[Embracing Renovation and Innovation During the Pandemic: Application of Virtual Simulation Technology in Nurse Practitioner Education].
During pandemics, physical interactivity in the delivery of teaching content are reduced and opportunities to gain clinical experience in healthcare settings are limited. Thus, pandemics may be viewed as tipping points in terms of willingness to embrace renovation and innovation, as using technology properly has the potential to assist educators and students to achieve learning goals and sustain teaching quality. Nursing education integrates knowledge and skills. Nurse practitioners are advanced practice nurses who need more-advanced interactive and clinical experience to cultivate the high levels of professionalism necessary to make health care decisions and manage health conditions appropriately. This article begins by introducing nurse practitioners (NPs) and current nurse practitioner education, and then describes the contents of simulation-based education and virtual simulation technology. In addition, steps and applications of simulation-based education in nurse practitioners are illustrated. Lastly, examples of virtual simulation technology applications in NP education are reported. The author hopes this article will encourage all nurses, including nursing students, first line registered nurses, nurse practitioners, nursing administrators, nursing faculty, and nurse officers, to work as a mutually supportive team and use integrated teaching-examine-application aligned with innovative technology to infuse new vitality into nursing education.


Early pathogenesis of Listeria monocytogenes infection in the mouse spleen.
Histological observations suggested that in the spleen, blood-borne Listeria monocytogenes bacteria were preferentially ingested by two morphologically distinct mononuclear phagocyte populations present in the marginal zone of the white pulp. The morphologies of these phagocytes corresponded to those of marginal zone macrophages or marginal zone dendritic cells. Moreover, during the first day of infection, the same phagocytes containing listeria apparently translocated from the marginal zone into the white pulp where they established secondary infectious foci. This event was associated with a large influx of neutrophil polymorphonuclear leucocytes (PMNLs) into infected white pulp, and with the disappearance of lymphocytes from this compartment. White pulp lymphocytopenia also occurred in the spleens of listeria-infected mice selectively depleted of neutrophil PMNLs, indicating that these phagocytes were not responsible for displacing or destroying lymphocytes. The implications of these findings for explaining the virulence and immunogenicity of L. monocytogenes are discussed.


Legacy and Current-Use Contaminants in Sediments Alter Macroinvertebrate Communities in Southeastern US Streams.
Sediment contamination of freshwater streams in urban areas is a recognized and growing concern. As a part of a comprehensive regional stream-quality assessment, stream-bed sediment was sampled from streams spanning a gradient of urban intensity in the Piedmont ecoregion of the southeastern United States. We evaluated relations between a broad suite of sediment contaminants (metals, current-use pesticides, organochlorine pesticides, polychlorinated biphenyls, brominated diphenyl ethers, and polycyclic aromatic hydrocarbons), ambient sediment toxicity, and macroinvertebrate communities from 76 sites. Sediment toxicity was evaluated by conducting whole-sediment laboratory toxicity testing with the amphipod Hyalella azteca (for 28 d) and the midge Chironomus dilutus (for 10 d). Approximately one-third of the sediment samples were identified as toxic for at least one test species endpoint, although concentrations of contaminants infrequently exceeded toxicity benchmarks. Ratios of contaminant concentrations relative to their benchmarks, both individually and as summed benchmark quotients, were explored on a carbon-normalized and a dry-weight basis. Invertebrate taxa measures from ecological surveys tended to decline with increasing urbanization and with sediment contamination. Toxicity test endpoints were more strongly related to sediment contamination than invertebrate community measures were. Sediment chemistry and sediment toxicity provided moderate and weak, respectively, explanatory power for the similarity/dissimilarity of invertebrate communities. The results indicate that current single-chemical sediment benchmarks may underestimate the effects from mixtures of sediment contaminants experienced by lotic invertebrates. Environ Toxicol Chem 2020;39:1219-1232. Published 2020. This article is a U.S. Government work and is in the public domain in the USA.


Partial fat-saturated contrast-enhanced three-dimensional MR angiography compared with non-fat-saturated and conventional fat-saturated MR angiography.
Abdominal three-dimensional magnetic resonance angiography was performed in 35 patients in the equilibrium phase without fat saturation, with conventional fat saturation, and with fast partial fat saturation. Qualitative and quantitative evaluation demonstrated significantly better vessel visualization with both fat-saturated techniques. The partial fat-saturated technique provided water-specific images within a breath hold, reducing motion artifacts significantly.


Decisions and revisions: the affective forecasting of changeable outcomes.
People prefer to make changeable decisions rather than unchangeable decisions because they do not realize that they may be more satisfied with the latter. Photography students believed that having the opportunity to change their minds about which prints to keep would not influence their liking of the prints. However, those who had the opportunity to change their minds liked their prints less than those who did not (Study 1). Although the opportunity to change their minds impaired the postdecisional processes that normally promote satisfaction (Study 2a), most participants wanted to have that opportunity (Study 2b). The results demonstrate that errors in affective forecasting can lead people to behave in ways that do not optimize their happiness and well-being.


Deciphering minimal antigenic epitopes associated with Burkholderia pseudomallei and Burkholderia mallei lipopolysaccharide O-antigens.
Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm), the etiologic agents of melioidosis and glanders, respectively, cause severe disease in both humans and animals. Studies have highlighted the importance of Bp and Bm lipopolysaccharides (LPS) as vaccine candidates. Here we describe the synthesis of seven oligosaccharides as the minimal structures featuring all of the reported acetylation/methylation patterns associated with Bp and Bm LPS O-antigens (OAgs). Our approach is based on the conversion of an L-rhamnose into a 6-deoxy-L-talose residue at a late stage of the synthetic sequence. Using biochemical and biophysical methods, we demonstrate the binding of several Bp and Bm LPS-specific monoclonal antibodies with terminal OAg residues. Mice immunized with terminal disaccharide-CRM197 constructs produced high-titer antibody responses that crossreacted with Bm-like OAgs. Collectively, these studies serve as foundation for the development of novel therapeutics, diagnostics, and vaccine candidates to combat diseases caused by Bp and Bm.Melioidosis and glanders are multifaceted infections caused by gram-negative bacteria. Here, the authors synthesize a series of oligosaccharides that mimic the lipopolysaccharides present on the pathogens' surface and use them to develop novel glycoconjugates for vaccine development.


Circulating Adipokines and Inflammatory Markers and Postmenopausal Breast Cancer Risk.
Adipokines and inflammation may provide a mechanistic link between obesity and postmenopausal breast cancer, yet epidemiologic data on their associations with breast cancer risk are limited. In a case-cohort analysis nested within the Women's Health Initiative Observational Study, a prospective cohort of postmenopausal women, baseline plasma samples from 875 incident breast cancer case patients and 839 subcohort participants were tested for levels of seven adipokines, namely leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-α, hepatocyte growth factor, and plasminogen activator inhibitor-1, and for C-reactive protein (CRP), an inflammatory marker. Data were analyzed by multivariable Cox modeling that included established breast cancer risk factors and previously measured estradiol and insulin levels. All statistical tests were two-sided. The association between plasma CRP levels and breast cancer risk was dependent on hormone therapy (HT) use at baseline (P interaction = .003). In a model that controlled for multiple breast cancer risk factors including body mass index (BMI), estradiol, and insulin, CRP level was positively associated with breast cancer risk among HT nonusers (hazard ratio for high vs low CRP levels = 1.67, 95% confidence interval = 1.04 to 2.68, P trend = .029). None of the other adipokines were statistically significantly associated with breast cancer risk. Following inclusion of CRP, insulin, and estradiol in a multivariable model, the association of BMI with breast cancer was attenuated by 115%. These data indicate that CRP is a risk factor for postmenopausal breast cancer among HT nonusers. Inflammatory mediators, together with insulin and estrogen, may play a role in the obesity-breast cancer relation.


Covid-19 and mental disorders in children and adolescents: Experience of the child and adolescent psychiatry department of the Mongi Slim Hospital of Tunis.
The Covid-19 pandemic had a major psychosocial impact on the mental health of children and adolescents, especially when the childhas mental health problems. During containment, the healthcare structures were subject to a significant restriction of their activities. The child and adolescent psychiatry department of the Mongi Slim Hospital in Tunis has set up telephone follow-up for patients deemed to be at risk. This follow-up involved 166 cases, the majority of them were suffering from neurodevelopmental disorders, followed by depressive disorders and adjustment disorders. A third of the patients had reported a worsening of the symptoms during the containment and a third had reported clinical improvement. During this follow-up, recommendations were made to parents to limit the negative impact of Covid-19 pandemic. Maintaining follow-up of patients with mental disorders by telemedicine is a major challenge in order to prevent the repercussions of this pandemic in the long term.


Cell-type-specific visualisation and biochemical isolation of endogenous synaptic proteins in mice.
In recent years, the remarkable molecular complexity of synapses has been revealed, with over 1,000 proteins identified in the synapse proteome. Although it is known that different receptors and other synaptic proteins are present in different types of neurons, the extent of synapse diversity across the brain is largely unknown. This is mainly due to the limitations of current techniques. Here, we report an efficient method for the purification of synaptic protein complexes, fusing a high-affinity tag to endogenous PSD95 in specific cell types. We also developed a strategy, which enables the visualisation of endogenous PSD95 with fluorescent-protein tag in Cre-recombinase-expressing cells. We demonstrate the feasibility of proteomic analysis of synaptic protein complexes and visualisation of these in specific cell types. We find that the composition of PSD95 complexes purified from specific cell types differs from those extracted from tissues with diverse cellular composition. The results suggest that there might be differential interactions in the PSD95 complexes in different brain regions. We have detected differentially interacting proteins by comparing data sets from the whole hippocampus and the CA3 subfield of the hippocampus. Therefore, these novel conditional PSD95 tagging lines will not only serve as powerful tools for precisely dissecting synapse diversity in specific brain regions and subsets of neuronal cells, but also provide an opportunity to better understand brain region- and cell-type-specific alterations associated with various psychiatric/neurological diseases. These newly developed conditional gene tagging methods can be applied to many different synaptic proteins and will facilitate research on the molecular complexity of synapses.


