino acids (lysine, methionine, and threonine) determined not only the activity of transport ATPases and the phospholipid content of sarcoplasmic reticulum membranes but also the features of the toxic effects of hydrogen fluoride and phosphine. The enrichment of the diet with retinol, tocopherol, ascorbic acid and thiamine reduces the toxic effects of these gases under the conditions of acute and chronic priming as well.


Modified receptor internalization upon coexpression of 5-HT1B receptor and 5-HT2B receptors.
Serotonin 5-HT(2B) receptors are often coexpressed with 5-HT(1B) receptors, and cross-talk between the two receptors has been reported in various cell types. However, many mechanistic details underlying 5-HT(1B) and 5-HT(2B) receptor cross-talk have not been elucidated. We hypothesized that 5-HT(2B) and 5-HT(1B) receptors each affect the others' signaling by modulating the others' trafficking. We thus examined the agonist stimulated internalization kinetics of fluorescent protein-tagged 5-HT(2B) and 5-HT(1B) receptors when expressed alone and upon coexpression in LMTK(-) murine fibroblasts. Time-lapse confocal microscopy and whole-cell radioligand binding analyses revealed that, when expressed alone, 5-HT(2B) and 5-HT(1B) receptors displayed distinct half-lives. Upon coexpression, serotonin-induced internalization of 5-HT(2B) receptors was accelerated 5-fold and was insensitive to a 5-HT(2B) receptor antagonist. In this context, 5-HT(2B) receptors did internalize in response to a 5-HT(1B) receptor agonist. In contrast, co-expression did not render 5-HT(1B) receptor internalization sensitive to a 5-HT(2B) receptor agonist. The altered internalization kinetics of both receptors upon coexpression was probably not due to direct interaction because only low levels of colocalization were observed. Antibody knockdown experiments revealed that internalization of 5-HT(1B) receptors (expressed alone) was entirely clathrin-independent and Caveolin1-dependent, whereas that of 5-HT(2B) receptors (expressed alone) was Caveolin1-independent and clathrin-dependent. Upon coexpression, serotonin-induced 5-HT(2B) receptor internalization became partially Caveolin1-dependent, and serotonin-induced 5-HT(1B) receptor internalization became entirely Caveolin1-independent in a protein kinase Cepsilon-dependent fashion. In conclusion, these data demonstrate that coexpression of 5-HT(1B) and 5-HT(2B) receptors influences the internalization pathways and kinetics of both receptors.


WHO Standard Acupuncture Point Locations.
'WHO Standard Acupuncture Point Locations in the Western Pacific Region (WHO Standard) was released in 2008. Initially, there were 92/361 controversial acupuncture points (acupoints). Through seven informal consultations and four task force team meetings, 86 points were agreed upon among the 92 controversial acupoints, leaving 6 remaining controversial acupoints, demanding active research in the future. This will enhance the reproducibility and validity of acupuncture studies. It will also lead to a better understanding of acupuncture mechanisms in order to optimize its clinical efficacy for a range of diseases and syndromes. This book has two parts: General Guidelines for Acupuncture Point Locations and WHO Standard Acupuncture Point Locations. First of all, familiarity with the General Guidelines for Acupuncture Point Locations in this book can help the reader to understand and use the contents of this book in depth. I would like to thank all of the participating experts and scholars for this great work, who have overcome the limits of previous acupuncture references. I also appreciate the dedicated effort and harmonious leadership of Dr Choi Seung-hoon, former Regional Adviser in Traditional Medicine of Western Pacific Office, WHO.


Candid albicans associated with the gastrointestinal tract of the common pigeon (Columbia livia).
Candida albicans was cultured from the upper gastrointestinal tract of 44% and from the lower alimentary tract in 6% of 50 common pigeons (Columba livia). Thirty per cent of samples of pigeon droppings collected from different locations were positive for the yeast. The colony forming units for positive samples ranged from 2 times 10-2-2-8times 10-6 per g dry feces. The percentage of antigenic Groups A and B for the strains of C. albicans isolated was approximately the same as for strains isolated from human sources.


Enhanced Recovery After Surgery for Suspected Ovarian Malignancy: A Survey of Perioperative Practice Among Gynecologic Oncologists in Australia and New Zealand to Inform a Clinical Trial.
The objective of this survey was to review the current standard of perioperative care of patients with suspected advanced ovarian cancer in Australia and New Zealand in order to determine the level of equipoise for specific interventions. In May 2016, a web-based questionnaire (SurveyMonkey Inc, Palo Alto, CA) was sent to all gynecologic oncologists in Australia and New Zealand (n = 56). Descriptive statistics were used. Response rate was 75%. Prevention of hypothermia, extended thromboembolic prophylaxis, antibiotic prophylaxis, and the avoidance of the routine use of drains were standard of care. Bowel preparation was given by 10% routinely and by 35% when bowel resection was planned. Fasting times for fluids of six hours or more were common (55%). Only 26% had shortened fasting times of two hours. Twelve percent used carbohydrate loading. The majority of patients started a light diet within the first postoperative day and advanced diet subsequently as tolerated. Six respondents (15%) used thoracic epidural, whereas the majority (73%) administered an opioid-based intravenous patient-controlled analgesia as the predominant postoperative analgesia, mainly as part of a multimodal pain management. The majority of respondents expressed an interest in a trial concept of individual ERAS interventions. Only a minority of ERAS interventions can be considered standard of care in ovarian cancer surgery. The existing level of equipoise among gynecologic oncologists in Australia and New Zealand, and their interest in a trial concept of individual ERAS interventions allows further assessment of the feasibility and efficacy of interventions in a randomized controlled trial.


Autosomal dominant polycystic kidney disease: clinical and genetic aspects.
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease caused by at least three different genes. The renal and extrarenal clinical manifestations, and the systemic complications due to cystic and non-cystic abnormalities in ADPKD patients have been widely investigated. Cellular and molecular aspects of cystogenetic mechanisms concern epithelial tubular cell proliferation, remodelling of extracellular matrix, fluid secretion and accumulation, and relations between cell proliferation and apoptosis. In vitro studies on cystogenesis suggest a key role of cell-to-cell or cell-to-matrix interactions. Surface proteins mediating cell-to-cell contact, such as E-cadherin (polycystin?), integrin interactions, growth factors, receptor expression, are involved in the process of differentiation of the cellular condition and of the extracellular matrix. Blocking any one of these complex mechanisms should influence the orientation and polarization of epithelial tubular cells and should mediate the inversion of fluid secretion which ends in renal cystogenesis. ADPKD comprises at least three phenotypically indistinguishable but genetically distinct entities, caused by mutations in three autosomal genes: PKD1 (chromosome 16p13.3) is present in about 85% of patients; PKD2 (chromosome 4q13q23) in 10%; PKD3 (unknown chromosome) in a few families. PCR-based mutation detection methods, automated DNA sequencing, and other "functional" methods are used to screen and analyse ADPKD patients. It is not yet known whether the mutations identified so far in PKD1 and PKD2 inactivate the genes or generate an aberrant product. The products of PKD1 and PKD2 genes have been called polycystin 1 and 2. Polycystins are members of a family of interactive proteins involved in complex adhesive cell-cell, cell-matrix, protein-protein, and protein-carbohydrate interactions in the extracellular compartment, and are involved in the same pathway (ion channel regulator? ion channel? pore?) where mutations in only one of the simple genes (PKD3 too?) may cause the ADPKD phenotype. Genotype-phenotype correlations, in terms of disease severity and/or progression to end-stage renal disease, probably depend on other factors, both genetic and environmental (for instance: DD genotype of the ACE gene in ADPKD hypertensive patients), that might influence the clinical course and progression of ADPKD. The hypothesis of the "two hits" has been proposed to explain at the molecular level the focal nature of cyst formation.