Sodium channel inactivation is altered by substitution of voltage sensor positive charges.
The role of the voltage sensor positive charges in fast and slow inactivation of the rat brain IIA sodium channel was investigated by mutating the second and fourth conserved positive charges in the S4 segments of all four homologous domains. Both charge-neutralizing mutations (by glutamine substitution) and charge-conserving mutations were constructed in a cDNA encoding the sodium channel alpha subunit. To determine if fast inactivation altered the effects of the mutations on slow inactivation, the mutations were also constructed in a channel that had fast inactivation removed by the incorporation of the IFMQ3 mutation in the III-IV linker (West, J.W., D.E. Patton, T. Scheuer, Y. Wang, A.L. Goldin, and W.A. Catterall. 1992. 89:10910- 10914). Most of the mutations shifted the vof fast inactivation in the negative direction, with the largest effects resulting from mutations in domains I and II. These shifts were in the opposite direction compared with those observed for activation. The effects of the mutations on slow inactivation depended on whether fast inactivation was intact or not. When fast inactivation was eliminated, most of the mutations resulted in positive shifts in the v of slow inactivation. The largest effects again resulted from mutations in domains I and II. When fast inactivation was intact, the mutations in domains II and III resulted in negative shifts in the v of slow inactivation. Neutralization of the fourth charge in domain I or II resulted in the appearance of a second component in the voltage dependence of slow inactivation that was only observable when fast inactivation was intact. These results suggest the S4 regions of all four domains of the sodium channel are involved in the voltage dependence of inactivation, but to varying extents. Fast inactivation is not strictly coupled to activation, but it derives some independent voltage sensitivity from the charges in the S4 domains. Finally, there is an interaction between the fast and slow inactivation processes.


Insights into the structure and RNA-binding specificity of Caenorhabditis elegans Dicer-related helicase 3 (DRH-3).
DRH-3 is critically involved in germline development and RNA interference (RNAi) facilitated chromosome segregation via the 22G-siRNA pathway in Caenorhabditis elegans. DRH-3 has similar domain architecture to RIG-I-like receptors (RLRs) and belongs to the RIG-I-like RNA helicase family. The molecular understanding of DRH-3 and its function in endogenous RNAi pathways remains elusive. In this study, we solved the crystal structures of the DRH-3 N-terminal domain (NTD) and the C-terminal domains (CTDs) in complex with 5'-triphosphorylated RNAs. The NTD of DRH-3 adopts a distinct fold of tandem caspase activation and recruitment domains (CARDs) structurally similar to the CARDs of RIG-I and MDA5, suggesting a signaling function in the endogenous RNAi biogenesis. The CTD preferentially recognizes 5'-triphosphorylated double-stranded RNAs bearing the typical features of secondary siRNA transcripts. The full-length DRH-3 displays unique structural dynamics upon binding to RNA duplexes that differ from RIG-I or MDA5. These features of DRH-3 showcase the evolutionary divergence of the Dicer and RLR family of helicases.


Coeliac disease, gluten-free diet, and malignancy.
Two hundred and two patients with coeliac disease or idiopathic steatorrhoea previously reported from this unit have been reviewed after a further 10 years of follow-up. Of 20 more deaths, 10 were due to malignancy. A separate study was made of all patients with histologically confirmed coeliac disease seen to the end of 1972 and followed up to the end of 1974. Twenty-one of the 43 deaths in this series were due to malignant tumours, of which 13 were reticulum cell sarcomas. There was no evidence that patients showing sub-optimal clinical response to gluten withdrawal or persisting falt jejunal biopsies were more prone to die of cancer. A gluten-free diet did not appear to be effective in preventing malignant complications, but a longer follow-up of patients will be necessary to provide a final answer to this question.


A Simple and Fast Kinetic Assay for the Determination of Fructan Exohydrolase Activity in Perennial Ryegrass (Lolium perenne L.).
Despite the fact that fructans are the main constituent of water-soluble carbohydrates in forage grasses and cereal crops of temperate climates, little knowledge is available on the regulation of the enzymes involved in fructan metabolism. The analysis of enzyme activities involved in this process has been hampered by the low affinity of the fructan enzymes for sucrose and fructans used as fructosyl donor. Further, the analysis of fructan composition and enzyme activities is restricted to specialized labs with access to suited HPLC equipment and appropriate fructan standards. The degradation of fructan polymers with high degree of polymerization (DP) by fructan exohydrolases (FEHs) to fructosyloligomers is important to liberate energy in the form of fructan, but also under conditions where the generation of low DP polymers is required. Based on published protocols employing enzyme coupled endpoint reactions in single cuvettes, we developed a simple and fast kinetic 1-FEH assay. This assay can be performed in multi-well plate format using plate readers to determine the activity of 1-FEH against 1-kestotriose, resulting in a significant time reduction. Kinetic assays allow an optimal and more precise determination of enzyme activities compared to endpoint assays, and enable to check the quality of any reaction with respect to linearity of the assay. The enzyme coupled kinetic 1-FEH assay was validated in a case study showing the expected increase in 1-FEH activity during cold treatment. This assay is cost effective and could be performed by any lab with access to a plate reader suited for kinetic measurements and readings at 340 nm, and is highly suited to assess temporal changes and relative differences in 1-FEH activities. Thus, this enzyme coupled kinetic 1-FEH assay is of high importance both to the field of basic fructan research and plant breeding.


Aerobic training and cardiovascular responses at rest and during exercise in older men and women.
The effects of an intense 8-wk aerobic training program on cardiovascular responses at rest and during exercise, including heart rate variability (HRV) as an expression of autonomic modulation, were evaluated in subjects over 70 yr (mean: 73.9 +/- 3.5 yr). Before and after training in 7 men and 8 women: a) heart rate (HR), blood pressures (BPs), pulse pressure (PP), and oxygen uptake were measured at rest, during, and after exhausting incremental exercise; b) HRV power spectra were calculated at rest in supine and sitting, and during and after two submaximal constant loads (5 min). Power in low-frequency (LF, 0.04-0.15 Hz) and high-frequency (HF, >0.15 Hz) bands were expressed as a percent of total power minus power < 0.04 Hz. After training: a) at rest HR and HRV parameters (in both body positions) were unchanged, whereas BPs decreased; b) peak cycle resistance and oxygen consumption increased by 25% and 18%, respectively, but no change in maximal HR and BPs were found; c) during submaximal loads HR was unchanged at the same metabolic demand, whereas SBP and DBP were lower than before at low loads whereas PP was unchanged. LF power decreased and HF increased at oxygen uptakes above about 0.7 L.min-1 similarly before and after training; and d) recovery of all parameters was similar to pretraining and complete after 10 min The increase in exercise capacity without changes in cardiovascular parameters suggests that 8 wk of aerobic training augmented peripheral gas exchange but not delivery to muscle. The lack of effect on HRV indicates that the improvements in aerobic power and cardiac autonomic modulation, at least in subjects over 70 yr, are dissociated. Moreover, the metabolic demand seems to be the main factor for the changes in HRV power spectra that occur during exercise.


Detection of neutrophils in late-onset interface inflammation associated with flap injury after laser in situ keratomileusis.
To report a case with late-onset interface inflammation associated with traumatic flap injury at 7 months after laser in situ keratomileusis (LASIK) and to describe the type of infiltrating cells in the tears of the patient. Interventional case report. A 24-year-old male patient who underwent uneventful LASIK on both eyes received blunt trauma from the tip of a shoe in the left eye 7 months after surgery. The corneal flap of his left eye was lacerated across the pupillary area. Inflammatory cells were observed under the lacerated flap segment. Tear fluid was collected from his left eye 3 days after the injury and assessed by tear cytology. For controls, tears of 2 patients who underwent LASIK and developed no interface inflammation were collected the next day after their surgeries and examined. Tear fluid of the patient with interface inflammation contained numerous neutrophils. Tears of control patients contained only a few epithelial cells and cell debris but no inflammatory cells. The inflammation was decreased by systemic and topical steroids. However, irregular astigmatism caused by stromal scarring remained, resulting in decreased best-corrected visual acuity. Interface inflammation can be caused by late-onset flap injury. Neutrophils detected in the tears may reflect a major component of cells infiltrating the interface after LASIK.


Functional neuroanatomy in depressed patients with sexual dysfunction: blood oxygenation level dependent functional MR imaging.
To demonstrate the functional neuroanatomy associated with sexual arousal visually evoked in depressed males who have underlying sexual dysfunction using Blood Oxygenation Level Dependent-based fMRI. Ten healthy volunteers (age range 21-55: mean 32.5 years), and 10 depressed subjects (age range 23-51: mean 34.4 years, mean Beck Depression Inventory score of 39.6+/-5.9, mean Hamilton Rating Scale Depression (HAMD)-17 score of 33.5+/-6.0) with sexual arousal dysfunction viewed erotic and neutral video films during functional magnetic resonance imaging (fMRI) with 1.5 T MR scanner (GE Signa Horizon). The fMRI data were obtained from 7 oblique planes using gradient-echo EPI (flip angle/TR/TE= 90 degrees /6000 ms/50 ms). The visual stimulation paradigm began with 60 sec of black screen, 150 sec of neutral stimulation with a documentary video film, 30 sec of black screen, 150 sec of sexual stimulation with an erotic video film followed by 30 sec of black screen. The brain activation maps and their quantification were analyzed by SPM99 program. There was a significant difference of brain activation between two groups during visual sexual stimulation. In depressed subjects, the level of activation during the visually evoked sexual arousal was significantly less than that of healthy volunteers, especially in the cerebrocortical areas of the hypothalamus, thalamus, caudate nucleus, and inferior and superior temporal gyri. On the other hand, the cerebral activation patterns during the neutral condition in both groups showed no significant differences (p < 0.01). This study is the first demonstration of the functional neuroanatomy of the brain associated with sexual dysfunction in depressed patients using fMRI. In order to validate our physiological neuroscience results, further studies that would include patients with other disorders and sexual dysfunction, and depressed patients without sexual dysfunction and their treatment response are needed.


A polymeric nanocarrier with a tumor acidity-activatable arginine-rich (R9) peptide for enhanced drug delivery.
Cell-penetrating peptides (CPPs) have been considered as a powerful tool to improve the intracellular and nuclear delivery efficiency of nanocarriers. However, their clinical application is limited because of their nonspecific targeting function, short half-life, and severe system toxicity. Herein, we have developed a polymeric nanocarrier with a tumor acidity-activatable arginine-rich (R9) peptide for targeted drug delivery. The nanocarrier is fabricated with a R9-conjugated amphiphilic diblock polymer of poly(ethylene glycol) (PEG) and poly(hexyl ethylene phosphate) (PHEP), and then further coated with tumor acidity-activatable polyanionic polyphosphoester through electrostatic interaction in order to block the nonspecific targeting function of the R9 peptide. In the slightly acidic tumor extracellular environment (∼pH 6.5), tumor acidity-activatable polyanionic polyphosphoester would be deshielded from the nanoparticles, resulting in the re-exposure of the R9 peptide to enhance tumor cellular uptake. As a result, intracellular concentration of payload in 4T1 tumor cells significantly increased at pH 6.5. And, we further demonstrate that such a delivery system remarkably promoted the anti-tumor efficiency of chemotherapeutic drugs in tumor-bearing mice, offering great potential for drug delivery and cancer therapy.