[Evaluation of the Norwegian Medical Association's campaign for improved contraception and fewer induced abortions].
Two thirds of the young women who want induced abortions have not used contraception, and it is likely that improved education in contraception will lead to a decline in induced abortions. The Norwegian Medical Association sees this as its responsibility, and in 1995 proposed a campaign to improve the quantity and quality of physicians' advice on contraceptive use. A booklet was produced and mailed with a poster to all general practitioners in May 1997. Before the distribution of the information package a questionnaire on how contraception was taught was sent to a representative sample of 211 general practitioners. Six months later the same 211 received a similar questionnaire with a few questions added on the possible effect of the information package. 132 physicians responded the first time and 105 the second. Four out of five general practitioners have consultations where they advise on contraception at least weekly. 70% had attended courses on sexology or contraception. 80% found the booklet useful, and 12% had changed their routines as a consequence of the campaign. Routine examinations before prescription of contraceptives were more extensive than the booklet advises. There was no measurable difference in reported practice before and after the campaign, but by using the more than 20,000 potential annual consultations as the unit instead of the physicians, there were significant moves in the right direction. Even if the evaluation cannot document improved contraception as a result of the campaign, the quality of the physicians' advice on contraception has improved.


Sjögren-larsson syndrome: a study of clinical symptoms and dermatological treatment in 34 Swedish patients.
Sjögren-Larsson syndrome (SLS) is a recessively inherited disease with congenital ichthyosis, spastic diplegia or tetraplegia and mental retardation, caused by a deficiency of fatty aldehyde dehydrogenase. The aim of this study was to examine all 34 Swedish patients with SLS, emphasizing skin symptoms, dermatological treatment, and neurological symptoms (evaluated in some cases for more than 25 years by one and the same investigator). Structured interviews were conducted with the patients and their close relatives. All patients had generalized ichthyosis. The degree of scaling varied markedly inter-individually from moderate to severe, but there was no obvious change with age. Most patients had pruritus, suffered from hypohidrosis, and had palmo-plantar keratoderma. Nineteen patients (56%) were on oral acitretin and all patients were using some type of topical therapy. Motor disability with spasticity and muscular paresis was most pronounced in the legs and fairly slight in the arms. Twenty patients (59%) were dependent on a wheelchair for mobility. Poor blood circulation in the lower legs and oedematous feet were frequently found in adults. All patients had learning disability, which varied from slight to pronounced and was expressed in their speech disorders. Thirteen patients (38%) were being treated medically for epilepsy and all had photophobia. In conclusion, SLS is a chronic, severely disabling neurocutaneous disease in which optimal dermatological therapy is essential to relieve at least the patient's ichthyosis problem.


Latrunculin-A causes mydriasis and cycloplegia in the cynomolgus monkey.
To determine the effect of latrunculin (LAT)-A, which binds to G-actin and disassembles actin filaments, on the pupil, accommodation, and isolated ciliary muscle (CM) contraction in monkeys. Pupil diameter (vernier calipers) and refraction (coincidence refractometry) were measured every 15 minutes from 0.75 to 3.5 hours after topical LAT-A 42 microg (approximately 10 microM in the anterior chamber [AC]). Refraction was measured every 5 minutes from 0.5 to 1.5 hours after intracameral injection of 10 microl of 50 microM LAT-A (approximately 5 microM in AC), with intramuscular infusion of 1.5 mg/kg pilocarpine HCl (PILO) during the first 15 minutes of measurements. Pupil diameter was measured at 1 and 2 hours, and refraction was measured every 5 minutes from 1 to 2 hours, after intravitreal injection of 20 microl of 1.25 mM LAT-A (approximately 10 microM in vitreous), with intramuscular infusion of 1.5 mg/kg PILO during the first 15 minutes of measurements (all after topical 2.5% phenylephrine), and contractile response of isolated CM strips, obtained <1 hour postmortem and mounted in a perfusion apparatus, to 10 microM PILO +/- LAT-A was measured at various concentrations. Topical LAT-A of 42 microg dilated the pupil without affecting refraction. Intracameral LAT-A of 5 microM inhibited miotic and accommodative responses to intramuscular PILO. Intravitreal LAT-A of 10 microM had no effect on accommodative or miotic responses to intramuscular PILO. LAT-A dose-dependently relaxed the PILO-contracted CM by up to 50% at 3 microM in both the longitudinal and circular vectors. In monkeys, LAT-A causes mydriasis and cycloplegia, perhaps related to its known ability to disrupt the actin microfilament network and consequently to affect cell contractility and adhesion. Effects of LAT-A on the iris and CM may have significant physiological and clinical implications.


Molecular dissection of the Y chromosome haplogroup E-M78 (E3b1a): a posteriori evaluation of a microsatellite-network-based approach through six new biallelic markers.
The human Y chromosome haplogroup E-M78 (E3b1a) occurs commonly and is distributed in northern and eastern Africa, western Asia, and all of Europe. Previously, only two rarely observed internal biallelic markers (UEPs) were known within the E-M78 clade. Here we report the identification of six novel UEPs that significantly refine the phylogeny of this haplogroup. Then, we evaluate the correspondence between the newly defined sub-haplogroups and the E-M78 haplotype clusters previously identified by an 11-microsatellite loci-based network encompassing 232 chromosomes (Cruciani et al., 2004). We observed considerable correspondence between the trees generated by the two types of markers, but also noted important discrepancies between microsatellite and UEP findings. Overall, this analysis reveals that the currently visible terminal branches of the Y tree still contain a large amount of information, in terms of undiscovered biallelic markers, and that caution is needed when using the microsatellite alleles as surrogates of unique event polymorphisms.


Physiotherapy Methods Applied in the Prevention of Functional Loss Associated with Human T-Lymphotropic Virus 1 Infection: An Overview.
To achieve the objective of this study, we conducted a narrative review on physical therapeutic modalities applied to prevent functional losses associated with human T-lymphotropic virus 1 (HTLV-1) infections to promote health education and viable and accessible alternatives in the development of health education technology adapted to the home environment. This study comprised a qualitative stage of theoretical development to construct a digital booklet with an observational basis based on studies that reiterate themes about educational technologies as tools to conduct a home protocol of guided exercises without the direct supervision of professional physical therapists. Results indicate a lack of research on the development of health education technologies to assist patients with HTLV-1 without tropical spastic paraparesis or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We believe that this narrative review can initiate a theoretical framework to conduct a home exercise program aimed at people with HTLV-1 who have subtle symptoms, and also at people without the clinical definition of HAM/TSP, helping to train human resources for care and research on the subject and increase scientific production in physical therapy.


Squamous cell carcinoma of the oropharynx: single-institution outcome analysis of patients treated with concurrent chemoradiotherapy.
The object of this study was to analyse our experience with the effects of concurrent chemoradiotherapy for oropharyngeal squamous cell carcinoma, the treatment results of this therapeutic strategy and a salvage treatment for recurrent oropharyngeal squamous cell carcinoma. Seventy-five patients with oropharyngeal squamous cell carcinoma were treated with chemoradiotherapy. The study included twenty-five of these patients who had recurrent oropharyngeal squamous cell carcinoma after chemoradiotherapy Results: The three-year actuarial survival rates for 75 patients by disease stage were as follows: stage II, 100 per cent; stage III, 71.1 per cent; stage IV, 51.7 per cent and overall, 58.2 per cent. The mean time of detection of recurrence was 6.2 months. The total salvage rates of recurrence were 21 per cent. The one and three-year tumour-free actuarial survival rates of those patients who received salvage treatment were 83 and 33 per cent. Surgical salvage was only feasible for early recurrent tumour. Close follow-up surveillance of early recurrence is essential after primary treatment of patients with chemoradiotherapy.


Cancer CD39 drives metabolic adaption and mal-differentiation of CD4+ T cells in patients with non-small-cell lung cancer.
While ectonucleotidase CD39 is a cancer therapeutic target in clinical trials, its direct effect on T-cell differentiation in human non-small-cell lung cancer (NSCLC) remains unclear. Herein, we demonstrate that human NSCLC cells, including tumor cell lines and primary tumor cells from clinical patients, efficiently drive the metabolic adaption of human CD4+ T cells, instructing differentiation of regulatory T cells while inhibiting effector T cells. Of importance, NSCLC-induced T-cell mal-differentiation primarily depends on cancer CD39, as this can be fundamentally blocked by genetic depletion of CD39 in NSCLC. Mechanistically, NSCLC cells package CD39 into their exosomes and transfer such CD39-containing exosomes into interacting T cells, resulting in ATP insufficiency and AMPK hyperactivation. Such CD39-dependent NSCLC-T cell interaction holds well in patients-derived primary tumor cells and patient-derived organoids (PDOs). Accordingly, genetic depletion of CD39 alone or in combination with the anti-PD-1 immunotherapy efficiently rescues effector T cell differentiation, instigates anti-tumor T cell immunity, and inhibits tumor growth of PDOs. Together, targeting cancer CD39 can correct the mal-differentiation of CD4+ T cells in human NSCLC, providing in-depth insight into therapeutic CD39 inhibitors.


Health disparities based on socioeconomic inequities: implications for urban health care.
Health is unevenly distributed across socioeconomic status. Persons of lower income, education, or occupational status experience worse health and die earlier than do their better-off counterparts. This article discusses these disparities in the context of urban medical practice. The article begins with a discussion of the complex relationship among socioeconomic status, race, and health in the United States. It highlights the effects of institutional, individual, and internalized racism on the health of African Americans, including the insidious consequences of residential segregation and concentrated poverty. Next, the article reviews health disparities based on socioeconomic status across the life cycle, beginning in fetal health and ending with disparities among the elderly. Potential explanations for these socioeconomic-based disparities are addressed, including reverse causality (e.g., being poor causes lower socioeconomic status) and confounding by genetic factors. The article underscores social causation as the primary explanation for health disparities and highlights the cumulative effects of social disadvantage across stages of the life cycle and across environments (e.g., fetal, family, educational, occupational, and neighborhood). The article concludes with a discussion of the implications of health disparities for the practice of urban medicine, including the role that concentration of disadvantage plays among patients and practice sites and the need for quality improvement to mitigate these disparities.


Exposure to low-frequency electromagnetic fields does not alter HSP70 expression or HSF-HSE binding in HL60 cells.
Environmental exposure to extremely low-frequency electromagnetic fields (ELF EMFs) has been identified as a possible contributor to increased cancer incidence and other diseases. In vitro studies designed to probe for biological mechanisms that might explain such relationships have included several studies of gene expression. While gene expression studies have focused on MYC, effects of ELF EMFs on the expression of beta-actin, histone H2B, beta-tubulin, SRC, FOS and JUN have also been reported. In addition, some investigators have reported both an induction of HSP70 expression and an increase in HSF-HSE binding in HL60 (human promyelocytic leukemia) cells after exposure to a 60 Hz magnetic field. In this study, HL60 cells were exposed to a weak 60 Hz magnetic field (6.3 or 8.0 microT) or to a positive control heat shock (42 or 44 degrees C). While heat shock led to reproducible induction of HSP70 expression and HSF-HSE binding, no significant effect of exposure to ELF EMFs on either of these end points was observed.


A Wireless Wearable Patch for Remote Monitoring of Respiratory and Cardiac Rhythm in Children.
Remote patient monitoring (RPM) is an innovative strategy to promote health and improve patient management and care. Recent advances in healthcare technologies have seen the emergence of wearable sensors allowing longitudinal physiological measurements in any environment. This paper introduces a wireless wearable patch 'Leo' for continuous remote monitoring of physiological data at home and healthcare settings. This includes single lead ECG, chest impedance, heart rate (HR), respiration rate (RR) and body posture. To test Leo's ability to capture longitudinal physiological data at home, 15 children experiencing acute severe asthma exacerbations were recruited during their emergency department (ED) visits. Participants wore the Leo device for 7 (+/-2) days post-hospital discharge. Nocturnal RR and HR and variability were higher during the first half of the night on Day1 compared to Day7 (p<0.005). Participants also completed a usability questionnaire and reported the patch wear to be comfortable (average score of 3.3 out of 5) and easy to wear during the night (average score of 3.5 out of 5) with 5/15 (33%) reported very slight barely perceptible skin irritation/redness and 2 (13%) reported well defined skin irritation and redness.Clinical Relevance- These results highlight the potential use of the Leo device in clinical practice for continuous un-obstructive monitoring of diseased populations, such as asthma.


[HRCA and application in detection of genetically modified plant].
In this article primary studies of the application of hyperbranched rolling cycle amplification (HRCA) in exogenous genes detection of transgenic plants were done. Four padlock probes were designed according to the sequences of four genes/DNA fragments that are used widely in transgenic plants; part of the sequence of pKK233 was chosen as the linking part of padlock probes and a pair of HRCA primers was designed according to the sequence of linking part. Study of the specificity of ligation in HRCA with isotope labeled padlock probes indicated padlock probes could be ringed effectively only when corresponding target DNA exited in the same reaction system and could not be ringed when there was no corresponding target DNA exited. Ligation time is very different according to the characteristic of target DNA being used. 5 min to 10 min is enough if the target DNA is plasmid; 30 min to 60 min is needed if the target is genome DNA of plant because it's sequence is more complex than that of plasmid's. HRCA time was analyzed which indicated longer reaction time can obviously increase the amount of products. Quantity of enzyme in HRCA was also analyzed. Different amount of enzyme (from 0.5 unit to 4 units) can give similar result when other conditions are not changed. On the basis of the research, transgenic tobacco was detected with these four padlock probes and the results were just as prospective. In order to increase the efficiency of detection, multiplex HRCA (MHRCA)was used. In MHRCA more than one padlock probes are used at the same time in the same reaction system to detect more than one targets. Because the amplification products of MHRCA will be complex and it is almost impossible to analyze with electrophoresis, so reverse-blot is used. Detection results of transgenic tobacco with this method are the same with anticipation. Compare to MPCR method we established before MHRCA is more convenient to operate and more effective in detecting exogenous genes in transgenic plants.


Vitamins D, C, and E in the prevention of type 2 diabetes mellitus: modulation of inflammation and oxidative stress.
The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide, and certain population subgroups are especially vulnerable to the disease. To reduce T2DM risk and progression at the population level, preventative strategies are needed that can be implemented on a population-wide scale with minimal cost and effort. Chronic low-grade inflammation resulting from oxidative stress and imbalances in the innate immune system has been associated with obesity, metabolic syndrome, and insulin resistance - critical stages in the development and progression of T2DM. Therefore, inflammation may play a causal role in the pathogenesis of T2DM, and reducing it via modulation of oxidative stress and the innate immune response could lead to a status of improved insulin sensitivity and delayed disease onset. Dietary supplementation with anti-inflammatory and antioxidant nutritional factors, such as micronutrients, might present a novel strategy toward the prevention and control of T2DM at the population level. This review examines current knowledge linking oxidation, inflammatory signaling pathways, and vitamin supplementation or intake to the risk of T2DM. The concept that micronutrients, via attenuation of inflammation, could be employed as a novel preventive measure for T2DM is evaluated in the context of its relevance to public health.


Using primary site as a predictor of survival in mantle cell lymphoma.
Mantle cell lymphoma (MCL) is a rare B cell lymphoma that varies in clinical behavior with some patients experiencing aggressive disease with short survival, whereas others have indolent behavior. We examined the association between primary disease site and survival in MCL patients to identify subgroups with distinct characteristics. We analyzed the United States Surveillance, Epidemiology and End Results Program database for MCL cases reported from 2000 through 2009. Kaplan-Meier curves and Cox proportional hazard models were used to estimate the effect of primary site on survival. Among 4477 cases included in our study, 19.6% of patients presented with an extranodal primary site. The most common extranodal primary sites were of the gastrointestinal (GI) tract (7.8%), the head and neck (6.2%), and the hematologic/reticuloendothelial systems (3.6%). Asians/Pacific Islanders were more likely than whites or blacks to have GI tract or head and neck disease (P < .0001 and P = .002, respectively). Advanced disease and B symptoms were less common in those with primary disease of the GI tract or head and neck than in those with primary disease of the lymph nodes (both P < .0001). In a multivariate Cox regression model, patients with primary disease of the GI tract and head and neck had superior survival compared to those with primary disease of the lymph nodes; hazard ratios 0.75 (95% CI = 0.62-0.90) and 0.68 (95% CI = 0.55-0.85), respectively. Primary site of disease may be an important prognostic factor for patients with MCL. Further studies elucidating a biological basis for these differences are needed.