Sulfasalazine suppresses thyroid cancer cell proliferation and metastasis through T-cell originated protein kinase.
Thyroid cancer patients with radioactive iodine-refractory or rapidly progressing presentation require effective treatment. T-cell originated protein kinase (TOPK) is highly expressed in a number of different tumor types, where it promotes proliferation and metastasis. However, the expression of TOPK in thyroid cancer is poorly documented. Therefore, immunohistochemistry was used to detect the expression of TOPK in thyroid cancer tissues, and its clinical significance in this disease was investigated. Sulfasalazine, a targeted inhibitor of TOPK that directly binds the protein with a dissociation constant (Kd) of 228 µM, was also investigated using microscale thermophoresis. Sulfasalazine inhibited TOPK activity, as determined by an in vitro pull-down assay. Furthermore, sulfasalazine inhibited the proliferation and metastasis of thyroid cancer cells. The results indicated that TOPK may be a potential therapeutic target and diagnostic biomarker for thyroid cancer and may be used as an index to evaluate malignant thyroid nodules. Therefore, sulfasalazine is a potential novel compound for the targeted treatment of thyroid cancer.


The role of immune reconstitution in cytomegalovirus infection.
Cytomegalovirus (CMV) causes high morbidity and mortality in immunocompromised patients. The host immune response to CMV comprises specific and nonspecific cellular and humoral responses, but current knowledge supports a protective role only for cell-mediated immune responses. Although complete CMV eradication is unusual even in immunocompetent hosts, its morbidity can be limited by CMV-specific CD8+ cytotoxic lymphocytes supported by CD4+-mediated T lymphocyte helper activity. In patients with congenital or acquired deficiencies of cell-mediated immunity, recovery of CD4+ lymphocyte numbers and/or function coincides with cessation of CMV-associated morbidity. However, an immunological test that can predict protection against CMV disease across different types of high-risk patients is not yet available. In recent years, the introduction of antivirals active against CMV has improved the outcome of CMV disease. In addition, there is a continuous effort to develop CMV-specific immune-based therapies including vaccines and immune modulators such as cytokines, which may be of supplemental benefit in the control of CMV disease.


Stabilization of the Surface of ZnO Films and Elimination of the Aging Effect.
Zinc oxide is a promising multifunctional material. The practical use of nano- and polycrystalline ZnO devices faces a serious problem of instability of electrical and luminescent characteristics, due to the adsorption of oxygen by the surface during aging. In this paper, the aging effect in ZnO films and nanorod arrays was studied. It was found that ZnO samples demonstrate different behavior of the degradation process, which corresponds to at least two different types of adsorbing surface sites for O2, where O2 adsorption is of a different nature. The first type of surface sites is rapidly depassivated after hydrogen passivation and the aging effect takes place due to these centers. The second type of surface sites has a stable structure after hydrogen passivation and corresponds to HO-ZnO sites. The XPS components of these sites include the Zn2p3/2 peak at 1022.2 ± 0.2 eV and Zn2p1/2 peak at 1045.2 ± 0.2 eV, with a part of the XPS O1s peak at 531.5 ± 0.3 eV. The annealing transforms the first type of site into the second one, and the subsequent short-term plasma treatment in hydrogen results in steady passivation, where the degradation of characteristics is practically reduced to zero.


Calcium-dependent mitochondrial formation of species promoting strand scission of genomic DNA in U937 cells exposed to tert-butylhydroperoxide: the role of arachidonic acid.
Treatment of U937 cells with a sublethal concentration of tert-butylhydroperoxide generates DNA single strand breakage in U937 cells and this response is increased by caffeine, ATP, pyruvate or antimycin A. As we previously reported (Guidarelli, Clementi, Brambilla and Cantoni, (1997) Biochem. J. 328, 801-806), the enhancing effects of antimycin A are mediated by inhibition of complex III and the ensuing formation of superoxides and hydrogen peroxide in a reaction in which ubisemiquinone serves as an electron donor. Active electron transport was required in pyruvate-supplemented cells since the increased genotoxic response occurred as a consequence of enforced mitochondrial Ca2+ accumulation, a process driven by the increased electrochemical gradient. The enhancing effects of caffeine or ATP were also the consequence of mitochondrial Ca2+ accumulation but these responses were independent on electron transport. The increased formation of DNA lesions resulting from exposure to tert-butylhydroperoxide associated with the Ca2+-mobilizing agents or the respiratory substrate was mediated by arachidonic acid generated by Ca2+-dependent activation of phospholipase A2. Melittin, a potent phospholipase A2 activator, and reagent arachidonic acid mimicked the effects of caffeine, ATP or pyruvate on the tert-butylhydroperoxide-induced DNA single strand breakage.


CO2 emission accounting and emission reduction analysis of the steel production process based on the material-energy-carbon correlation effect.
This paper develops a process-level carbon emission calculation model for iron and steel enterprises through the carbon emission mechanism of the whole production process. The relationship between material, energy and carbon flows is considered and combined. The carbon emissions of enterprises are divided into industrial emissions and combustion emissions, and the indirect emissions of purchased intermediate products and electricity purchased from the grid are also considered. Carbon emission targets and corresponding emission reduction strategies are formulated at the enterprise and process levels. For example, consider an iron and steel enterprise. The different types of carbon emissions are accounted for, with their reduction potential analysed based on the carbon material flow analysis method. The results show that the carbon emission of this enterprise is 1930.87 kgCO2/t (CS), and the combustion emission caused by energy flow is the main contributor to the enterprise's carbon emission, accounting for 57.02% of the total emission. The carbon emission during iron-making accounts for 69.06% of the entire process and is critical in any carbon emission reduction of the enterprise. Among them, process emissions from the blast furnace process account for 81.79% of industrial emissions of the whole process, which is 356.51 kgCO2/t (CS), and is the main challenge of low carbon transformation in this extensive process. This study highlights that increasing the integrated steel-making scrap ratio and electric furnace steel production can break through the existing emission reduction limits. A 65.02% carbon emission reduction can be achieved, and using green electricity can reduce emissions by 24.15%. Reasonably determining the amount of purchased coke and paying attention to the high-value recycling of byproduct gas resources in the plant are essential to achieve low-carbon economic development of steel.


Xeno-Free Spheroids of Human Gingiva-Derived Progenitor Cells for Bone Tissue Engineering.
Gingiva has been identified as a minimally invasive source of multipotent progenitor cells (GPCs) for use in bone tissue engineering (BTE). To facilitate clinical translation, it is important to characterize GPCs in xeno-free cultures. Recent evidence indicates several advantages of three-dimensional (3D) spheroid cultures of mesenchymal stromal cells (MSCs) over conventional 2D monolayers. The present study aimed to characterize human GPCs in xeno-free 2D cultures, and to test their osteogenic potential in 3D cultures, in comparison to bone marrow MSCs (BMSCs). Primary GPCs and BMSCs were expanded in human platelet lysate (HPL) or fetal bovine serum (FBS) and characterized based on in vitro proliferation, immunophenotype and multi-lineage differentiation. Next, 3D spheroids of GPCs and BMSCs were formed via self-assembly and cultured in HPL. Expression of stemness- (SOX2, OCT4, NANOG) and osteogenesis-related markers (BMP2, RUNX2, OPN, OCN) was assessed at gene and protein levels in 3D and 2D cultures. The cytokine profile of 3D and 2D GPCs and BMSCs was assessed via a multiplex immunoassay. Monolayer GPCs in both HPL and FBS demonstrated a characteristic MSC-like immunophenotype and multi-lineage differentiation; osteogenic differentiation of GPCs was enhanced in HPL vs. FBS. CD271+ GPCs in HPL spontaneously acquired a neuronal phenotype and strongly expressed neuronal/glial markers. 3D spheroids of GPCs and BMSCs with high cell viability were formed in HPL media. Expression of stemness- and osteogenesis-related genes was significantly upregulated in 3D vs. 2D GPCs/BMSCs; the latter was independent of osteogenic induction. Synthesis of SOX2, BMP2 and OCN was confirmed via immunostaining, and in vitro mineralization via Alizarin red staining. Finally, secretion of several growth factors and chemokines was enhanced in GPC/BMSC spheroids, while that of pro-inflammatory cytokines was reduced, compared to monolayers. In summary, monolayer GPCs expanded in HPL demonstrate enhanced osteogenic differentiation potential, comparable to that of BMSCs. Xeno-free spheroid culture further enhances stemness- and osteogenesis-related gene expression, and cytokine secretion in GPCs, comparable to that of BMSCs.


Evaluation of early complications related to De Novo cardioverter defibrillator implantation insights from the Ontario ICD database.
This study examined the predictors of early complications after defibrillator implantation. Although implantable cardioverter-defibrillators are widely used, predictors of procedural complications and the consequences of these events have not been determined. In a prospective, multicenter, population-based clinical outcomes registry of all newly implanted defibrillator patients at 18 centers in Ontario, Canada, we examined 45-day complications and all-cause mortality from February 2007 to May 2009. Complications were determined longitudinally and were categorized as direct implant-related or indirect events. Among 3,340 patients (mean age 63.8 +/- 12.5 years, 78.5% men), major complications occurred in 4.1% of de novo procedures. Compared with those undergoing a single-chamber device, implantation of a cardiac resynchronization defibrillator (adjusted hazard ratio [HR]: 2.17, 95% confidence interval [CI]: 1.38 to 3.43, p < 0.001) or dual-chamber device (adjusted HR: 1.82, 95% CI: 1.19 to 2.79, p = 0.006) was associated with increased risk of major complications. Major complications were increased in women (adjusted HR: 1.49, 95% CI: 1.02 to 2.16, p = 0.037) and when left ventricular end-systolic dimension exceeded 45 mm (adjusted HR: 1.54, 95% CI: 1.08 to 2.20, p = 0.018). Major complications (excluding death) occurring early after defibrillator implantation were associated with increased adjusted risk of subsequent death up to 180 days after defibrillator implant (adjusted HR: 3.70, 95% CI: 1.64 to 8.33, p = 0.002). Direct implant-related complications were associated with increased risk of early death (adjusted HR: 24.89, p = 0.01), whereas indirect clinical complications conferred increased risk of near-term death (adjusted HR: 12.35, p < 0.001) after defibrillator implantation. Complications after de novo defibrillator implantation were strongly associated with device type. Major complications were associated with increased risk of mortality.