A simulation study of BrachyShade, a shadow-based internal source tracking system for HDR prostate brachytherapy.
This paper presents a simulation study of BrachyShade, a proposed internal source-tracking system for real time quality assurance in high dose rate prostate brachytherapy. BrachyShade consists of a set of spherical tungsten occluders located above a pixellated silicon photodetector. The source location is estimated by minimising the mean squared error between a parametric model of the shadow image and acquired images of the shadows projected on the detector plane. A novel algorithm is finally employed to correct the systemic error resulting from Compton scattering in the medium. The worst-case error obtained with BrachyShade for a 13.5 ms image acquisition is less than 1.3 mm in the most distant part of the treatment volume, while for 75% of source locations an error of less than 0.42 mm was achieved.


A Statewide Survey Report of Roles and Responsibilities in Current Utah Care Management Processes.
Measure current roles and responsibilities of care managers in the state of Utah. All settings of health care including inpatient, outpatient, community, payer, post-acute, and transitional care settings. A quantitative descriptive survey design was used to assess and describe current care management roles and responsibilities of 191 care managers within the state of Utah. Quantitative variables of roles and responsibilities were collected an electronic database (REDCap). Major results conclude that care managers spend most of their time on direct patient interactions including discharge planning, population care, and utilization review. These care managers are highly experienced in their field, with most being in their professional practice for more than 10 years. Most of the care managers are bachelor's prepared nurses. To create or expand care management processes to meet the goals of health care reform, systems first need to know what care managers/coordinators are doing and where their current focus on care presides. Educators, leaders, and, indeed, the care managers themselves are a part of preparing this dynamic workforce. The major responsibility of care management continues to be direct patient interactions, meaning that care managers are performing vital interpersonal patient interaction needed to achieve highly personalized patient care with assurances of quality and safety. No matter the name-care management, case management, or care coordination-these activities are an essential part of health care, with highly specialized skills that promote patient engagement and activation.


Major Depressive Disorder Classification Based on Different Convolutional Neural Network Models: Deep Learning Approach.
The human brain is characterized by complex structural, functional connections that integrate unique cognitive characteristics. There is a fundamental hurdle for the evaluation of both structural and functional connections of the brain and the effects in the diagnosis and treatment of neurodegenerative diseases. Currently, there is no clinically specific diagnostic biomarker capable of confirming the diagnosis of major depressive disorder (MDD). Therefore, exploring translational biomarkers of mood disorders based on deep learning (DL) has valuable potential with its recently underlined promising outcomes. In this article, an electroencephalography (EEG)-based diagnosis model for MDD is built through advanced computational neuroscience methodology coupled with a deep convolutional neural network (CNN) approach. EEG recordings are analyzed by modeling 3 different deep CNN structure, namely, ResNet-50, MobileNet, Inception-v3, in order to dichotomize MDD patients and healthy controls. EEG data are collected for 4 main frequency bands (Δ, θ, α, and β, accompanying spatial resolution with location information by collecting data from 19 electrodes. Following the pre-processing step, different DL architectures were employed to underline discrimination performance by comparing classification accuracies. The classification performance of models based on location data, MobileNet architecture generated 89.33% and 92.66% classification accuracy. As to the frequency bands, delta frequency band outperformed compared to other bands with 90.22% predictive accuracy and area under curve (AUC) value of 0.9 for ResNet-50 architecture. The main contribution of the study is the delineation of distinctive spatial and temporal features using various DL architectures to dichotomize 46 MDD subjects from 46 healthy subjects. Exploring translational biomarkers of mood disorders based on DL perspective is the main focus of this study and, though it is challenging, with its promising potential to improve our understanding of the psychiatric disorders, computational methods are highly worthy for the diagnosis process and valuable in terms of both speed and accuracy compared with classical approaches.


Interaction of GABA receptor/channel rho(1) and gamma(2) subunit.
To determine whether protein-protein and functional interactions can occur between gamma-aminobutyric acid (GABA)(A) receptor/channels gamma(2) subunit and the retina-specific GABA(C) rho(1) subunit. Protein-protein interaction was characterized by immunocoprecipitation of these subunits in brain and spinal cord with anti-gamma(2) subunit antibody and by Western blot analysis with anti-rho(1) subunit antibody. The rho(1) and gamma(2) subunits were detected in the adult rat brain and spinal cord lysates that had been previously precipitated with the specific antibodies against the rho(1) and gamma(2) subunits, respectively. A two-microelectrode voltage clamp was used to measure GABA-induced currents in oocytes. In addition, a yeast two-hybrid system was used to detect the interactions of these subunits in vivo. Based on yeast transformed with the N-terminal fragment of the gamma(2) subunit (gamma(2)-N'), the N-terminal fragment of the rho(1) subunit (rho(1)-N'), and the full-length rho(1) subunit, the protein-protein interaction of the GABA(A) gamma(2) subunit and the GABA(C) rho(1) subunit was found in yeast grown in triple-dropout medium (deficient in Leu, Trp, and His) and expressing the LacZ reporter gene. Interaction of the rho(1) and gamma(2) subunits was investigated by functional studies in which gamma(2) (gamma(2)-N' with 837 bp) and rho(1) cRNAs were coinjected in Xenopus oocytes. In studies of the functional interaction, after injection of the gamma(2) subunit mutant cRNA containing a N-terminal fragment, GABA-induced rho(1) originated currents declined to 16% of the control level of homooligomeric rho(1) current. This inhibitory effect of coexpressing gamma(2) subunit mutants with rho(1) subunit on the rho(1)-originated current in oocytes was dose dependent. In addition, coexpression of the GABA rho(1) and gamma(2) subunits in oocytes altered pharmacologic properties of the homooligomeric receptor/channel formed by rho(1) or gamma(2) subunits. Further evidence was provided by results obtained with specific antibodies showing that the rho(1) subunit was coimmunoprecipitated with the gamma(2) subunit from the retina, brain, and spinal cord. The results indicate that protein-protein and functional interactions can occur between the GABA(A) gamma(2) subunit and the GABA(C) rho(1) subunit. Therefore, the functional role of GABA receptor/channels in the brain, retina, and spinal cord is more diversified because of the possible assembly between the GABA(A) gamma(2) subunit and GABA(C) rho(1) subunit.


[Neurological evaluation of behavior].
The evaluation of behavior is becoming increasingly important in neurology, mainly because the behavior disorders are an important factor in overburdening carers and leading to institutionalization of patients with dementia. In this article we review the methodology and scope of the evaluation of conduct in cognitive deterioration and in dementia, with special attention to Alzheimer's disease. We also describe the instruments for evaluation which the author considers to be most relevant. From an initial broad concept, the scales of evaluation have been reduced to a limited concept of behavior disorder, which is an equivalent phenomenon to a 'psychiatric disorder'. The behavioral manifestations of the different dementias overlap completely, so that there is only limited usefulness in the evaluation of behavior for differential diagnosis. However, detailed evaluation of behavior contributes to a more rational approach to these patients, which would reduce the career's burden. Development of sensitive scales during all the phases of deterioration and of instruments which allow one to investigate the genesis of the different disorders are urgently needed, preferably with an intercultural approach.


Molecular targeting regulation of proliferation and differentiation of the bone marrow-derived mesenchymal stem cells or mesenchymal stromal cells.
The bone marrow-derived mesenchymal stem cells or mesenchymal stromal cells (MSCs), with pluripotent differentiation capacity, present an ideal source for cell transplantation or tissue engineering therapies, but exact understanding of regulating mechanism underling MSC proliferation and differentiation remains a critical issue in securing their safe and efficient clinical application. This review outlines current knowledge regarding MSC cell surface biomarkers and molecular mechanisms of MSC differentiation and proliferation with emphasis on Wnt/β-catenin signaling, Notch signaling pathway, bone morphogenesis proteins and various growth factors functioning in regulation of differentiation and proliferation of MSCs. Possible relation of oncogene and immunosuppressive activities of MSCs with tumorigenicity or tumor generation is also addressed for safe translational clinical application. Fast increase of MSC knowledge and techniques has led to some successful clinical trials and helped devising new tissue engineering therapies for bone and cartilage diseases that severely afflict human health. Production of adult MSC-derived functional neurons can further extend their therapeutic application in nerve injury and neurodegenerative diseases. It is promising that MSCs shall overcome ethical and immunorejection problems appeared in human embryonic stem cells, and specific molecular targeting manipulation may result in practical MSC therapy for personalized treatment of various diseases in the regeneration medicine.


Medical-attention injuries in community Australian football: a review of 30 years of surveillance data from treatment sources.
In recent reports, Australian football has outranked other team sports in the frequency of hospitalizations and emergency department (ED) presentations. Understanding the profile of these and other "medical-attention" injuries is vital for developing preventive strategies that can reduce health costs. The objective of this review was to describe the frequency and profile of Australian football injuries presenting for medical attention. A systematic search was carried out to identify peer-reviewed articles and reports presenting original data about Australian football injuries from treatment sources (hospitals, EDs, and health-care clinics). Data extracted included injury frequency and rate, body region, and nature and mechanism of injury. Following literature search and review, 12 publications were included. In most studies, Australian football contributed the greatest number of injuries out of any sport or recreation activity. Hospitals and EDs reported a higher proportion of upper limb than lower limb injuries, whereas the opposite was true for sports medicine clinics. In hospitals, fractures and dislocations were most prevalent out of all injuries. In EDs and clinics, sprains/strains were most common in adults and superficial injuries were predominant in children. Most injuries resulted from contact with other players or falling. The upper limb was the most commonly injured body region for Australian football presentations to hospitals and EDs. Strategies to prevent upper limb injuries could reduce associated public health costs. However, to understand the full extent of the injury problem in football, treatment source surveillance systems should be supplemented with other datasets, including community club-based collections.


Mechanically Strong, Scalable, Mesoporous Xerogels of Nanocellulose Featuring Light Permeability, Thermal Insulation, and Flame Self-Extinction.
Scalability is a common challenge in the structuring of nanoscale particle dispersions, particularly in the drying of these dispersions for producing functional, porous structures such as aerogels. Aerogel production relies on supercritical drying, which exhibits poor scalability. A solution to this scalability limitation is the use of evaporative drying under ambient pressure. However, the evaporative drying of wet gels comprising nanoscale particles is accompanied by a strong capillary force. Therefore, it is challenging to produce evaporative-dried gels or "xerogels" that possess the specific structural profiles of aerogels such as mesoscale pores, high porosity, and high specific surface area (SSA). Herein, we demonstrate a structure of mesoporous xerogels with high porosity (∼80%) and high SSA (>400 m2 g-1) achieved by exploiting cellulose nanofibers (CNFs) as the building blocks with tunable interparticle interactions. CNFs are sustainable, wood-derived materials with high strength. In this study, the few-nanometer-wide CNFs bearing carboxy groups were structured into a stable network via ionic inter-CNF interaction. The outline of the resulting xerogels was then tailored into a regular, millimeter-thick, board-like structure. Several characterization techniques highlighted the multifunctionality of the CNF xerogels combining outstanding strength (compression E = 170 MPa, σ = 10 MPa; tension E = 290 MPa, σ = 8 MPa), moderate light permeability, thermal insulation (0.06-0.07 W m-1 K-1), and flame self-extinction. As a potential application of the xerogels, daylighting yet insulating, load-bearing wall members can be thus proposed.


Association of polyfluoroalkyl chemical exposure with serum lipids in children.
Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as well as polymers of PFASs, have been widely used in commercial applications and have been detected in humans and the environment. Previous epidemiological studies have shown associations between particular PFAS chemicals and serum lipid concentrations in adults, particularly perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). There exists, however, limited information concerning the effect of PFASs have on serum lipids among children. In the present cross-sectional study, 225 Taiwanese children (12-15 years of age) were recruited to determine the relationship between serum level PFASs and lipid concentration. Results showed that eight out of ten particular PFASs were detected in the serum of >94% of the participants. Serum PFOS and perfluorotetradecanoic acid (PFTA) levels were at an order of magnitude higher than the other PFASs, with arithmetical means of 32.4 and 30.7 ng/ml in boys and 34.2 and 27.4 ng/ml in girls, respectively. However, the variation in serum PFTA concentration was quite large. Following covariate adjustment, linear regression models revealed that PFOS, PFOA, and perfluorononanoic acid (PFNA) were positively associated with total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides (TG), particularly for PFOS and PFTA. Quartile analysis, with the lowest exposure quartile as a reference, yielded associations between serum PFTA and elevations in TC (p=0.002) and LDL (p=0.004). Though not statistically significant, high-density lipoprotein (HDL) appeared to decrease linearly across quartiles for PFOS and PFOA exposure. In conclusion, a significant association was observed between serum PFASs and lipid level in Taiwanese children. These findings for PFTA are novel, and emphasize the need to investigate the exposure route and toxicological evidence of PFASs beyond PFOS and PFOA.


The response of Pseudomonas aeruginosa to azlocillin, ticarcillin and cefsulodin.
The morphological response of Pseudomonas aeruginosa to azlocillin, ticarcillin and cefsulodin was investigated by electron microscopy. Each antibiotic initially caused the formation of filaments. On further incubation in the presence of azlocillin, deposits of dense intracellular material were observed; these were absent from cells exposed to the other two antibiotics. On continued incubation, lysis of the filaments occurred, but the mode of lysis differed between the antibiotics: azlocillin caused breakage at a restricted number of sites in the cell wall, ticarcillin produced breakage at many points and cefsulodin caused extensive cell-wall damage. In addition, ticarcillin and cefsulodin appeared to cause more lysis and spheroplast formation than did azlocillin. The morphological changes correlated with turbidimetric measurements of bacterial response to the three antibiotics, which showed ticarcillin and cefsulodin to act more rapidly than azlocillin.


Collaboration and involvement of persons with lived experience in planning Canada's At Home/Chez Soi project.
Planning the implementation of evidence-based mental health services entails commitment to both rigour and community relevance, which entails navigating the challenges of collaboration between professionals and community members in a planning environment which is neither 'top-down' nor 'bottom-up'. This research focused on collaboration among different stakeholders (e.g. researchers, service-providers, persons with lived experience [PWLE]) at five project sites across Canada in the planning of At Home/Chez Soi, a Housing First initiative for homeless people with mental health problems. The research addressed the question of what strategies worked well or less well in achieving successful collaboration, given the opportunities and challenges within this complex 'hybrid' planning environment. Using qualitative methods, 131 local stakeholders participated in key informant or focus group interviews between October 2009 and February 2010. Site researchers identified themes in the data, using the constant comparative method. Strategies that enhanced collaboration included the development of a common vision, values and purpose around the Housing First approach, developing a sense of belonging and commitment among stakeholders, bridging strategies employed by Site Co-ordinators and multiple strategies to engage PWLE. At the same time, a tight timeline, initial tensions, questions and resistance regarding project and research parameters, and lack of experience in engaging PWLE challenged collaboration. In a hybrid planning environment, clear communication and specific strategies are required that flow from an understanding that the process is neither fully participatory nor expert-driven, but rather a hybrid of both.


Interactions between the aryl hydrocarbon receptor and P-TEFb. Sequential recruitment of transcription factors and differential phosphorylation of C-terminal domain of RNA polymerase II at cyp1a1 promoter.
The expression of the cytochrome P450 1A1 gene (cyp1a1) is regulated by the aryl hydrocarbon receptor (AhR), which is a ligand-activated transcription factor that mediates most toxic responses induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In the nucleus, ligand-activated AhR binds to the xenobiotic response elements, initiating chromatin remodeling and recruitment of coregulators, leading to the formation of preinitiation complex followed by elongation. Here, we report that ligand-activated AhR recruits the positive transcription elongation factor (P-TEFb) and RNA polymerase II (RNA PII) to the cyp1a1 promoter with concomitant phosphorylation of the RNA PII carboxyl domain (CTD). Interestingly, the serine 2 and serine 5 of the heptapeptide repeats (YSPTSPS) were sequentially phosphorylated upon TCDD treatment. Inhibition of P-TEFb kinase activity by 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole (DRB) suppressed CTD phosphorylation (especially serine 2 phosphorylation) and abolished processive elongation without disrupting the assembly of the preinitiation complex at the cyp1a1 promoter. Remarkably, we found that activation of NF-kappaB by TNF-alpha selectively inhibited TCDD-induced serine 2 phosphorylation in mouse liver cells, suggesting that residue-specific phosphorylation of RNA PII CTD at the cyp1a1 promoter is an important regulatory point upon which signal "cross-talk" converges. Finally, we show that ligand-activated AhR associated with P-TEFb through the C terminus of cyclin T1, suggesting that AhR recruit the P-TEFb to the cyp1a1 promoter whereupon its kinase subunit phosphorylates the RNA PII CTD.