Effects of different subanaesthetic doses of (S)-ketamine on psychopathology and binocular depth inversion in man.
The role of the N-methyl-D-aspartate (NMDA) neurotransmitter system in relation to psychoses is not completely understood, but represent a challenge in neurobiological research. The psychotic states induced by NMDA antagonists such as phencyclidine and ketamine have been described as being most similar to schizophrenia and the NMDA system has been implicated in the pathogenesis of schizophrenia. Binocular depth inversion, an illusion of visual perception, has been shown to be impaired in psychotic and psychotomimetic states in healthy and schizophrenic subjects. In this study, pictures of natural and artificial objects were presented stereoscopically to 12 healthy male volunteers and depth perception assessed using an operationalized method. The effects of the psychotomimetic S-enantiomer of the anaesthetic ketamine in two different subanaesthetic doses were compared with those of a placebo. In spite of dose dependence and grave subjective and significant objective psychopathology, no significant impairment of binocular depth perception was found with (S)-ketamine. Implications related to memory function, perceptogenesis and 'bottom-up' processing in ketamine model psychosis and schizophrenia are discussed.


Analysis of HPV distribution in patients with cervical precancerous lesions in Western China.
Cervical human papillomavirus (HPV) infection is a dangerous disease, whose subtypes exhibit different distribution patterns in particular countries, regions, and races. In this study, the HPV distribution in patients with cervical precancerous lesions in Western China was investigated to assess a probability for prevention of cervical cancer and the clinical application of an HPV vaccine in China. The retrospective study of patients with different HPV subtypes and cervical precancerous lesions, who have undergone loop eelectrosurgical excision procedure, cold knife conization, or a total hysterectomy in our hospital from January 2016 to August 2016, was performed. All patients were tested for 27 HPV subtypes via the liquid suspension chip technology (Luminex 200). A total of 3393 cases of cervical intraepithelial neoplasia (CIN) were investigated, including 1098 cases of CIN I, 762 cases of CIN II, and 1533 cases of CIN III. The overall HPV infection rate was 82.58%. The high-risk HPV infection rate was 76.61%, and the low-risk rate was 9.88%. The most common 5 subtypes were HPV16, HPV52, HPV58, HPV33, and HPV18. The patients were grouped into 6 age groups: ≤20, 21 to 30, 31 to 40, 41 to 50, 50 to 64, and ≥65. The HPV subtypes' distribution varied across different age groups. In patients with cervical precancerous lesions in Western China, the top 5 HPV subtypes with the highest infection rates were HPV16, HPV52, HPV58, HPV33, and HPV18. The rate of cervical precancerous lesions unrelated to HPV was 17.42%. Thus, HPV screening with no cytology may leave unobserved about 20% of cervical precancerous lesions, which is worth of significant clinical attention.


Developmental regulation of GABAergic signalling in the hippocampus of neuroligin 3 R451C knock-in mice: an animal model of Autism.
Autism Spectrum Disorders (ASDs) comprise an heterogeneous group of neuro-developmental abnormalities, mainly of genetic origin, characterized by impaired social interactions, communications deficits, and stereotyped behaviors. In a small percentage of cases, ASDs have been found to be associated with single mutations in genes involved in synaptic function. One of these involves the postsynaptic cell adhesion molecule neuroligin (NL) 3. NLs interact with presynaptic neurexins (Nrxs) to ensure a correct cross talk between post and presynaptic specializations. Here, transgenic mice carrying the human R451C mutation of Nlgn3, were used to study GABAergic signaling in the hippocampus early in postnatal life. Whole cell recordings from CA3 pyramidal neurons in slices from NL3(R451C) knock-in mice revealed an enhanced frequency of Giant Depolarizing Potentials (GDPs), as compared to controls. This effect was probably dependent on an increased GABAergic drive to principal cells as demonstrated by the enhanced frequency of miniature GABAA-mediated (GPSCs), but not AMPA-mediated postsynaptic currents (EPSCs). Changes in frequency of mGPSCs were associated with an acceleration of their decay kinetics, in the absence of any change in unitary synaptic conductance or in the number of GABAA receptor channels, as assessed by peak scaled non-stationary fluctuation analysis. The enhanced GABAergic but not glutamatergic transmission early in postnatal life may change the excitatory/inhibitory balance known to play a key role in the construction and refinement of neuronal circuits during postnatal development. This may lead to behavioral deficits reminiscent of those observed in ASDs patients.


Exploration of sexual dimorphism and inter-individual variability in multivariate parameter spaces for a pharmacokinetic compartment model.
Pharmacokinetic models are particularly useful to study the underlying and complex physiological mechanisms contributing to clinical differences across patient subgroups or special populations. Unfortunately, the inherent variability of biological systems and knowledge gaps in physiological data limit confidence in model predictions for special populations. Sourcing data to reflect the desired physiologies can be resource intensive, particularly for a larger model. Thus, a critical step in model development for special populations involves an in-depth analysis of model inputs, which can be guided by Monte Carlo simulations. Such an approach enables the generation of parameter values by stochastic sampling that are subsequently restricted to the combinations that describe biologically plausible or target model output. Our approach utilized a published pharmacokinetic compartmental model to demonstrate how sampling in conjunction with global sensitivity analysis can be used to explore sexual dimorphism and inter-individual variability in multivariate parameter spaces for differentiation of model input and behavior across phenotypes. Despite limiting the model output to relatively narrow ranges, male and female phenotypes were associated with wide variability in both individual parameter values and combinations of parameters. Through an integrated approach using a support vector machine, principal component analysis and global sensitivity analysis, our approach revealed that specific combinations of parameters gave rise to a certain phenotype, while individual parameters influenced the shape of plasma concentration profile. Augmenting analysis of the model input with global sensitivity analysis enabled an understanding of both sexual dimorphism and inter-individual variability in pharmacokinetics. While the current study revealed how model input could be separated by sex for a simple compartment model, the approach could be extended to other patient factors, such as age or disease, and to a more complex physiologically-based model that describes absorption, distribution, metabolism, and elimination with more detail.


Sjögren's syndrome: a review of aetiology, pathogenesis, diagnosis and management.
Sjögren's syndrome is a chronic autoimmune disease that affects many individuals within the community. Despite this, its exact aetiology and pathogenesis is still unclear. Sjögren's syndrome affects many organ systems in the body. However, for dental practitioners it is important to recognize the many oral and dental manifestations that are associated with the syndrome. In addition to these oral manifestations, this review will discuss the systemic manifestations of Sjögren's syndrome as well as the current understanding of factors that have a role in its aetiology and pathogenesis. Furthermore, this review will highlight the difficulties and complexities that are inherent in the diagnosis of Sjögren's syndrome and the important role that dental practitioners can play in the management of its oral manifestations. The effective management of oral manifestations and minimization of oral disease in patients with Sjögren's syndrome can result in improved quality of life for these patients.


Intraoperative Completion Angiogram May Be Superior to Transesophageal Echocardiogram for Detection of Pulmonary Artery Residual Lesions in Congenital Heart Surgery.
The purpose of this study was to assess the diagnostic capabilities of transesophageal echocardiography (TEE) compared to completion angiography for detection of residual post-operative pulmonary artery lesions. This is a retrospective review of 19 consecutive surgical cases involving the pulmonary arteries that had post-operative TEE and completion angiography from 2014 to 2017. The echocardiograms were reviewed by 2 blinded examiners and categorized as adequate or inadequate visualization of the surgical repair. Based on TEE images, the surgical repair was graded as no revision necessary, residual lesion present requiring revision, or unable to assess. TEE was compared to completion angiography to determine the ability of each method to detect residual pulmonary artery lesions. Fifty-three percent of TEE imaging was graded as inadequate. Based on TEE, surgical revision was indicated in 2 of 19 cases. Completion angiography documented 4 additional residual lesions resulting in surgical revision in 6 of 19 patients. TEE sensitivity for detecting residual pulmonary artery lesions was 40%. One Glenn patient with adequate image quality and repair by TEE had moderate left pulmonary artery stenosis by completion angiography. All other discrepancies occurred in patients with inadequate TEE imaging. No patient with pulmonary artery abnormalities had hemodynamic instability or excessive desaturations. Completion angiography-related complications included three transient arrhythmias with no increased incidence of acute kidney injury. Completion angiography may be more effective than TEE at detecting post-operative pulmonary artery lesions even in patients not manifesting clinical symptoms. Documentation of residual lesions with completion angiography allows immediate surgical revision potentially limiting necessity for future interventions.


Epithelial mucin-1 (MUC1) expression and MA5 anti-MUC1 monoclonal antibody targeting in multiple myeloma.
Multiple myeloma (MM) is the second most common hematological cancer in the United States. It is typically incurable, even with myeloablative chemotherapy and stem-cell transplantation. The epithelial mucin-1 (MUC1) glycoprotein is expressed by normal and malignant epithelial cells but has also been shown to be expressed by MM cells. MUC1 is a useful antigenic target in solid tumors for clinical diagnostic and therapeutic monoclonal antibody (mAb)-based approaches. The MA5 mAb, as well as other anti-MUC1 mAbs reactive with the MUC1 variable number tandem repeat domain, exhibited moderate to strong reactivity with both MM cell lines and clinical samples. To explore the biochemical nature and potential of MUC1 as an antigenic target in MM, studies were performed to: (a) compare the mRNA and the MUC1 glycoprotein species between epithelial cancer and MM cell lines; and (b) develop and use a human MM tumor xenograft model system to study the biodistribution of the MA5 mAb. MA5 mAb was strongly reactive with six of eight human MM cell lines by flow cytometry. In seven of eight MM patient samples (bone marrow and/or peripheral blood) reactivity was found in 10-90% of the cells, whereas normal control (n = 5) and leukemia and lymphoma (n = 5) cells showed only 0-6% reactivity. 125I-labeled MA5 whole-cell binding studies showed quantitatively similar amounts of binding between strongly positive MM lines and high-MUC1-expressing breast carcinoma lines. mRNA expression was assessed by Northern blotting and reverse transcription-PCR. MM cell lines were positive by both methods, with strong similarity in the sizes of the mRNAs and cDNAs that were obtained. Finally, biodistribution experiments were carried out with 131I-labeled MA5 versus a nonbinding control 125I-labeled mAb in a s.c. MM xenograft model. Selective MM tumor uptake of the MA5 mAb was demonstrated, with a potential for delivering a tumor radiation absorbed dose of 8540 cGy/mCi of injected dose compared with 3099 cGy/mCi of tumor-absorbed dose delivered by nonspecific antibody.