Stress analysis of a complete maxillary denture under various drop impact conditions: a 3D finite element study.
Complete maxillary dentures are one of the most economic and easy ways of treatment for edentulous patients and are still widely used. However, their survival rate is slightly above three years. It is presumed that the failure reasons are not only due to normal fatigue but also emerge from damage based on unavoidable improper usage. Failure types other than long-term fatigue, such as over-deforming, also influence the effective life span of dentures. A hypothesis is presumed, stating that the premature/unexpected failures may be initiated by impact on dentures, which can be related to dropping them on the ground or other effects such as biting crispy food. Thus, the behavior of a complete maxillary denture under impact loading due to drop on a rigid surface was investigated using the finite element method utilizing explicit time integration and a rate-sensitive elastoplastic material model of polymethylmethacrylate (PMMA). Local permanent deformations have been observed along with an emphasis on frenulum region of the denture, regardless of the point of impact. Contact stresses at the tooth-denture base were also investigated. The spread of energy within the structure via wave propagation is seen to play a critical role in this fact. Stress-wave propagation is also seen to be an important factor that decreases the denture's fatigue life.


A prospective study of immune and inflammation markers and risk of lung cancer among female never smokers in Shanghai.
There is a paucity of data on risk factors for lung cancer among never smokers. Here, we have carried out the first large study of circulating inflammation markers and lung cancer risk among female never smokers in Shanghai. A study of 248 lung cancer cases in female never smokers and 263 controls was nested within the Shanghai Women's Health Study (n = 75221), matched by dates of birth and blood collection (mean follow-up time = 7.5 years). Prediagnostic plasma levels of 65 inflammation markers were measured using a Luminex bead-based assay. Odds ratios (ORs) were estimated with multivariable logistic regression. Nine of 61 evaluable markers were statistically significantly associated with lung cancer risk among never smoking Chinese women (P-trend across categories <0.05). Soluble interleukin-6 receptor [sIL-6R; highest versus lowest category OR = 2.37; 95% confidence interval (CI) 1.40-4.02) and chemokine (C-C motif) ligand 2/monocyte chemotactic protein 1; (OR = 1.62; 95% CI 0.94-2.80) were associated with an increased risk of lung cancer, whereas interleukin (IL)-21 (OR = 0.53; 95%CI 0.31-0.93), chemokine (C-X3-C motif) ligand 1/fractalkine (OR = 0.54; 95% CI 0.30-0.96), soluble vascular endothelial growth factor receptor 2 (sVEGFR2, OR = 0.45; 95% CI 0.26-0.76), sVEGFR3 (OR = 0.53; 95% CI 0.32-0.90), soluble tumor necrosis factor receptor I (OR = 0.49; 95% CI 0.29-0.83), IL-10 (OR = 0.60; 95% CI 0.34-1.05) and C-reactive protein (OR = 0.63; 95% CI 0.37-1.06) were associated with a decreased risk. sIL-6R remained significantly associated with lung cancer risk >7.5 years prior to diagnosis. Markers involved in various aspects of the immune response were associated with subsequent lung cancer risk, implicating inflammation in the etiology of lung cancer among female never smokers.


HUMAN TISSUE LEGISLATION AND MEDICAL PRACTICE: A BENEFIT OR A BURDEN?
The scandals surrounding organ removal and retention throughout the United Kingdom provoked several Inquiries and ultimately led to law reform. Although the medical professions were well represented at the Inquiries, little was heard of the voices of those at the 'coal face'. In this scoping study, funded by the Wellcome Trust, we interviewed a number of doctors and others engaged in the uses of human tissue and organs to explore their hopes, concerns and fears about the role of the law in their practices. We found that those involved in transplantation were more aware of, and more actively involve with, the law, whereas others, such as pathologists, had less direct engagement with the law. Most of those we interviewed expressed the hope that law reform would provide much-needed clarity. Although some expressed concern that the law might be over-intrusive, most felt that the placing of authority firmly in the hands of the person him or her self to decide what should happen to their bodies was to be welcomed.


Transcranial magnetic stimulation for treating depression.
Transcranial magnetic stimulation can either excite or inhibit cortical areas of the brain, depending on whether the speed of the repetitive stimulation is applied at high or low frequencies. It has been used for physiological studies and it has also been proposed as a treatment for depression. To assess the clinical efficacy and safety of transcranial magnetic stimulation for treating depression. An electronic search was performed including the Cochrane Collaboration Depression, Neurosis and Anxiety Review Group trials register (last searched June, 2001), the Cochrane Controlled Trials Register (Issue 2, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), PsycLIT (1980-2001), and bibliographies from reviewed articles. Unpublished data and grey literature were searched through personal communications with researchers. Randomised controlled trials assessing the therapeutic efficacy and safety of transcranial magnetic stimulation for depression. All reviewers independently extracted the information and verified it by cross-checking. Disagreements were resolved through discussion. Continuous data: When similar studies were grouped, the overall standardised mean difference was calculated under a fixed effect model weighted by the inverse variance method with 95% confidence intervals. (In the presence of statistical heterogeneity, a random effects model was to be used.) Sixteen trials were included in the review and fourteen contained data in a suitable form for quantitative analysis. Most comparisons did not show differences between rTMS and other interventions. No difference was seen between rTMS and sham TMS using the Beck Depression Inventory or the Hamilton Depression Rating Scale, except for one time period (after two weeks of treatment) for left dorsolateral prefrontal cortex and high frequency; and also for right dorsolateral prefrontal cortex and low frequency, both in favour of rTMS and both using the Hamilton scale. Comparison of rTMS (left dorsolateral prefrontal cortex and high frequency) with electroconvulsive therapy showed no difference except for psychotic patients after two weeks treatment, using the Hamilton scale, which indicated that electroconvulsive therapy was more effective than rTMS. The information in this review suggests that there is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit.


Worldwide estimates of incidence, prevalence and mortality of type 1 diabetes in children and adolescents: Results from the International Diabetes Federation Diabetes Atlas, 9th edition.
This article describes the methods, results and limitations of the International Diabetes Federation (IDF) Diabetes Atlas 9th edition estimates of worldwide numbers of cases of type 1 diabetes in children and adolescents. Most information in the published literature is in the form of incidence rates derived from registers of newly-diagnosed cases. After systematic review of the published literature and recent conference abstracts, identified studies were quality graded. If no study was available, extrapolation was used to assign a country the rate from an adjacent country with similar characteristics. Estimates of incident cases were obtained by applying incidence rates to United Nations 2019 population estimates. Estimates of prevalent cases were derived from incidence rates after making allowance for higher mortality rates in less-developed countries. Incidence rates were available for 45% of countries (ranging from 6% in the sub-Saharan Africa region to 77% in the European region). Worldwide annual incidence estimates were 98,200 (128,900) new cases in the under 15 year (under 20 year) age-groups. Corresponding prevalence estimates were 600,900 (1,110,100) existing cases. Compared with estimates in earlier Atlas editions, numbers have increased in most IDF regions, reflecting incidence rate increases, but prevalence estimates have decreased in sub-Saharan Africa because allowance has been made for increased mortality in those with diabetes. Worldwide estimates of numbers of children and adolescents with type 1 diabetes continue to increase.