Direct isolation of satellite cells for skeletal muscle regeneration.
Muscle satellite cells contribute to muscle regeneration. We have used a Pax3(GFP/+) mouse line to directly isolate (Pax3)(green fluorescent protein)-expressing muscle satellite cells, by flow cytometry from adult skeletal muscles, as a homogeneous population of small, nongranular, Pax7+, CD34+, CD45-, Sca1- cells. The flow cytometry parameters thus established enabled us to isolate satellite cells from wild-type muscles. Such cells, grafted into muscles of mdx nu/nu mice, contributed both to fiber repair and to the muscle satellite cell compartment. Expansion of these cells in culture before engraftment reduced their regenerative capacity.


[Underreporting of deaths in children and birth certification in a representative sample of the 101 municipalities with lowest human development index in Mexico].
To measure the underregistry of mortality in children under five years old, and the coverage of the Birth Certificate (BC) in municipalities with very low human development index (HDI) in Mexico. We studied all deaths of children under five years old occurred in 2007 and all births occurred in 2007 and 2008 in a sample of 20 municipalities with very low HDI in Mexico. We conducted an intentional search of births and deaths. We identified 12 additional deaths not included in official registries, for an underregistration of 22.6%, and 68.1% of births did not have a BC. Lack of BC was more frequent if the mother did not speak Spanish, if she did not have Seguro Popular if the birth was attended by a traditional midwife. Conclusions. It is necessary to strengthen the registry of deaths and births in municipalities with very low HDI.


Epidermal growth factor receptors and effect of epidermal growth factor on growth of human breast cancer cells in long-term tissue culture.
Epidermal growth factor (EGF) may be important in regulating the proliferation of mammary epithelial cells. In the present study, we examined EGF binding and effect on growth in nine human mammary cell lines. The T-47D, MCF-7, SK-Br-3, AIAb 496, BT-20, and BT-474 tumor cell lines and a cell line (HBL-100) derived from milk exhibited EGF binding; both high (Ka 10(10) M-1)- and low (Ka 10(9) M-1)-affinity sites were detected. The total number of EGF receptors per cell of different cell lines varied from 1.6 X 10(3) sites/cell (for AIAb 496) to 1.5 X 10(6) sites/cell (for BT-20). The two floating cell lines, DU4475 and Lev III, had no detectable EGF binding. Effect of EGF on growth was studied by monitoring cell number and the incorporation of [3H]thymidine into DNA of cells maintained in Dulbecco's modified Eagle's medium supplemented with 0.1% fetal bovine serum. Using these procedures, only T-47D cells were stimulated by EGF at low concentrations (0.1 to 1 ng/ml). At concentrations higher than 10 ng/ml, EGF was inhibitory to varying degrees in most cell lines that contained EGF receptors. The growth of the two floating cell lines that had no detectable EGF binding was unaffected by EGF. Our results show that EGF receptors are not present in all human breast cancer cell lines. There is no apparent correlation between EGF binding and its mitogenic activity in cell lines with EGF receptors. EGF may have biological roles in human breast cancer other than growth regulation.


Patellar Tendon Adaptations to Downhill Running Training and Their Relationships With Changes in Mechanical Stress and Loading History.
Bontemps, B, Gruet, M, Louis, J, Owens, DJ, Miríc, S, Vercruyssen, F, and Erskine, RM. Patellar tendon adaptations to downhill running training and their relationships with changes in mechanical stress and loading history. J Strength Cond Res 38(1): 21-29, 2024-It is unclear whether human tendon adapts to moderate-intensity, high-volume long-term eccentric exercise, e.g., downhill running (DR) training. This study aimed to investigate the time course of patellar tendon (PT) adaptation to short-term DR training and to determine whether changes in PT properties were related to changes in mechanical stress or loading history. Twelve untrained, young, healthy adults (5 women and 7 men) took part in 4 weeks' DR training, comprising 10 sessions. Running speed was equivalent to 60-65% V̇O2max, and session duration increased gradually (15-30 minutes) throughout training. Isometric knee extensor maximal voluntary torque (MVT), vastus lateralis (VL) muscle physiological cross-sectional area (PCSA) and volume, and PT CSA, stiffness, and Young's modulus were assessed at weeks 0, 2, and 4 using ultrasound and isokinetic dynamometry. Patellar tendon stiffness (+6.4 ± 7.4%), Young's modulus (+6.9 ± 8.8%), isometric MVT (+7.5 ± 12.3%), VL volume (+6.6 ± 3.2%), and PCSA (+3.8 ± 3.3%) increased after 4 weeks' DR (p < 0.05), with no change in PT CSA. Changes in VL PCSA correlated with changes in PT stiffness (r = 0.70; p = 0.02) and Young's modulus (r = 0.63; p = 0.04) from 0 to 4 weeks, whereas changes in MVT did not correlate with changes in PT stiffness and Young's modulus at any time point (p > 0.05). To conclude, 4 weeks' DR training promoted substantial changes in PT stiffness and Young's modulus that are typically observed after high-intensity, low-volume resistance training. These tendon adaptations seemed to be driven primarily by loading history (represented by VL muscle hypertrophy), whereas increased mechanical stress throughout the training period did not seem to contribute to changes in PT stiffness or Young's modulus.


Achievements of risk-based produced water management on the Norwegian continental shelf (2002-2008).
In 1996, the Norwegian government issued a White Paper requiring the Norwegian oil industry to reach the goal of "zero discharge" for the marine environment by 2005. To achieve this goal, the Norwegian oil and gas industry initiated the Zero Discharge Programme for discharges of produced formation water from the hydrocarbon-containing reservoir, in close communication with regulators. The environmental impact factor (EIF), a risk-based management tool, was developed by the industry to quantify and document the environmental risks from produced water discharges. The EIF represents a volume of recipient water containing concentrations of one or more substances to a level exceeding a generic threshold for ecotoxicological effects. In addition, this tool facilitates the identification and selection of cost-effective risk mitigation measures. The EIF tool has been used by all operators on the Norwegian continental shelf since 2002 to report progress toward the goal of "zero discharge," interpreted as "zero harmful discharges," to the regulators. Even though produced water volumes have increased by approximately 30% between 2002 and 2008 on the Norwegian continental shelf, the total environmental risk from produced water discharges expressed by the summed EIF for all installations has been reduced by approximately 55%. The total amount of oil discharged to the sea has been reduced by 18% over the period 2000 to 2006. The experience from the Zero Discharge Programme shows that a risk-based approach is an excellent working tool to reduce discharges of potential harmful substances from offshore oil and gas installations.


[Comorbidity of internal inpatients in the german diagnosis related groups-system].
The representation of comorbid mental disorders within the German Diagnosis Related Groups-System was investigated. First the complication and complexity level CCL of diagnoses of mental disorders (ICD-10 category F) within the G-DRG-calculation handbooks 2004 and 2005 were checked. Second the revenue based on a fictitious base rate of 3000 with the G-DRG versions 2004/2005 respectively was calculated with and without inclusion of diagnosed comorbid mental disorders of 6610 cases of both medical departments of a hospital of tertiary care level (year 2004). Only F0-diagnoses could lead to a CCL of 3. In 28.2 % of the patients at least one comorbid diagnosis of the category F of the International Classification of Diseases (mental and substance induced disorders) had been coded. Renunciation of the diagnosed mental disorders would have been resulted in a fictitious reduction in revenues based on the G-DRG version 2004 of 93 600 and on the G-DRG version 2005 of 69 000 . The Patient Clinical Complexity Level PCCL was increased 0.15 by the comorbid mental disorders in each year. To achieve an adequate representation of comorbid mental disorders in the G-DRG-system and to ensure a financial survival of psychosomatic/psychiatric CL-services coordinated efforts of psychosomatic scientific societies and hospitals taking part in the G-DRG-calculation sample are necessary.


In situ X-ray powder diffraction studies of hydrogen storage and release in the Li-N-H system.
We report the experimental investigation of hydrogen storage and release in the lithium amide-lithium hydride composite (Li-N-H) system. Investigation of hydrogenation and dehydrogenation reactions of the system through in situ synchrotron X-ray powder diffraction experiments allowed for the observation of the formation and evolution of non-stoichiometric intermediate species of the form Li1+xNH2-x. This result is consistent with the proposed Frenkel-defect mechanism for these reactions. We observed capacity loss with decreasing temperature through decreased levels of lithium-rich (0.7 ≤ x ≤ 1.0) non-stoichiometric phases in the dehydrogenated material, but only minor changes due to multiple cycles at the same temperature. Annealing of dehydrogenated samples reveals the reduced stability of intermediate stoichiometry values (0.4 ≤ x ≤ 0.7) compared with the end member species: lithium amide (LiNH2) and lithium imide (Li2NH). Our results highlight the central role of ionic mobility in understanding temperature limitations, capacity loss and facile reversibility of the Li-N-H system.


Impaired preparatory re-mapping of stimulus-response associations and rule-implementation in schizophrenic patients--the role for differences in early processing.
An accurate representation of task-set information is needed for successful goal directed behavior. Recent studies point to disturbances in the early processing stages as plausible causes for task-switching deficits in schizophrenia. A task-cueing protocol was administered to a group of schizophrenic patients and compared with a sample of age-matched healthy controls. Patients responded slower and less accurate compared with controls in all conditions. The concurrent recording of event-related brain potentials to contextual cues and target events revealed abnormalities in the early processing of both cue-locked and target-locked N1 potentials. Abnormally enhanced target-locked P2 amplitudes were observed in schizophrenic patients for task-switch trials only, suggesting disrupted stimulus evaluation and memory retrieval processes. The endogenous P3 potentials discriminated between task conditions but without further differences between groups. These results suggest that the observed impairments in task-switching behavior were not specifically related to anticipatory set-shifting, but derived from a deficit in the implementation of task-set representations at target onset in the presence of irrelevant and conflicting information.


Development and characterization of polyethylene glycol-carbon nanotube hydrogel composite.
Carbon nanotube (CNT)-hydrogel composites are attractive for a variety of neural tissue engineering and drug delivery applications as well as biosensor coatings, transducers and leads. Both materials contribute unique and beneficial properties to the composites. Hydrogels are an excellent mimic of the extracellular matrix due to their hydrophilicity, viscoelasticity and biocompatibility. CNTs, on the other hand, can impart electroconductivity to otherwise insulating materials, improve mechanical stability and guide neuronal cell behavior as well as elicit axon regeneration. Not surprisingly, there has been a surge in the development of various CNT-hydrogel composites including both natural and synthetic polymers. Here, we describe a CNT-polyethylene glycol (PEG) hydrogel composite where the CNTs are entrapped in the hydrogel phase during gelation. The hydrogel crosslinking reaction is based on Michael-type addition which is ideal for in situ cell and protein encapsulation. To adequately disperse the highly hydrophobic CNTs in the aqueous polymer solution, we used sonication and surfactants, where bovine serum albumin was found to be an effective and non-cytotoxic dispersant. We demonstrate that the inclusion of the CNTs impeded the hydrogel crosslinking leading to longer gelation times, higher swelling and porosity, and lower storage modulus above a threshold CNT concentration. As anticipated, composite hydrogel resistivity decreased with the incorporation of CNTs and was dependent on both CNT loading and dispersion. Importantly, unlike the PEG hydrogel alone, the PEG-CNT hydrogel composite was capable of supporting high neural cell viability where the CNTs provided sites for cell attachment.


Machine Learning Techniques in Predicting BRAF Mutation Status in Cutaneous Melanoma From Clinical and Histopathologic Features.
Melanoma is the cutaneous neoplasm responsible for more patient deaths in all countries. BRAF mutations are the most common driver mutation and with the development of molecular targeted therapy, the precise knowledge of BRAF status has become increasingly important. Evaluation of BRAF mutation status has routinely been performed by polymerase chain reaction, a time consuming and expensive technique. Immunohistochemistry has been suggested as a cheaper alternative, but it has not gained general acceptance. A retrospective observational study in a cohort of 106 patients with invasive melanoma was conducted in order to develop and evaluate a machine learning approach to predict BRAF status using clinical and histologic variables. We compared the performance of different common machine learning algorithms and use SHapley Additive exPlanations (SHAP) to explain individual predictions and extract medical insights to define a heuristic model to estimate BRAF mutation probability. The Extreme Gradient Boosting algorithms obtained the best performance. Interpretability of models shows that the most important variables to estimate BRAF mutation probability are: age, Breslow thickness, and Breslow density. Based in this interpretation and medical knowledge, a simplify heuristic model is proposed to predict BRAF status using only 7 variables and obtain a performance of 0.878 of area under the curve. We propose a heuristic model that could be used by clinicians to obtain a good estimator of BRAF mutation probability.


GL13K-modified titanium regulates osteogenic differentiation via the NF-κB pathway.
The osteoimmune response plays a crucial regulatory role in the osseointegration of dental implants. Previous studies found the antimicrobial peptide coating (GL13K) could activate the immunomodulatory potential of macrophages (Raw 264.7) and promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). To further investigate the mechanism of interaction between immunomodulation and differentiation, a co-culture model of the representative cells (Raw 264.7 and BMSCs) was constructed to mimic the immune microenvironment. In this system, GL13K coating of titanium implant effectively inhibited the polarization of the inflammatory M1 type and promoted the polarization of the anti-inflammatory M2 type. Furthermore, the inhibited NF-κB signaling pathway and Mip-2 gene expression were found and validated by bioinformatics analysis and virus-induced gene silencing, which significantly affected the tissue repair process. It can be concluded that the GL13K coating had the potential to establish a localized immune microenvironment conducive to osteogenic differentiation through cellular interactions. Subsequent investigations would be dedicated to a thorough examination of the osseointegration effects of GL13K coating.


Imaging kidney development.
Development of the kidney involves interactions between several cell lineages and complex morphogenetic processes, such as branching of the ureteric bud (UB) to form the collecting duct system and condensation and differentiation of the mesenchymal progenitors to form the nephron epithelia. One of the advantages of the mouse kidney as an experimental system is that it can develop in culture, from the stage of initial branching of the UB (E11.5) for up to a week (although it achieves the size and degree of development of only an E13.5-E14.5 kidney in vivo). The availability of fluorescent proteins (FPs) has provided powerful tools for visualizing the morphogenesis of specific renal structures in organ cultures. Two categories of genetically modified mice that express FPs are useful for visualizing different cell lineages and developmental processes in these organ cultures: (1) transgenic mice that express a fluorescent reporter in the pattern of a specific gene; and (2) Cre reporter mice, which turn on an FP in cells with Cre recombinase activity (and their daughter cells), used in conjunction with cell type-specific Cre transgenic mice. Here, we describe some of the currently available Cre and FP transgenic lines that are useful for the study of kidney development.


Contributions of changes in physical activity, sedentary time, diet and body weight to changes in cardiometabolic risk.
Increased physical activity (PA), reduced time spent sedentary (SED), healthier diet and reduced body weight may all have a positive impact on cardiometabolic risk. The relative importance of change in each of these variables on cardiometabolic risk, however, is unclear. We therefore sought to investigate the relative contributions of changes in PA, SED, diet and body weight on cardiometabolic risk. This is a secondary analysis of data collected from the EuroFIT randomised controlled trial, which was a 12-week group-based lifestyle intervention for overweight middle-aged men delivered by coaches in football club stadia aiming to improve PA, SED, diet, and body weight. PA and SED were assessed by accelerometry, diet using the Dietary Instrument for Nutrition Education (DINE). An overall cardiometabolic risk score was derived from combining z-scores for glucose, HbA1c, insulin, lipids and blood pressure. In total, 707 men (from the overall cohort of 1113) with complete data for these variables at baseline and 12-month follow-up were included in the multivariable linear regression analyses. In multivariable analyses, change in number of steps (explaining 5.1% of R2) and dietary factors (less alcohol, fatty and sugary food, and more fruit and vegetables) (together explaining 4.5% of R2), but not changes in standing time or SED, were significantly associated with change in body weight. Changes in number of steps (R2 = 1.7%), fatty food score (R2 = 2.4%), and sugary food score (R2 = 0.4%) were significantly associated with change in cardiometabolic risk score in univariable models. However, in multivariable models which included changes in weight as well as changes in steps and dietary variables, change in weight explained a substantially larger proportion of the change in cardiometabolic risk score, explaining 14.1% of R2 (out of an overall model R2 of 19.0%). When baseline (as well as change) values were also included in the model, 38.8% of R2 for change in cardiometabolic risk score was explained overall, with 14.1% of R2 still explained by change in weight. Change in body weight, together with baseline cardiometabolic risk explained most of the change in cardiometabolic risk. Thus, the benefits of increasing physical activity and improving diet on cardiometabolic risk appear to act largely via an effect on changes in body weight. International Standard Randomised Controlled Trials, ISRCTN-81935608. Registered 06052015. https://www.isrctn.com/ISRCTN81935608?q=&filters=recruitmentCountry:Portugal&sort=&offset=7&totalResults=92&page=1&pageSize=10&searchType=basic-search.


[A case of lyme disease requiring over 1 year to diagnose at an infectious-disease clinic].
A 42-year-old woman presenting with years of fever and vague symptoms could not be satisfactorily diagnosed in physical examination or conventional workups. She was presumptively diagnosed with chronic fatigue syndrome and treated symptomatically. Fourteen months after the initial visit, she developed left facial palsy. Lyme disease serology was positive. Four weeks of oral amoxicillin ameliorated symptoms. Only 5 to 15 cases of Lyme disease are reported annually in Japan, mostly from the northeastern-most island of Hokkaido. It may occur anywhere in Japan, however; probably is underdiagnosed. Lyme disease may cause fevers of unknown origin. Astute clinical suspicion and appropriate workups are thus needed to diagnose this infection.


Enhanced fitness of SARS-CoV-2 variant of concern Alpha but not Beta.
Emerging variants of concern (VOCs) are driving the COVID-19 pandemic1,2. Experimental assessments of replication and transmission of major VOCs and progenitors are needed to understand the mechanisms of replication and transmission of VOCs3. Here we show that the spike protein (S) from Alpha (also known as B.1.1.7) and Beta (B.1.351) VOCs had a greater affinity towards the human angiotensin-converting enzyme 2 (ACE2) receptor than that of the progenitor variant S(D614G) in vitro. Progenitor variant virus expressing S(D614G) (wt-S614G) and the Alpha variant showed similar replication kinetics in human nasal airway epithelial cultures, whereas the Beta variant was outcompeted by both. In vivo, competition experiments showed a clear fitness advantage of Alpha over wt-S614G in ferrets and two mouse models-the substitutions in S were major drivers of the fitness advantage. In hamsters, which support high viral replication levels, Alpha and wt-S614G showed similar fitness. By contrast, Beta was outcompeted by Alpha and wt-S614G in hamsters and in mice expressing human ACE2. Our study highlights the importance of using multiple models to characterize fitness of VOCs and demonstrates that Alpha is adapted for replication in the upper respiratory tract and shows enhanced transmission in vivo in restrictive models, whereas Beta does not overcome Alpha or wt-S614G in naive animals.


Beneficial Effects of Theta-Burst Transcranial Magnetic Stimulation on Stroke Injury via Improving Neuronal Microenvironment and Mitochondrial Integrity.
Recent work suggests that repetitive transcranial magnetic stimulation (rTMS) may beneficially alter the pathological status of several neurological disorders, although the mechanism remains unclear. The current study was designed to investigate the effects of rTMS on behavioral deficits and potential underlying mechanisms in a rat photothrombotic (PT) stroke model. From day 0 (3 h) to day 5 after the establishment of PT stroke, 5-min daily continuous theta-burst rTMS (3 pulses of 50 Hz repeated every 200 ms, intensity at 200 G) was applied on the infarct hemisphere. We report that rTMS significantly attenuated behavioral deficits and infarct volume after PT stroke. Further investigation demonstrated that rTMS remarkably reduced synaptic loss and neuronal degeneration in the peri-infarct cortical region. Mechanistic studies displayed that beneficial effects of rTMS were associated with robust suppression of reactive micro/astrogliosis and the overproduction of pro-inflammatory cytokines, as well as oxidative stress and oxidative neuronal damage especially at the late stage following PT stroke. Intriguingly, rTMS could effectively induce a shift in microglial M1/M2 phenotype activation and an A1 to A2 switch in astrocytic phenotypes. In addition, the release of anti-inflammatory cytokines and mitochondrial MnSOD in peri-infarct regions were elevated following rTMS treatment. Finally, rTMS treatment efficaciously preserved mitochondrial membrane integrity and suppressed the intrinsic mitochondrial caspase-9/3 apoptotic pathway within the peri-infarct cortex. Our novel findings indicate that rTMS treatment exerted robust neuroprotection when applied at least 3 h after ischemic stroke. The underlying mechanisms are partially associated with improvement of the local neuronal microenvironment by altering inflammatory and oxidative status and preserving mitochondrial integrity in the peri-infarct zone. These findings provide strong support for the promising therapeutic effect of rTMS against ischemic neuronal injury and functional deficits following stroke.