Rest/Stress Intradermal Lymphoscintigraphy for the Functional Imaging of the Lymphatic System.
Lymphoscintigraphy is the criterion-standard method for diagnosing lymphedema, and there is no universally standardized imaging modality. In our center, we use a new approach: rest/stress intradermal lymphoscintigraphy. We tested 231 consecutive patients with suspected lymphedema. All patients were studied after a complex physical therapy program to reduce edema. Two doses of 99m Tc-nanocolloid were injected intradermally. Two static planar scans were taken at rest following tracer injection. Next, patients performed an isotonic muscular exercise for 2 minutes followed by postexercise scans. Subsequently, a prolonged exercise was performed for 30 to 40 minutes, after which delayed scans were taken. Abnormal patterns were distinguished into minor or major findings, according to severity. We identified superficial lymphatic vessels and regional lymph nodes in approximately 80% of limbs. Deep vessels were visualized in 26% of limbs. Minor findings were reported in 22.7% of limbs examined, whereas major findings were reported in 53.2% of limbs. We observed major findings including lymph stagnation, extravasation, or dermal backflow in a significantly higher percentage of limbs with secondary lymphedema than in primary. We also observed the deep lymphatic pathways in a significantly higher percentage of limbs with primary lymphedema. Intradermal radiotracer injection, combined with isotonic muscular exercise, may offer a better and faster imaging of lymphatic pathways, evaluating the effects of muscular exercise on lymphatic drainage. Based on the in-depth information of the lymphatic pathways provided by rest/stress intradermal lymphoscintigraphy, microsurgeons can obtain important functional information to perform supermicrosurgical lymphatic-venous anastomosis or vascularized lymph node transfer.


Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer's disease: a translational overview.
Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Since both cAMP and cGMP signaling are essential in a variety of cellular functions, including neuroplasticity and neuroprotection, PDE-Is are receiving increased attention as possible targets for treatment of age-related cognitive decline as well as Alzheimer's disease (AD). In this review we will give a translational overview of the preclinical and clinical data on PDE-Is and cognition enhancement focusing on aging and AD. PDE2, 4 and 5 inhibitors improved memory performance in both aged animals and models of AD. Treatment with a PDE3-I or PDE7-I has not been tested in aged animals yet, but in mouse models of AD both PDE-Is improved memory performance. Unfortunately, there are no peer-reviewed studies on the effects of PDE-I treatment in aged human subjects except the possible positive effect on memory impairment of the PDE1-I vinpocetine. Three other types of PDE-Is have been tested on cognition in mild to moderate AD patients: the PDE3-I cilostazol is being tested as a co-treatment to the acetylcholinesterase inhibitor donepezil, but with inconsistent results; the PDE4-I MK-0952 has been tested, although the outcome has not been disclosed yet; and the PDE9-I PF- 04447943 was reported to have no effects on cognition. Obviously, the demonstration of clinical proof of concept for cognition enhancing effects of PDE-Is and the generation of isoform selective PDE-Is are the final hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-associated cognitive decline or AD.


Cryptotanshinone and tanshinone IIA enhance IL-15-induced natural killer cell differentiation.
Natural killer (NK) cells are a subset of lymphocytes crucial for innate and adaptive immune responses. Here we show a stimulatory effect of cryptotanshinone (CTS) and tanshinone IIA (TS), isolated from Salvia miltiorrhiza Bunge, on the differentiation of NK cells. In the presence of IL-15, tanshinones increased NK cell maturation, NK cell differentiation and the expression of several transcription factors, including Id2, GATA3, T-bet, and Ets-1. Additionally, tanshinones increased p38 MAPK phosphorylation during NK cell differentiation. Furthermore, the p38 inhibitor SB203580 blocked the developmental effects of the tanshinones and suppressed Id2, T-bet, and Ets-1 expression during NK cell differentiation. These results suggest that tanshinones significantly increased IL-15-induced NK cell differentiation via enhancing the p38 phosphorylation and the expression of transcription factors.


Four-layered [3.3]meta-cyclo-phane with ethene-tetra-carbo-nitrile.
The title complex C42H48·2C6N4 {systematic name: hepta-cyclo[184.108.40.206(5,19).1(6,18).1(10,14).1(24,36).1(28,32)]do-tetra-conta-1(37),5(40),6(41),10(42),11,13,18,23,28,30,32(39),36(38)-dodeca-ene-ethene-tetra-carbo-nitrile (1/2)}, consisting of four-layered [3.3]meta-cyclo-phane (MCP) with two tetra-cyano-ethyl-ene (TCNE) mol-ecules, was grown from a mixture of MCP and TCNE in chloro-form solution. The four-layered [3.3]MCP has an S-shaped structure in which three [3.3]MCP moieties take syn-(chair-boat), anti-(chair-boat) and syn-(chair-boat) conformations. The two outer [3.3]MCP moieties with syn geometry contain benzene rings with a tilt of 32.95 (7)°. The central [3.3]MCP moiety has an anti geometry, in which the two benzene rings are oriented parallel to each other at a transannular distance of 2.31 Å. The TCNE mol-ecules are stacked on either side of the outer [3.3]MCP units at a distance of 3.19 Å on one side and 3.24 Å on the other, and showed 0.80:0.20 and 0.44:0.56 disorder, respectively.


Understanding nurses' psychosomatic complications that relate to the practice of nursing.
The literature acknowledges that nursing practice can create physical and emotional stresses for its practitioners. This study aimed to acquire an in-depth understanding of being a nurse in the Greek National Health System. Interpretive phenomenology was used and Van Manen's method of analysis was implemented. Conversational interviews were conducted with a purposive sample of nine nurses employed at the University Hospital of Ioannina in Greece. The findings produced three essential themes: a dissonance between the images and reality of nursing, emotional burnout, and psychosomatic entanglement. The dissonance between the idealization of nursing and the reality of nursing, along with the emotional crisis created by daily practice, constituted the two fundamental factors for developing psychosomatic complications. These impacted negatively on the participants' personal and professional well-being. Psychosomatic complications can be prevented by clearly delineating roles, enabling collaboration between education and practice, developing mentorship programs, and using reflection in practice.


Margelopsid species search taxonomic home within Corymorphidae and Boreohydridae.
Planktonic lifestyle of polyps in representatives of Margelopsidae are very different from all other species in the hydrozoan clade Aplanulata. Their evolutionary origin and phylogenetic position have been the subject of significant speculation. A recent molecular study based only on COI data placed Margelopsidae as a sister group to all Aplanulata, an unexpected result because margelopsid morphology suggests affiliation with Tubulariidae or Corymorphidae. Here we used multigene analyses, including nuclear (18S rRNA and 28S rRNA) and mitochondrial (16S rRNA and COI) markers of the hydroid stage of the margelopsid species Margelopsis haeckelii and the medusa stage of Margelopsis hartlaubii to resolve their phylogenetic position with respect to other hydrozoans. Our data provide strong evidence that M. haeckelii, the type species of Margelopsis, is a member of the family Corymorphidae. In contrast, M. hartlaubii is sister to Plotocnide borealis, a member of Boreohydridae. These results call into question the validity of the genus Margelopsis and the family Margelopsidae. The systematic position of M. haeckelii is discussed in light of the phylogeny of Corymorphidae.


Olanzapine: interaction study with imipramine.
Olanzapine is an "atypical" antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity. An open-label, three-way randomized crossover study was done to determine the safety, pharmacokinetics, and potential for a drug interaction between olanzapine (5 mg) and imipramine (75 mg). Each drug was administered alone and in combination. Nine healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor performance capacities, plasma olanzapine, imipramine, desipramine concentrations, and clinical laboratory tests were measured. Pharmacokinetic variables, vital signs, subjective tests for liveliness, and psychomotor outcomes were analyzed using a two-way ANOVA. Olanzapine was safe. Sedation, postural hypotension, and minor vital sign alterations occurred during all treatments. On the liveliness questionnaire, patients generally reported poorer (less lively) scores with olanzapine alone or coadministered with imipramine versus baseline scores. These effects disappeared within 24 hours after administration. Olanzapine alone and in combination decreased motor-speed tasks (finger tapping and visual-arm random reach) compared with baseline or imipramine treatment. Peak 6-hour changes were statistically significant but clinical importance was only marginal. Olanzapine concentrations were < 19% greater than with imipramine. But olanzapine did not affect the kinetics of imipramine or desipramine and, therefore, did not show a metabolic drug interaction involving CYP2D6.