Large-amplitude undulatory fish swimming: fluid mechanics coupled to internal mechanics.
The load against which the swimming muscles contract, during the undulatory swimming of a fish, is composed principally of hydrodynamic pressure forces and body inertia. In the past this has been analysed, through an equation for bending moments, for small-amplitude swimming, using Lighthill's elongated-body theory and a 'vortex-ring panel method', respectively, to compute the hydrodynamic forces. Those models are outlined in this review, and a summary is given of recent work on large-amplitude swimming that has (a) extended the bending moment equation to large amplitude, which involves the introduction of a new (though probably usually small) term, and (b) developed a large-amplitude vortex-ring panel method. The latter requires computation of the wake, which rolls up into concentrated vortex rings and filaments, and has a significant effect on the pressure on the body. Application is principally made to the saithe (Pollachius virens). The calculations confirm that the wave of muscle activation travels down the fish much more rapidly than the wave of bending.


Wave Propagation of Junctional Remodeling in Collective Cell Movement of Epithelial Tissue: Numerical Simulation Study.
During animal development, epithelial cells forming a monolayer sheet move collectively to achieve the morphogenesis of epithelial tissues. One driving mechanism of such collective cell movement is junctional remodeling, which is found in the process of clockwise rotation of Drosophila male terminalia during metamorphosis. However, it still remains unknown how the motions of cells are spatiotemporally organized for collective movement by this mechanism. Since these moving cells undergo elastic deformations, the influence of junctional remodeling may mechanically propagate among them, leading to spatiotemporal pattern formations. Here, using a numerical cellular vertex model, we found that the junctional remodeling in collective cell movement exhibits spatiotemporal self-organization without requiring spatial patterns of molecular signaling activity. The junctional remodeling propagates as a wave in a specific direction with a much faster speed than that of cell movement. Such propagation occurs in both the absence and presence of fluctuations in the contraction of cell boundaries.


Putting back respiration into respiratory sinus arrhythmia or high-frequency heart rate variability: Implications for interpretation, respiratory rhythmicity, and health.
Research on respiratory sinus arrhythmia, or high-frequency heart rate variability (its frequency-domain equivalent), has been popular in psychology and the behavioral sciences for some time. It is typically interpreted as an indicator of cardiac vagal activity. However, as research has shown for decades, the respiratory pattern can influence the amplitude of these noninvasive measures substantially, without necessarily reflecting changes in tonic cardiac vagal activity. Although changes in respiration are systematically associated with experiential and behavioral states, this potential confounder in the interpretation of RSA, or HF-HRV, is rarely considered. Interpretations of within-individual changes in these parameters are therefore only conclusive if undertaken relative to the breathing pattern. The interpretation of absolute levels of these parameters between individuals is additionally burdened with the problem of residual inspiratory cardiac vagal activity in humans. Furthermore, multiple demographic, anthropometric, life-style, health, and medication variables can act as relevant third variables that might explain associations of RSA or HF-HRV with experiential and behavioral variables. Because vagal activity measured by these parameters only represents the portion of cardiac vagal outflow that is modulated by the respiratory rhythm, alternative interpretations beyond cardiac vagal activity should be considered. Accumulating research shows that activity of multiple populations of neurons in the brain and the periphery, and with that organ activity and function, are modulated rhythmically by respiratory activity. Thus, observable health benefits ascribed to the cardiac vagal system through RSA or HF-HRV may actually reflect beneficial effects of respiratory modulation. Respiratory rhythmicity may ultimately provide the mechanism that integrates central, autonomic, and visceral activities.


Crystal structure of a ternary complex of the alcohol dehydrogenase from Sulfolobus solfataricus.
The crystal structure of a ternary complex of the alcohol dehydrogenase from the archaeon Sulfolobus solfataricus (SsADH) has been determined at 2.3 A. The asymmetric unit contains a dimer with a NADH and a 2-ethoxyethanol molecule bound to each subunit. The comparison with the apo structure of the enzyme reveals that this medium chain ADH undergoes a substantial conformational change in the apo-holo transition, accompanied by loop movements at the domain interface. The extent of domain closure is similar to that observed for the classical horse liver ADH, although some differences are found which can be related to the different oligomeric states of the enzymes. Compared to its apo form, the SsADH ternary complex shows a change in the ligation state of the active site zinc ion which is no longer bound to Glu69, providing additional evidence of the dynamic role played by the conserved glutamate residue in ADHs. In addition, the structure presented here allows the identification of the substrate site and hence of the residues that are important in the binding of both the substrate and the coenzyme.


Using task analysis in healthcare design to improve clinical efficiency.
To review the functionality of the proposed soiled workroom design for efficient and safe clinical activities. As part of a hospital refurbishment program, the planning team of a United Kingdom National Health Service hospital requested a review of a proposed standardized room design. A 7-day observational study was conducted in five clinical departments at three hospitals. Link analysis was used to record and analyze the movements among components, i.e., nursing staff, equipment/devices, and furniture. Fifty-four observations were recorded for 18 clinical tasks. The most frequent tasks were the disposal of urine and used urine bottles, and returning used commode chairs. Minor recommendations were made to improve the proposed design, and major revisions were suggested to address functionality problems. It was found that the proposed design did not offer the optimal layout for efficient and safe clinical activities. Link analysis was found to be effective for plotting the movements of the staff and accounting for the complexity of tasks. This ergonomic method, in combination with observational field studies, provided a simple and effective way to determine functional space requirements for clinical activities and should be used in all healthcare building design projects.


Rationality versus reality: the challenges of evidence-based decision making for health policy makers.
Current healthcare systems have extended the evidence-based medicine (EBM) approach to health policy and delivery decisions, such as access-to-care, healthcare funding and health program continuance, through attempts to integrate valid and reliable evidence into the decision making process. These policy decisions have major impacts on society and have high personal and financial costs associated with those decisions. Decision models such as these function under a shared assumption of rational choice and utility maximization in the decision-making process. We contend that health policy decision makers are generally unable to attain the basic goals of evidence-based decision making (EBDM) and evidence-based policy making (EBPM) because humans make decisions with their naturally limited, faulty, and biased decision-making processes. A cognitive information processing framework is presented to support this argument, and subtle cognitive processing mechanisms are introduced to support the focal thesis: health policy makers' decisions are influenced by the subjective manner in which they individually process decision-relevant information rather than on the objective merits of the evidence alone. As such, subsequent health policy decisions do not necessarily achieve the goals of evidence-based policy making, such as maximizing health outcomes for society based on valid and reliable research evidence. In this era of increasing adoption of evidence-based healthcare models, the rational choice, utility maximizing assumptions in EBDM and EBPM, must be critically evaluated to ensure effective and high-quality health policy decisions. The cognitive information processing framework presented here will aid health policy decision makers by identifying how their decisions might be subtly influenced by non-rational factors. In this paper, we identify some of the biases and potential intervention points and provide some initial suggestions about how the EBDM/EBPM process can be improved.


Clinical and Morphologic Features of ETV6-NTRK3 Translocated Papillary Thyroid Carcinoma in an Adult Population Without Radiation Exposure.
The ETV6-NTRK3 translocation characterizes a subset of radiation associated and pediatric papillary thyroid carcinomas (PTCs). We now describe the clinicopathologic features of ETV6-NTRK3 translocated PTC in an adult population without radiation exposure. Twelve cases were identified by next-generation sequencing (ThyroSeq version 2). The mean patient age was 37 years with a female predilection (10:2). Preoperative fine needle aspiration was performed on 6 patients of which 4 were classified as "malignant," whereas 2 were classified as "follicular lesion of undetermined significance." One third (4/12) of patients demonstrated extrathyroidal extension and one half of patients (5/10) demonstrated lymph node metastases. One patient presented with brain metastasis. Tumors typically (8/12) demonstrated an admixture of follicular and papillary patterns and were usually infiltrative and multinodular (6/12 cases). Tumors often showed clear cell or oncocytic foci and demonstrated overt nuclear features of PTC, though characteristically, interspersed bland areas were common, even in metastases. Cytoplasmic vacuolization resembling that of mammary analog secretory carcinoma was also common but focal. TTF-1 was positive and S100 was negative in all tested cases confirming a thyroid phenotype. Unique morphologies included glomeruloid follicles, reverse polarization of nuclei. Survey of the TCGA datasets revealed similar findings. Thus, ETV6-NTRK3 translocated PTC are locoregionally aggressive and can metastasize distantly. They are characterized by mixture of papillary and follicular architecture and may show cytoplasmic vacuolization akin to other ETV6 translocated carcinomas. Although nuclear features are typically overt, interspersed bland regions may cause diagnostic difficulty in metastatic sites, and may explain discordance on fine needle aspiration.


High-accuracy extrapolated ab initio thermochemistry of the vinyl, allyl, and vinoxy radicals.
Enthalpies of formation at both 0 and 298 K were calculated according to the HEAT (High-accuracy Extrapolated Ab initio Thermochemistry) protocol for the title molecules, all of which play important roles in combustion chemistry. At the HEAT345-(Q) level of theory, recommended enthalpies of formation at 0 K are 301.5 ± 1.3, 180.3 ± 1.8, and 23.4 ± 1.5 kJ mol(-1) for vinyl, allyl, and vinoxy, respectively. At 298 K, the corresponding values are 297.3, 168.6, and 16.1 kJ mol(-1), with the same uncertainties. The calculated values for the three radicals are in excellent agreement with the corresponding experimental values, but the uncertainties associated with the HEAT values for vinoxy are considerably smaller than those based on experimental studies.


Distribution and pharmacokinetics of methamphetamine in the human body: clinical implications.
Methamphetamine is one of the most toxic of the drugs of abuse, which may reflect its distribution and accumulation in the body. However no studies have measured methamphetamine's organ distribution in the human body. Positron Emission Tomography (PET) was used in conjunction with [(11)C]d-methamphetamine to measure its whole-body distribution and bioavailability as assessed by peak uptake (% Dose/cc), rate of clearance (time to reach 50% peak-clearance) and accumulation (area under the curve) in healthy participants (9 Caucasians and 10 African Americans). Methamphetamine distributed through most organs. Highest uptake (whole organ) occurred in lungs (22% Dose; weight ∼1246 g), liver (23%; weight ∼1677 g) and intermediate in brain (10%; weight ∼1600 g). Kidneys also showed high uptake (per/cc basis) (7%; weight 305 g). Methamphetamine's clearance was fastest in heart and lungs (7-16 minutes), slowest in brain, liver and stomach (>75 minutes), and intermediate in kidneys, spleen and pancreas (22-50 minutes). Lung accumulation of [(11)C]d-methamphetamine was 30% higher for African Americans than Caucasians (p<0.05) but did not differ in other organs. The high accumulation of methamphetamine, a potent stimulant drug, in most body organs is likely to contribute to the medical complications associated with methamphetamine abuse. In particular, we speculate that methamphetamine's high pulmonary uptake could render this organ vulnerable to infections (tuberculosis) and pathology (pulmonary hypertension). Our preliminary findings of a higher lung accumulation of methamphetamine in African Americans than Caucasians merits further investigation and questions whether it could contribute to the infrequent use of methamphetamine among African Americans.


Therapeutic effects of human STRO-3-selected mesenchymal precursor cells and their soluble factors in experimental myocardial ischemia.
Stromal precursor antigen (STRO)-3 has previously been shown to identify a subset of adult human bone marrow (BM)-derived mesenchymal lineage precursors, which may have cardioprotective potential. We sought to characterize STRO-3-immunoselected and culture-expanded mesenchymal precursor cells (MPCs) with respect to their biology and therapeutic potential in myocardial ischemia. Immunoselection of STRO-3(+) MPCs enriched for fibroblastic colony forming units from unfractionated BM mononuclear cells (MNCs). Compared to mesenchymal stem cells conventionally isolated by plastic adherence, MPCs demonstrated increased proliferative capacity during culture expansion, expressed higher levels of early 'stem cell' markers and various pro-angiogenic and cardioprotective cytokines, and exhibited greater trilineage developmental efficiency. Intramyocardial injection of MPCs into a rat model of myocardial infarction (MI) promoted left ventricular recovery and inhibited left ventricular dilatation. These beneficial effects were associated with cardioprotective and pro-angiogenic effects at the tissue level, despite poor engraftment of cells. Treatment of MI rats with MPC-conditioned medium (CM) preserved left ventricular function and dimensions, reduced myocyte apoptosis and fibrosis, and augmented neovascularization, involving both resident vascular cells and circulating endothelial progenitor cells (EPCs). Profiling of CM revealed various cardioprotective and pro-angiogenic factors, which had biological activity in cultures of myocytes, tissue-resident vascular cells and EPCs. Prospective immunoselection of STRO-3(+) MPCs from BM MNCs conferred advantage in maintaining a population of immature MPCs during ex vivo expansion. Transplantation of culture-expanded MPCs into the post-MI heart resulted in therapeutic benefit, attributable at least in part to paracrine mechanisms of action. Thus, MPCs represent a promising therapy for myocardial ischemia.


Different resuscitation strategies and novel pharmacologic treatment with valproic acid in traumatic brain injury.
Traumatic brain injury (TBI) is a leading cause of death in young adults, and effective treatment strategies have the potential to save many lives. TBI results in coagulopathy, endothelial dysfunction, inflammation, cell death, and impaired epigenetic homeostasis, ultimately leading to morbidity and/or mortality. Commonly used resuscitation fluids such as crystalloids or colloids have several disadvantages and might even be harmful when administered in large quantities. There is a need for next-generation treatment strategies (especially in the prehospital setting) that minimize cellular damage, improve survival, and enhance neurological recovery. Pharmacologic treatment with histone deacetylase inhibitors, such as valproic acid, has shown promising results in animal studies of TBI and may therefore be an excellent example of next-generation therapy. This review briefly describes traditional resuscitation strategies for TBI combined with hemorrhagic shock and describes preclinical studies on valproic acid as a new pharmacologic agent in the treatment of TBI. It finally discusses limitations and future directions on the use of histone deacetylase inhibitors for the treatment of TBI.


Ultrafast dynamics of single-walled carbon nanotubes dispersed in polymer films.
Wavelength-resolved femtosecond transient absorption spectroscopy is used to follow the electronic dynamics of single-walled carbon nanotubes in polymers following visible photoexcitation. Electron-hole (e-h) pairs give rise to sharp features in the transient spectra that decay in amplitude and exhibit rapid spectral shifts. The decay reflects (e-h) recombination on both short (1.3 ps) and long (35 ps) time scales. Transient spectra also exhibit a broad photobleach at early times that arises from the cooling of a hot electron gas created via excitation at the red edge of a pi-plasmon band.


Uvulopalatopharyngoplasty funded by the Australian government's Medicare scheme (1995-2007).
To describe the provision, through the Australian state-funded Medicare system, of uvulopalatopharyngoplasty (UPPP) and its laser-assisted variation (LAUP) to the population of Australia between 1995 and 2007. Case series using a comprehensive national administrative database. The Commonwealth of Australia. Subjects comprised the population of Australia. The raw numbers of procedures, reimbursement amounts in Australian dollars, and per capita adjustment nationwide and in each state/territory for UPPP and LAUP for each calendar year from 1995 to 2007 were downloaded from a publicly accessible database run by Medicare. The Australian federal government paid AUD 8.2 million for 19,534 UPPP procedures and AUD 1.1 million for 3270 LAUP procedures in the calendar years 1995 to 2007, inclusive. There is substantive variability between states in provision. Over time, provision of UPPP has declined slightly compared with population growth and overall Medicare provision. LAUP provision has declined markedly. Provision of UPPP under Medicare in Australia has declined slowly relative to population growth and overall growth in Medicare per capita provision. Laser-assisted UPPP (LAUP) has steadily declined and is now rarely used compared with the peak in its provision in the mid 1990s.


Hepatic serum amyloid A1 aggravates T cell-mediated hepatitis by inducing chemokines via Toll-like receptor 2 in mice.
Serum amyloid A is a proinflammatory molecule that induces leukocyte infiltration and promotes neutrophil adhesion to endothelial cells under inflammatory conditions. The aim of this study was to examine whether Saa1 aggravates T cell-mediated hepatitis by inducing chemokines in a liver-specific, Saa1-overexpressing, transgenic (TG) mouse model. We generated TG mice in which Saa1 was overexpressed specifically in liver tissue. The chemokines monocyte chemotactic protein 1 (MCP1), MIP1α, MIP1β, interferon γ-induced protein 10 (IP-10), and eotaxin were induced in Saa1 TG mice. After concanavalin A treatment, Saa1 expression was higher in Saa1 TG mice than in WT mice. More severe liver injury, increased hepatocyte apoptosis, and higher levels of hepatic enzymes were observed in Saa1 TG mice than in WT mice. Liver infiltration of CD4(+) T cells and macrophages increased after inducing hepatitis. Activation of T cells was higher in Saa1 TG mice than in WT mice, and the populations of Th17 cells and regulatory T cells were altered by overexpressing Saa1 in TG mice. Secretion of various cytokines, such as interferon γ, tumor necrosis factor α, and interleukin 6, increased in Saa1 TG mice. Injecting a Toll-like receptor 2 (TLR2) antagonist in vivo inhibited chemokine expression and IκBα phosphorylation and showed that the induction of chemokines by Saa1 was dependent on TLR2. Hepatic Saa1 accelerated T cell-mediated hepatitis by inducing chemokine production and activating T cells by TLR2. Therefore, Saa1 might be a novel inflammatory factor that acts as a chemokine modulator in hepatitis.


Paritaprevir, ritonavir, ombitasvir, and dasabuvir with and without ribavirin in people with HCV genotype 1 and recent injecting drug use or receiving opioid substitution therapy.
Direct-acting antiviral therapy for hepatitis C virus (HCV) infection is safe and effective, but there are little data among people who have recently injected drugs. This study evaluated the efficacy, and safety of paritaprevir/ritonavir, ombitasvir, dasabuvir with or without ribavirin for chronic HCV genotype (G) 1 among people with recent injecting drug use and/or receiving OST. D3FEAT is an international open-label study that recruited treatment-naïve participants with recent injecting drug use (previous 6 months) and/or receiving OST with chronic HCV G1 infection between June 2016 and February 2017 in seven countries. Participants received paritaprevir/ritonavir, ombitasvir, dasabuvir with (G1a) or without ribavirin (G1b) administered twice daily in a one-week electronic blister pack (records timing of each dose) for 12 weeks. The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (SVR12). Among 87 participants (median age 48 years), 23% were female, 8% had cirrhosis, and 90% had G1a. Overall, 71% were receiving OST, 61% injected in the previous six months, 45% injected in the previous month, and 15% injected > daily. Treatment completion was 97% (84 of 87). There were no virological breakthroughs, but three discontinuations (loss to follow-up, n = 1; non-adherence, n = 1; incarceration, n = 1). SVR was 91% (79 of 87, 95% CI, 83%-96%). Five participants who completed treatment did not have SVR (loss to follow-up, n = 1; death, n = 1; virologic relapse, n = 3). Drug use prior to and during treatment did not impact SVR12. Treatment-related adverse events were observed in 46 (53%) patients (six grade 3, no grade 4). Five (6%) patients had at least one serious adverse event (two possibly/probably related to therapy; nausea and myoclonus). Two cases of reinfection were observed. Paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for 12 weeks is effective among people with HCV genotype 1 with recent injecting drug use and/or receiving OST.


Peroxynitrite elevation in exhaled breath condensate of COPD and its inhibition by fudosteine.
Peroxynitrite (PN) formed by the reaction of nitric oxide and superoxide is a powerful oxidant/nitrosant. Nitrative stress is implicated in COPD pathogenesis, but PN has not been detected due to a short half-life (< 1 s) at physiologic condition. Instead, 3-nitrotyrosine has been measured as a footprint of PN release. PN was measured using oxidation of 2',7'-dichlorofluorescein (DCDHF) in exhaled breath condensate (EBC) collected in high pH and sputum cells. The PN scavenging effect was also evaluated by the same system as PN-induced bovine serum albumin (BSA) nitration. The mean (+/- SD) PN levels in EBC of COPD patients (7.9 +/- 3.0 nmol/L; n = 10) were significantly higher than those of healthy volunteers (2.0 +/- 1.1 nmol/L; p < 0.0001; n = 8) and smokers (2.8 +/- 0.9 nmol/L; p = 0.0017; n = 6). There was a good correlation between PN level and disease severity (FEV(1)) in COPD (p = 0.0016). Fudosteine (FDS), a unique mucolytic antioxidant, showed a stronger scavenging effect of PN than N-acetyl-cysteine on DCDHF oxidation in vitro and in sputum macrophages, and also on PN-induced BSA nitration. FDS (0.1 mmol/L) reduced PN-enhanced interleukin (IL)-1beta-induced IL-8 release and restored corticosteroid sensitivity defected by PN more potently than those induced by H(2)O(2) in A549 airway epithelial cells. This noninvasive PN measurement in EBC may be useful for monitoring airway nitrative stress in COPD. Furthermore, FDS has the potential to inhibit PN-induced events in lung by its scavenging effect.