What We Know About Massively Multiplayer Online Role-Playing Games.
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders defines internet gaming disorder without differentiating games from their respective genres, such as first-person shooter versus real-time strategy versus online gaming. Our review of the literature on massively multiplayer online role-playing games (MMORPGs) suggests that MMORPGs are different from other games because they are the most addictive, and therefore deserve to be looked at separately. MMORPGs are internet platforms for online users to interact with each other in a virtual story line. The overview of the existing literature delineates the positive and negative aspects of MMORPGs and also the available evidence on neuroscientific and neuroanatomical correlates between internet gaming disorder and other addictions. Evidence shows that a player's characteristics and motivations can determine his or her risk of developing problematic play. Problematic MMORPG use may lead to mental disorders such as depression and addiction, and can negatively affect quality of life, and vice versa. Conversely, some players may benefit from being part of a social community and from using it as a learning platform or as a safe space to explore gender-identity issues. Brain circuitry and metabolism are changed through problematic MMORPG use, with the affected areas including the ventral striatum and left angular gyrus.


The Cancer Chemopreventive and Therapeutic Potential of Tetrahydrocurcumin.
In recent decades, cancer has been one of the leading causes of death worldwide. Despite advances in understanding the molecular basis of tumorigenesis, diagnosis, and clinical therapies, the discovery and development of effective drugs is an active and vital field in cancer research. Tetrahydrocurcumin is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in tetrahydrocurcumin research is increasing because it is superior to curcumin in its solubility in water, chemical stability, bioavailability, and anti-oxidative activity. Many in vitro and in vivo studies have revealed that tetrahydrocurcumin exerts anti-cancer effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. Despite the pharmacological similarities between tetrahydrocurcumin and curcumin, the structure of tetrahydrocurcumin determines its distinct and specific molecular mechanism, thus making it a potential candidate for the prevention and treatment of cancers. However, the utility of tetrahydrocurcumin is yet to be evaluated as only limited pharmacokinetic and oral bioavailability studies have been performed. This review summarizes research on the anti-cancer properties of tetrahydrocurcumin and describes its mechanisms of action.


Mesenchymal Stem Cell Infusion Shows Promise for Combating Coronavirus (COVID-19)- Induced Pneumonia.
A new study published by the journal Aging & Disease reported that intravenous administration of clinical-grade human mesenchymal stem cells (MSCs) into patients with coronavirus disease 2019 (COVID-19) resulted in improved functional outcomes (Leng et al., Aging Dis, 11:216-228, 2020). This study demonstrated that intravenous infusion of MSCs is a safe and effective approach for treating patients with COVID-19 pneumonia, including elderly patients displaying severe pneumonia. COVID-19 is a severe acute respiratory illness caused by a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, treating COVID-19 patients, particularly those afflicted with severe pneumonia, is challenging as no specific drugs or vaccines against SARS-CoV-2 are available. Therefore, MSC therapy inhibiting the overactivation of the immune system and promoting endogenous repair by improving the lung microenvironment after the SARS-CoV-2 infection found in this study is striking. Additional studies in a larger cohort of patients are needed to validate this therapeutic intervention further, however.


Hypoglycemic effect of astragaloside IV via modulating gut microbiota and regulating AMPK/SIRT1 and PI3K/AKT pathway.
Radix Astragali, the dried root of Astragalus mongholicus Bunge, has long been used in traditional Chinese Medicine to treat diabetes. Astragaloside IV (AS-IV), one of the most active ingredients in the root, has been shown to have anti-diabetes ability; however, its underlying mechanism is still unclear. In this study, we evaluated the hypoglycemic effect and possible mechanisms of AS-IV in diabetic mice and insulin resistance-HepG2 cells. The components of the intestinal microflora in mice with type 2 diabetes mellitus (T2DM) were determined using high-throughput 16S rRNA gene sequencing. Moreover, the molecular mechanisms of specific members of insulin signaling pathways were analyzed. AS-IV significantly reversed the abnormalities in blood lipids, glucose, insulin resistance, as well as oxidative stress levels in T2DM mice. Histological finding showed that AS-IV could protect the cellular architecture of the liver and pancreas. AS-IV also regulated the abundance and diversity of intestinal flora of T2DM mice in a positive direction and increased butyric acid levels. The active role of AS-IV as an anti-diabetic compound by regulating the AMPK/SIRT1 and PI3K/AKT signaling pathways was revealed using a T2DM model and verified through the intervention of inhibitors using insulin-resistance HepG2 cells. Our results suggested that AS-IV may be used as an anti-diabetic drug candidate owing to its effects of regulating gut microbiota and AMPK/SIRT1 and PI3K/AKT signaling pathways.


Functional analysis of TiO2 nanoparticle toxicity in three plant species.
Titanium dioxide nanoparticles (nano-TiO2) are manufactured and used worldwide in large quantities. However, phytotoxicity research on nano-TiO2 has yielded confusing results, ranging from strong toxicity to positive effects. Therefore, in this research, the effects of nano-TiO2 on the germination and root elongation of seed and seedlings were studied. Additionally, the uptake and physiological responses of mature plants were investigated. Physical chemistry data were analyzed to assess the availability of nano-TiO2. Finally, a hydroponic system designed to overcome nano-TiO2 precipitation was used to reproduce the environmental conditions of actual fields. Nano-TiO2 did not have any effect on seed germination or on most of the plant species tested. Nano-TiO2 had positive effects on root elongation in some species. No physiological differences in enzyme activities or chlorophyll content were detected, even though the plants absorbed nano-TiO2. Physical chemistry data showed that nano-TiO2 agglomerated rapidly and formed particles with much bigger hydrodynamic diameters, even in distilled water and especially in a hydroponic system. Furthermore, agglomerated nano-TiO2 formed precipitates; this would be more severe in an actual field. Consequently, nano-TiO2 would not be also readily available to plants and would not cause any significant effects on plants. Our results and other reports suggest that titanium itself is not phytotoxic, even though plants absorb titanium. In conclusion, nano-TiO2 is not toxic to the three plant species, in vitro or in situ.


Genetic dissection of Nucleoporin 160 (Nup160), a gene involved in multiple phenotypes of reproductive isolation in Drosophila.
Previous reports have suggested that the Nucleoporin 160 (Nup160) gene of Drosophila simulans (Nup160(sim)) causes the hybrid inviability, female sterility, and morphological anomalies that are observed in crosses with D. melanogaster. Here we have confirmed this observation by transposon excision from the P{EP}Nup160(EP372) insertion mutation of D. melanogaster. Null mutations of the Nup160 gene resulted in the three phenotypes caused by Nup160(sim), but revertants of the gene did not. Interestingly, several mutations produced by excision partially complemented hybrid inviability, female sterility, or morphological anomalies. In the future, these mutations will be useful to further our understanding of the developmental mechanisms of reproductive isolation. Based on our analyses with the Nup160(sim) introgression line, the lethal phase of hybrid inviability was determined to be during the early pupal stage. Our analysis also suggested that homozygous Nup160(sim) in D. melanogaster leads to slow development. Thus, Nup160(sim) is involved in multiple aspects of reproductive isolation between these two species.


Care of a child dying of cancer: the role of the palliative care team in pediatric oncology.
The last period of life of a child suffering from cancer is of crucial importance not only for the child himself but for his parents and relatives as well. The way the child dies will remain in the memory of his parents for ever. Multiple problems in management of dying child may arise during this last phase. Timely and sensitive discussion of such aspects of management as implementation of Do Not Resuscitate order, possible provision of fluids and parenteral nutrition, initiation of palliative sedation and management of depression is necessary and may help parents to better cope with this tragic situation. Palliative care team consisting of medical and psychosocial staff plays vital role conveying comprehensive and timely management of all these problems and providing all necessary assistance for parents and other involved during ones' last weeks, days, and hours of child's life. The palliative care team cannot avert approaching death but it is responsible for making it as peaceful and as free of suffering as possible. This is achieved by vigorous control of all physical symptoms in the dying child and by paying close attention to all existential, emotional, and social demands of both the child and his relatives.


Geometrical aspects of sorted patterned ground in recurrently frozen soil.
A model for sorted patterned ground shows that some types arise from density-driven Rayleigh free convection that occurs during thawing of water-saturated recurrently frozen soils. The regularly spaced convection cells result in an uneven melting of the underlying ice front. Frost action causes stones to be upthrusted and to form in a pattern on the ground surface that mirrors the corrugation in the underlying ice front. The implications of the water circulation direction in the cells on the sorting process are considered.